Health Research Report #172
10 JAN 2014 / White paper draft
Compiled by Ralph Turchiano
- · Detailed research references and further affiliations on each article are posted at www.healthreserachreport.me .
In This issue:
1. Most clinical studies on vitamins flawed by poor methodology
2. Use of vitamin E by patients with mild to moderate Alzheimer disease slows functional decline
3. Molecule discovered that protects the brain from cannabis intoxication – pregnenolone
4. Brief fever common in kids given influenza, pneumococcal vaccines together
5. BPA increases risk of cancer in human prostate tissue
6. Several forms of vitamin E protect against memory disorders
Most clinical studies on vitamins flawed by poor methodology
. – “More than 90 percent of U.S. adults don’t get the required amounts of vitamins D and E for basic health,” Frei said. “More than 40 percent don’t get enough vitamin C, and half aren’t getting enough vitamin A, calcium and magnesium.
– It suggested that if every adult in the U.S. took such supplements it could prevent up to 130,000 cases of cancer each year
– it’s foolish to suggest that a multivitamin which costs a nickel a day is a bad idea
The study this story is based on is available online: http://bit.ly/1lbi4PB
CORVALLIS, Ore. – Most large, clinical trials of vitamin supplements, including some that have concluded they are of no value or even harmful, have a flawed methodology that renders them largely useless in determining the real value of these micronutrients, a new analysis suggests.
Many projects have tried to study nutrients that are naturally available in the human diet the same way they would a powerful prescription drug. This leads to conclusions that have little scientific meaning, even less accuracy and often defy a wealth of other evidence, said Balz Frei, professor and director of the Linus Pauling Institute at Oregon State University, in a new review published in the journal Nutrients.
Vitamin or mineral supplements, or an improved diet, will primarily benefit people who are inadequate or deficient to begin with, OSU researchers said. But most modern clinical studies do not do baseline analysis to identify nutritional inadequacies and do not assess whether supplements have remedied those inadequacies. As a result, any clinical conclusion made with such methodology is pretty much useless, they said.
“It’s fine to tell people to eat better, but it’s foolish to suggest that a multivitamin which costs a nickel a day is a bad idea.”
Beyond that, many scientists studying these topics are unaware of ways in which nutrients may behave differently in something like a cell culture or lab animal, compared to the human body.
Even though such studies often significantly understate the value of vitamin supplements, the largest and longest clinical trial of multivitamin/mineral supplements found a total reduction of cancer and cataract incidence in male physicians over the age of 50. It suggested that if every adult in the U.S. took such supplements it could prevent up to 130,000 cases of cancer each year, Frei said.
“The cancer reduction would be in addition to providing good basic health by supporting normal function of the body, metabolism and growth,” he said. “If there’s any drug out there that can do all this, it would be considered unethical to withhold it from the general public. But that’s basically the same as recommending against multivitamin/mineral supplements.”
Use of vitamin E by patients with mild to moderate Alzheimer disease slows functional decline
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Among patients with mild to moderate Alzheimer disease, a daily dosage of 2,000 IUs of vitamin E, compared to placebo, was effective in slowing functional decline and in reducing caregiver time in assisting patients, according to a study appearing in the January 1 issue of JAMA.
Alpha tocopherol, a fat-soluble vitamin (E) and antioxidant, has been studied in patients with moderately severe Alzheimer disease (AD) and in participants with mild cognitive impairment (MCI) but has not been studied in patients with mild to moderate AD. In patients with moderately severe AD, vitamin E was shown to be effective in slowing clinical progression. The drug memantine has been shown to be effective in patients with AD and moderately severe dementia, according to background information in the article.
Maurice W. Dysken, M.D., of the Minneapolis VA Health Care System, and colleagues examined the effectiveness and safety of vitamin E, memantine, and the combination for treatment of functional decline in patients with mild to moderate AD who were taking an acetylcholinesterase inhibitor (a chemical that increases the level and duration of action of the neurotransmitter acetylcholine). The trial included 613 patients at 14 Veterans Affairs medical centers. Participants received either 2,000 IU/day of vitamin E (n = 152), 20 mg/d of memantine (n = 155), the combination (n = 154), or placebo (n = 152). Change in functional decline was gauged via the Alzheimer’s Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Inventory score (range, 0-78).
Over the average follow-up time of 2.3 years, participants receiving vitamin E had slower functional decline than those receiving placebo, with the annual rate of decline in ADLs reduced by 19 percent. This treatment effect translates into a clinically meaningful delay in progression in the vitamin E group of 6.2 months. Neither memantine nor the combination of vitamin E and memantine showed clinical benefit in this trial.
In addition, caregiver time was reduced by about 2 hours per day in the vitamin E group.
All-cause death and safety analyses showed a difference only on the serious adverse event of “infections or infestations” with greater frequencies in the memantine (31 events in 23 participants) and combination groups (44 events in 31 participants) compared with placebo (13 events in 11 participants).
The authors write that the current study is one of the largest and longest treatment trials in patients with mild to moderate AD, and that it provides information on reported safety issues of vitamin E, with results from previous trials resulting in decreased prescribing for patients with AD. “In contrast to the conclusion drawn from a 2005 meta-analysis of vitamin E, which showed that high-dose vitamin E (≥ 400 IU/d) may increase the risk of all-cause mortality, we found no significant increase in mortality with vitamin E. The annual mortality rate was 7.3 percent in the alpha tocopherol group vs. 9.4 percent for the placebo group.”
The researchers note that decline in functioning in AD is increasingly recognized as an important determinant of both patient quality of life and social and economic costs. “In the current study, the placebo group lost approximately 3 units more on the ADCS-ADL Inventory than the alpha tocopherol group. A loss of this magnitude could translate into either the complete loss of being able to dress or bath independently, for example, or losing independence on any 3 different ADLs. Because vitamin E is inexpensive, it is likely these benefits are cost-effective as alpha tocopherol improves functional outcomes and decreases caregiver burden.”
(doi:10.l001/jama.2013.282834; Available pre-embargo to the media at http://media.jamanetwork.com)
Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.
There will also be a digital news release available for this study, including the JAMA Report video, embedded and downloadable video, audio files, text, documents, and related links. This content will be available at 3 p.m. CT Tuesday, December 31 at this link.
Editorial: Vitamin E, Memantine, and Alzheimer Disease
Denis A. Evans, M.D., of Rush University Medical Center, Chicago, and colleagues comment on the findings of this study in an accompanying editorial.
“Many features of the trial by Dysken et al reflect the best in trials of AD therapy, especially its size, duration, and separation from commercial motivation. However, as with almost all previous AD trials, the therapeutic effect seen was modest and more relevant to AD symptoms and consequences than to reversal of the disease process. The importance of treating patients with AD is clear, but finding the best balance between treatment and prevention efforts is challenging for this grim disease affecting millions of people from all developed countries.”
“Considering the difficulties inherent in trying to treat rather than prevent very high-prevalence diseases and the limitations thus far of the therapeutic efforts for people with AD, shifting to more emphasis on prevention seems warranted.”
Molecule discovered that protects the brain from cannabis intoxication – pregnenolone
PUBLIC RELEASE DATE:
– Pregnenolone prevents THC, the main active principle in cannabis, from fully activating its brain receptor, the CB1 receptor, that when overstimulated by THC causes the intoxicating effects of cannabis
Two INSERM research teams led by Pier Vincenzo Piazza and Giovanni Marsicano (INSERM Unit 862 “Neurocentre Magendie” in Bordeaux) recently discovered that pregnenolone, a molecule produced by the brain, acts as a natural defence mechanism against the harmful effects of cannabis in animals. Pregnenolone prevents THC, the main active principle in cannabis, from fully activating its brain receptor, the CB1 receptor, that when overstimulated by THC causes the intoxicating effects of cannabis. By identifying this mechanism, the INSERM teams are already developing new approaches for the treatment of cannabis addiction.
These results are to be published in Science on 3 January.
Over 20 million people around the world are addicted to cannabis, including a little more than a half million people in France. In the last few years, cannabis addiction has become one of the main reasons for seeking treatment in addiction clinics. Cannabis consumption is particularly high (30%) in individuals between 16 to 24 years old, a population that is especially susceptible to the harmful effects of the drug.
While cannabis consumers are seeking a state of relaxation, well-being and altered perception, there are many dangers associated to a regular consumption of cannabis. Two major behavioural problems are associated with regular cannabis use in humans: cognitive deficits and a general loss of motivation. Thus, in addition to being extremely dependent on the drug, regular users of cannabis show signs of memory loss and a lack of motivation that make quite hard their social insertion.
The main active ingredient in cannabis, THC, acts on the brain through CB1 cannabinoid receptors located in the neurons. THC binds to these receptors diverting them from their physiological roles, such as regulating food intake, metabolism, cognitive processes and pleasure. When THC overstimulates CB1 receptors, it triggers a reduction in memory abilities, motivation and gradually leads to dependence.
Traduction d’image: Effects of cannabis related to the development of addiction
Reduced inhibition of the activity of dopaminergic neurons
Increase of dopamine release
Developing an efficient treatment for cannabis addiction is becoming a priority of research in the fiend of drug addiction.
In this context, the INSERM teams led by Pier Vincenzo Piazza and Giovanni Marsicano have investigated the potential role of pregnenolone a brain produced steroid hormone. Up to now, pregnenolone was considered the inactive precursor used to synthesize all the other steroid hormones (progesterone, estrogens, testosterone, etc.). The INSERM researchers have now discovered that pregnenolone has quite an important functional role: it provide a natural defence mechanism that can protect the brain from the harmful effects of cannabis.
Essentially, when high doses of THC (well above those inhaled by regular users) activate the CB1 cannabinoid receptor they also trigger the synthesis of pregnenolone. Pregnenole then binds to a specific site on the same CB1 receptors (see figure) and reducing the effects of THC.
The administration of pregnenolone at doses that increase the brain’s level of this hormone even more, antagonize the behavioral effects of cannabis.
At the neurobiological level, pregnenolone greatly reduces the release of dopamine triggered by THC. This is an important effect, since the addictive effects of drugs involve an excessive release of dopamine.
This negative feedback mediated by pregnenolone (THC is what triggers the production of pregnenolone, which then inhibits the effects of THC) reveal a previously unknown endogenous mechanism that protects the brain from an over-activation of CB1 receptor.
A protective mechanism that opens the doors to a new therapeutic approach.
The role of pregnenolone was discovered when, rats were given equivalent doses of cocaine, morphine, nicotine, alcohol and cannabis and the levels of several brain steroids (pregnenolone, testosterone, allopregnenolone, DHEA etc..) were measured. It was then found that only one drug, THC, increased brain steroids and more specifically selectively one steroid, pregnenolone, that went up3000% for a period of two hours.
The effect of administering THC on the pregnenolone synthesis (PREG) and other brain steroids
This increase in pregnenolone is a built-in mechanism that moderates the effects of THC. Thus, the effects of THC increase when pregnenolone synthesis is blocked. Conversely, when pregnenolone is administered to rats or mice at doses (2-6 mg/kg) that induce even greater concentrations of the hormone in the brain, the negative behavioural effects of THC are blocked. For example, the animals that were given pregnenolone recover their normal memory abilities, are less sedated and less incline to self-administer cannabinoids.
Experiments conducted in cell cultures that express the human CB1 receptor confirm that pregnenolone can also counteract the molecular action of THC in humans.
Pier Vincenzo Piazza explains that pregnenolone itself cannot be used as a treatment “Pregnenolone cannot be used as a treatment because it is badly absorbed when administerd orally and once in the blood stream it is rapidly transformed in other steroids”.
However, the researcher says that there is strong hope of seeing a new addiction therapy emerge from this discovery. “We have now developed derivatives of pregnenolone that are well absorbed and stable. They then present the characteristics of compounds that can be used as new class of therapeutic drugs. We should be able to begin clinical trials soon and verify whether we have indeed discovered the first pharmacological treatment for cannabis dependence.”
Brief fever common in kids given influenza, pneumococcal vaccines together
PUBLIC RELEASE DATE:
– Parents should be made aware that their child might develop a fever following simultaneous influenza and pneumococcal vaccinations
– children who received simultaneous influenza and pneumococcal vaccines, about a third (37.6 percent) had a fever of 100.4 F (38 C) or higher on the day of or day after vaccination, compared with children who received only the pneumococcal (9.5 percent) or only the influenza (7.5 percent) vaccine.
Findings suggest utility of text messaging to monitor safety
NEW YORK, NY (Jan. 6, 2014) – Giving young children the influenza and pneumococcal vaccines together appears to increase their risk of fever, according to a study led by researchers from Columbia University Medical Center (CUMC) and the Centers for Disease Control and Prevention (CDC). However, the fever was brief, and medical care was sought for few children, supporting the routine immunization schedule for these vaccines, including the recommendation to administer them simultaneously. The study, which looked at children 6-23 months old, was published online on Jan. 6, 2014, in JAMA Pediatrics.
Public health experts agree that timely immunizations are an important means of protection against serious diseases and infections for people of all ages. The CDC and other medical professional organizations often recommend giving the influenza and pneumococcal vaccines at the same visit, if both are due—both to prevent getting influenza or other infections between visits and to avoid a possible delay in vaccinations due to difficulty returning to the clinic (because of work schedules or other competing priorities).
“While our data suggest that giving children the influenza and pneumococcal vaccines together at the same visit increases the risk of fever, compared with getting only one of the vaccines at the visit, these findings should be viewed in context of the benefit of vaccines to prevent serious illness in young children, as well as the recognized need to increase vaccination rates overall,” said study first author Melissa S. Stockwell, MD, MPH, Florence Irving Assistant Professor of Pediatrics and Population and Family Health at Columbia College of Physicians and Surgeons, with a joint appointment at Columbia’s Mailman School of Public Health.
“Parents should be made aware that their child might develop a fever following simultaneous influenza and pneumococcal vaccinations—but that the benefits of these vaccines outweigh the risk of fever and, in most cases, the fever will be brief,” said Dr. Stockwell. “For the small group of children who must avoid fever, these findings provide important information for clinicians and parents.”
The study followed 530 children recruited during the 2011-2012 influenza season from three community-based clinics affiliated with NewYork-Presbyterian /Columbia University Medical Center, who were receiving their usual vaccinations.
Parents received a text message on the night of vaccination and the seven subsequent nights, asking them to report the highest temperature in their child since the temperature had last been taken. Messages were sent in English or Spanish, based on parent preference. More than 90 percent of families who were confirmed to have received a text message on the day of or day after vaccination responded to the message, and 85 percent of parents reported being very satisfied with their participation in the study.
After controlling for age and other factors, among children who received simultaneous influenza and pneumococcal vaccines, about a third (37.6 percent) had a fever of 100.4 F (38 C) or higher on the day of or day after vaccination, compared with children who received only the pneumococcal (9.5 percent) or only the influenza (7.5 percent) vaccine. In other words, children receiving the influenza and pneumococcal vaccine together were about three times as likely to have a fever on the day of or day after vaccination, compared with children who received either vaccine alone. There were no differences among the groups in rates of fever in the 2 days after vaccination.
Overall, for every 100 children there were an additional 20-23 cases of temperatures of 100.4 F (38 C) or higher in children with simultaneous influenza and pneumococcal vaccination, compared with those who received only one of the vaccines. There were also 15 additional cases of temperatures of 102.2 F (39 C) or higher in children who received both vaccines, compared with the influenza vaccine alone, but not compared with the pneumococcal vaccine.
“We are committed to making sure that the safety of vaccines is continuously monitored and to better understanding any potential risks associated with vaccination,” said Claudia Vellozzi, MD, MPH, deputy director of the Immunization Safety Office at the Centers for Disease Control and Prevention, and the study’s senior author. “This study also demonstrates how novel approaches, like text messaging to assess fever following vaccination, can be used to enhance vaccine-safety monitoring.”
“Before our study, text messaging had not been used to address a specific vaccine-safety question,” said Dr. Stockwell, who is also medical director of the NewYork-Presbyterian Hospital Immunization Registry (EzVac) and a pediatrician at NewYork-Presbyterian/Morgan Stanley Children’s Hospital. “Unlike conventional surveillance methods, such as paper or phone, in which reporting may be delayed, text messaging appears to enable rapid, large-scale data collection.”
“These findings are a first step; the next step is to figure out if there are any measurable biological markers, such as findings in a blood sample, that are associated with increased risk of fever after vaccination,” said study co-author Philip S. LaRussa, MD, professor of pediatrics at CUMC and specialist in pediatric infectious diseases at NewYork-Presbyterian/Columbia.
BPA increases risk of cancer in human prostate tissue
Fetal exposure to a commonly used plasticizer found in products such as water bottles, soup can liners and paper receipts, can increase the risk for prostate cancer later in life, according to a study from the University of Illinois at Chicago published Jan. 7 online in the journal Endocrinology.
Bisphenol A, or BPA, is widely used to soften plastics. Steering clear of the chemical is nearly impossible, says Gail Prins, professor of physiology at UIC and lead author of the paper.
“Previous studies have shown that people who avoided all contact with plastics or other BPA-containing objects for up to a month or more still had BPA in their urine, which means they must have come into contact with BPA in the last 24 to 48 hours, since it clears the body rather quickly,” said Prins, who is director of the UIC andrology laboratory. “It’s very hard to avoid.”
Exposure of the fetus to BPA in utero is of particular concern, because the chemical, which mimics the hormone estrogen, has been linked to several kinds of cancer, including prostate cancer, in rodent models. The new findings show that human prostate tissue is also susceptible.
“Our research provides the first direct evidence that exposure to BPA during development, at the levels we see in our day-to-day lives, increases the risk for prostate cancer in human prostate tissue,” Prins said. “The findings of adverse effects of BPA in human tissue are highly relevant and should encourage agencies like the Food & Drug Administration to re-evaluate their policies in the near future.”
Prins investigated the effect of BPA on human cells by implanting human prostate stem cells taken from deceased young-adult men into mice. Prostate stem cells are very long-lived. They arise during early fetal development and produce and maintain a man’s prostate tissue throughout his life.
To mimic exposure to BPA during embryonic development, for two weeks following implantation the mice were fed BPA — in amounts in line with those seen in pregnant American women — as the cells produced humanized prostate tissue.
“The amount of BPA we fed the mice was equivalent to levels ingested by the average person,” Prins said. “We didn’t feed them exorbitantly high doses.”
After the tissue was allowed to mature for one month, the mice were given estrogen to mimic the naturally rising estrogen levels seen in aging men. This rise in estrogen later in life is one of the known drivers of prostate cancer.
Tissue was collected after two to four months and analyzed for prostate disease. Prins found that a third of tissue samples taken from mice fed BPA had either pre-cancerous lesions or prostate cancer, compared to only 12 percent in a control group of mice fed oil. If the prostate stem cells were exposed to BPA before implantation and again as they produced prostate tissue in the mice, 45 percent of the tissue samples had pre-cancerous lesions or cancer.
“We believe that BPA actually reprograms the stem cells to be more sensitive to estrogen throughout life, leading to a life-long increased susceptibility to diseases including cancer,” Prins said.
Several forms of vitamin E protect against memory disorders
Elderly people with high serum vitamin E levels are less likely to suffer from memory disorders than their peers with lower levels, according to a study published recently in Experimental Gerontology. According to the researchers, various forms of vitamin E seem to play a role in memory processes. The study was carried out in cooperation between the University of Eastern Finland, the Finnish National Institute for Health and Welfare, Karolinska Institutet, and the University of Perugia.
Studies investigating the link between vitamin E and memory disorders have usually focused on a single form of vitamin E, namely α-tocopherol, which is also used in vitamin E supplements. However, vitamin E exists in eight different natural forms, tocopherols and tocotrienols, all of which have antioxidant properties.
This recently published study comprises a sample of 140 over 65-year-old Finnish persons with no memory impairment at the onset of the study. During the eight-year follow-up, it was discovered that higher total serum levels of vitamin E, and higher levels of γ-tocopherol, β-tocotrienol and total tocotrienols in particular, seemed to protect against memory disorders. According to the researchers, the results show that the entire vitamin E family plays a role in memory processes. Accordingly, measuring the levels of vitamin E from serum is the most reliable way to determine whether they are sufficiently high.
The study comprised part of the more extensive Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study, which focuses on the association between the risk factors of cardiovascular diseases and memory disorders.
These reports are done with the appreciation of all the Doctors, Scientist, and other Medical Researchers who sacrificed their time and effort. In order to give people the ability to empower themselves. Without the base aspirations for fame, or fortune. Just honorable people, doing honorable things.