Autoimmune Thyroid Disease

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Food chemical intolerance medical and scientific references

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Food chemical intolerance medical and scientific references for intolerance to salicylates, amines, glutamates and additives are now available on CiteULike.

It’s half past three in the morning and I’ve just finished adding them all! There are almost six hundred and fifty abstracts available as of this moment.

There are a handful of full text PDFs available too under the tag ‘fulltext’.

These are mostly taken from the Feingold website, Fed up with food additives, and the RPAH website, but I keep stumbling across new ones all the time.

Phew. What a way to spend boxing day. This has been epic. I’m going to get some sleep now!

Written by alienrobotgirl

27 December, 2008 at 4:34 am

Posted in The Science of FCI

Pregnancy supplements may trigger asthma in kids

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Another New Scientist article of interest to failsafers.

The same vitamins and supplements that mothers-to-be take to protect their kids from birth defects could predispose children and even grandchildren to asthma.

If mice studies are confirmed by studies in humans, expectant mums may need to strike a balance between amounts of supplements such as folate, which reduces the risk of spina bifida, and those that bring on asthma, says John Hollingsworth, a doctor who specialises in diseases of the respiratory system – pulmonology – at Duke University Medical Center in Durham, North Carolina. “A little could be helpful and a lot could be harmful,” he says.

He and his colleagues fed pregnant mice supplements including folate, vitamin B12 and zinc in doses roughly equivalent to those recommended for pregnant women. These chemicals turn down the expression of certain genes and mark the DNA of a developing embryo so that the effect is passed from generation to generation, a process known as epigenetics.

Mice who ate the supplement-rich diet delivered pups with some signs of asthma. Their lungs contained high levels of immune cells and proteins that predict asthma in humans compared with mice that ate a supplement-poor diet.

To future generations

When Hollingsworth’s team bred these pups on a normal diet, their offspring still showed some signs of asthma – an indication of epigenetics in action.

Indeed in a genome-wide search for genes epigenetically marked for lowered expression in the first generation of mice pups, the researchers turned up several genes important for harnessing the immune system. Mice completely lacking one such gene, called Runx3, develop spontaneous asthma, and the researchers suspect epigenetically reduced expression of the gene could have the same effect.

“It’s a nice mouse model, but it’s a mouse model,” says Rachel Miller, an allergist and pulmonologist at New York Presbyterian Hospital. She says that to prove that maternal supplements could predispose kids to asthma, researchers would need to closely track the diets of expectant mothers, as well as any asthma that develops in their children.

“I think it needs to be tied back with human disease,” agrees Hollingsworth. But if confirmed by such human studies, the link between dietary supplements and asthma might explain the mysterious rise of the disease in developed countries, where pregnant women are advised to take folate supplements.

However foods such as leafy greens, broccoli and nuts, also contain folate and can silence genes. Cigarette smoke makes the same epigenetic changes, and one retrospective study found that grandmothers who smoked while pregnant are more likely to have asthmatic grandchildren than non-smoking grannies.

“You are what you eat – or you are what your grandma eats,” Hollingsworth says.

Journal reference: Journal of Clinical Investigation, DOI: 10.1172/JCI134378 (in press)

Pregnancy supplements may trigger asthma in kids

Yes, there is such thing as too much of a vitamin. In fact, too many can vitamins damage the correct function of your immune system.

Although only a mouse study, this is the first significant evidence I have come across suggesting epigenetic factors could be involved in a food chemical intolerance related symptom. This theory makes a lot more sense to me than the usual speculation banded about over vitamin deficiencies causing epigenetic alterations. Food chemical intolerance would be much less common today, if it were correlated with vitamin deficiency. According to the hype (though not necessarily the reality), asthma is more common today.

Other genes that can accidentally be switched off by methylation include a handful of important genes designed to help the immune system detect and destroy cancer cells.

The same genes that predispose to asthma also predispose to eczema. I know of a lot of mothers who have given birth to babies with eczematous rashes in the last few years, including a several dedicated WAPF members.  They have followed WAPF advice to the letter, eating liver and other high folate and vitamin A sources during their pregnancy (vitamin A is also involved in gene methylation). Asthma takes a few years to develop, but usually appears between the ages of three and six. I feel sorry for those mothers, because they really thought they were doing right and now they have this possibility to look forward to.

Bipolar disorder, autism, ADHD and fibromyalgia are also more likely in individuals with asthma, possibly due to leukotriene overproduction or COX II inhibition – the science is at a very early stage here, but this is the main system salicylates act on.

I have been in a dilemma over what I should do if I should get pregnant. To supplement or not supplement? Folate makes me quite ill, and it makes my asthma and eczema worse. Perhaps I should be listening to my body instead of to yet more flaky medical/nutritional advice. Rhetorical question: how come medical authorities never test anything properly before they advise the population to do it, á la low fat diets, fibre, statins, thalidomide, resting babies on their faces, five-a-day…? Since when was mass experimentation on the populace an okay thing to do?

Written by alienrobotgirl

21 September, 2008 at 11:49 pm

The New Scientist on pain

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I highly recommend a subscription to the excellent New Scientist magazine. Every week there’s something great in there. Here are two articles about the differing male and female perception of pain, very interesting, if, like me, most of your symptoms are chronic pain symptoms.

JON LEVINE was just testing painkillers on people who’d had a wisdom tooth extracted, when he uncovered rather more than he’d bargained for. The women in his study group found that strong painkillers related to morphine, called kappa-opioids, were most effective at numbing pain. But the same drugs didn’t work for the men at all. “In fact, the doses used in the clinical trial made pain worse for men,” says Levine, a clinical neuroscientist from the University of California in San Francisco.

He was shocked. “The idea that a therapy that had been around for decades could affect women and men in such dramatically different ways was anathema,” he says. “It was such an incredible mindset in the field of pain, missing what had clearly gone on in front of their eyes for years.”

It’s not an effect specific to opioids, either. Another recent study showed that ibuprofen, a widely used anti-inflammatory drug, can be much less effective for women than for men. Researchers at the University of New South Wales found that when they used mild electric shocks to induce pain in healthy young people, only the men got any relief with ibuprofen. It was only a small study, but still worrying, as the drug is often marketed with women in mind.

It’s been five years now since Levine first spotted a sex difference, yet we still don’t really understand why it exists. And when it comes to testing or prescribing painkillers, or studying pain, nothing much has changed. Remarkably, even many of those involved in pain research are unaware of these findings. “I myself have never been able to get relief from ibuprofen and now I understand why,” says Marietta Anthony, a pharmacologist at Georgetown General Clinical Research Center. “This is very dramatic, and has a direct impact for the clinic.”

There have always been playful stereotypes of how men and women suffer pain differently. Women are more delicate—but endure childbirth. Men are stoical—until they see a dentist’s chair. But these few studies show there’s more to the caricatures than meets the eye. Real differences in the underlying biochemistry of male and female pain are revealing themselves. The differences are also starting to suggest some surprising strategies for sex-specific painkillers.

It’s perhaps no surprise that the differences have eluded scientists for so long. Pain is multidimensional and highly subjective, and therefore very difficult to study. It varies with the time of day, age, diet, stress, genetic background, location, past and present injuries, and in women, reproductive status and the menstrual cycle.

But not only that. Only 10 years ago, pharmaceutical compounds were tested almost exclusively on men. Women were left out of tests in case their inconveniently fluctuating hormones messed up the analysis. The testers also feared harming a pregnant woman’s fetus, while ignoring the obvious safeguard of a pregnancy test and contraceptives.

Only in 1993 did the US make it a legal requirement for women to be included in clinical trials. According to a recent report, on average, 52 per cent of subjects in large-scale trials are women. This looks like progress—but it’s not. This figure includes women-only studies such as those investigating hormone therapies or drugs to treat breast cancer. And when testing medications for diseases common to both sexes, women’s and men’s results are often still lumped together, burying any differences in a statistical quagmire.

In Britain, things are not much better. The Department of Health advises that gender should be taken into account when determining whether a medicinal product is safe and effective. But how strictly this advice is heeded is anyone’s guess.

To Marietta Anthony, who was previously acting deputy director of the Office of Women’s Health at the FDA, change is imperative. If a drug works differently in men and women, this information should be displayed clearly on the label. “Side effects and efficacy really are different in men and women,” says Anthony, “[and] there may be a very fundamental biological reason.”

One of the more obvious biological reasons is that men and women tend to suffer from different disorders, mostly the result of a complex bag of hormones, reproductive status and anatomy (see Diagram). So differences in how women and men report feeling pain have often been dismissed as being solely down to the pain’s different origins. But origins aside, there’s growing evidence that even when the source is the same, the biochemical signals, nerve connections and the way the brain handles pain are all quite different in the two sexes.

Sex hormones are one reason for the differences in pain perception. Women always cry “ouch” first. Whether it’s in the clinic or the lab, using the heat of a small laser, the pressure of a tourniquet or electrodes placed on the skin, women are less tolerant of pain. But women’s pain sensitivity also yo-yos throughout the menstrual cycle, and just before a period, pain thresholds take a dive. “There is a view that oestrogen is excitatory and could enhance pain transmission in the peripheral nervous system, the spinal cord and in the brain,” explains Roger Fillingim from the University of Florida at Gainsville.

Progesterone has quite the opposite effect: it dampens the nervous system’s response to any nasty stimulus. And it’s most obvious during pregnancy. When progesterone levels rocket in the third trimester, they induce a state of profound analgesia in preparation for labour. Indeed, these hormonal influences are being turned to medical advantage (see “Make your own Valium”). The rest of the time—when not pregnant—women’s tolerance generally remains below that of men.

Levine was one of the first to get an inkling of how sex hormones might be setting men’s and women’s pain thresholds at different levels. His team found that women consistently reported more severe pain than men after removal of a wisdom tooth. Since inflammation is known to underlie most aches and pains, Levine decided to investigate whether inflammatory signals differed between sexes. He gave oestrogen to castrated male rats, and found their pain tolerance plummeted to female levels. And giving testosterone to sterilised females gives them masculine tolerance. In other words, if you switch the sex hormones around, you switch their pain sensitivity around too.

Looking deeper into the biochemical pathways, he has recently found that sex hormones alter the chemical signals involved in inflammation and tissue repair. The female hormone oestrogen quenches the production of bradykinin—a potent inflammatory mediator that protects injured tissues. He believes these differences might account for the different responses to opioids seen in his trial. “As difficult as it is for many of us to acknowledge differences other than in reproductive function, there really are differences between men and women,” says Levine.

Another curious difference caused by our distinct physiology is that—especially in women—the visceral organs “talk” to each other, so that pain in one internal organ can be triggered or enhanced by pain in another. Maria Adele Giamberardino at the University of Chieti, Italy, first noticed this effect in women with kidney stones. She has found that when women have painful periods—a condition called dysmenorrhoea—the typical searing back pain from the urinary tract caused by the stones is much more vicious.

Giamberardino’s findings ring true to pain specialists. In the clinic, both men and women who suffer from chronic conditions such as irritable bowel syndrome often also experience fibromyalgia, headaches and chronic pelvic pain. But this coexistence of painful disorders is greater in females than in males. Giamberardino’s hypothesis is that the female reproductive organs are highly interconnected with the other organs, and that pain in one organ may trigger painful conditions in others that have linked nerve supplies. The flipside is that these links could become new avenues for treating pain. By tapping into the same communication channels, treating period pains, for example, might help to alleviate other aches.

Our different reproductive organs can also lead to differences in how our diet affects pain ratings, says Beverly Whipple, a neurophysiologist and obstetric nurse from Rutgers University in New Jersey. She noticed that Hispanic women seemed to experience more pain during labour, and at first she attributed this to culture. “I told my students that these women were just more comfortable expressing their pain.” Then she became aware of studies in which neonatal rats injected with capsaicin—the chemical that gives chilli its hot bite—did not experience a certain pain-blocking effect that females normally get when pressure is applied to the cervix. Could a diet rich in hot peppers be interfering with the Hispanic women’s natural analgesia?

To find out, Whipple set up a study with Mexican women whose consumption of chillies ranged from one or two a week to three a day. “We found that the women who ate a diet high in hot chilli peppers do not get the pain-blocking effect,” she says.

The physiological differences don’t stop at our reproductive organs and hormones, however. They run all the way to the brain. In a study soon to be published, Anthony Jones, director of the human pain research group at the University of Manchester, has scanned the brains of people experiencing pain from a variety of natural causes. Although many parts of the brain are engaged when a person is in pain, Jones pinpointed one main area of disparity between the sexes. “Women tend to process pain more in one part of the brain concerned with attention and emotion,” he says. He suggests that the experience of pain is bound to differ between men and women. “Women tend to process things in a more affective way,” he says. For women, pain depends on how much attention they pay to a tender spot. So when it comes to treatment, for women it may be as important to provide them with distractions, coping mechanisms and psychological care as painkilling drugs.

Distractions may work in a different way for men. It seems to be important for men to act tough in public. In experiments performed at the State University of New York, Fredric Levine and Laura Lee De Simone found that men’s pain thresholds soared if an attractive female technician was conducting the tests. Women, however, seemed immune to the charms of hunky men. And according to Knox Todd, a specialist in the assessment and treatment of pain at Emory University in Atlanta, Georgia, the differences make their way into the clinic. “What we see in the emergency department is that males make a public display of stoicism, ask for no pain medication, and keep up a good public front.” But their stoicism evaporates as soon as men leave the hospital to go home, he says.

But who wins out in the end? Is having a higher pain threshold good or bad? To women, pain is a wake-up call to sort out the problem before it gets too big. Men, who can put up with more, postpone asking for help until it’s too late. Women’s prompt action could be at least part of the key to their longer life expectancy. In the meantime, a message to dithering males: stop procrastinating, make that dental appointment, and your niggling shoulder pain might get sorted into the bargain. And to overdue pregnant women: ignore the advice that a curry will bring on labour. Chillies are the last thing you need when the contractions kick in.

* * *

Make your own Valium

Sex hormones might complicate our understanding of pain, but one day they might help us beat it, too. Locked inside your brain is the most powerful sedative, anti-anxiety drug and painkiller rolled into one. This magical compound derives from the sex hormone progesterone and, if medicinal chemists get it right, it may soon lead to an analgesic to rival morphine.

Scientists have known since the 1940s that progesterone—the female hormone we usually associate with the Pill and making babies—is also an incredibly potent sedative. Now researchers have found that it is the breakdown products of progesterone that have such a potent anaesthetic and analgesic effect. “During pregnancy, for example, as a woman comes close to term, the levels of these breakdown products of progesterone are extremely high,” says Jeremy Lambert, a neuropharmacologist at the University of Dundee in Scotland. Only the natural hormone will do—the synthetic compounds used in contraceptive pills do not work in the same way.

Fortunately, this natural analgesia and anxiolysis is not exclusive to women. There are enzymes in the brain and spinal cord of both men and women that produce similar breakdown compounds, known as neurosteroids, from cholesterol or progesterone. In mounting doses, they may act as analgesics, anticonvulsants and even anaesthetics.

Researchers are now intent on harnessing these effects. The trick is to untangle one neurosteroid action from another: to induce pain relief without knocking you unconscious and without affecting fertility. Colin Goodchild, an anaesthesiologist at Monash University in Victoria, Australia, may have already hit on a compound—alphadolone—that can do exactly that. “It can work as a pain-relieving drug without causing sedation,” says Goodchild.

Goodchild hopes that alphadolone may eventually replace opioids such as morphine, or at least reduce their usage. Progesterone metabolites might also lead to an “all-natural” sleeping pill and antiepileptic with few, if any, side effects. “I think neurosteroids are going to be the pharmaceuticals of the future,” says Goodchild. His pain, her pain, 19 January 2002, New Scientist

***

ANYONE in a long-term relationship will tell you that, at times, men are indeed from Mars, and women are almost certainly from Venus. It’s common knowledge that the sexes often think very differently, but until recently these differences were explained by the action of adult sex hormones or by social pressures which encouraged males and females to behave in a certain way. For the most part, the basic architecture of the brain, and its fundamental workings, were thought to be the same for both sexes.

Increasingly, though, those assumptions are being challenged. Research is revealing that male and female brains are built from markedly different genetic blueprints, which create numerous anatomical differences. There are also differences in the circuitry that wires them up and the chemicals that transmit messages between neurons. All this is pointing towards the conclusion that there is not just one kind of human brain, but two.

It’s giving neuroscientists something of a headache. Most of what we know about the brain comes from studies of male animals and male human volunteers. If even a small proportion of what has been inferred from these studies does not apply to females, it means a huge body of research has been built on shaky foundations. Working out exactly how women are different could explain some long-running mysteries, such as why men and women are prone to different mental health problems and why some drugs work well for one sex but have little effect on the other.

It has long been known that some differences exist between male and female brains, but they were widely believed to be restricted to the hypothalamus, which is involved in regulating food intake and controlling sex drive, among other things. Unless they were studying the hypothalamus, researchers generally avoided using female animals in their experiments because the ups and downs of oestrogen and progesterone during the female menstrual cycle made interpreting results more complicated. So, hypothalamus aside, neuroscientists continued to believe that male and female brains were the same.

But it’s becoming obvious that the hypothalamus is only the beginning of the story. For a start, the relative sizes of many of the structures inside female brains are different from those of males. In a 2001 study, Jill Goldstein of Harvard Medical School and colleagues measured and compared 45 brain regions in healthy men and women. They found that parts of the frontal lobe, which houses decision-making and problem-solving functions, were proportionally larger in women, as was the limbic cortex, which regulates emotions. Other studies have found that the hippocampus, involved in short-term memory and spatial navigation, is proportionally larger in women than in men, perhaps surprisingly given women’s reputation as bad map-readers. In men, proportionally larger areas include the parietal cortex, which processes signals from the sensory organs and is involved in space perception, and the amygdala, which controls emotions and social and sexual behaviour. “The mere fact that a structure is different in size suggests a difference in functional organisation,” says neurobiologist Larry Cahill at the University of California, Irvine.

Cahill has found evidence that sex also influences how some brain regions are used. In brain-imaging experiments, he asked groups of men and women to recall emotionally charged images they had been shown earlier. Both men and women consistently recruited the amygdala – a pair of almond-sized bundles of neurons which make up part of the limbic system – for the task. However, the men enlisted the right side of it, whereas women used the left. What’s more, each group recalled different aspects of the image. The men recalled the gist of the situation whereas the women concentrated on the details. This suggests men and women process information from emotional events in very different ways, using different mechanisms, says Cahill.

The same may be true for the brain circuits used to dampen pain. It is well known that women are more likely to seek help for chronic pain than men. Some of this can be chalked up to the fact that women use healthcare services more than men, but even taking this into account, there’s strong evidence that women – and female animals – experience more pain than males. Not all studies show sex differences but, when they do, it’s always the females that feel more pain.

Anne Murphy at the University of Georgia in Athens is trying to find out why chronic pain affects women more than men. She is particularly interested in a pain-suppressing circuit that links two parts of the brain – the periaqueductal grey (PAG) and the rostral ventromedialRVM) – with the spinal cord. When this circuit is activated by a pain signal it can dampen pain by setting off a chain reaction that leads to the release of endorphins, which bind to opioid receptors and inhibit the pain signal. medulla ( “This circuit is the Mecca of pain modulation in humans and all vertebrates, yet no one has asked how it is organised in females,” says Murphy.

There is no clear answer yet, but Murphy’s investigations have yielded some intriguing results. Females have a denser connection between PAG and RVM than males, yet Murphy’s work suggests that this pathway is not activated in females to suppress pain. “This pathway is obviously not being used for pain in females, so what’s the function for it and why is it so much bigger?” she asks.

That question remains unanswered for now, but Jeff Mogil at McGill University in Montreal, Canada, thinks he may have found at least part of the female pain circuitry. In experiments in mice, he chemically blocked a particular receptor found on neurons in the mouse PAG and spinal cord. Mogil discovered that male mice use these N-methyl-D-aspartate (NMDA) receptors to dampen pain, but that blocking this pathway had little impact on females’ ability to deal with pain. “It suggests that females have a separate pathway that doesn’t involved the NMDA receptor,” he says.

Genetic experiments in mice have since led him to suspect that female pain inhibition may be linked to sex-specific variations in the gene for the melanocortin-1 receptor (Mc1r), which regulates hair and skin colour in humans and is also expressed in the PAG. Female mice that lacked a functional version of these genes were less able to block pain, as were female human volunteers with red hair, who also lack functional Mc1r genes. Male redheads had no problems blocking pain, presumably because they were using the NMDA circuit instead.

It’s early days, but if women do have a different pain-damping circuit to men, it could explain why there are sex differences in responses to opioid painkillers. Women get more relief from the opioid painkiller nalbuphine compared to morphine, whereas in men morphine is more effective and nalbuphine actually increases the pain intensity. The findings could eventually lead to new painkillers tailored to be more effective in women, but Mogil isn’t holding his breath. “For now there isn’t a big enough and uncontroversial enough literature in any of these differences to justify drug development of any single one of them,” he says.

Similar difficulties have blighted developments in mental health – another area where there are known to be sex differences. Women are diagnosed with depression twice as often as men, for example, and their brains typically produce about half as much serotonin – a neurotransmitter linked to depression. Earlier this year, Anna-Lena Nordström, from the Karolinska Institute in Stockholm, Sweden, found that healthy women have more of the most common type of serotonin receptor than men but fewer serotonin transporters, which are needed to recycle serotonin. It hasn’t been shown that variations of this set-up make some women more prone to depression, but Nordström points out that transporter differences between men and women are of particular interest because this is where antidepressants like Prozac act, and because there is evidence that women respond better to such drugs than antidepressants that act on neurotransmitters other than serotonin.

Males may be less likely to suffer depression, but that doesn’t mean they get an easy ride. Boys are more likely to be diagnosed with autism, Tourette’s syndrome, dyslexia, stuttering, attention-deficit disorder and early-onset schizophrenia. Margaret McCarthy of the University of Maryland in Baltimore believes that hormone-like substances called prostaglandins, which help masculinise the male brain shortly before or after birth may be at least partly to blame. Prostaglandins are also known to cause inflammation, so McCarthy is investigating whether their action, if altered by infection or certain drugs, could cause inflammation and damage to the developing brain.

The ways in which men and women abuse drugs is another area that could reveal brain differences. While men are almost twice as likely as women to use cocaine, possibly due to social factors, when women take it they get addicted more quickly and have a more severe habit when they seek treatment.

Jane Taylor from Yale University suggested in 2007 that genetic differences may help to explain why. She compared mice that were engineered to either be genetically male with testes, genetically male with ovaries, genetically female with testes or genetically female with ovaries. She found that genetically female mice formed drug habits more quickly than the genetically male mice, regardless of which gonads they carried (Nature Neuroscience, vol 10, p 1398).

Jill Becker at the University of Michigan, Ann Arbor, has found something similar. She trained rats to poke their noses into a hole to get a dose of cocaine and compared the cocaine intake of female rats which had had their ovaries removed with castrated male rats. The females were bigger bingers. But when these females were given oestrogen, their total intake nearly tripled. That means that a genetic vulnerablility plus circulating sex hormones can add up to a crippling addiction.

Several studies have since found that women report that cocaine has a bigger positive effect when their oestrogen levels are high and their progesterone levels low. Suzette Evans at the Columbia University College of Physicians and Surgeons in New York City is running a clinical trial to test whether cocaine-dependent women can be treated by increasing their progesterone levels.

There’s much left to learn, but as the evidence mounts for sex-related influences on brain structure and function, the development of medicines better suited to a woman’s biology may yet take off. Before that can occur, however, more work is needed to uncover the differences between the brains of male and female animals. Despite recent progress, such work is very much in the minority.

Mogil, who has demonstrated big differences in pain processing in males and females, is astonished that so many researchers have failed to include female animals in their studies, especially when it comes to pain research. “It’s scandalous,” he says. “Women are the most common pain sufferers, and yet our model for basic pain research is the male rat.” On the flip side, it’s also an area ripe for exploration: “Every year or two we write a paper that says that something someone reported earlier is actually only true in males. We keep making people look bad. They are missing stuff completely.”

***

Myths and misconceptions

DON’T ASK A WOMAN FOR DIRECTIONS

Give a man a sheet of paper printed with tangled streets and he can tell you where you need to go. But don’t be afraid to ask a woman for directions. Chances are she’ll get you there, too, but using a different technique. Drawing on her hippocampus, she’ll offer you physical cues like the bakery, the post office and the Chinese restaurant.

MEN AREN’T EMOTIONALLY TUNED-IN

He might not remember the details of the big blow-up you had during your honeymoon, ladies, but just because you can it doesn’t mean he’s insensitive. Women are simply better at remembering the details surrounding emotional events, because their amygdala is tuned to capture them.

WOMEN ARE MORE TALKATIVE THAN MEN

Modern folklore claims women speak nearly three times as many words as men. Don’t believe the hype. Women and men both say 16,000 words a day, on average.

OESTROGEN IS THE FEMALE HORMONE

While it’s true that males mainly secrete testosterone from the testes, oestrogen is important to male brain development in the womb. In the male brain, testosterone is converted into oestradiol, which acts on oestrogen receptors and sets the hypothalamus to “male”. Brains apart: The real difference between the sexes, 16 July 2008, New Scientist

Written by alienrobotgirl

15 August, 2008 at 9:35 pm

Posted in The Science of FCI

Protein On 'Speed' Linked To ADHD

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Good old Chris from Conditioning Research always comes up with the goods. This is a story he sent me last month. My sister and I both have AD(H)D. She has the hyperactive variety. We’re both somewhat bipolar too.

A genetic change in the dopamine transporter — one of the brain’s dopamine-handling proteins — makes it behave as if amphetamine is present and “run backward,” Vanderbilt University Medical Center investigators report this week in The Journal of Neuroscience.

The altered function of the transporter gene variant, discovered in two brothers with attention deficit hyperactivity disorder (ADHD), supports a role for dopamine signaling in the disease. ADHD is one of the most common mental health disorders in children and adolescents, affecting up to 5 percent of school-age children in the United States.

“We believe that this is important evidence that ADHD can be caused by a functional deficit in the brain’s dopamine signaling pathway,” said Randy Blakely, Ph.D., director of the Center for Molecular Neuroscience.

The researchers propose that because the altered transporter runs backward and pushes dopamine out into the space between neurons — like normal transporters do when amphetamine, or ‘speed,’ is present — it alters dopamine signaling and contributes to the symptoms of ADHD.

“It’s like these kids are on amphetamine all the time,” said Aurelio Galli, Ph.D., an investigator in the center. Amphetamine causes hyperactivity, paranoia and psychosis in normal subjects.

Variations in brain dopamine signaling have long been suspected to participate in the development ADHD and other neuropsychiatric disorders. Dopamine has roles in brain circuits linked to attention, motor function, reward and cognition, and drugs that target dopamine transporters and receptors are used to treat ADHD, bipolar disorder and schizophrenia.

Because the dopamine transporter is a key member of the dopamine-signaling network, Blakely and colleagues searched for changes in this protein in patients with ADHD. They found a single “letter” change in the transporter gene in two brothers. The particular mutation had been reported once before in a patient with bipolar disorder, which also has connections to dopamine signaling, but the functional impact of the mutation had not been pursued, Blakely said.

In initial studies of the variant transporter in cultured cells, the group found no differences in function compared to the normal transporter — the mutant transporter moved dopamine into the cell and was appropriately regulated by dopamine transporter blockers and cellular signaling pathways.

Turning to a sensitive technology called amperometry that uses a small carbon fiber to “listen in” on how single cells release or transport dopamine, the Galli and Blakely laboratories discovered that the altered transporters were running backward at an exaggerated rate, literally pushing dopamine out of the cell.

“We think this activity would short circuit the normal synaptic transmission process,” Blakely said. “Instead of the precise ‘pop-pop-pop’ of dopamine being released from vesicles (tiny packets of neurotransmitter), there’s a cloud of dopamine bleeding out, and the dopamine signaling system is not as sharp as it should be.”

To their surprise, the investigators also found that amphetamine blocks the leak of dopamine through variant transporter. Normally, amphetamine does just what the mutation does — it causes the dopamine transporter to run in the reverse direction.

The findings offer a new perspective on a conundrum in the ADHD field — the fact that two of the medications that successfully treat the disease have opposing effects on their molecular target, the dopamine transporter. With the normal dopamine transporter, methylphenidate (Ritalin) blocks the ability of amphetamine (Adderall) to make the transporter run backward, yet both drugs are equally beneficial to patients with ADHD.

But when the transporter runs backward of its own accord — as it does with this rare mutant version — both agents act as blockers and stop the leak of dopamine.

“This observation unifies the action of these drugs and strongly suggests that backward-running transporters may be an important mechanism in ADHD, even for those who do not have this particular mutation,” Blakely said.

Researchers studying the dopamine transporter have found that there are multiple ways to cause the transporter to run backward, Galli pointed out, and the team is now screening other genes in the “network of signaling pathways that target the transporter and reverse dopamine flow” as potential contributors to ADHD risk.

The investigators also speculate that backward-running transporters may represent a more general phenomenon, giving rise to multiple types of neuropsychiatric disorders.

“Millions of patients have taken drugs that block transporter proteins, such as those that handle brain norepinephrine and serotonin, to treat anxiety and depression,” Blakely said. “We used to think that the only thing these drugs could do is block uptake — now we wonder if reducing the backward leak of neurotransmitter is a key component of their utility.”

M. Mazei-Robison, Ph.D., and E. Bowton at Vanderbilt, and collaborators at the Medical University Vienna contributed to the current study. The National Institutes of Health supported the research. Galli is an associate professor of Molecular Physiology & Biophysics. Blakely is the Allan D. Bass Professor of Pharmacology and Professor of Psychiatry. Protein On ‘Speed’ Linked To ADHD

Written by alienrobotgirl

13 August, 2008 at 1:48 pm

Posted in The Science of FCI

Soy isoflavones and monoamine oxidase

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A 51-year-old postmenopausal non-Hispanic white woman was treated for a hypertensive crisis at a regional medical center in eastern Arizona. She had complained of symptoms for one week prior to admission, including light-headedness, headaches, and high blood pressure by self-measurement. Ten days prior to admission, the patient had been enrolled in a university-sponsored research trial designed to investigate the extent to which vitamin C and soy isoflavones, as supplements to a habitual diet, could provide antioxidant effects by reducing in vivo oxidative damage to cells, either alone or synergistically. During trial screening the patient reported typically consuming soy or soy products twice a week; no regular alcohol consumption; no history of hypertension or cardiovascular disease (although there was a family history of mild hypertension); no current medical supervision or care for any chronic health problems; no current use of over-the-counter or prescription medications and a routine exercise pattern of three times a week for 30-60 minutes. The participant weighed 175 pounds (79.5 kg), stood 5’8″ (1.73 m), with a body mass index of 26.7 kg/m2.Early in the research trial, the patient was randomized to receive 500 mg vitamin C plus 5 mg/kg body weight soy isoflavones. On trial day 3, the patient reported to the investigators that she felt “odd” and “light-headed.” At the time, this was not attributed to the study-related supplements because the participant reported experiencing infrequent headaches for the past 20 years. On trial days 6 and 7 of the treatment period, the participant had her blood pressure checked by an automated machine; the readings were in the range of 140-150/92-98 mmHg vs. her usual BP of 120/82 mmHg. Due to this unexpected occurrence, the investigators requested that she stop consuming the supplements and drop out of the study. The incident was reported the university’s Institutional Review Board Research Compliance Office, and the research trial was allowed to continue. Unbeknownst to the investigators, the participant chose to ignore the request to discontinue the supplements and continued to take the supplements on trial days 8 and 9. On trial day 9 she found her BP to be 159/110 mmHg. That night, she experienced an intense headache, a feeling of anxiety, and difficulty sleeping. Around midday on trial day 10, she stopped by a regional medical center to have her BP checked by a medical professional before going hiking. At that time, her BP was 226/117 mmHg; she reported that “my head feels like it is going to explode” and she was admitted to the emergency room.

[…]

One plausible explanation for the hypertensive crisis experienced by this participant is the inhibition of monoamine oxidase by the isoflavones (e.g., daidzin, daidzein) or their metabolites (e.g., equol). Rooke et al.[2] and Gao et al.[3] both reported that daidzin, the plant precursor of the mammalian metabolite daidzein, and some of its structural analogs can inhibit mitochondrial monoamine oxidase in vitro. Additionally, Dewar et al.[4] reported that equol, a mammalian metabolite of daidzein, was an effective inhibitor of rat liver monoamine oxidase in vitro. Since the soy isoflavone supplements used in the research trial consisted of 63% (178 mg aglycone units/g) genistein, 28% (79.1 mg aglycone units/g) daidzein and 9% (24.6 aglycone units/g) glycitein (percentages based on aglycone units), the daidzein in the supplement may have interacted with monoamine oxidase.

Monoamine oxidase is responsible for the deamination of monoamines, including serotonin, epinephrine, norepinephrine, dopamine and tyramine. Its inhibition will cause an increase in the blood levels of these compounds. Since tyramine acts as a vasoconstrictor, an increased tyramine level will cause an increase in blood pressure [5,6]. Review of the two-day food records recorded prior to the participant’s entering the study in addition to dietary information obtained after the hypertensive event indicated the participant’s normal diet typically contained multiple tyramine-containing foods. The participant confirmed that she had consumed several tyramine-containing foods during the study, including the day before and the day of her emergency room admission (Table 2). Thus, the high dose of supplemental isoflavones [397.5 mg isoflavones (aglycone units) containing approximately 111 mg daidzein (aglycone units)], in conjunction with her typical moderate to high tyramine diet, may have contributed to a monoamine oxidase inhibitor-type reaction. Although the studies by Rooke et al.[2], Gao et al. [3] and Dewar et al.[4] suggest such a reaction might be possible, we believe this is the first report published of a possible monoamine oxidase inhibitor reaction and subsequent blood pressure spike occurring in vivo due to intake of a soy isoflavone supplement. Hypertensive crisis associated with high dose soy isoflavone supplementation in a post-menopausal woman: a case report

Written by alienrobotgirl

3 May, 2008 at 2:01 pm

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Aspartame and neurotoxicity

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Excessive intake of aspartame may inhibit the ability of enzymes in the brain to function normally, suggests a new review that could fan the flames of controversy over the sweetener.
The review, by scientists from the University of Pretoria and the University of Limpopo and published recently in the European Journal of Clinical Nutrition, indicated that high consumption of the sweetener may lead to neurodegeneration. Aspartame is made up of phenylalanine (50 per cent), aspartic acid (40 per cent) and methanol (10 per cent). It is commonly used in food products for the diet or low calorie market, including soft drinks and chewing gums. It was approved for use in foods in the US and EU member states in the early 1980s.The sweetener has caused much controversy amid suspicions on whether it is entirely safe, with studies linking the ingredient and cancer in rats.

It has also previously been found that aspartame consumption can cause neurological and behavioural disturbances in sensitive individuals. Symptoms that have been reported include headaches, insomnia and seizures.

Despite strong concerns being raised from some quarters over the sweetener, both the European Food Safety Authority (EFSA) and the US Food and Drug Administration (FDA) have not changed their guidelines regarding the safety of the ingredient or intake advice.

The new review also challenges finding published last year in the journal Critical Reviews in Toxicology (Informa Healthcase) that considered over 500 studies, articles and reports conducted over the last 25 years – including work that was not published, but that was submitted to government bodies as part of the regulatory approvals process.

The earlier review concluded: “The weight of existing evidence s that aspartame is safe at current levels of consumption… No credible evidence was found that aspartame is carcinogenic, neurotoxic, or has any other adverse effect on health when consumed even at quantities many times the established ADI [acceptable daily intake] levels.”

New review

Writing in the European Journal of Clinical Nutrition, a Nature journal, the scientists behind the new review state: “The aim of this study was to discuss the direct and indirect cellular effects of aspartame on the brain, and we propose that excessive aspartame ingestion might be involved in the pathogenesis of certain mental disorders, and also in compromised learning and emotional functioning.”

The researchers found a number of direct and indirect changes that occur in the brain as a result of high consumption levels of aspartame, leading to neurodegeneration.

They found aspartame can disturb the metabolism of amino acids, protein structure and metabolism, the integrity of nucleic acids, neuronal function and endocrine balances. It also may change the brain concentrations of catecholamines, which include norepinephrine, epinephrine and domapine.

Additionally, they said the breakdown of aspartame causes nerves to fire excessively, which can indirectly lead to a high rate of neuron depolarisation.

The researchers added: “The energy systems for certain required enzyme reactions become compromised, thus indirectly leading to the inability of enzymes to function optimally.

“The ATP stores [adenosine triphosphate] in the cells are depleted, indicating that low concentrations of glucose are present in the cells, and this in turn will indirectly decrease the synthesis of acetylcholine, glutamate and GABA (gamma-aminobutyric acid).”

Furthermore, the functioning of glutamate as an excitatory neurotransmitter is inhibited as a result of the intracellular calcium uptake being altered, and mitochondria are damaged, which the researchers said could lead to apoptosis (cell death) of cells and also a decreased rate of oxidative metabolism.

As a result of their study, the researchers said more testing is required to further determine the health effects on aspartame and bring an end to the controversy.

Source: European Journal of Clinical Nutrition
2008, doi: 10.1038/sj.ejcn.1602866
“Direct and indirect cellular effects of aspartame on the brain”
Authors: P. Humphries, E. Pretorius, H. Naude

Review raises questions over aspartame and brain health

Written by alienrobotgirl

2 May, 2008 at 5:33 pm

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Histamine intolerance review

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Histamine and histamine intolerance is an excellent review.

Diamine oxidase (DAO) is the main enzyme for the metabolism of ingested histamine. It has been proposed that DAO, when functioning as a secretory protein, may be responsible for scavenging extracellular histamine after mediator release. Conversely, histamine N-methyltransferase, the other important enzyme inactivating histamine, is a cytosolic protein that can convert histamine only in the intracellular space of cells.

DAO is more important than HNMT in histamine metabolism.

Ingestion of histamine-rich food (6), alcohol (7-9), or drugs (10-13) that release histamine or block DAO may provoke diarrhea, headache (14), congestion of the nose, asthmatoid wheezing (6, 8, 15), hypotension, arrhythmia, urticaria (16, 17), pruritus, flushing, and other conditions in these patients. Approximately 1% of the population has histamine intolerance, and 80% of those patients are middle-aged (18). Because of the multifaceted symptoms, the existence of histamine intolerance is frequently underestimated, or its symptoms are misinterpreted. Clinical symptoms and their provocation by certain foods and beverages appear similar in different diseases, such as food allergy and intolerance of sulfites, histamine, or other biogenic amines (eg, tyramine).

It’s virtually impossible to tell the difference between different food chemical reactions.

In mammals, DAO expression is restricted to specific tissues; the highest activities are shown for small bowel and colon ascendens (4, 5, 33) and for placenta and kidney (28, 31). Lower DAO activity has been discussed as a potential indicator of intestinal mucosa damage in inflammatory and neoplastic diseases (17, 24, 34) and in persons undergoing chemotherapy (35). HNMT is widely expressed in human tissues; the greatest expression is in kidney and liver, followed by spleen, colon, prostate, ovary, spinal cord cells, bronchi, and trachea (36). HNMT is regarded as the key enzyme for histamine degradation in the bronchial epithelium (37).

When these scientists talk about ‘intestinal mucosa damage’ they are not talking about intestinal dysbiosis. They are talking about Crohn’s disease, ulcerative colitis and coeliac disease, quite serious diseases.

Histamine can be metabolized by extracellular oxidative deamination of the primary amino group by diamine oxidase (DAO) (2) or intracellular methylation of the imidazole ring by histamine-N-methyltransferase (HNMT) (3). Therefore, insufficient enzyme activity caused by enzyme deficiency or inhibition may lead to accumulation of histamine. Both enzymes can be inhibited by their respective reaction products in a negative feedbackloop (4). N-Methylhistamine is oxidatively deaminated to N-methyl-imidazole acetaldehyde by monoamine oxidase B (MAO B) (5) or by DAO (6).

After histamine is methylated by HNMT, it still needs further metabolism by DAO or MAO B.

Recently, a potential genetic background of a reduced histamine metabolism has also been investigated. The human DAO gene spans {approx}10 kbp and is located on chromosome 7q35 (27) Various single-nucleotide polymorphisms (SNPs) in the DAO gene have been shown to be associated with inflammatory and neoplastic gastrointestinal diseases, such as food allergy (44), gluten-sensitive enteropathy, Crohn disease, ulcerative colitis, and colon adenoma (45-47). No significant difference in the distribution of the investigated HNMT alleles could be shown between patients with gastrointestinal diseases and control subjects (45, 47), but a functional relevant polymorphism of the HNMT gene (chromosome 2q22) has been described for white asthma patients (48). Conversely, this association could not be observed in Japanese (49), German pediatric (50), and East Indian (51) populations. Thus, histamine intolerance seems to be acquired mostly through the impairment of DAO activity caused by gastrointestinal diseases or through the inhibition of DAO, but the high interindividual variations in the expression of DAO in the gut and the association of SNPs in the DAO gene with gastrointestinal diseases provide evidence for a genetic predisposition in a subgroup of patients with histamine intolerance (27).

So impairments in DAO activity (whether genetic or acquired) are thought to be the main cause of histamine intolerance. I wonder whether that HNMT polymorphism in white asthma patients is actually interacting with another ‘white’ (i.e disproportionately present in caucasians) gene that causes it to be significant?

Headache can be induced dose-dependently by histamine in healthy persons as well as in patients with migraine (53, 61). Histamine-induced headache is a vascular headache caused mainly by nitrate monoxide (62). Histamine releases endothelial nitrate monoxide upon stimulation of H1R, which is also expressed in the large intracranial arteries (63). In migraine patients, plasma histamine concentrations have been shown to be elevated both during headache attacks and during symptom-free periods.

Everyone is adversely affected by a dose of histamine that exceeds their own personal tolerance levels.

Besides headache, gastrointestinal ailments including diffuse stomach ache, colic, flatulence, and diarrhea are leading symptoms of histamine intolerance. Elevated histamine concentrations and diminished DAO activities have been shown for various inflammatory and neoplastic diseases such as Crohn disease (17), ulcerative colitis (67), allergic enteropathy (39), food allergy (33, 68, 69), and colorectal neoplasmas (24). In the colonic mucosa of patients with food allergy, a concomitant reduced HNMT (70) and an impaired total histamine degradation capacity (THDC) (69) have been found (33), so that the enzymes cannot compensate each other. Therefore, an impaired histamine metabolism has been suggested to play a role in the pathogenesis of these diseases.

During or immediately after the ingestion of histamine-rich food or alcohol, rhinorrea or nasal obstruction may occur in patients with histamine intolerance; in extreme cases, asthma attacks also may occur. Reduced HNMT activity has been shown for patients with food allergy (70) and asthma bronchiale (71).

Possibly a methylation cycle related connection for some but not all individuals.

In addition to histamine-rich food, many foods such as citrus foods are considered to have the capacity to release histamine directly from tissue mast cells, even if they themselves contain only small amounts of histamine (Table 4). In vitro studies of persons with a history of pseudoallergic reactions to food have shown a fragility of duodenal mast cells with massive degranulation in the presence of histamine-releasing substances that is significantly greater than that shown by control subjects (85). However, clinical studies using oral challenge tests to support the hypothesis for the histamine-releasing capacity of foods are required (22).

You don’t need to have a problem with salicylates to have a reaction to citrus fruits!

Alcohol, especially red wine, is rich in histamine and is a potent inhibitor of DAO (9, 86). The relation between the ingestion of wine, an increase in plasma histamine, and the occurrence of sneezing, flushing, headache, asthma attacks, and other anaphylactoid reactions and a reduction of symptoms by antihistamines has been shown in various studies (7, 8, 14, 65, 87, 88). However, among the multitude of substances contained in wine, other biogenic amines such as tyramine (80) and sulfites (89) have been supposed to contribute to symptoms summarized as “wine intolerance” or “red wine asthma” (19, 89, 90).

How about red wine-violently-throwing-up-sickness? I’ve never been able to tolerate more than a small glass.

In the female genital tract, histamine is mainly produced by mast cells, endothelial cells, and epithelial cells in the uterus and ovaries. Histamine-intolerant women often suffer from headache that is dependent on their menstrual cycle and from dysmenorrhea. Besides the conctractile action of histamine, these symptoms may be explained by the interplay of histamine and hormones. Histamine has been shown to stimulate, in a dose-dependent manner, the synthesis of estradiol via H1R; meanwhile, only a moderate effect on progesterone synthesis was observed (117). The painful uterine contractions of primary dysmenorrhea are mainly caused by an increased mucosal production of prostaglandine F2{alpha} stimulated by estradiol and attenuated by progesterone. Thus, histamine may augment dysmenorrhea by increasing estrogen concentrations. And, in reverse, estrogen can influence histamine action. A significant increase in weal and flare size in response to histamine has been observed to correspond to ovulation and peak estrogen concentrations (118). In pregnancy, DAO is produced at very high concentrations by the placenta (119, 120), and its concentration may become 500 times that when the woman is not pregnant (120). This increased DAO production in pregnant women may be the reason why, in women with food intolerance, remissions frequently occur during pregnancy (14).

Interesting, because oestrogen also decreases monoamine oxidase activity. I’ve thought for ages that I have too much oestrogen.

I’ve also noticed that some women who are usually complete crazy bitches seem perfectly sweet and lovely during pregnancy, whilst other women who seem like perfectly lovely people go nuts. Coming from a family who were closely involved in the administration of a fibromyalgia support network, I’m familiar with the anecdotal ‘fibromyalgia sufferers always get better during pregnancy then relapse again’ phenomenon.

Written by alienrobotgirl

27 April, 2008 at 10:21 am

Posted in The Science of FCI