Our 2010 Accomplishments

Sleep: An Evolutionary Imperative. Are You Getting Enough?

Download the Autumn/Winter 2010 issue (2.2 MB): [PDF]

Papers Published

Scent Identification in Criminal Investigations and Prosecutions. In this comprehensive summary of the use of canine scent lineups in the investigation of crimes, we review the proper procedures helping establish scent lineups can be valuable evidence for a jury to consider. Click here to read the full paper.

Papers Submitted

We’ve submitted for publication a landmark cancer survival study in collaboration with Kaiser Permanente, the Northern California Cancer Center, and the University of California at Berkeley. This research project encompasses a 10-year follow-up of patients with lung cancer and colon cancer, addressing the question of whether complementary and alternative medical therapy in combination with standard treatments can help extend survival. By using data about these patients gathered over a ten-year period, this study will explore the potential survival benefits associated with long-term use of an herbal-vitamin combination protocol. These two papers are now in the peer-review process.

Papers Presented

We’re presented our research results at two conferences:

• The Annie Appleseed Foundation, in Florida
• A conference for researchers in canine scent detection, in the Netherlands

Avenues Newsletter Distributed

In 2010, we physically distributed nearly 15,000 copies of our newsletter, Avenues, bringing our audience important information such as our comprehensive reviews on the benefits of vitamin D3 and uncovering some of the many issues surrounding the massive efforts directed against the swine flu outbreak. Additionally, thousands copies have been electronically downloaded from our website.

New Research Initiative Launched

We’ve launched a new research initiative, a systematic review and meta-analysis of all published randomized trials in which patients treated with Chinese herbal medicine combined with chemotherapy were compared to those treated with chemotherapy alone. Pine Street researchers will be looking for the impact of Chinese herbal medicine on both immediate results (do people using herbal medicine experience less damage to white blood cells or less drug toxicity?) and long-term results (do people using herbal medicine live longer after treatment and is their quality of life better?), as compared to treatment with chemotherapy alone. We will also be looking carefully at the quality of the published studies. Most of the studies we have located in our systematic search of the medical literature were published in China and one of our goals with this meta-analysis is to better understand the level of scientific quality of these studies; many researchers in the Western scientific community have criticized Chinese studies for their low quality of design and reporting. By analyzing these studies, we’ll determine what study quality problems are most significant and where improvement is needed. Pine Street has three primary aims in conducting this meta-analysis. First, we are using the results of this study as a basis for designing a double-blinded, randomized trial for patients with colon cancer. Second, by pointing out where improvements in study methodology are needed, we hope to contribute to the improvement in quality of clinical studies in China. Third, we want to educate readers outside of China on the vast quantity of research being conducted there, research that highlights the potential clinical benefits of integrative medical care.

A Selection of Media Clippings from 2010

Parade Magazine: Our work was prominently featured in the article “Cancer In America: Sniffing Out Disease.”

Huffington Post: In an op-ed in the Huffington Post, John Robbins wrote: “If you want to support an organization fighting breast cancer, you might want to know about the little known but extraordinary Pine Street Foundation.”

We were included in Cesar Milan’s new book, Cesar’s Rules: Your Way to Train a Well-Behaved Dog. Click here to read the chapter.

OUR 2010 ACCOMPLISHMENTS

This past year has been a productive one for the Pine Street Foundation. We’ve published peer-reviewed research, presented papers at conferences, received lots of media coverage in the national press, and reached thousands of patients and doctors through our newsletter, Avenues. Click here for some of the highlights from our successful year.

CAN DOGS DETECT OVARIAN CANCER?

Is there meaningful information contained within the breath that could lead to the early detection of ovarian cancer? In a collaboration with the University of Maine and the University of California at San Francisco, we are using dogs to find biomarkers in the breaths of women with ovarian cancer that could lead to earlier detection – and better treatment outcomes – for this disease.

So far, we’ve received breath samples from more than 100 wom- en and now just need:

» 12 More Women with Ovarian Cancer » 13 More Women with Endometriosis or PCOS

Visit pinestreetfoundation.org/ovarian to learn more about this project.

Recruiting patients for any research project is costly. But your donation – of any size – will directly help us locate enough eligible women and obtain samples of their breath to complete this important research.

Visit pinestreetfoundation.org/donate to show your support.

AS THE YEAR DRAWS TO A CLOSE…

Whether you’ve known us since 1989 or have only recently dis- covered our work, it is important to note that the Pine Street Foundation is one of the most efficient and cost-effective research organizations of its kind in the country. And since the vast major- ity of all our funding comes from individual donors like you, your financial support truly helps us advance the field of integrative medicine and benefits those in need of better treatments.

As you consider your year-end charitable giving, please keep the Pine Street Foundation in mind. We really appreciate it!

Vitamin D3: A Review of the Evidence for its Role in Human Health

Download the Spring/Summer 2010 issue (0.7 MB): [PDF]

Vitamin D is made from cholesterol and plays an essential role in immune function. (Sigmundsdottir, Pan et al. 2007) Specifically, vitamin D regulates genes that facilitate several important body functions, such as (1) helping absorption of calcium and phosphorus in the intestines from food, (2) regulating reabsorption of calcium in the kidneys, (3) governing the transport of calcium into bone, (4) regulating bone growth and remodeling (repair), (5) helping regulate thyroid and parathyroid function, (6) modulating neuromuscular and immune function, and (7) reducing inflammation.(van den Berg 1997; Cranney, Horsley et al. 2007)

There are currently over 400 clinical research studies in progress focusing on vitamin D. These studies are all listed on the National Cancer Institute’s website (www.ClinicalTrials.gov) and they range from studies seeking to understand how vitamin D works in the body, to those for the treatment of numerous different diseases.

Deficiencies of serum vitamin D can lead to many different health problems, including osteoporosis,(Cranney, Horsley et al. 2007; Macdonald, Mavroeidi et al. 2008) autoimmune diseases, such as multiple sclerosis and rheumatoid arthritis,(Hayes and Acheson 2008; Holick 2008) prostate cancer,(Gupta, Lammersfeld et al. 2009) infectious diseases, and several other forms of cancer.(Holick 2008; Perez-Lopez 2008) Vitamin D is also used clinically to prevent osteoporosis, muscle weakness, chronic obstructive pulmonary disease (COPD), cancer, asthma, and bronchitis.(Natural Medicines Comprehensive Database 2009)

WHAT IS VITAMIN D? WHAT ARE ITS VARIOUS FORMS?

Vitamin D goes through three different stages in its formation and metabolism: First from cholecalciferol to calcidiol and then to its active form, calcitriol.

The cycle of vitamin D’s activity begins as cholecalciferol (vitamin D3), the naturally occurring form of vitamin D, which is made in large quantities in your bare skin when sunlight strikes it. It can be taken as a supplement and is also found in small amounts in some foods. Cholecalciferol is first transformed by the body into calcidiol (25-OH-D3, or 25D3), a pre-hormone.

The second step, calcidiol (also called 25-hydroxyvitamin D or 25-OH-D), is the form of vitamin D that is measured when your blood is drawn to test for deficiency. Vitamin D then goes through one more transformation before it becomes the active form in the body, calcitriol (1,25-dihydroxyvitamin D). It was once thought that this transformation happens primarily in the kidneys, but recent studies indicate most organs independently make and regulate calcitriol. Calcitriol is a potent seco-steroid hormone that has powerful anti-cancer properties.(Vitamin D Council 2009)

WHEN WAS VITAMIN D DISCOVERED?

The discovery of vitamin D resulted from the confluence of two different streams of research thinking that had been in progress for several decades: a search for understanding of the chemical nature of cholesterol, and the search for a cure for the crippling bone disease called rickets. Adolf Windaus (1876–1959) was a German chemist who devoted his entire career to the study of the molecular structure of cholesterol, for which he was awarded the Nobel Prize in 1928. Windaus was unusual among scientists in Germany in that he openly opposed the Nazi party and, in 1933, protected a Jewish graduate student from dismissal from his university.

His discovery of vitamin D was the result of a collaboration with two other researchers: Alfred Hess who, as early as 1926, had proposed the idea that “it would seem quite possible that the cholesterol in the skin is normally activated by UV-irradiation and rendered anti-rachitic [preventing rickets] – that the solar rays and artificial radiations can bring about this conversion. This point of view regards the superficial skin as an organ, which reacts to particular light waves rather than as a mere protective covering.” They worked together with researcher Otto Rosenheim in London, and together demonstrated that Hess’ theory was correct. Windaus contributed understanding of the structure of the cholesterol molecule, Hess discovered that cholesterol could be converted to a rickets-preventing compound, and Rosenheim conducted the laboratory experiment demonstrating that a component of cholesterol could be converted into vitamin D by exposing it to UV light.(Wolf 2004)

BLOCK THE SUN, BLOCK VITAMIN D

Our ancestors lived naked in the sun for several million years. 50,000 years ago, some of us migrated north and south to places with less sun. Then we put on clothes, started working inside, and began living in cities where buildings blocked the sun. Then we started traveling in cars instead of walking or riding horses. Glass windows, sunscreen, and heavy clothing block even more of the UVB in the sunlight. Then, only a few years ago, we started actively avoiding the sun and putting on sunscreen. All this time we humans have been steadily reducing the tissue levels of the most potent steroid hormone in our bodies, one with powerful anti-cancer properties. The really significant reductions in sunlight exposure have occurred since the industrial revolution, just the time the “diseases of civilization” like cardiovascular disease, diabetes, and cancer seem to have greatly increased.(Vitamin D Council 2009) Essentially, protecting yourself against the sun causes vitamin D deficiency.(Reichrath 2007)

Conversely, the use of supplemental vitamin D appears to be an effort to compensate for this lack of direct sunshine in our lives.(Vieth 1999)

It appears that sunlight is good for the entire body, as most tissues in the body have vitamin D receptors.(Holick 2008) The tongue-in-cheek dialogue line from the movie Over the Hedge (Dreamworks Animation, 2006) states, “humans are gradually losing their ability to walk.” This may be due not just to the fact that we travel more by car than by foot, but also because we’re getting less sunlight; low levels of serum vitamin D are also associated with loss of knee joint cartilage.(Ding, Cicuttini et al. 2009)

Studies conducted by the US government have found that three out of every four Americans have very low levels of vitamin D in their blood (below 30 mg/mL). The ideal range is between 50 and 70 mg/mL. This is especially important to consider, given that there is virtually no vitamin D in most of the foods we typically eat. For example, the of Vitamin D found in fortified milk is only 100 IU per glass, which is a clinically meaningless amount. (NIH: Office of Dietary Supplements 2009)

HOW DOES THE BODY MAKE VITAMIN D FROM SUNLIGHT?

Cholecalciferol, a form of vitamin D that is also called vitamin D3, is formed in the skin when it is struck by ultraviolet light of the correct wavelength, UVB.(Vitamin D Council 2009)

Only 20 to 30 minutes of full-body noontime summer sun exposure stimulates the skin to produce as much as 10,000 IU vitamin D, which is 50 times higher than the US government’s recommended 200 IU per day.(Vitamin D Council 2009) Or, one can obtain that same amount by drinking 100 glasses of milk.

The skin does another amazing thing with cholecalciferol: it prevents vitamin D toxicity. Once the body makes about 20,000 units, the same ultraviolet light that created cholecalciferol begins to degrade it. A steady state is reached that prevents the skin from making too much cholecalciferol. This is why vitamin D toxicity does not occur from the sun, though it is possible when taking vitamin D supplements orally.(Vitamin D Council 2009)

WHAT ABOUT THE HAZARDS OF SUN EXPOSURE?

With basal and squamous skin cancers, there is a large body of research including quantitative and mechanistic proof that sun exposure causes these diseases. These cancers are clearly linked to sun exposure in people with pale skin, are related to the amount of sun exposure and latitude of residence, and are successfully prevented by sun avoidance and exposure protection.(Shuster 2008)

With melanoma, however, the evidence is not so clear-cut, with most cases occurring on body areas with less sun exposure (according to two different meta-analyses of 24 studies including nearly 20,000 people.)(Siskind, Whiteman et al. 2005; Caini, Gandini et al. 2009) Although there is clear evidence that a history of intermittent sun exposure and sunburn significantly increase the risk of melanoma, conversely a high occupational history of sun exposure seems to reduce that risk.(Gandini, Sera et al. 2005) It appears that people who live further from the equator, and whose sun exposure is more intermittent than continuous, will be more likely to develop melanoma. However, more research needs to be done to evaluate the risk-benefit ratio of possibly increased risk of melanoma, versus the overall health benefits of extra vitamin D3 achieved by increasing sun exposure.

ANIMALS FROM CHOLECALCIFEROL IN THEIR FUR & FEATHERS

Fur bearing animals, and many birds, make cholecalciferol in their fur or feathers since sunlight can not get to their skin. Interestingly, mammals and birds then eat the cholecalciferol by licking their fur (grooming) or rubbing their beaks on their feathers (preening). So, when you take cholecalciferol by mouth, you are doing what a number of other mammals do.(Vitamin D Council 2009)

WHAT HAPPENS IN THE MAKING OF VITAMIN D, AFTER SUNLIGHT STARTS THE PROCESS?

Calcidiol Made In Liver

After cholecalciferol is made in the skin, or taken by mouth, it is transported to the liver where it is metabolized into calcidiol or 25(OH)D. Calcidiol is now thought by some scientists to have steroid hormone properties. It certainly helps maintain your blood calcium levels, but calcidiol’s main importance is that it is the form of vitamin D circulating in the blood. Calcidiol is what tells you if your vitamin D “gas tank” is full. If your serum calcidiol level is less than 40 to 50 ng/mL, your tank is low and should be filled up, keeping it that way unless you have a rare medical condition called vitamin D hypersensitivity.(Vitamin D Council 2009)

In order to understand why you should keep your vitamin D tank full, you need to understand the next step in the metabolism of cholecalciferol. After your liver turns cholecalciferol into calcidiol, calcidiol follows one of two pathways. The first pathway takes priority — as your life literally depends on it — but the second pathway is causing all the excitement among researchers today (discussed below). However, if your tank is low, most of your calcidiol takes the first pathway, leaving little to no vitamin D available for your immune system.(Vitamin D Council 2009)

First Pathway: Calcitriol Made in Kidneys

The first pathway leads to the kidneys, where calcidiol is turned into calcitriol. Calcitriol is a potent steroid hormone, one of the most potent in the human body, active in tiny pictogram quantities. A steroid hormone is simply any molecule in the body that is made from cholesterol and that acts on specific receptors to turn your genes on and off and regulate cellular function. They are important to health, always need to be handled with care, and are often quite potent, which is why supplemental calcitriol is only available by prescription.(Vitamin D Council 2009)

Calcitriol made by the kidney circulates in the blood to maintain your blood calcium levels through its action on calcium absorption, excretion, and storage in bone. Calcium is vital to the function of the cells in the body. Without enough calcitriol in the blood, calcium levels will fall and a variety of different illness will develop. Therefore, the first priority for calcidiol is to go to the kidneys where it makes enough calcitriol to secrete into the blood in order to regulate serum calcium.(Vitamin D Council 2009)

Second Pathway: More Calcitriol Produced in Tissues

The second vitamin D pathway leads to your tissues and that is the source of many of the important immune-regulating and inflammation-reducing capabilities of vitamin D. Virtually all of the health benefits of vitamin D discovered in the last 10 years are from vitamin D going down the second pathway. If any calcidiol is left over — that is, if your tank is full and your kidneys are getting all the calcidiol they need to maintain serum calcium — then calcidiol is able to take multiple other pathways, ones that leads directly to the cells. This path is only now being fully understood and is causing excitement among researchers and clinicians all around the world, especially concerning cancer. Specifically, these are the autocrine (inside the cell) and paracrine (around the cell) functions of the vitamin D system.(Vitamin D Council 2009)

These functions are crucial to understanding why you should keep your vitamin D tank full. If you only have a small amount of calcidiol in your blood, virtually all of it goes to your kidney, which then makes extra calcitriol to keep your serum calcium levels from falling. Almost no calcidiol gets to your tissues to make tissue calcitriol.(Vitamin D Council 2009)

Tissue Calcitriol: A Cancer Fighter

But when your tank is full from the first pathway, the left over calcidiol goes down that second pathway to benefit the many cells in the body that are able to make their own calcitriol to fight cancer. The more calcidiol they get, the more calcitriol those cells can make. (Vitamin D Council 2009)

Other steroids limit their own production by inhibiting the very chemical reactions that make them. For example, a chemical reaction in the body turns cholesterol into progesterone, a female hormone. When enough progesterone is made, progesterone shuts down (inhibits) the chemical reaction so no more progesterone is made. This is called negative feedback. This occurs with all other steroids somewhere in the metabolic process. If it didn’t, the body would not be able to precisely regulate steroid hormone levels. However, this process does not appear to occur with calcitriol in the tissues: throughout the entire range of average human calcidiol levels, tissue calcitriol levels continue to increase. (Vitamin D Council 2009)

This is a crucial piece of information, because it has such profound implications for human health. Just as modern humans have been living (and dying) with historically low levels of calcidiol in their blood, their tissues have been living (and dying) with historically low levels of calcitriol. And calcitriol is the most potent steroid hormone in the human body. It turns genes on and off: genes that are either making proteins that are essential to fighting cancer or genes that are making proteins that are promoting diseases like cancer.(Vitamin D Council 2009)

Built-in Toxicity Protection

What prevents tissue calcitriol levels from getting too high? Something has to or your tissues would make too much. One thing that helps is called catabolism, or breakdown. The more calcitriol made, the more metabolized and excreted in the bile. But that does not prevent too much from being made in the first place. In most humans, the more cholecalciferol in the blood, the more calcidiol the liver makes, until calcidiol levels reach about 50 ng/ml. (Vitamin D Council 2009)

The crucial rate-limiting step for the production of calcitriol for most humans in the tissues is the skin, or how much you go into the sun. The body has a fool-proof method of limiting cholecalciferol, in that only about 20,000 units can be made in the skin every day because the same sunlight that makes it, begins to break it down. After your skin turns dark (tans) even less cholecalciferol is made. Humans have a natural system in the skin that prevents toxicity. Another way of saying this is that the rate-limiting step for the production of calcitriol in the tissues is your behavior: how often you go into the sun or how much cholecalciferol you take as a supplement. This makes vitamin D unique.(Vitamin D Council 2009)

Why Is There Controversy About Recommended Levels of Vitain D?

In the United States, adult dietary requirements of 200 IU/day are established as just enough to prevent osteomalacia (softening of the bones due to a lack of vitamin D) in the absence of sunlight.

For the past decade, the number of research studies published every year on the health benefits of vitamin D has dramatically increased. Despite all this new evidence, however, the recommended level of vitamin D intake set by the Food and Nutrition board (an agency of the US government) has remained at 200 IU/day for those up to age 50 years, 400 IU for those age 51-70 years, and 600 IU for 71 years and above. (NIH: Office of Dietary Supplements 2009) The problem with waiting until age 71 to increase the intake is that most of the diseases associated with insufficient vitamin D3 intake have already occurred by that age. Inadequate vitamin D early in life can lead to long latency diseases such as autoimmune disease, bone disease, and certain types of cancers.(Kimball, Fuleihan Gel et al. 2008) Encouragingly, the Institute of Medicine (an independent, non-governmental, nonprofit organization that is part of the National Academy of Sciences) has undertaken a study to assess current clinical and laboratory research data andupdate the recommended intake levels for vitamin D and calcium, including a focus on obesity, age-related chronic diseases, with results expected by May 2010.(Institute of Medicine 2009)

The upper tolerable limit of vitamin D established by the Food and Nutrition board is 2000 IU/day. These conservative dosing guidelines persist today, in spite of dozens of studies; these include a 2007 analysis that used the Food and Nutrition Board’s own risk assessment approach to determine that, based on well-designed human trials that found no toxicity from vitamin D dose at or above 10,000 IU/day, this should be established as the new upper limit. Extended use of 10,000 IU/d of vitamin D3, even in people with a high physiologic background level of vitamin D, introduces no risk of toxicity for adults.(Vieth 2009) Perhaps not coincidentally, this level of 10,000 IU/day is the same amount of vitamin D that can be created by the body in response to sunshine.(Hathcock, Shao et al. 2007)

The growing weight of new evidence on vitamin D shows benefits far beyond its role in bone growth. The authors of the sunshine study wrote that in spite of the new evidence for a wide range of benefits, the established upper limits for vitamin D (2000 IU) “is not based on current evidence and is viewed by many as being too restrictive, thus curtailing research, commercial development, and optimization of nutritional policy.”(Hathcock, Shao et al. 2007) Some of the most renowned vitamin D researchers have called for upward revisions of these limits.(Vieth 2006; Vieth, Bischoff-Ferrari et al. 2007)

Another controversy comes from physicians opposing the use of vitamin D because of interactions with medications. Fortunately, there are only a few recognized interaction problems with vitamin D and prescription medications, which are listed here:

Digoxin: The combination can increase risk of fatal cardiac arrhythmias, because of the possibility that high doses of vitamin D over 2000 IU/day may cause hypercalcemia.(Mckevoy Gk 1998)

Atorvastatin (Lipitor): The combination can result in lower than desired levels of atorvastatin, because vitamin D increases levels of the drug-metabolizing enzyme cytochrome P450. It should be noted, however, that even though atorvastatin serum levels decreased in a study of this drug combination, nevertheless there was no significant change in total cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol.(Schwartz 2009)

Diltiazem (Cardizem, Dilacor, Tiazac): The combination may reduce the effectiveness of these medications in atrial fibrillation, because of the possibility that doses of vitamin D over 2000 IU/day may cause hypercalcemia.(Schwartz 2009)

Verapamil (Calan, Covera, Isoptin, verelan): The combination may reduce the effectiveness of these medications in atrial fibrillation, because of the possibility that doses of vitamin D over 2000 IU/day may cause hypercalcemia.(Bar-Or and Yoel 1981)

Calcipotriene (Dovonex): This vitamin D analog is used topically for psoriasis and, like vitamin D, can cause hypercalcemia.(Mckevoy Gk 1998)

Thiazide Diuretics: The combination may cause hypercalcemia because these diuretics decrease urinary calcium excretion. (Parfitt 1972)

The following medications can cause vitamin D depletion: Carbamazepine (Tegretol), cholestyramine (Questran, Locholest, Prevalite), colestipol (Colestid), corticosteroids, mineral oil, orlistat (xenical, Alli), phenobarbital, fosphenytoin (Cerebyx), rifampin (Rifampicin, Rifadin, Rimactane), stimulant laxatives such as senna (Senokot) or visacodyl (Dulcolax), and sunscreens.(Natural Medicines Comprehensive Database 2009)

WHY ARE THE LOW LEVELS OF RECOMMENDED INTAKE A PROBLEM?

The problem is several-fold: (1) vitamin D plays such an important role in human physiology and immune function, as described previously; (2) it helps the body in healing a wide range of illnesses; (3) we spend far less time outdoors than our ancestors; (4) many studies have shown low vitamin D blood levels, even in countries such as Pakistan which have plenty of sunlight;(khan and Iqbal 2009) and (5) there is little vitamin D present in most foods, meaning that without additional supplementation, many people have very low vitamin D blood levels.

THE POLITICS OF VITAMIN D: HOW DID THIS HAPPEN?

The first established recommended dietary allowance of vitamin D in infants was 400 IU/day.(National Academy of Sciences 1989) Unfortunately, the scientific basis for how this dose level was established is cursory and somewhat arbitrary: (1) it is roughly equivalent to the vitamin D contents of a teaspoon of cod-liver oil, and (2) had been generally accepted as the amount needed to safely prevent rickets, a disease in which the long bones of the body become stunted and deformed.(Holick 2004) The recommended adult dosing levels were established in a similarly cursory manner: a committee of experts recommended adults take one-half the infant dose, 200 IU vitamin D per day, even though there were no research data demonstrating that this level of intake had any ability to affect serum blood levels of vitamin D.(Vieth 1999)

There are many other instances of the illogical and cursory manner in which vitamin D nutritional levels have been established. In the Uk, for example, the basis for the adult dietary requirement of 100 IU/day was a small study with only of 7 adult women with osteomalacia, in whom there were increases in bone mineral density after being given that dose.(Dent and Smith 1969)

HOW IS DOSAGE OF VITAMIN D MEASURED?

Dosage of vitamin D is generally measured in International Units (IU), a system of units based on the biological effect of the substance in question. For vitamin D, 400 IU equals 10 micrograms (μg). Because IUs are specific to the substances they measure, one IU of vitamin D, for example, does not equal one IU of vitamin A.

WHAT ARE SOME OF THE BENEFITS OF VITAMIN D SUPPLEMENTATION?

Improvement in Congestive Heart Failure

Several clinical trials have shown a variety of benefits: In one randomized trial, patients with congestive heart failure (average age of 75) received a vitamin combination with vitamin D at a daily dose of 400 IU, or placebo. Patients in the vitamin D group had no difference in their levels of immune signaling molecules called cytokines, but did achieve significant improvement in their left ventricular function and quality of life.(Witte and Clark 2005)

Another randomized trial of men with congestive heart failure (in this study, they were younger, with average age of 55) gave patients either a placebo or vitamin D but at a higher dose of 2000 IU per day. By contrast, this study showed the opposite effect: a decline in serum cytokines levels, but no change in either left ventricular function or survival. The authors of this study acknowledged several possible reasons for the lack of clinical effectiveness: (Schleithoff, Zittermann et al. 2006) They saw an increase of 26.8 ng of vitamin D in the treatment group, which may have been insufficient to achieve any clinically relevant change. Additionally, patients’ baseline levels prior to treatment were a very low 14 to 15 ng/ml. There was also a high number of dropouts in this study, probably related to the fact that patients were very ill. The researchers also gave calcium supplements to both the vitamin D and placebo groups, which may have improved heart function in both study groups. In neither did the researchers specify their reason for establishing vitamin D dose levels, one at 400 IU/ day and the other at 2000. We are still lacking a well-designed study that includes a dose-finding phase monitored closely enough to clearly see how much vitamin D is needed to pro-

duce an immune response specific to inflammatory cytokines. (Vieth and kimball 2006)

Prevention of Breast Cancer

One of the ways in which vitamin D may reduce the risk of developing breast cancer is by reducing hormone levels in pre-menopausal women. In a study designed to examine the relationship between vitamin D and hormone levels, 101 women aged 18 to 22 who were not using hormonal contraceptives, were recruited during summer and winter. For women recruited in summer, one blood sample was taken, and for those recruited in winter, an additional sample was taken after 4 weeks of daily vitamin D. The researchers found that for every increase in serum vitamin D levels of 4 ng/ml (10 nmol/l), progesterone decreased by 10% and estradiol decreased by 3%.(knight, Wong et al. 2009)

Another study found that in comparing women with breast cancer to controls, higher intake of vitamin D through combined use of food, supplements, and sunlight exposure, reduced risk of developing estrogen receptor-positive/progesterone receptor-positive (ER+/PR+) breast cancer by nearly half, and both ER-/PR- and mixed (ER+/PR-) by nearly one quarter.(Blackmore, Lesosky et al. 2008) Another study published one year earlier found similarly strong results, although the researchers did not distinguish between types of breast cancer. (knight, Lesosky et al. 2007)

Other compelling human trials data are available. A Phase II study conducted at Princess Margaret Hospital, Toronto, enrolled 40 women with bone metastases from breast cancer to receive 10,000 IU vitamin D3 and 1000 mg calcium daily for 4 months. There were several beneficial (and no harmful) outcomes of this treatment: while there were no significant changes in bone resorption markers or change in global pain scales, there was however a significant reduction in the number of sites of pain. This study also found two women with previously unknown diagnoses of primary hyperparathyroidism, who were found to have hypersensitivity to vitamin D3 supplementation (this was due to their underlying parathyroid abnormality, not to direct toxicity of vitamin D3). Intriguingly, vitamin D3 treatment also led to a reduction in elevated parathyroid hormone levels which may have been caused in women by long-term treatment with bisphosphonate drugs (such as Actonel, Aredia, Boniva, Fosamax and Zometa).(Amir, Simmons et al. 2010)

Prevention of Osteoarthritis Progression

In older adults, maintaining blood levels of serum vitamin D above 75 nmol/L reduces risk of fracture.(Mocanu, Stitt et al. 2009)

Improvement of Multiple Sclerosis

Abnormally low levels of serum vitamin D may be a significant risk factor for multiple sclerosis, and most people with this condition have low serum levels of vitamin D. The latitude at which a person resides affects their risk of developing multiple sclerosis, with higher rates of occurrence found in countries farther from the equator where they receive less sunlight. Vitamin D apparently helps to regulate immune function within the central nervous system. Results of phase I/II studies suggest that vitamin D can be helpful for people with multiple sclerosis. Furthermore, there are no studies which have shown a lack of benefit for vitamin D in people with multiple sclerosis.(Pierrot-Deseilligny 2009)

In fact, a small six-month open study of 12 people with multiple sclerosis found that calcium at 1200 mg per day, combined with progressively increasing of vitamin D3 from 28,000 to 280,000 IU per week led to a reduction in the number of brain lesions by over half (on nuclear magnetic brain scan), no toxicity and no changes in liver enzymes, serum creatinine, electrolytes, serum protein, or parathyroid hormone.(kimball, Ursell et al. 2007)

Slowing the Progression of Prostate Cancer

During the spring and summer seasons, when there is usually more sun exposure, men with localized, low- to intermediate- grade prostate cancer who are on watchful waiting experience a slower rise in PSA than during the fall and winter.(Vieth, Choo et al. 2006)

Prevention and Treatment of Influenza

A significant contributor to winter-time flu susceptibility may be a combination of reduced exercise resulting in weaker respiratory fitness, and vitamin D deficiency induced in part by less exposure to sunlight.(See Avenues 27-28, 2009) Vitamin D3’s ability to prevent flu infection was studied by Dr. John Cannell, Executive Director of the Vitamin D Council. Cannell has estimated that vitamin D plays a role in the repair and maintenance of more than 1000 human genes in a wide variety of tissues. Included in these genes is the one responsible for the polypeptide called cathelicidin, a naturally occurring broad-spectrum antibiotic made in your white blood cells. Cannell also cogently suggests that vitamin D deficiency may be one of the chief culprits behind seasonal influenza epidemics,(Cannell, Vieth et al. 2006) pointing out evidence from intervention trials that have shown vitamin D3 prevents respiratory infections in children.(Cannell, Zasloff et al. 2008)

HOW IS VITAMIN D MEASURED? WHAT ARE OPTIMAL BLOOD LEVELS OF VITAMIN D?

There are two measurement systems for monitoring levels of vitamin D in the blood. The first is a measurement of vitamin D by weight found in a given volume of blood: nanograms per milliliter (ng/ml). The second measures vitamin D by its molecular concentration for a given volume of blood: nanomoles per milliliter (nM/L). The Vitamin D Council recommends maintaining vitamin D blood levels between 50–80 ng/mL (or 125–200 nM/L) year-round.(Vitamin D Council 2009)

For people living in sunny areas, normal serum vitamin D levels are between 40-70 ng per ml. There are three ways to boost vitamin D levels: sunlight, artificial ultraviolet B (UVB) radiation, and vitamin D3 supplements. 2,000-7,000 IU vitamin D per day should be sufficient to maintain year-round levels of vitamin D in the blood.(Cannell and Hollis 2008)

Reinhold Vieth has recently addressed the question of long-term vitamin D dosing. The question of what represents optimal vitamin D levels in the blood is not a simple one. The human body has a regulatory capability that responds to fluctuations in dietary intake of vitamin D, and there is evidence that fluctuations in serum concentrations of vitamin D could be problematic. When levels of serum vitamin D decrease, the ratio of enzymes which regulate vitamin D levels must increase to maintain the optimal set-point of tissue 1,25(OH)2D. According to Dr. Vieth, this adaptive regulatory system of vitamin D is not well understood, and suggests that higher summertime vitamin D levels, when followed by much lower winter levels, can lead to body tissue levels of vitamin D well below the ideal set-point. Therefore, desirable vitamin D concentrations are both high and steady. (Vieth 2009)

WHO IS AT RISK FOR LOWER VITAMIN D LEVELS?

Most people, according to several studies, have vitamin D levels that are well below the optimum 75 nmol/L. Vitamin D inadequacy is described by experienced vitamin D researchers Reinhold Veith and John Cannel MD as “an epidemic.”(Cannell, Vieth et al. 2008) A study of 107 healthy adults in Toronto found that over 90% had blood levels below 75, and over three quarters had levels below 50. Vitamin D levels were lowest in non-Causasians with darker skin pigmentation.(Gozdzik, Barta et al. 2008) Dr. Veith has also identified that if sun-deprived adults want to maintain their levels of vitamin D above 75, they would need to take much more than the currently recommended dietary amounts.(Vieth 2007)

WHAT ARE OPTIMAL LEVELS OF DIETARY INTAKE OF VITAMIN D?

Safe levels of vitamin D appear to be much higher than the reccomended daily allowance. In a study of vitamin D supplementation in older adults given 5000 IU/day for 12 months, serum vitamin D levels increased from an average baseline of 28.5 nmol/L to 125.6 +/- 38.8 nmol/L, and both lumbar spine and hip bone mineral density increased significantly. With respect to safety, serum parathyroid hormone was lower than at baseline, and there were no cases of hypercalcemia.(Mocanu, Stitt et al. 2009)

There has also been research that specifically compared the effectiveness of different doses and time intervals of vitamin D3 supplements in achieving higher serum levels of vitamin D. In one study, volunteers were given 600 IU/day, or 4200 IU/week, or 18,000 IU/month, or placebo. After 4 months, researchers found that daily vitamin D3 was more effective than weekly, and monthly dosing the least effective, in achieving higher serum vitamin D levels.(Chel, Wijnhoven et al. 2008) However, another study of women in their 80s found that vitamin D3 daily at 1,500 IU, weekly at 10,500 IU, or monthly at 45,000 IU provided similar increases in serum vitamin D levels.(Ish-Shalom, Segal et al. 2008)

There are differences between individual people in the body’s ability to achieve higher serum vitamin D levels in response to taking it in supplement form. These differences appear to arise from a genetic trait called the vitamin D binding protein, of which there are three known genotypes. A dose evaluation study of 98 adults sought to identify what effect this protein would have on the body’s ability to absorb two different doses of vitamin D: 600 or 4000 IU over a one-year period. The most common genotype (TT genotype, found in 48 of 98 people) achieved a 97% increase (nearly double the baseline). Slightly less common (31 of 98 people) is the Tk genotype, where a 151% increase was observed (two and a half times baseline levels). The most rare genotype (kk genotype, found in 3 of 98 people) achieved a 307% increase in vitamin D levels from supplementation (reaching over four times their baseline levels).(Fu, Yun et al. 2009) This suggests that response to vitamin D supplements differs between individuals and, therefore, testing blood levels before and during supplementation is reccomended.

SAFETY

The only known toxicities of vitamin D are related to its effect on metabolism of the mineral calcium.(kimball, Ursell et al. 2007) To date, there is no evidence of toxicity with vitamin D up to 10,000 IU/day, except in cases of sensitivity such as those with parathyroid disorders. known cases of vitamin D toxicity in which hypercalcemia occurred all involve using over 40,000 IU per day.(Vieth 1999)

In a study assessing both short and long term safety, 25 teenage students were randomly assigned to receive either placebo or vitamin D3 at 14,000 IU per week, for 8 weeks, to test short-term safety. To assess long-term safety, 340 students received placebo, vitamin D3 at 1,400 IU per week, or at 14,000 IU per week for a one-year time-span. There were no adverse effects at any dose level or duration. In the short-term group, there was a modest 25% increase in vitamin D serum levels; in the long-term group, vitamin D levels also increased only modestly in the low-dose group receiving 1,400 IU per week, but more than doubled in the high-dose group receiving 14,000 IU per week.(Maalouf, Nabulsi et al. 2008)

It is nevertheless essential to recognize the importance of vitamin D toxicity in those with primary hyperparathyroidism and various granulomatous diseases like sarcoidosis. The parathyroid gland makes parathyroid hormone, which helps the body regulate calcium levelss. When it malfunctions, it can cause primary hyperparathyroidism, and an exquisite sensitivity to vitamin D3 supplementation occurs. In an unusual case, a 77-year-old woman who had been taking vitamin D2 at 50,000 IU daily for two years developed dramatically elevated calcium levels. During her clinical evaluation it was discovered she had primary hyperparathyroidism. After stopping vitamin D, her serum 25-hydroxyvitamin D remained elevated years, most likely because her parathyroid disorder prevented adequate availability of an enzyme that normally metabolizes vitamin D-catabolizing enzyme, called 25(OH)D-24-hydroxylase.(Taskapan, Vieth et al. 2008)

In a study of smokers from Finland, higher blood levels of vitamin D (without supplementation) were associated with a three-fold increase in risk of pancreatic cancer. However, it is important to note that this study took place in the same group in which an earlier study found that beta-carotene caused an increase in the rate of developing lung cancers.(Stolzenberg-Solomon, Vieth et al. 2006) This suggests that in smokers, vitamin D supplementation may have a paradoxical effect, much like that seen with beta-carotene.

WHAT KINDS OF VITAMIN D SUPPLEMENTS ARE RECOMMENDED?

Although there are more than 5000 vitamin D containing supplements currently on the market, only 178 of these products have been verified by the USP (United States Pharmacopeia); they can be identified at the following website: www.naturaldatabase.com. (Natural Medicines Comprehensive Database 2009)

HOW CAN YOU DETERMINE WHAT YOUR VITAMIN D INTAKE IS?

The USDA’s website contains an online reference for locating dietary nutrient levels of commonly eaten foods, the National Nutrient Database, providing an extensive list which can be sorted by alphabetically by food or in descending order of concentration: http://tinyurl.com/ya6xvze (USDA 2009)

HOW CAN YOU DETERMINE YOUR SERUM VITAMIN D LEVELS?

The best way is with laboratory tests. There are at least four types of laboratory tests available to determine vitamin D levels in serum: the classic calf-thymus receptor assay, DiaSorin radioimmunoassay (RIA), DiaSorin “LIAISON 25 OH Vitamin D TOTAL”, and Roche Modular “Vitamin D3 (25-OH)”.(Seiden-Long and Vieth 2007; Wagner, Hanwell et al. 2009) The DiaSorin LIAISON was the most accurate and precise automated tool for serum vitamin D testing.(Wagner, Hanwell et al. 2009)

Blood levels of 25-hydroxy-vitamin D (25-OH-D), the active form of Vitamin D, can be tested by most medical laboratories, with the order of a blood test from a medical provider.

Additionally, through a collaboration between the Vitamin D Council and ZRT Laboratories of Beaverton, OR (503-466-2445), individuals can order their own 25-OH-D test at www.zrtlab.com/vitamindcouncil. According to the Vitamin D Council, “This is a home test for 25(OH)D, requiring a finger or heel stick to get several drops of blood. You order the test kit, which ZRT will ship to you. After receiving your kit either you, or someone you know in the medical field, will do a finger or heel stick and put the blood on the blotter included in the kit. You will then send the blotter paper back to ZRT in the envelope provided. ZRT will perform the 25(OH)D test in their lab and send the results directly back to you. The Vitamin D Council has verified that results obtained by ZRT are accurate and correspond very well to the results given by both LabCorp and DiaSorin RIA.”(Vitamin D Council 2009)

SUMMARY

Vitamin D plays an essential role in maintaining important body functions such as the immune system and bone health. While vitamin D supplementation is helpful in preventing and treating many health conditions, it is certainly not a substitute for going outdoors. We hope that this comprehensive examination of the evidence for vitamin D safety and efficacy will stimulate many engaging and productive dialogues between physician and patient about safe levels of vitamin D supplementation and the advisability of vitamin D blood level monitoring and therapy.

REFERENCES

Amir, E., C. E. Simmons, et al. (2009). “A phase 2 trial exploring the effects of high-dose (10,000 IU/day) vitamin D(3) in breast cancer patients with bone metastases.” Cancer.

Bar-Or, D. and G. Yoel (1981). “Calcium and calciferol antagonize effect of verapamil in atrial fibrillation.” Br Med J 282: 1585-1586.

Blackmore, K. M., M. Lesosky, et al. (2008). “Vitamin D from dietary intake and sunlight exposure and the risk of hormone-receptor-defined breast cancer.” Am J Epidemiol 168(8): 915-924.

Cannell, J. J. and B. W. Hollis (2008). “Use of vitamin D in clinical practice.” Altern Med Rev 13(1): 6-20.

Cannell, J. J., R. Vieth, et al. (2008). “Cod liver oil, vitamin A toxicity, frequent respiratory infections, and the vitamin D deficiency epidemic.” Ann Otol Rhinol Laryngol 117(11): 864-870.

Cannell, J. J., M. Zasloff, et al. (2008). “On the epidemiology of influenza.” Virol J 5: 29.

Cranney, A., T. Horsley, et al. (2007). “Effectiveness and safety of vitamin D in relation to bone health.” Evid Rep Technol Assess (Full Rep)(158): 1-235.

Dent, C. E. and R. Smith (1969). “Nutritional osteomalacia.” Q J Med 38(150): 195-209.

Ding, C., F. Cicuttini, et al. (2009). “Serum levels of vitamin D, sunlight exposure, and knee cartilage loss in older adults: the Tasmanian older adult cohort study.” Arthritis Rheum 60(5): 1381-1389.

Fu, L., F. Yun, et al. (2009). “Common genetic variants of the vitamin D binding protein (DBP) predict differences in response of serum 25-hydroxyvitamin D [25(OH )D] to vitamin D supplementation.” Clin Biochem 42(10-11): 1174-1177.

Gozdzik, A., J. L. Barta, et al. (2008). “Low wintertime vitamin D levels in a sample of healthy young adults of diverse ancestry living in the Toronto area: associations with vitamin D intake and skin pigmentation.” BMC Public Health 8: 336.

Gupta, D., C. A. Lammersfeld, et al. (2009). “Vitamin D and prostate cancer risk: a review of the epidemiological literature.” Prostate Cancer Prostatic Dis 12(3): 215-226.

Hathcock, J. N., A. Shao, et al. (2007). “Risk assessment for vitamin D.” Am J Clin Nutr 85(1): 6-18.

Hayes, C. E. and E. Donald Acheson (2008). “A unifying multiple sclerosis etiology linking virus infection, sunlight, and vitamin D, through viral interleukin-10.” Med Hypotheses 71(1): 85-90.

Holick, M. F. (2004). “Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease.” Am J Clin Nutr 80(6 Suppl): 1678S-1688S.

Holick, M. F. (2008). “Vitamin D and sunlight: strategies for cancer prevention and other health benefits.” Clin J Am Soc Nephrol 3(5): 1548-1554.

Institute of Medicine. (2009). “Food and Nutrition Board.” Retrieved December 30, 2009, from http://tinyurl.com/yjyr8f4

Ish-Shalom, S., E. Segal, et al. (2008). “Comparison of daily, weekly, and monthly vitamin D3 in ethanol dosing protocols for two months in elderly hip fracture patients.” J Clin Endocrinol Metab 93(9): 3430-3435.

Khan, A. H. and R. Iqbal (2009). “Vitamin D deficiency in an ample sunlight country.” J Coll Physicians Surg Pak 19(5): 267-268.

Kimball, S., H. Fuleihan Gel, et al. (2008). “Vitamin D: a growing perspective.” Crit Rev Clin Lab Sci 45(4): 339-414.

Kimball, S. M., M. R. Ursell, et al. (2007). “Safety of vitamin D3 in adults with multiple sclerosis.” Am J Clin Nutr 86(3): 645-651.

Knight, J. A., M. Lesosky, et al. (2007). “Vitamin D and reduced risk of breast cancer: a population-based case-control study.” Cancer Epidemiol Biomarkers Prev 16(3): 422-429.

Knight, J. A., J. Wong, et al. (2009). “Vitamin D association with estradiol and progesterone in young women.” Cancer Causes Control.

Maalouf, J., M. Nabulsi, et al. (2008). “Short- and long-term safety of weekly high-dose vitamin D3 supplementation in school children.” J Clin Endocrinol Metab 93(7): 2693-2701.

Macdonald, H. M., A. Mavroeidi, et al. (2008). “Vitamin D status in postmenopausal women living at higher latitudes in the UK in relation to bone health, overweight, sunlight exposure and dietary vitamin D.” Bone 42(5): 996-1003.

McKevoy GK, e. (1998). AHFS Drug Information. Bethesda, MD, American Society of Health-System Pharmacists.

Mocanu, V., P. A. Stitt, et al. (2009). “Long-term effects of giving nursing home residents bread fortified with 125 microg (5000 IU) vitamin D(3) per daily serving.” Am J Clin Nutr 89(4): 1132-1137.

National Academy of Sciences (1989). Recommended dietary allowances. 10th ed. Washington, DC, National Academy Press.

Natural Medicines Comprehensive Database. (2009). “Vitamin D.” Retrieved January 14, 2009, from http://www.naturaldatabase.com

NIH: Office of Dietary Supplements (2009). “Dietary Supplement Fact Sheet: Vitamin D.”

Norman, A. W. (1998). “Sunlight, season, skin pigmentation, vitamin D, and 25-hydroxyvitamin D: integral components of the vitamin D endocrine system.” Am J Clin Nutr 67(6): 1108-1110.

Parfitt, A. M. (1972). “Thiazide-induced hypercalcemia in vitamin D-treated hypoparathyroidism.” Ann Intern Med 77: 557-563.

Perez-Lopez, F. R. (2008). “Sunlight, the vitamin D endocrine system, and their relationships with gynaecologic cancer.” Maturitas 59(2): 101-113.

Pierrot-Deseilligny, C. (2009). “Clinical implications of a possible role of vitamin D in multiple sclerosis.” J Neurol 256(9): 1468-1479.

Reichrath, J. (2007). “Sunlight, skin cancer and vitamin D: What are the conclusions of recent findings that protection against solar ultraviolet (UV) radiation causes 25-hydroxyvitamin D deficiency in solid organ-transplant recipients, xeroderma pigmentosum, and other risk groups?” J Steroid Biochem Mol Biol 103(3-5): 664-667.

Rosso, S., F. Sera, et al. (2008). “Sun exposure prior to diagnosis is associated with improved survival in melanoma patients: results from a long-term follow-up study of Italian patients.” Eur J Cancer 44(9): 1275-1281.

Schleithoff, S. S., A. Zittermann, et al. (2006). “Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial.” Am J Clin Nutr 83(4): 754-759.

Schwartz, J. B. (2009). “Effects of vitamin D supplementation in atorvastatin-treated patients: a new drug interaction with an unexpected consequence.” Clin Pharmacol Ther 85(2): 198-203.

Seiden-Long, I. and R. Vieth (2007). “Evaluation of a 1,25-dihydroxyvitamin D enzyme immunoassay.” Clin Chem 53(6): 1104-1108.

Shuster, S. (2008). “Is sun exposure a major cause of melanoma? No.” Bmj 2008/07/24. 337, from http://tinyurl.com/ydsbgw6

Sigmundsdottir, H., J. Pan, et al. (2007). “DCs metabolize sunlight-induced vitamin D3 to ‘program’ T cell attraction to the epidermal chemokine CCL 27.” Nat Immunol 8(3): 285-293.

Stolzenberg-Solomon, R. Z., R. Vieth, et al. (2006). “A prospective nested case-control study of vitamin D status and pancreatic cancer risk in male smokers.” Cancer Res 66(20): 10213-10219.

Taskapan, H., R. Vieth, et al. (2008). “Unusually prolonged vitamin D intoxication after discontinuation of vitamin D: possible role of primary hyperparathyroidism.” Int Urol Nephrol 40(3): 801-805.

U.S. National Library of Medicine. “PTH.” Medline Plus Retrieved January 9, 2009, from http://tinyurl.com/do6w7

USDA. (2009). “USDA National Nutrient Database for Standard Reference, Release 22, Nutrient Lists “, from http://tinyurl.com/ya6xvze

van den Berg, H. (1997). “Bioavailability of vitamin D.” Eur J Clin Nutr 51 Suppl 1: S76-79.

Vieth, R. (1999). “Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety.” Am J Clin Nutr 69(5): 842-856.

Vieth, R. (2006). “Critique of the considerations for establishing the tolerable upper intake level for vitamin D: critical need for revision upwards.” J Nutr 136(4): 1117-1122.

Vieth, R. (2007). “Vitamin D toxicity, policy, and science.” J Bone Miner Res 22 Suppl 2: V64-68.

Vieth, R. (2009). “How to optimize vitamin D supplementation to prevent cancer, based on cellular adaptation and hydroxylase enzymology.” Anticancer Res 29(9): 3675-3684.

Vieth, R. (2009). “Vitamin D and cancer mini-symposium: the risk of additional vitamin D.” Ann Epidemiol 19(7): 441-445.

Vieth, R., H. Bischoff-Ferrari, et al. (2007). “The urgent need to recommend an intake of vitamin D that is effective.” Am J Clin Nutr 85(3): 649-650.

Vieth, R., R. Choo, et al. (2006). “Rise in prostate-specific antigen in men with untreated low-grade prostate cancer is slower during spring-summer.” Am J Ther 13(5): 394-399.

Vieth, R. and S. Kimball (2006). “Vitamin D in congestive heart failure.” Am J Clin Nutr 83(4): 731-732.

Vitamin D Council. (2009). “Am I Vitamin D Deficient?”, from http://tinyurl.com/7qouw9

Vitamin D Council. (2009). “Understanding Vitamin D Cholecalciferol.” Retrieved December 27, 2009, from http://www.vitamindcouncil.org/

Wagner, D., H. E. Hanwell, et al. (2009). “An evaluation of automated methods for measurement of serum 25-hydroxyvitamin D.” Clin Biochem 42(15): 1549-1556.

Wikipedia. “Vitamin D.” Retrieved December 27, 2009, from http://en.wikipedia.org/wiki/Vitamin_d

Witte, K. K. and A. L. Clark (2005). “Chronic heart failure and multiple micronutrient supplementation: realistic hope or idealistic conjecture?” Heart Fail Monit 4(4): 123-129.

Wolf, G. (2004). “The discovery of vitamin D: the contribution of Adolf Windaus.” J Nutr 134(6): 1299-1302.

Wu, H., A. Gozdzik, et al. (2009). “The development and evaluation of a food frequency questionnaire used in assessing vitamin D intake in a sample of healthy young Canadian adults of diverse ancestry.” Nutr Res 29(4): 255-261.

VITAMIN D3: A REVIEW OF THE EVIDENCE FOR ITS ROLE IN HUMAN HEALTH
Vitamin D is crucial to immune health and general well-being, yet one out of every three Americans has very low levels of vitamin D in their blood. In this evidence-based review article, we examine vitamin D’s history and discuss its role in helping us achieve optimal health. Click here for more.

THANK YOU
On behalf of the entire board, we would like to thank you for your generosity and support. Your donations make all of the Pine Street Foundation’s educational programs, clinical trials, and research initiatives possible and we hope you will continue to follow our progress and support our work in the coming year. If you’d like to learn more about how to help support our mission or join our team, please visit: www.pinestreetfoundation.org/support

IS “SWINE FLU” THE RIGHT NAME?
Swine flu is a new type of flu virus genetically similar to flu viruses normally occurring in pigs. Often called H1N1, which refers to the two molecules Hemagglutinin and Neuraminidase that are found on the outside of viruses, swine flu is different from the virus normally found in pigs in that it combines genes from flu viruses found in pigs together with genes from bird and humans.(CDC 2009)

The H1N1 flu virus has adapted and exchanged genetic information with the common flu viruses, allowing transmission from human to human. This is in contrast with the Avian Flu outbreak, which started in China in 2003, in which the virus responsible (H5N1) was not able to change as readily from an animal-to-human transmitted form to one that could move from human-to-human. Furthermore, it is not yet known precisely how swine flu developed, which animal first passed it to a human, or when that actually occurred.(Fidler 2009) Therefore, swine flu is more accurately called the 2009 H1N1 flu.

WHAT MAKES THE 2009 H1N1 FLU DIFFERENT?
While most 2009 H1N1 flu cases have been mild, with symptoms similar to those of seasonal flu, there are several more serious symptoms that can signal infection with H1N1. The Centers for Disease Control and Prevention has created a website that helps evaluate symptoms (flu.gov/evaluation), which presents a stepwise series of questions designed to help evaluate symptom relevance and severity. The interview concludes with an opinion as to whether your pattern of symptoms might represent likely 2009 H1N1 flu infection. In contrast to many of the self-check questionnaires available in the popular media, this site correctly places high importance on several cardinal symptoms that could signal serious H1N1 flu with complications: (1) your condition suddenly getting much worse, (2) shortness of breath or cough, (3) diarrhea or vomiting, and (4) your condition still getting worse after seven days (five for a child). Most people whose death has been attributed to 2009 H1N1 infection died because they developed a second infection, usually bacterial pneumonia.(Chowell, Bertozzi et al. 2009)

England’s National Health Service has more precisely defined the specific circumstances under which people are known to be at increased risk of developing serious 2009 H1N1 flu complications. These would be people with:

» chronic (long-term) lung, heart, kidney, or liver disease
» chronic neurological disease, multiple sclerosis, or Parkinson’s
» immune system suppression (from disease or treatment)
» diabetes mellitus
» patients treated for asthma in the past three years
» pregnant women
» people aged 65 and older
» young children under five

Their report also emphasized that people in these groups who develop flu symptoms should get tested quickly to identify whether they do in fact have 2009 H1N1 influenza and, if so, that they be treated with antiviral medications.

WHY IS 2009 H1N1 FLU POTENTIALLY A MAJOR CONCERN?
There are reasons for both heightened – and reduced – concern about the 2009 H1N1 flu. It has shown the ability to spread very quickly through the global population, aided by modern air travel. As of October 17th, 2009, in 191 countries and territories, over 414,000 laboratory-confirmed cases of 2009 H1N1 flu have been documented and, of those, nearly 5,000 people have died of the flu.(World Health Organization 2009) The anticipated fall/winter resurgence of the flu is happening, and earlier in the season than expected.

One reason for heightened concern is the October 10th announcement by the CDC that 76 children in the US have died of 2009 H1N1 flu, 19 of them in that prior week. The usual seasonal flu kills between 46 and 88 children a year, suggesting that the new H1N1 virus could claim more children than seasonal flu.(CDC 2009)

This strain of flu virus is also of concern because most of us have no immunity to it, since it has a very different structure and activity than the more common seasonal flu viruses that hit every year. The World Health Organization has predicted that over one third of the world’s population will be infected with 2009 H1N1 flu in the next few years.(WHO 2009)

SOME SIGNS THAT THE 2009 H1N1 FLU MAY NOT BE AS DANGEROUS AS ORIGINALLY FEARED
The symptoms of 2009 H1N1 flu have, so far and for most people, been milder than the deadly influenzas of the past century. This has led many health experts to predict that the 2009 H1N1 flu pandemic will not be as dire as the original projections. Some have hypothesized that older people might actually be less affected because those born before 1957 may still have immunity to the types of viruses that spread during outbreaks in the 1950s.

It also appears that the actual death rate related to H1N1 flu virus is much lower than originally feared. The overall death rate due to H1N1 flu virus in Mexico was estimated to be around 0.4% of all people infected.(Fraser, Donnelly et al. 2009) The rate in the United States is approximately 1%.(WHO, 2009) This is a similar rate to that seen with the ordinary flu virus. The death rate from laboratory-confirmed cases officially reported to WHO as of August 2009 is much lower (0.08%). Furthermore, because the true number of H1N1 cases is likely to be much higher than what has been reported to WHO, these are likely to be overestimates of the true death rate.

WHO laboratory surveillance has demonstrated that viruses from all of the 2009 H1N1 flu outbreaks are virtually genetically identical, meaning the virus has not mutated to a more virulent form. Similarly, symptom patterns within these different 2009 H1N1 flu outbreaks are consistent in different countries, and most patients have only mild illness. Furthermore, the incidence of severe and fatal illness is low.(WHO 2009)

Even though a low proportion of all people who develop 2009 H1N1 flu will ultimately die of it, because a higher proportion of people will become infected than they would from seasonal flu, this may still mean that there may be many deaths overall from 2009 H1N1 flu.

Since the 2009 H1N1 flu competitively infects animals more quickly than seasonal flu, but does not share genetic information with other flu strains, it is therefore not likely to mutate into a “superbug”.

WHAT ABOUT VACCINES?
Availability of 2009 H1N1 flu vaccines is already limited, and 2009 H1N1 flu shots will be prioritized for groups most at risk of contracting the virus or developing severe complications of influenza infection. Those would include children, people caring for young infants, younger adults, women who are pregnant, health care workers, and people with chronic illness. In most states, 2009 H1N1 flu shots will be available at hospitals, public health clinics, and pharmacies, with requests evaluated by state health departments. Businesses, which are used to obtaining and providing seasonal flu vaccines, will not be able to obtain 2009 H1N1 flu vaccines unless they have medical providers licensed to provide vaccinations.

Although the regular seasonal flu vaccine became available earlier than is normally seen, nevertheless it is 2009 H1N1 flu that is the dominant strain and the first 2009 H1N1 flu vaccine was not available until October 2009. The CDC estimates that approximately 195 million doses are expected to be available over the next six months. It remains to be seen how effective the 2009 H1N1 flu vaccine will be.(CDC 2009)

In an in-depth analysis of the uncertainties surrounding the effectiveness of vaccination, the magazine The Atlantic asks the question “what if everything we think we know about fighting influenza is wrong? What if flu vaccines do not protect people from dying — particularly the elderly, who account for 90 percent of deaths from seasonal flu?” Health authorities have claimed the death rate due to influenza in elderly persons is reduced by half, thanks to vaccination. (Govaert, Thijs et al. 1994) However, this is an incredible number. The Atlantic writes on, saying that “Tom Jefferson, a physician based in Rome and the head of the Vaccines Field at the Cochrane Collaboration, a highly respected international network of researchers who appraise medical evidence, says: ‘For a vaccine to reduce mortality by 50 percent and up to 90 percent in some studies means it has to prevent deaths not just from influenza, but also from falls, fires, heart disease, strokes, and car accidents. That’s not a vaccine, that’s a miracle.’”(Brownlee and Lenzer 2009) Dr. Jefferson’s three meta-analysis publications summarizing the results of hundreds of studies on vaccine safety and effectiveness are discussed below.

Researcher Lisa Jackson in 2006 published a critical analysis of vaccine effectiveness, suggesting there is a temporal (time-related) bias present in most influenza effectiveness studies. She did something no researcher had done before: she analyzed death rates comparing vaccine users and non-users not only during flu season, but also before flu season began. In her study, she examined the health records of 72,527 people age 65 or older that had been followed over an 8-year period. She found that the risk of death from any cause in vaccine users was 60% lower before influenza season. This tells us that there is, in fact, a “healthy user effect” at work: people who are already healthier are choosing vaccines. She concluded that the magnitude of the time-related bias account entirely for the lower risk of death among vaccine users during the flu season.(Jackson, Jackson et al. 2006) This suggests what we’re seeing about the benefits of flu vaccine may be more about who’s choosing to get vaccinated than it is about the vaccine’s effectiveness itself.

DO FlU VACCINES WORK?
Dozens of studies have been conducted showing the ability of influenza vaccines to successfully induce an immune reaction in the body. However, few studies have been conducted using the gold standard of clinical research — the randomized, placebo-controlled trial — in testing whether influenza vaccines actually prevent the flu or prevent deaths due to the flu.

There are several important questions to consider when reading the results of influenza research studies, questions that rarely appear in reporting in major media outlets. It is well known that the goal of influenza vaccination policy is to reduce the death rate due to influenza by specifically targeting people aged 65 or older. But is this an effective strategy? Researchers at the National Institutes of Health in 2007 pointed out that even though the proportion of people in the United States vaccinated for the flu has increased over the past two decades from 15% to 65%, there has been no decline in influenza-related deaths since 1980.(Simonsen, Taylor et al. 2007)

A SUMMARY OF RECENT RELEVANT RESEARCH
Research results presented at the Infectious Diseases Society of America’s 2009 annual meeting in Philadelphia: Pregnant women who receive flu vaccinations are protected not only for themselves, but for their babies as well. They studied 350 pregnant women and found that when women received the flu vaccine during pregnancy, the vaccine prevented hospitalization up to 85 percent of the time in their babies age 6 months or younger. (Reuters Health, 2009)

2009, Statistics Collaborative, Inc., Washington, DC: A meta-analysis combined the results of nine randomized clinical trials, including a total of nearly 25,000 children aged 6 to 71 months and 2,000 children aged 6 to 17 years. Compared to placebo, live-attenuated vaccines in young children reduced the occurrence of flu infection by two-thirds. Compared to the inactivated form of vaccine, live attenuated vaccines reduced the occurrence of flu infection by nearly half.(Rhorer, Ambrose et al. 2009)

2009, University of Michigan School of Public Health: In a randomized, double-blind, placebo-controlled trial of licensed inactivated and live attenuated influenza vaccines in healthy adults during the 2007-2008 influenza season, there was a two-thirds reduction in risk of flu with the inactivated vaccine, and one-third reduction with the live attenuated vaccine. This finding contrasts with results from the above-mentioned meta-analysis, where the live-attenuated vaccine was more effective.(Monto, Ohmit et al. 2009)

2009, Cochrane Collaboration: A team led by Tom Jefferson, one of the few experienced influenza researchers apparently willing to critically question vaccination research and policy, conducted a systematic review paper that examined the relationship between who funded a study, the prestige level of journals publishing this research, and whether the authors’ conclusions are supported by the data. They identified 259 studies comparing influenza vaccines to placebo or no intervention. They found that studies published in prestigious journals were almost always funded by pharmaceutical industry sources. They also found that the studies conducted with higher quality methods and writing were significantly less likely to find effectiveness of vaccines than lower quality studies. It should be noted that the Cochrane Collaboration is an independent group of researchers worldwide who volunteer their time in the interest of conducting critical evaluations of evidence from clinical research, unconstrained by political influence of governing bodies or research funding.

2008, Cochrane Collaboration: Another effort by Jefferson’s group assessed the effectiveness of influenza vaccines in healthy children, documenting adverse events from influenza vaccines, and seeking studies of any influenza vaccine in healthy children under 16 years of age. His team found fifty-one studies, including nearly 300,000 children; data from randomized controlled trials showed the live attenuated vaccines had an ability of between 33% and 82% to prevent influenza in children older than two, compared with either placebo or no treatment. With inactivated vaccines, that ranged between 36% and 59%.

This meta-analysis found “extensive evidence of reporting bias of safety outcomes from trials of live attenuated vaccines.” Furthermore, the authors concluded that “influenza vaccines are efficacious in children older than two but little evidence is available for children under two.”(Jefferson, Rivetti et al. 2008)

2006, Cochrane Collaboration: Jefferson’s group published a meta-analysis of studies on anti-viral medication, concluding that “the use of amantadine and rimantadine should be discouraged. Because of their low effectiveness, neuraminidase inhibitors should not be used in seasonal influenza control and should only be used in a serious epidemic or pandemic alongside other public-health measures.”(Jefferson, Demicheli et al. 2006) It is important to note that another unanticipated consequence of widespread use of antiviral medications for flu prevention is their accumulation in river water, leading to the development of resistant strains of flu. When Tamiflu is passed through the body, nearly all of it will end up in the environment in the active form as it is removed by sewage treatment plants. Should Tamiflu resistance develop in birds, it is most likely that those will be the typical seasonal flu and avian viral strains, which cause more deaths than H1N1 and, unlike H1N1, pass through birds.(Raloff 2009)

WHAT ABOUT THE ORDINARY SEASONAL FLU VACCINE?
On October 8th, 2009, researchers from Mexico reported in the British Medical Journal an astonishing finding: that the ordinary seasonal inactivated vaccine provided protection against this year’s pandemic influenza, A/H1N1 2009. Working in a hospital in Mexico City over a three-month period, they analyzed the case records of 60 patients with laboratory-confirmed influenza A/H1N1, and compared those to 180 controls with other diseases not related to influenza or pneumonia. To make them more comparable, cases were matched with controls by age and socioeconomic status. They found that none of the 8 flu patients who had been vaccinated with seasonal flu vaccine died (0%), whereas 18 of the 52 unvaccinated patients died (35%). Additionally, while only 1 of the 8 flu patients (13%) required intensive respiratory support, nearly half (25 of 52, or 48%) of the unvaccinated patients did require it. The authors concluded that since “none of the vaccinated cases of influenza A/H1N1 died… seasonal vaccination might protect against the most severe forms of the disease.”(Garcia-Garcia, Valdespino-Gomez et al. 2009)

WHAT ARE THE FINANCIAL INCENTIVES FOR VACCINE MANUFACTURERS?
Since the first outbreak of H1N1 in the spring of this year, five biopharmaceutical companies – Novartis, GlaxoSmithkline, MedImmune, CSL, and Sanofi-Pasteur – have been developing and testing vaccines. The blog The scientist reports that CSL (Australia) stands to make approximately US$218 to $262 million in profit from the manufacture of vaccines. Maryland-based MedImmune has a contract to provide 40 million doses of vaccine, worth over $450 million; 3.5 million doses of that vaccine have been approved for release by the FDA. Sanofi-Pasteur has a contract to provide over a million doses of H1N1 flu vaccine. Novartis has received a $690 million order from the US government. The government has also invested $35 million into Connecticut-based Protein Sciences to develop a recombinant 2009 H1N1 flu vaccine infecting insect cells with the virus, an approach that may be faster for developing vaccines than the traditional egg yolk-based method.(The Scientist: Newsblog 2009)

It is estimated that $1.5 billion will be spent for the 250 million doses of 2009 H1N1 flu vaccine ordered by the US government, which will be distributing at no cost to doctors, pharmacies, and schools. This money ultimately comes from the taxpayers.(Fahmy 2009)

It is not clear what the relationships are between these bio-pharmaceutical companies and government officials. Because the development, testing, and manufacturer of vaccines is very costly, the market for vaccines is much smaller than for other drugs, and pharmaceutical companies have over the past decade have been reducing their investment in vaccines, or abandoning them altogether.(Offit 2005) However, fears of bioterrorism have opened new opportunities for profitability. Developers of H1N1 vaccines will be protected until March 31, 2013 from liability under the Public Readiness and Emergency Preparedness Act, signed into law by then-President Bush in 2005.(Copper 2007; Office of General Counsel Texas Department of State Health Services (DSHS) 2009)

CONTROVERSIES SURROUNDING THE PANDEMIC ALERT
Human rights concerns have been expressed about the actions of certain governments following the pandemic-alert, such as trade and travel bans, and China’s quarantining of Mexican and Canadian nationals recently arrived or already present in China. Allegations of unfairness have also been raised by Indonesia and other developing countries revolving around their limited access to new discoveries from research on influenza virus specifically related to H1N1.(Fidler 2009)

SHOULD YOU GET A FLU SHOT?
There is early evidence that the newly developed H1N1 flu vaccines are doing their intended job: to provoke an immune response by exposing the vaccinated person to small amounts of viral material. Two new randomized trials, one with 240 people(Greenberg, Lai et al. 2009) and one with 175(Clark, Pareek et al. 2009), have demonstrated that a single-dose vaccine has prompted a positive immune response. While the level of enduring protection is as yet unknown, the authors of one trial write that the immune response is “likely to be associated with protection within 14 days after a single dose is administered.”(Clark, Pareek et al. 2009) The CDC’s Advisory Committee on Immunization Practices recommends that the following five groups receive vaccination priority:

» pregnant women
» persons who live with or provide care for infants aged <6 months (e.g., parents, siblings, and daycare providers)
» health-care and emergency medical services personnel
» persons aged 6 months to 24 years
» persons aged 25 to 64 years who have medical conditions that put them at higher risk for influenza-related complications.(Clark, Pareek et al. 2009)

However, the long-term safety is as yet unknown. An editorial in a recent issue of the medical journal The Lancet questions the safety of an H1N1 vaccine, which due to the widespread fear of pandemic, is being rushed through fast-track regulatory approval processes that won’t include the usual safety testing given other vaccines. This means vaccine safety can only be monitored with post-marketing surveillance, implemented after the vaccine has been distributed and delivered. This is potentially a concern, given long-term complications that followed mass vaccination during the 1976 H1N1 outbreak in the United States.(2009) Because of those complications, which included the neurologic disorder Guillain-Barre syndrome,(Nachamkin, Shadomy et al. 2008) the vaccination program was stopped and the vaccine withdrawn.(2009) Cases of Guillain-Barre syndrome attributed to vaccination were about 1 more case for every 100,000 people who got the swine flu vaccine. By comparison, it appears that the chance of severe flu complications is higher than the chance of getting Guillain-Barre after getting the flu vaccine. Additionally, monitoring systems for this complication have been established, which were not present in 1976.(CDC, 2009) Nevertheless, over one-third of parents oppose H1N1 vaccination, according to an Associated Press-Gfk poll.

IF YOU DECIDE TO BECOME VACCINATED
If you decide to become vaccinated, avoid acetaminophen (paracetamol) at the time of and following your vaccination. While it successfully prevents developing fever related to the vaccine, it also reduces the body’s immune response to the vaccine, perhaps lowering the vaccine’s effectiveness.(Reuters 2009)

Take practical steps to lower your stress levels. In meta-analysis research published this year, self-reported stressful life events or perceived stress led to lower antibody responses to influenza vaccination, regardless of age. (Pedersen, Zachariae et al.
2009) It is ironic that global information campaigns have served to increase stress related to fear of influenza.

WHAT TO DO IF YOU GET THE FLU?
On September 25th, WHO issued new treatment guidelines based on their assessment of international clinical experience in acute flu treatment. These guidelines state that early treatment after appearance of symptoms with the antiviral drugs oseltamivir (Tamiflu) or zanamivir (Relenza) reduces the risk of flu complications, especially in people are at increased risk of developing complications, those with severe illness or those with worsening signs and symptoms. Most samples of 2009 H1N1 influenza tested worldwide are responsive to Tamiflu (WHO, 2009)

There are two scenarios in which a person with acute flu infection may have high risk resistance to Tamiflu: in patients with severely compromised or suppressed immune systems who have prolonged illness or patients who have already been treated with Tamiflu (especially for an extended duration), but in whom there is persistent evidence of viral replication.

To date, 28 flu viruses that are Tamiflu-resistant have been detected worldwide, but none of these have shown resistance to Relenza. Of these 28, nearly half were isolated from patients who had been using Tamilflu for post-exposure prophylaxis (the use of a drug preventively following exposure to someone with known 2009 H1N1 flu).(World Health Organization 2009)

WHAT IF YOU’VE BEEN EXPOSED TO SOMEONE WITH KNOWN 2009 H1N1 INFECTION?
WHO recommends against using antiviral drugs for prevention (antiviral drugs are different from vaccines). If you’ve been exposed to someone infected with 2009 H1N1 flu, and you have a compromised immune system, are pregnant, are under age 25, or have a history of previous lung weakness, then WHO recommends close monitoring for symptoms, followed by prompt early antiviral treatment if you develop symptoms.(World Health Organization 2009)

HOW CAN YOU PROTECT YOURSELF?
While the common sense ideas suggested by public health experts are useful (hand washing, fresh air, coughing into your elbow), there are many more approaches that could provide additional protection. Research results of these approaches are reviewed here.

Vitamin D3: Although the winter season’s closer proximity to other people and reduced air circulation makes it easier for flu viruses to transmit from one person to the next, this is by no means the whole story. A greater culprit may be a combination of reduced exercise resulting in weaker respiratory fitness and vitamin D deficiency induced, in part, by less exposure to sunlight. Children admitted to intensive care for respiratory infection have vitamin D levels that are nearly half the level of other children. (McNally, Leis et al. 2009)

Vitamin D3’s ability to prevent flu infection was studied by Dr. John Cannell, Executive Director of the Vitamin D Council. Cannell has estimated that vitamin D plays a role in the repair and maintenance of more than 200 human genes in a wide variety of tissues. Included in these genes is the one responsible for the polypeptide called cathelicidin, a naturally occurring broad-spectrum antibiotic made in your white blood cells. For people living in sunny areas, normal serum vitamin D levels are between 40-70 ng per mL. There are three ways to boost vitamin D levels: sunlight, artificial ultraviolet B (UVB) radiation, and vitamin D3 supplements. 2,000-7,000 IU vitamin D per day should be sufficient to maintain year-round levels of vitamin D in the blood(Cannell and Hollis 2008), although people with chronic kidney disease should stay below 2,000 IU daily. Cannell also cogently suggests that vitamin D deficiency may be one of the chief culprits behind seasonal influenza epidemics,(Cannell, Vieth et al. 2006) pointing out evidence from intervention trials that have shown vitamin D3 prevents respiratory infections in children. (Cannell, Zasloff et al. 2008)

There has also been research that specifically compared the effectiveness of different doses and time intervals of vitamin D3 supplements in achieving higher serum levels of vitamin D. Volunteers were given 600 IU/day, 4200 IU/week, 18,000 IU/ month, or placebo. After 4 months, researchers found that daily vitamin D3 was more effective than weekly, and monthly was the least effective, in achieving higher serum vitamin D levels.(Chel, Wijnhoven et al. 2008)

Chinese Herbal Medicines: A 2005 meta-analysis analyzed 11 studies totaling 2,088 participants. Some of those studies yielded positive results showing better effectiveness of Chinese herbal medicines for flu symptoms, compared to antiviral or antipyretic-analgesic drugs or the combination of both. Three studies mentioned adverse reactions but there was no detailed reporting of those effects. Beneficial effects included such outcomes as quicker reduction of fever and symptom improvement.(Chen, Wu et al. 2005) All 11 studies used different herbal combinations, and practitioner guidance would be recommended for the selection of herbs. None of these preparations are within the range of Chinese herbal patent medicines commercially available in the United States in pill form, but nearly all are composed of herbal roots and leaves commonly found in Chinese herbal pharmacies. We have permission from the publisher to provide you, upon request, a copy of the table of herbs used in these preparations.(Wiley Interscience 2009) One preparation, called Gan Mao Capsule, compared favorably with the antiviral medication amantadine (Symmetrel).

Probiotics: The use of probiotics shows early promise of both improving the body’s innate protection against developing influenza infection and also strengthening immune response to influenza vaccine. In an animal study, probiotics helped mice prevent influenza infection.(Liaskovs’kyi, Rybalko et al. 2007)

For older people, influenza vaccination results in weaker immune responses compared to younger adults. Researchers in France tested the effect of a twice-daily probiotic drink on immune response to influenza vaccination in a study involving healthy volunteers over age 70. A total of 308 elderly volunteers took probiotics or placebo twice daily for 7 weeks or 13 weeks. At 4 weeks into the trial, a vaccine containing 3 viral strains (H1N1, H3N2, and B) was given. Immune response against the 3 viral strains was significantly higher in the probiotic group. These benefits were still present 5 months after vaccination.(Boge, Remigy et al. 2009) The study was sponsored by Dannon Yogurt.

Rhodiola Root: Flavonols extracted from Rhodiola rosea root showed neuraminidase inhibitory activity. This means that the drug blocks the activity of the viral neuraminidase protein, which prevents the virus from reproducing. This potent inhibitory effect was demonstrated in two flu strains, H1N1 (swine flu) and H9N2 (another type of influenza virus).(Jeong, Ryu et al. 2009)

The active ingredient in this herb is a member of the class of antioxidant compounds called flavonoids (or bioflavonoids). Important dietary sources for flavonoids are citrus, ginkgo, tea, red grapes and red wine, green leafy spices (such as parsley), soybeans and other soy foods, legumes, red, purple and blue berries, and dark chocolate.(Beecher 2003) Flavonoids frequently possess neuraminidase inhibitory activity,(Liu, Wang et al. 2008) suggesting that perhaps diets featuring flavonoid-rich foods may have flu-prevention effects.

Elderberry Extract: In a recent study from Florida, researchers found that flavonoids from the elderberry were able to bind to and prevent H1N1 infection in vitro. The formulation used was an ordinary crude extract prepared without separation of specialized derivatives or fractions. The elderberry extract was able to both inhibit H1N1 viral infection by binding to H1N1 virus particles and also block the ability of the virus to infect host cells. The ability of elderberry extract to inhibit H1N1 was similar to that seen with the anti-influenza drugs Tamiflu and Amantadine. (Roschek, Fink et al. 2009)

Ginseng: Four randomized, placebo-controlled trials of ginseng have been conducted: An extract of North American ginseng was tested for its ability to prevent upper respiratory tract infections. North American ginseng can favorably influence immune responses. In a randomized, double-blind, placebo-controlled study conducted at the onset of the influenza season, 323 subjects aged 18 to 65 with a history of at least 2 colds in the previous year were recruited into the study, which was conducted in Edmonton, Alberta and lasted 4 months. They were randomly assigned to take either 2 capsules daily of North American ginseng extract or a placebo. The researchers found that in the ginseng group, as compared to the placebo group, there were: a 25% lower average number of colds, a reduction by half in the proportion of subjects with 2 or more colds, and an over 1/3 reduction in the total number of days cold symptoms were reported.

In two other randomized trials involving 198 nursing home residents, ginseng extract at 200 mg compared to placebo achieved an 89% reduction in risk of respiratory infection (only 1 of the 97 ginseng users became infected).(McElhaney, Gravenstein et al. 2004)

In a follow-up study of 43 adults age 65 or older, ginseng reduced the likelihood of developing respiratory symptoms by 48%, similar to that reported with vaccines, and the severity of those symptoms was reduced by half.(McElhaney, Goel et al. 2006)

While it’s unknown whether ginseng would protect against H1N1 influenza virus, and not just less complicated respiratory symptoms, it nevertheless makes sense to discuss with a medical practitioner whether ginseng is compatible with currently used medications or medical conditions.

Chlorella: A 400 mg daily dose of chlorella failed to boost the immune response to trivalent inactivated vaccine, in a randomized, double-blind placebo-controlled trial of 124 healthy adults.(Halperin, Smith et al. 2003)

Bu Zhong Yi Qi Tang (a Chinese herbal formula also called Hochu-Ekki-To): This herbal formula failed to improve immune response to influenza vaccine (including H1N1) in a study of thirty-two healthy subjects randomly assigned to two groups (control and herbal groups).(Hamazaki, Sawazaki et al. 2007)

Learn and Regularly Practice Tai Chi: Researchers at the University of Illinois at Urbana-Champaign conducted a study to investigate whether the practice of tai chi and qigong would strengthen immune responses to the flu vaccine among older adults. Because their risk of flu complications such as pneumonia is higher, older adults are advised every year to have a flu shot. However, in many cases older adults’ immune response to the vaccine is not strong enough to provide them adequate protection from flu infection. Fifty adults in their 70s enrolled in this study, which began with a flu vaccine shot. Of those 50 people, approximately half learned tai chi and qigong, consisting of three weekly one-hour classes. The other half were the control group. After five months, blood tests revealed that people in the tai chi group developed more antibodies to the flu virus than the control group.(Yang, Verkuilen et al. 2008)

Exercise: A study of over 24,000 people, conducted in Hong kong in 1998, found that moderate exercise of up to three times per week substantially reduced both the severity of flu symptoms and the likelihood of dying from the flu.(Wong, Lai et al. 2008)

What About Masks?: Ordinary surgical masks are not effective protection against flu infection, according to a recent Institute of Medicine report. Best is the type called N95, which costs less than $5.

Keep Your Feet Warm: Many traditional medical systems have observed that cooling of the body surface leaves a person more vulnerable to common cold. In a study involving 180 healthy subjects, half were randomly assigned to either receive an ice water foot bath or be in the control group. All were asked to be alert for symptoms of common cold, both before and immediately after the foot chilling, and twice daily thereafter up to 5 days. Chilling of the feet was associated with common cold symptoms in 10% of chilled subjects, approximately twice the rate compared to the control group.(Johnson and Eccles, 2005) While it’s unknown whether this would protect against influenza virus as well, and not just common cold, nevertheless it makes sense and couldn’t hurt to follow this approach.

Low-dose Interferon: Researchers from Freiburg University and Friedrich Loeffler Institute in Germany announced animal research results showing that as little as one intranasal application of low-dose interferon reduced influenza viral concentration in the lungs sufficient to protect mice against influenza infections, which would have otherwise been lethal, without any evidence of toxicity.(Medical News Today 2009) Similar research was published in 2007.(Beilharz, Cummins et al. 2007) Additionally, a Phase 2 clinical trial of low-dose oral interferon is being conducted in Australia with healthy subjects being exposed to H1N1 and other viruses. US-based clinical trials are planned.(Medical News Today 2009)

CAN YOU CATCH H1N1 FROM EATING PORK?
That depends on which health agency you take more seriously. While eating pork has been declared safe by the CDC, the Food and Agriculture Organization of the United Nations (FAO) and the World Organization for Animal Health (OIE), nevertheless the WHO has said that meat from pigs infected with the new H1N1 virus shouldn’t be eaten by humans. The WHO has said that flu viruses may survive the freezing process and could therefore be found in thawed animal blood and meat. WHO is also recommending workers in pork processing plants wear protective equipment. While WHO also recommends that farm workers “minimize contact with sick pigs and report such animals to relevant animal health authorities,” labor conditions may not always allow workers the self-perceived authority to file such reports.

CONCLUSIONS
What We Know: The H1N1 virus has clearly been very successful at quickly establishing a global reach. Early characteristics of the flu’s Northern Hemisphere resurgence in fall 2009 are that infection severity and flu-related death rate are much lower than was originally feared. International regulatory response to the viral pandemic has triggered a global panic perhaps out of proportion to the actual lethality of the virus itself.

What We Don’t Know: Although a few small-scale studies have demonstrated that H1N1 vaccines are provoking the intended response of the immune system, we don’t yet know whether they will protect people in large populations from developing H1N1 flu infection, nor whether they will reduce the proportion of severe or fatal complications among those infected. We also don’t know whether the studies currently being done are giving us the information we need. It’s a curious anomaly that in the field of influenza vaccination, very little research is being conducted using the gold-standard demanded in many other medical conditions: placebo-controlled trials, which would randomly assign test subjects to receive either vaccine or placebo. Quoting from the above-mentioned meta-analysis by Tom Jefferson, “it was surprising to find only one study of inactivated vaccine in children under two years, given current recommendations to vaccinate healthy children from six months old in the USA and Canada. If immunization in children is to be recommended as a public health policy, large-scale studies assessing important outcomes and directly comparing vaccine types are urgently required.”(Jefferson, Rivetti et al. 2008)

In considering this discussion, it’s also important to recognize the difficulty of conducting influenza effectiveness trials, given the constrained timeline of a single influenza season, the ability of influenza viruses to mutate, variations in how many people are affected, and the difficulty of predicting in advance which viral strain will be dominant.(Beran, Wertzova et al. 2009)

The Bottom Line: While it’s too early to say whether vaccination is safe in humans and/or effective against H1N1 infection, nevertheless it’s important to be aware of the issues and controversies surrounding this globally important viral pandemic. The common-sense measures involving nutrition, exercise, and personal hygiene are clearly in the “could help/can’t hurt” category of sensibility.

REFERENCES
(2009). “Supply and safety issues surrounding an h1N1 vaccine.” Lancet 374(9687): 358.

Beecher, G. R. (2003). “Overview of dietary flavonoids: nomenclature, occurrence and intake.” J Nutr 133(10): 3248S-3254S.

Beilharz, M. W., J. M. Cummins, et al.(2007). “Protection from lethal influenza virus challenge by oral type 1 interferon.” Biochem Biophys Res Commun 355(3): 740-4.

Beran, J., V. Wertzova, et al. (2009). “Challenge of conducting a placebo-controlled randomized efficacy study for influenza vaccine in a season with low attack rate and a mismatched vaccine B strain: a concrete example.” BMc Infect Dis 9: 2.

Boge, T., M. Remigy, et al. (2009). “A probiotic fermented dairy drink improves antibody response to influenza vaccination in the elderly in two randomised controlled trials.” Vaccine 27(41): 5677-84.

Brownlee, S. and J. Lenzer. (2009). “Does the Vaccine Matter?” The Atlantic Retrieved Oct 15, 2009.

Cannell, J. J. and B. W. Hollis (2008). “Use of vitamin D in clinical practice.” Altern Med Rev 13(1): 6-20.

Cannell, J. J., R. Vieth, et al. (2006). “Epidemic influenza and vitamin D.” Epidemiol Infect 134(6): 1129-40.

Cannell, J. J., M. Zasloff, et al. (2008). “On the epidemiology of influenza.” Virol J 5: 29.

CDC. (2009). “2009 H1N1 Flu (Swine Flu) and You.” Retrieved Sept 24, 2009, from http://www.cdc.gov/h1n1flu/qa.htm

CDC. (2009). “2009 H1N1 Flu: Situation Update.” Retrieved Oct 09, 2009, from http://www.cdc.gov/h1n1flu/update.htm

CDC. (2009). “Seasonal Influenza: The Disease.” Retrieved Sept 24, 2009, from http://www.cdc.gov/flu/about/disease/index.htm

Chel, V., H. A. Wijnhoven, et al. (2008). “Efficacy of different doses and time intervals of oral vitamin D supplementation with or without calcium in elderly nursing home residents.” Osteoporos Int 19(5): 663-71.

Chen, X. Y., T. X. Wu, et al. (2005). “Chinese medicinal herbs for influenza.” Cochrane Database Syst Rev(1): cD004559.

Chowell, G., S. M. Bertozzi, et al. (2009). “Severe respiratory disease concurrent with the circulation of h1N1 influenza.” N Engl J Med 361(7): 674-9.

Clark, T. W., M. Pareek, et al. (2009). “Trial of influenza a (h1N1) 2009 Monovalent MF59- adjuvanted Vaccine — Preliminary Report.” N Engl J Med.

Copper, B. K. (2007). “Notes and comments ‘high and dry?’ The Public Readiness and emergency Preparedness act and liability protection for pharmaceutical manufacturers.” J Health Law 40(1): 65-105.

Fahmy, D. (2009). “Drugmakers, Doctors Rake in Billions Battling h1N1 Flu: Swine Flu is Bad for Victims, But Good for Businesses That cater to expanding Market.” ABC News Retrieved Oct 14, 2009, from http://abcnews.go.com/Business/big-business-swine-flu/story?id=8820642

Fidler, D. P. (2009). “H1N1 after action review: learning from the unexpected, the success and the fear.” Future Microbiol 4: 767-9.

Fraser, C., C. A. Donnelly, et al. (2009). “Pandemic potential of a strain of influenza a (h1N1): Early Findings.” Science 324(5934): 1557-61.

Garcia-Garcia, L., J. L. Valdespino-Gomez, et al. (2009). “Partial protection of seasonal trivalent inactivated vaccine against novel pandemic influenza a/h1N1 2009: case-control study in Mexico city.” Bmj 339: b3928.

Govaert, T. M., C. T. Thijs, et al. (1994). “The efficacy of influenza vaccination in elderly individu- als. a randomized double-blind placebo-controlled trial.” Jama 272(21): 1661-5.

Greenberg, M. E., M. H. Lai, et al. (2009). “Response after one Dose of a Monovalent influenza a (h1N1) 2009 Vaccine — Preliminary Report.” N Engl J Med.

Halperin, S. A., B. Smith, et al. (2003). “Safety and immunoenhancing effect of a chlorella- derived dietary supplement in healthy adults undergoing influenza vaccination: randomized, double-blind, placebo-controlled trial.” CMAJ 169(2): 111-7.

Hamazaki, K., S. Sawazaki, et al. (2007). “No effect of a traditional chinese medicine, hochu- ekki-to, on antibody titer after influenza vaccination in man: a randomized, placebo-controlled, double-blind trial.” Phytomedicine 14(1): 11-4.

Jackson, L. A., M. L. Jackson, et al. (2006). “Evidence of bias in estimates of influenza vaccine effectiveness in seniors.” Int J Epidemiol 35(2): 337-44.

Jefferson, T., V. Demicheli, et al. (2006). “Antivirals for influenza in healthy adults: systematic review.” Lancet 367(9507): 303-13.

Jefferson, T., A. Rivetti, et al. (2008). “Vaccines for preventing influenza in healthy children.” Cochrane Database Syst Rev(2): cD004879.

Jeong, H. J., Y. B. Ryu, et al. (2009). “Neuraminidase inhibitory activities of flavonols isolated from Rhodiola rosea roots and their in vitro anti-influenza viral activities.” Bioorg Med Chem 17(19): 6816-23.

Johnson, C. and R. Eccles (2005). “Acute cooling of the feet and the onset of common cold symptoms.” Fam Pract 22(6): 608-13.

Liaskovs’kyi, T. M., S. L. Rybalko, et al. (2007). “[Effect of probiotic lactic acid bacteria strains on virus infection].” Mikrobiol Z 69(2): 55-63.

Liu, A. L., H. D. Wang, et al. (2008). “Structure-activity relationship of flavonoids as influenza virus neuraminidase inhibitors and their in vitro anti-viral activities.” Bioorg Med Chem 16(15): 7141-7.

Mcelhaney, J. E., V. Goel, et al. (2006). “Efficacy of Cold-fX in the prevention of respiratory symptoms in community-dwelling adults: a randomized, double-blinded, placebo controlled trial.” J Altern Complement Med 12(2): 153-7.

Mcelhaney, J. E., S. Gravenstein, et al. (2004). “A placebo-controlled trial of a proprietary extract of North American ginseng (cVT-e002) to prevent acute respiratory illness in institutionalized older adults.” J Am Geriatr Soc 52(1): 13-9.

McNally, J. D., K. Leis, et al. (2009). “Vitamin D deficiency in young children with severe acute lower respiratory infection.” Pediatr Pulmonol 44(10): 981-8.

Medical News Today. (2009). “Amarillo Biosciences Reports on Research Supporting use of Interferon to Combat Influenza.” Retrieved Oct 11, 2009, from http://www.medicalnewstoday.com/articles/166961.php

Monto, A. S., S. E. Ohmit, et al. (2009). “Comparative efficacy of inactivated and live attenuated influenza vaccines.” N Engl J Med 361(13): 1260-7.

Mossad, S. B. (2008). “2008-2009 Influenza Update: A Better Vaccine Match.” Cleve Clin J Med 75(12): 865-70.

Nachamkin, I., S. V. Shadomy, et al. (2008). “Anti-ganglioside antibody induction by swine (a/ NJ/1976/h1N1) and other influenza vaccines: Insights into vaccine-associated Guillain-Barre syndrome.” J Infect Dis 198(2): 226-33.

National Institutes of Health. (2009). “NIH Prepares to launch 2009 H1N1 Influenza Vaccine Trial in People with Asthma.” Retrieved Oct 11, 2009, from http://www.nih.gov/news/health/oct2009/niaid-09.htm

Office of General Counsel Texas Department of State Health Services (DSHS) (2009). H1N1 Influenza and Immunity Under Public Readiness and Emergency Preparedness Act.

Offit, P. A. (2005). “Why are pharmaceutical companies gradually abandoning vaccines?” Health Aff (Millwood) 24(3): 622-30.

Pedersen, A. F., R. Zachariae, et al. (2009). “Psychological stress and antibody response to influenza vaccination: a meta-analysis.” Brain Behav Immun.

Raloff, J. (2009). “Tamiflu in Rivers could Breed Drug-Resistant Flu Strains.” Science News (Sept 30, 2009).

Reuters. (2009). “Prophylactic acetaminophen during vaccination reduces antibody response.” Retrieved Cct 19, 2009.

Rhorer, J., C. S. Ambrose, et al. (2009). “Efficacy of live attenuated influenza vaccine in children: a meta-analysis of nine randomized clinical trials.” Vaccine 27(7): 1101-10.

Roschek, B., Jr., R. C. Fink, et al. (2009). “Elderberry flavonoids bind to and prevent H1N1 infection in vitro.” Phytochemistry 70(10): 1255-61.

Simonsen, L., R. J. Taylor, et al. (2007). “Mortality benefits of influenza vaccination in elderly people: an ongoing controversy.” Lancet Infect Dis 7(10): 658-66.

The Scientist: Newsblog. (2009). “Swine flu windfall.” from http://www.the-scientist.com/blog/print/55993/

Wiley Interscience. (2009). “Terms and conditions of use.” from http://www3.interscience.wiley.com/tacou.html

Wong, C. M., H. K. Lai, et al. (2008). “Is exercise protective against influenza-associated mortality?” PloS One 3(5): e2108.

World Health Organization. (2009). “Antiviral use and the risk of drug resistance.” Retrieved Sept 25, from http://www.who.int/csr/disease/swineflu/notes/h1n1_antiviral_use_20090925/en/index.html

World Health Organization (2009). “Pandemic (h1N1) 2009 – update 63.”

World Health Organization. (2009). “Pandemic (h1N1) 2009 – update 67.” Retrieved Sept 25, from http://www.who.int/csr/don/2009_09_25/en/index.html

Yang, Y., J. Verkuilen, et al. (2008). “Effects of a traditional Taiji/Qigong curriculum on older adults’ immune response to influenza vaccine.” Med Sport Sci 52: 64-76.

COMPREHENSIVE ANALYSIS: THE DEBATE ON H1N1 (SWINE FLU)
There are few public health issues in the news right now that are more prominent than H1N1, the so-called “Swine Flu.” In a comprehensive review, we discuss how this flu is different from seasonal flu, whether or not it’s really a major concern, the differ- ent approaches to preventing and treating it, and how to decide if getting vaccinated is right for you. Click here for answers to these important questions and more.

RECRUITMENT UPDATE: OVARIAN CANCER EARLY DETECTION PROJECT
Is there meaningful information contained within the breath? Could this information lead to the early detection of ovarian cancer? The Pine Street Foundation’s ground-breaking study on the early detection of ovarian cancer using one of the most sensitive and sophisticated scent detection devices on the planet, a dog’s nose, has been going incredibly well. As of publication, we have recruited the following women for our study:

Control Group: 60 out of 60 People (Recruitment Complete!)
Disease Control Group: 18 out of 30 people
Ovarian Cancer (New and Recurring): 16 out of 30 people

One of the most challenging aspects of any clinical trial is recruiting participants. Through our large network and strong personal relationships with local hospitals and oncologists, we are thankful we’ve been able to be so successful finding eligible participants for our study. Click here to learn more about this project.

THANK YOU
On behalf of the entire board, we would like to thank you for your generosity and support. Your donations make all of the Pine Street Foundation’s educational programs, clinical trials, and research initiatives possible and we hope you will continue to follow our progress and support our work in the coming year. If you’d like to learn more about how to help support our mission or join our team, please visit: www.pinestreetfoundation.org/support

Avenues 27/28 - Autumn/Winter 2009

From the Board

Swine Flu Vaccination, Treatment, and Prevention: A Common Sense Discussion and Review of the Evidence

Download the Autumn/Winter 2009 issue (2.2 MB): [PDF]

INTERPRETING THE RESULTS OF MEDICAL RESEARCH
There are few things in life that are black and white and medical research is certainly no exception. In this next installment of our Becoming Your Own Advocate series, we turn our focus to how patients and health care providers can better understand and apply the results of published medical research. Click here for more.

RESEARCH UPDATE:
OVARIAN CANCER EARLY DETECTION PROJECT
Is there meaningful information contained within the breath? Could this information lead to the early detection of ovarian cancer? The Pine Street Foundation seeks to answer these questions with a ground-breaking new study. Click here for an update on our progress.

NEW WEBSITE
We’ve recently redesigned our website to include great new features and easier navigation of our archives.

PINE STREET IN THE NEWS
We’re pleased that the media’s enthusiasm for our organization and research continues. Recently, the June issue of O, the Oprah Magazine included a feature about our canine scent detection work. Click here to read this article and other recent clippings.

THANK YOU
Your support is very important to us! From cash donations to office supplies, we’re very thankful for your generosity. Click here to learn more about how you can help or volunteer.