Autoimmune Thyroid Disease

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Why Britney is manic?

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If anyone reading this blog is remotely interested in the car-crash life of Britney Spears, here’s a little insight for you:

Britney admitted to to the doctors that she was on ADD medication Adderall, aka cocaine in a pill, and was taking up to ten laxatives a day. Perez Hilton

Adderall is an ADHD medication. Technically it’s speed in a pill, not cocaine. Here’s what it does:

Amphetamines, both as dextroamphetamine and levoamphetamine (or a racemic mixture of the two enantiomers), are believed to exert its [sic] effects by binding to the monoamine transporters and increasing extracellular levels of the biogenic amines dopamine, norepinephrine and serotonin.


Amphetamine also possesses the ability to inhibit the enzymes monoamine oxidase A and B (MAO-A and MAO-B) in high doses. MAO-A is responsible for the break down of serotonin, dopamine, norepinephrine and epinephrine. MAO-B is responsible for breaking down dopamine (more potently than MAO-A) and phenylethylamine (PEA), which has actions similar to amphetamine itself and is thought to be involved in feelings of lust, confidence, obsession and sexuality. Adderall

A side effect of adderall is weight loss, probably why Britney has been taking it, as she has struggled with her weight since her first pregnancy.

Adderall increases dopamine: great if you have a DRD4 polymorphism that leaves you with low dopamine levels. Not so great if you are bipolar as a result of high dopamine levels.

What does the FDA say about amphetamines and bipolar disorder?

The FDA also warned that stimulant therapy can exacerbate symptoms of behavior disturbance and thought disorder in patients with preexisting psychotic disorders.

Amphetamines should be used with caution in attention-deficit/hyperactive disorder patients with comorbid bipolar disorder because of the potential risk for induction of a mixed/manic episode. Pretreatment screening should therefore also include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.

Also, psychotic/manic symptoms (eg, hallucinations, delusional thinking, and mania) have been reported at normal amphetamine doses in children and adolescents without prior history of these conditions. Data from a pooled analysis of multiple short-term studies have revealed an incidence rate for these events of 0.4% in methylphenidate- or amphetamine-treated patients compared with 0% for those receiving placebo. A potential causal role for the stimulant should be considered in patients who develop symptoms of psychosis or mania; discontinuation of therapy may be indicated. Medscape Today

Whoever prescribed Britney amphetamines deserves to be struck off. I feel very sorry for her right now.

Edit: more on Britney. Risperdal and Seroquel are both prescribed to people with bipolar disorder and schizophrenia, and they have some really unpleasant side effects – like diabetes. Both currently have class action lawsuits underway against them. Risperdal is a dopamine blocker. Who the heck prescribes Risperdal and Adderall in the same patient?


Written by alienrobotgirl

31 January, 2008 at 8:19 pm

Posted in Neurotransmitters

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The genetics of chronic fatigue syndrome

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To begin with, here is an overview of the frequency of CFS and the factors thought to be involved:

The US case definition of CFS (the CDC-definition) is most widespread in research and clinical practice. Estimates of prevalence vary from 0.2% to above 2%. The female-male ratio is approximately 3:1. […] Present knowledge suggests that certain genetic polymorphisms and personality traits might be regarded as predisposing factors, some infections and severe psychosocial stress constitute precipitating factors, whereas disturbances of immunity, skeletal muscle, cognitive abilities, endocrine control and cardiovascular homeostasis are possible perpetuating factors. The chronic fatigue syndrome–an update

Angiotension converting enzyme (ACE) deletions are associated with Gulf War Syndrome:

Increased risk for CFS/ICF was associated with alterations of the insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme gene within the Gulf War veteran sample only. […] Veterans with the DD genotype were eight times more likely to develop CFS/ICF than were those with the II genotype. Association of medically unexplained fatigue with ACE insertion/deletion polymorphism in Gulf War veterans

Corticosteroid-binding globulin (CBG) polymorphisms are associated with CFS:

A trend toward relative hypocortisolism is described in CFS. Twin and family studies indicate a substantial genetic etiologic component to CFS. Recently, severe corticosteroid-binding globulin (CBG) gene mutations have been associated with CFS in isolated kindreds. Human leukocyte elastase, an enzyme important in CBG catabolism at inflammatory sites, is reported to be elevated in CFS. We hypothesized that CBG gene polymorphisms may act as a genetic risk factor for CFS. […] Sequencing and restriction enzyme testing of the CBG gene coding region allowed detection of severe CBG gene mutations and a common exon 3 polymorphism (c.825G–>T, Ala-Ser224). Plasma CBG levels were measured in 125 CFS patients and 198 controls by radioimmunoassay. Total and free (calculated and measured) cortisol levels were ascertained in single samples between 8-10 a.m. The age of onset (mid 30s) and gender ratio (2.2:1, female:male) of the patients were similar to those reported in U.S. epidemiologic studies. A trend toward a preponderance of serine224 homozygosity among the CFS patients was noted, compared with controls […] Despite higher CBG levels, there was a nonsignificant trend toward lower total and free plasma cortisol in serine allele positive patients […] Homozygosity for the serine allele of the CBG gene may predispose to CFS, perhaps due to an effect on hypothalamic-pituitary-adrenal axis function related to altered CBG-cortisol transport function or immune-cortisol interactions. Association between chronic fatigue syndrome and the corticosteroid-binding globulin gene ALA SER224 polymorphism

Serotonin (5-hydroxy-tryptamine) transport protein (5-HTT, also known as SERT) polymorphisms are associated with CFS:

Interaction between the hypothalamo-pituitary-adrenal axis and the serotonergic system is thought to be disrupted in chronic fatigue syndrome (CFS) patients. We examined a serotonin transporter (5-HTT) gene promoter polymorphism, which affects the transcriptional efficiency of 5-HTT […] A significant increase of longer (L and XL) alleic variants was found in the CFS patients compared to the controls […] Attenuated concentration of extracellular serotonin due to longer variants may cause higher susceptibility to CFS. Association between serotonin transporter gene polymorphism and chronic fatigue syndrome

We have recently reported the association of serotonin transporter gene polymorphism in CFS. A significant increase of longer (L and XL) alleic variants was found in the CFS patients compared to the controls. Compared to S allele, the L allele is believed to retain higher transcriptional activity, which causes decreased concentration of serotonin in the extracellular space, namely, active serotonin in CFS. These results thus support the serotonin hypothesis in the pathogenesis of CFS. Genetic background of chronic fatigue syndrome

Having serotonin levels that are too low can be caused by genetics, or by a viral infection:

Attenuation of serotonin neurotransmission can be caused by increased expression of serotonin transporter, which results either from viral infection and subsequent production of interferon–alpha or from abnormal promoter for serotonin transporter gene. Chronic fatigue syndrome and neurotransmitters

Yes, you read that right. The production of interferon-alpha due to a viral infection actually interferes with the genetic transcription of SERT, causing it to overproduce. This downregulates serotonin neurotransmission. Salicylate stimulates serotonin synthesis (the cause of the flavour chemical intolerant’s familiar ‘happy high’), so I suspect it works on CFS in a similar manner, by causing short term rebound deficiencies in substrates due to overproduction, and long-term downregulation of production. I know of several people who have complained of SSRI-like withdrawal symptoms when they begin the failsafe diet.

Serotonin receptor (HTR) polymorphisms are also involved in CFS:

The pathophysiology of CFS remains elusive, although abnormalities in the central nervous system (CNS) have been implicated, particularly hyperactivity of the serotonergic (5-hydroxytryptamine; 5-HT) system and hypoactivity of the hypothalamic-pituitary-adrenal (HPA) axis. Since alterations in 5-HT signaling can lead to physiologic and behavioral changes, a genetic evaluation of the 5-HT system was undertaken to identify serotonergic markers associated with CFS and potential mechanisms for CNS abnormality. A total of 77 polymorphisms in genes related to serotonin synthesis (TPH2), signaling (HTR1A, HTR1E, HTR2A, HTR2B, HTR2C, HTR3A, HTR3B, HTR4, HTR5A, HTR6, and HTR7), transport (SLC6A4), and catabolism (MAOA) were examined […] Of the polymorphisms examined, three markers (-1438G/A, C102T, and rs1923884) all located in the 5-HT receptor subtype HTR2A were associated with CFS when compared to NF controls. Additionally, consistent associations were observed between HTR2A variants and quantitative measures of disability and fatigue in all subjects. The most compelling of these associations was with the A allele of -1438G/A (rs6311) which is suggested to have increased promoter activity in functional studies. Further, in silico analysis revealed that the -1438 A allele creates a consensus binding site for Th1/E47, a transcription factor implicated in the development of the nervous system. Electrophoretic mobility shift assay supports allele-specific binding of E47 to the A allele but not the G allele at this locus. These data indicate that sequence variation in HTR2A, potentially resulting in its enhanced activity, may be involved in the pathophysiology of CFS. Genetic evaluation of the serotonergic system in chronic fatigue syndrome

Proopiomelanocortin (POMC), nuclear receptor subfamily 3, group C, member 1 (NR3C1), monoamine oxidase A (MAOA), monoamine oxidase B (MAOB), and tryptophan hydroxylase 2 (TPH2) polymorphisms are all associated with CFS:

This study examined whether genetic differences underlie the individual subgroups of the latent class solution. Polymorphisms in 11 candidate genes related to both hypothalamic-pituitary-adrenal (HPA) axis function and mood-related neurotransmitter systems were evaluated. […] Of the five classes of subjects with unexplained fatigue, three classes were distinguished by gene polymorphsims involved in either HPA axis function or neurotransmitter systems, including proopiomelanocortin (POMC), nuclear receptor subfamily 3, group C, member 1 (NR3C1), monoamine oxidase A (MAOA), monoamine oxidase B (MAOB), and tryptophan hydroxylase 2 (TPH2). These data support the hypothesis that medically unexplained chronic fatigue is heterogeneous and presents preliminary evidence of the genetic mechanisms underlying some of the putative conditions. Polymorphisms in genes regulating the HPA axis associated with empirically delineated classes of unexplained chronic fatigue

Catechol-O-methyltransferase (COMT) polymorphisms, along with some genes already listed above, are associated with CFS:

This paper asks whether the presence of chronic fatigue syndrome (CFS) can be more accurately predicted from single nucleotide polymorphism (SNP) profiles than would occur by chance. […] The top three genes containing the SNPs accounting for the highest accumulated importances were neuronal tryptophan hydroxylase (TPH2), catechol-O-methyltransferase (COMT) and nuclear receptor subfamily 3, group C, member 1 glucocorticoid receptor (NR3C1). CONCLUSION: The fact that only 28 out of several million possible SNPs predict whether a person has CFS with 76% accuracy indicates that CFS has a genetic component that may help to explain some aspects of the illness. Combinations of single nucleotide polymorphisms in neuroendocrine effector and receptor genes predict chronic fatigue syndrome

Wait. Let’s read that again: only twenty eight out of several million genetic polymorphisms predict whether a person has CFS with a 76% accuracy.

Yasko tests for some of the common polymorphisms listed above: ACE, MAO-A, and COMT. She doesn’t test for CBG, 5-HTT/SERT, POMC, NR3C1, MAO-B or TPH2.

You know you’re on to something when you can predict the genes that are involved in particular illnesses. Though Yasko doesn’t test for POMC variants, we’ve actually been discussing POMC on FailsafeNT recently. It is probably one of the primary genetic components of opioid sensitivity and pain perception. Also, I’ve also been puzzled for a while as to why Yasko doesn’t test for SERT polymorphisms, particularly as serotonin promotes sociability and for this reason is thought to be lacking in some autistics.

Of course, fibromyalgia is very closely related to CFS:

The exposure of a genetically predisposed individual to a host of environmental stressors is presumed to lead to the development of FMS. Fibromyalgia overlaps with several related syndromes, collectively compromising the spectrum of the functional somatic disorder. FMS is characterized by a strong familial aggregation. Recent evidence suggests a role for polymorphisms of genes in the serotoninergic, dopaminergic and catecholaminergic systems in the etiopathogenesis of FMS. These polymorphisms are not specific for FMS and are similarly associated with additional comorbid conditions. The mode of inheritance in FMS is unknown, but it is most probably polygenic. Recognition of these gene polymorphisms may help to better subgroup FMS patients and to guide a more rational pharmacological approach. The genetics of fibromyalgia syndrome

Written by alienrobotgirl

31 January, 2008 at 6:46 pm

Posted in The Genetics of FCI?

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A moment of smug boastfulness

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I’ve taken a few IQ tests recently. The highest came in at 145, the lowest 11 points below (to be fair, my attention-seeking puppy rather hindered me with that test). This means I have officially scraped the ‘genius’ category. Apparently this IQ is typical of top civil servants, professors, or research scientists. Which is kinda cool. This also means I’m even-stevens with my partner, but I’m still roughly 15 IQ points behind my Dad. Statistically, for every person as intelligent as my Dad in the world, there are at the very least 10,000 people who are less intelligent. He has savant spacial skills.

This is all very ironic because ever since I did sociology I haven’t really believed in IQ tests. When I was younger and a total leftie, I didn’t even believe in intelligence. Apart from problems with culturally specific questions, yada yada ya, if you change the weighting of questions that assess different skills between different tests, then of course you get different results. Different cultures place more emphasis on the value of different skills. I think it’s more helpful to assess different specific skills, like spacial rotation skills, pattern spotting, systemising, logic, etc, individually.

I’ve done quite a few psychometric tests recently. On left/right hemisphere tests I come out slap bang in the centre or marginally right-brained. My logic is impeccable. I’m also very good at pattern spotting. I’m pretty good at spacial visualisation for a girl. My weak spot really is maths. I don’t know why I am great at logic but bad at maths. Numbers just don’t add up automatically in my brain like they do in other people’s. I often end up adding up on my fingers or visualising dots in my head.

I think I’ve inherited the logic and spatial skills. They’re part of the aspie talent spectrum. Though bickering with my partner has definitely made me more logical! I’ve been working on some brain training during the last couple of years. Shortly after going on failsafe I got into sudoku, which has helped a bit with the maths. I also do lots of logic puzzles. I am sure they have improved my logic skills to the point where I can’t really score any higher. I think I’m going to have to teach myself maths again as it’s holding my score back. Can you even buy maths puzzlebooks?

IQ isn’t supposed to improve more than ten points in a lifetime. That’s funny, because mine has improved 18 points since the first IQ test I took as a teenager. I suspect my processed/vegetarian teenaged diet may have been holding me back. I’m sure adequate B12, folate and choline (eggs only) are quite important. Omega 3s are probably important for the 10% of the population who for genetic reasons can’t make their own.

I’m setting myself the task of breaking the 150 barrier this year. Not that I’m being competitive or want to beat my partner or anything you understand…

There are some extreme neurodiversity aspies out there who simply regard neurotypical/stupid on a scale with aspie/intelligent at the other end. I don’t think that. I know people just as intelligent as me who are far more social. I do think, however, that many of the genetic polymorphisms involved in asperger’s syndrome tend to increase intelligence. I also think there are other intelligence increasing genes that don’t affect sociability.

And I think there’s a good 20-40 points variation in the IQ that is influenced both by diet during pregnancy/lactation/childhood, and also by the environment. I was very lucky as a baby, because my mother was a trained nursery nurse who spent an awful lot of time mentally stimulating my sister and I as we grew. As a result I’m quite right-wing in my ideas about how children should be raised. I don’t care who is doing the raising (mum, dad, nursery nurse, whoever), as long as the child gets appropriate mental stimulation – something they may well not get at home, or in a nursery setting. I don’t really like neglectful mothers. It’s all I can do to keep myself from hot-housing my dog. Bless him.

Written by alienrobotgirl

30 January, 2008 at 6:02 pm

Posted in Personal Diary

Monoamine oxidase and oestrogen

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Why are women more prone to depression and mood disorders than men? And why do more women than men seem to suffer from food chemical related disorders, especially fibromyalgia?

Depressive disorders in women are commonly associated with reproductive events. This association may be due in part to the changing balance between estrogen, progesterone, and other hormones that affect neurotransmitter function throughout a woman’s lifecycle. […] Some data suggest that depression in women tends to respond differently to antidepressant treatment than depression in men, underscoring the need to examine the risk and treatment of depressive disorders in males and females separately. Women have benefited considerably from serotonin reuptake inhibitor anti-depressants that are currently available. These agents appear to be more effective than the older tricyclic antidepressants in treating various depressive disorders that occur commonly or exclusively in women. Additionally, serotonin reuptake inhibitors have increased tolerability in women, who generally experience more adverse effects from tricyclics and monoamine oxidase inhibitors than do men. Estrogen appears to enhance antidepressant response in postmenopausal women receiving estrogen replacement therapy. Special issues related to the treatment of depression in women.

Women have worse responses to monoamine oxidase inhibitors than men do? Why would that be? After all, it’s men who only have one copy of the MAO gene – which resides on the X chromosome.

Estrogen replacement treatment in menopausal women has been reported to have a positive effect on mood states. However, the addition of a progestin partially negates this positive effect in some women. The opposite effects of estrogen and progestin on mood may relate to their opposite effects on adrenergic and serotonergic neural function. In a double-blind, placebo-controlled, crossover study, 38 nondepressed menopausal women were cyclically treated with estrogen and estrogen plus progestin, or with placebo, for five 28-day cycles. This paper identifies the pretreatment attributes of women who do and do not have negative mood responses to progestin, and examines the relationship of these adverse side-effects to platelet monoamine oxidase (MAO), a marker of adrenergic and serotonergic functioning. Adverse mood responses to progestin occur in women with a long duration of menopause, low pretreatment serum estradiol and testosterone levels, high pretreatment serum FSH levels, low pretreatment platelet MAO activity, and pretreatment mood abnormalities. We conclude that adverse mood response to the addition of a progestin occurs in menopausal women who have low pretreatment gonadal hormone levels secondary to a long duration of menopause. Impaired central nervous system adrenergic and serotonergic functioning also may be a factor predisposing to a negative mood response to progestin. Individual differences in changes in mood and platelet monoamine oxidase (MAO) activity during hormonal replacement therapy in menopausal women.

In this case the above study finds that oestrogen decreases monoamine oxidase expression, and progesterone increases monoamine oxidase expression. Hence in these depressed women, decreasing monoamine oxidase activity with oestrogen (effectively giving them an MAOI), elevated their mood. More of the same:

the expression of several genes associated with embryo implantation (i.e. thrombomodulin, monoamine oxidase A, SPARC-like 1) can be induced by P[rogesterone] in vitro Progesterone regulation of implantation-related genes: new insights into the role of oestrogen.

It had previously been reported that estrogen treatment in menopausal women had a positive effect on mood, whereas the combination of estrogen plus a progestin had a negative effect on mood. We found that the women with a long duration of menopause and higher treatment serum estradiol levels had significantly more dysphoria when receiving a combination of estrogen plus progestin than did the women with a short duration of menopause and lower serum estradiol levels. However, both short and long duration menopausal groups showed improvement in mood when estrogen was administered alone. Platelet MAO levels, a marker of adrenergic and serotonergic function thought to relate to mood, were negatively correlated with serum estradiol levels during HRT. We suggest that these paradoxical findings may be secondary to a prolonged estrogen deficiency state in women with a long duration of menopause. Relationships of serum estradiol levels, menopausal duration, and mood during hormonal replacement therapy.

Of course if you have the kind of depressed monoamine oxidase activity that leads to food chemical intolerance, oestrogen is the last thing you need. When I first started to get more severe symptoms (during and shortly after coming off the pill), one of my theories was that I had ‘progesterone deficiency’ – a condition that exists only in alternative medicine. In mainstream medicine, you only have a deficiency or an excess of female hormones if your period has either stopped or your bleeding is abnormally heavy. So when I suggested progesterone deficiency to my (female) doctor at the time, she laughed at me and said hormonal problems were always caused by oestrogen deficiency, and the cure was the pill. Which fortunately I couldn’t take anymore as it had put me in hospital with deep vein thrombosis.

My cycle has always been as regular as clockwork. The pill did change my period – I never used to spot during the week before I was due. It’s only during the last few months that this after-effect of the pill has gone away and I stopped using the pill something like five years or more ago. Apparently some effects of the pill, including loss of sex drive and hormonal changes, can last up to ten years after the pill is discontinued. It’s no wonder so many women have problems getting pregnant these days!

Though I haven’t had my hormone levels tested, I’m fairly sure I have high oestrogen levels. I’m an hourglass shape and have a DD cup size, something that runs in my family. My grandmother had oestrogen-dependent breast cancer. At the time I started to get anxious about post-pill symptoms, progesterone deficiency fitted a lot of my symptoms. Of course I was on warfarin at the same time. Now it turns out that progesterone would have done me some good, by raising my MAO levels. I wonder how many other women with low MAO levels are out there thinking along the same lines as I did about progesterone deficiency?

But of course it’s always a bit more complicated than a simple inverse correlation between oestrogen and MAO:

The serotonin neural system plays a pivotal role in mood, affective regulation and integrative cognition, as well as numerous autonomic functions. We have shown that ovarian steroids alter the expression of several genes in the dorsal raphe of macaques, which may increase serotonin synthesis and decrease serotonin autoinhibition. Another control point in aminergic neurotransmission involves degradation by MAO. This enzyme occurs in two isoforms, A and B, which have different substrate preferences. […] MAO-A and -B mRNAs were detected in the dorsal raphe nucleus (DRN) and in the hypothalamic suprachiasmatic nucleus (SCN), preoptic area (POA), paraventricular nucleus (PVN), supraoptic nucleus (SON), lateral hypothalamus (LH) and ventromedial nucleus (VMN). MAO-A mRNA optical density was significantly decreased by E, P, and E+P in the DRN and in the hypothalamic PVN, LH and VMN. Ovarian hormones had no effect on MAO-B mRNA expression in the DRN. However, there was a significant decrease in MAO-B optical density in the hypothalamic POA, LH and VMN with E, P or E+P treatment. Pixel area generally reflected optical density. CONCLUSIONS: Ovarian steroids decreased MAO-A, but not B, in the raphe nucleus. However, both MAO-A and B were decreased in discrete hypothalamic nuclei by hormone replacement. These data suggest that the transcriptional regulation of MAO by ovarian steroids may play a role in serotonin or catecholamine neurotransmission and hence, mood, affect or cognition in humans. Ovarian steroid regulation of monoamine oxidase-A and -B mRNAs in the macaque dorsal raphe and hypothalamic nuclei.

Estrogen replacement therapy is widely used in postmenopausal women. The current study examines the effect of varying concentrations of estrogen on the levels of activity of monoamine oxidase A and -B in brain and in other tissues. […] High dose estrogen (5 mg/pellet) significantly decreased MAO-B activity and resulted in lesser or insignificant changes in MAO-A activity, respectively in liver (-30%, +1%), kidney (-22%, -11%), and uterus (-57%, -35%) (p Tissue-specific effects of estrogen on monoamine oxidase A and B in the rat.

These are shockingly large percentage changes. It’s the decreased MAO-A activity in the hypothalamus and amygdala that’s particularly interesting, as they are primitive parts of the brain. Hypothalamus, amygdala, and limbic system keep cropping up in my research as sites where the processing of amines and glutamate is altered somehow in food chemical intolerance spectrum syndromes including autism and fibromyalgia. One researcher even thinks that the amygdala is damaged in fibromyalgia. The hypothalamus controls body temperature, hunger, thirst, fatigue, anger, and circadian cycles, and links the nervous system to the endocrine system via the pituary gland. The amygdala plays a role in the processing and memory of emotional reactions.

So the next question is, if oestrogen levels make women more vulnerable than men to amines, why are there something like six male aspergers for every female asperger?

Well we know that asperger’s/autism/schizophrenia/bipolar disorder/epilepsy and other overlapping disorders seem to be connected to changes in dopamine processing in the brain.

This discussion is followed by a more detailed description of estrogen’s actions upon the dopamine transporter, which is hypothesized to serve as one of the major mechanism involved with nigrostriatal dopaminergic neuroprotection. Overall, estrogen appears to inhibit dopamine transporter function by decreasing the affinity of the transporter. Such an effect could prevent neurotoxic agents from entering dopamine nerve terminals, thereby decreasing nigrostriatal neurodegeneration. Neuroprotective effects of estrogen upon the nigrostriatal dopaminergic system.

Women seem to be less vulnerable to some dopamine related disorders because dopamine is processed differently in the presence of oestrogen. They seem to be less likely to suffer the effects of high dopamine. In addition to this, men have a special region on the Y chromosome called the Sex-determining Region Y (SRY), and it is this one region on the Y chromosome that determines whether you develop as a male or a female.

SRY has been linked to the fact that men are more likely than women to develop dopamine-related diseases such as schizophrenia and Parkinson’s disease. SRY makes a protein that controls concentrations of dopamine, the neurotransmitter that carries signals from the brain that control movement and coordination. Sex-determining Region Y (SRY)

Written by alienrobotgirl

26 January, 2008 at 9:58 pm

Posted in The Genetics of FCI?

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Homozygosity – not always a bad thing

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Marry your cousin to have long-lived kids? Inbreeding is not usually mooted as the key to longevity, but Giuseppe Passarino of the University of Calabria in Rende, Italy, thinks it might be. “Everyone knows that inbreeding is bad – it increases your chances of catching a range of diseases,” he says. “But on the other hand, our study suggests that if inbreds don’t get those diseases when they’re young, they might have a better chance of long life.”

Passarino and his colleagues used census data to identify a geographically isolated region of southern Italy with more than its fair share of male nonagerians. When the team looked at the local phone book, they found many people in the region shared the same surname, suggesting marriage between related individuals was common (Annals of Human Genetics, DOI: 10.1111/j.1469-1809.2007.00405.x).

“The level of inbreeding can be measured quite precisely by studying surname distribution,” says Passarino. Because a surname is passed through the paternal line, it behaves like a gene transmitted through the Y chromosome, he says.

Everyone has two copies of each gene. In a large gene pool there is a high chance that those copies will be distinct. But in a small, inbred community, the gene pool remains the same and it is more likely that an individual will be “homozygous” – with two identical copies of a gene.

“Longevity seems to be linked to homozygosity,” Passarino says. This may be because certain copies of some genes boost lifespan, and carrying two of them doubles the effect. A number of DNA analyses have located regions of the genome where centenarians show an unusually high level of homozygosity, he says.

“It is theoretically possible to observe more centenarians as a result of inbreeding,” says Leonid Gavrilov at the University of Chicago, but he wonders why only men were the beneficiaries.

Passarino says it may be because the genetic component of longevity plays a more important role in men, whereas in women, environmental factors come to the fore. Healthcare has improved in western Europe over the past 60 years, which has benefited women more than men. For example, in Denmark the number of male centenarians is 10 times as high because of better healthcare, but the number of females is 50 times higher, he says. The region that Passarino identified is economically poor and has limited healthcare. This could explain why fewer women than men live to old age there.

Bruce Carnes of the University of Oklahoma cautions against marrying a relative, however. “Homozygosity is typically a very bad thing,” he says. “Almost every discussion of inbreeding that I have ever read has emphasised its downside.” Inbred humans live to a ripe old age

Written by alienrobotgirl

26 January, 2008 at 7:52 pm

Monoamine oxidase activity and insulin

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FACT 1: Use of monoamine oxidase inhibitors (MAOIs) are associated with significant weight gain:

Antidepressants such as tricyclic antidepressants and monoamine oxidase (MAO) inhibitors are most often associated with significant weight gain. Pharmacodynamics of drug-induced weight gain.

FACT 2: Common low activity monoamine oxidase single nucleotide polymorphisms are associated with increased weight and increased risk of obesity:

We investigated the association between the monoamine oxidase A (MAO-A) gene and obesity. […] The TDT analysis of the EcoRV polymorphism showed in obese subjects with a body mass index (BMI) >/=35 kg/m(2) a preferential transmission of the low activity-related allele (chi(2)(TDT) = 8.0, p = 0.005). Our findings may provide evidence of a candidate gene involved in obese subjects with a BMI >/=35 kg/m(2). Family-based association study between the monoamine oxidase A gene and obesity: implications for psychopharmacogenetic studies.

We found, however, that both MAOA and MAOB show an excess of the low-activity genotypes in obese individuals. Additionally, the MAOA genotype was significantly associated with both weight and BMI. Obesity is associated with genetic variants that alter dopamine availability.

FACT 3: Monoamine oxidase activity is disturbed in diabetes:

MAO activity in pancreatic tissue is significantly reduced in diabetes. This decrease in MAO activity is associated with an increase in pancreatic tissue levels of adrenaline (ADR) and noradrenaline (NA). Studies on the level of 5-hydroxyindoleacetic acid of pancreatic tissues suggest that serotonin level is also increased in diabetics. Many studies show that MAO inhibits insulin secretion. However, some of its substrates including, serotonin, adrenaline and noradrenaline have been shown to stimulate insulin secretion. In conclusion, the activity and subcellular localisation of MAO suggests that MAO may play an important role in pancreatic beta cell function and hence in the pathogenesis of diabetes mellitus. The effect of diabetes mellitus on the morphology and physiology of monoamine oxidase in the pancreas.

In other words, high MAO activity inhibits insulin secretion. A number of monoamines (serotonin, adrenaline, noradrenaline etc) themselves stimulate insulin secretion, therefore low monoamine oxidase activity automatically leads to higher insulin levels.

FACT 4: Glucose regulates monoamine oxidase activity:

Islet beta-cell monoamines are known to influence the insulin-releasing mechanisms. These amines are localized in the insulin-secretory granules and are inactivated by the enzyme monoamine oxidase (MAO), a hydrogen peroxide (H2O2)-generating enzyme. The activity of islet MAO may consequently be of importance for insulin secretion. In the present investigation, we studied the relation between islet MAO activity and plasma levels of insulin and glucose in obese (ob/ob) hyperglycemic mice and their lean littermates. In addition, the effect of glucose on the MAO activity of in vitro-cultured islets was studied. MAO activity was assayed with serotonin, dopamine (DA), and beta-phenylethylamine (PEA) as substrates. After an overnight fast in adult (age, 6 months) lean mice, islet MAO activity was increased by 35% to 70%. Plasma levels of glucose and insulin were markedly decreased as expected. However, fasting in adult obese mice either did not affect islet MAO activity (PEA and DA) or induced a slight decrease (serotonin) of approximately 25% (P < .05). Plasma glucose levels in adult obese mice were not significantly affected by the overnight fast. However, a correlation analysis based on individual adult obese mice (fed and fasted) showed a negative correlation between plasma glucose concentration and islet MAO activity with PEA (r = -.65, P < .02) and DA (r = -.66, P < .02), respectively. Further, a positive correlation (r = +.58, P < .05) was found between glucose level and islet MAO activity when using serotonin as substrate. There was no difference in islet MAO activity with PEA and DA as substrates in fed obese versus fed lean mice. Glucose modulation of islet monoamine oxidase activity in lean and obese hyperglycemic mice.

In other words, lowering blood glucose through fasting caused monoamine oxidase activity to increase dramatically. In obese mice, blood glucose remained high and monoamine oxidase activity did not increase.

My own blood glucose levels are consistently on the edge of high-normal, even on a low-carb diet, and if they got any higher I would actually be classified as a T2 diabetic.

This explains to me why low carbohydrate diets and intermittent fasting have helped myself and a number of people I know who are sensitive to food chemicals. Even regular low calorie diets seem to help some people. I’ve often noted that the consumption of amine containing foods has the ability to cause massive, sudden weight gain in myself. I’ve also noted that when I am on a ketogenic diet I have a higher tolerance of amines.

It also explains something else. I’ve met a lot of people who really, really believe that low carbohydrate diets are THE answer to everything, and these people have been overweight for years and nothing worked except low carbing. Often they describe symptoms that correlate with food chemical sensitivity. What these people do not know is that they are overweight because they have low monoamine oxidase activity.

I imagine that when you combine low monoamine oxidase activity with other polymorphisms that increase insulin or insulin-like growth factor output (like the vitamin D receptor polymorphism VDR Fok), you have a recipe for reactive hypoglycaemia, weight gain and diabetes. Another reason for me to suspect I have both of these polymorphisms.

So now it seems that ALL failsafe food chemicals raise insulin levels – glutamates, salicylates, and amines.

I’ll spell this out again for the sake of the low-carbers whose eyes glaze over: the reason obesity is an increasing problem these days is not just due to increased consumption of carbohydrate. It is also due to the grossly increased amounts of food flavour chemicals eaten in the modern Western diet.

Written by alienrobotgirl

13 January, 2008 at 6:00 pm

Posted in The Genetics of FCI?

Tagged with

Back from outer space

with one comment

Or not as the case may be.

It seems I have somehow survived hosting Christmas for the extended family. I don’t think I sat down once in the week before the big day, and I mean that almost literally.

As you can see I have a tendency to disappear from the face of the planet when things get too much for me. This is a coping mechanism I’ve used since childhood, and it’s my response to stress, being put under pressure, or any situation I find too emotional. I have in the past flipped out and walked away from exams, bolted from relationships, and terminated friendships. At some point my brain just goes AAAAAAAaaaaarrgh and the duck and cover response kicks in.

I’ve spent the last few weeks thinking very hard and asking myself some questions that relate to all this. Such as:

  • How come I waste all of my energy posting in this blog and on forums when it isn’t what I want to do with my life?
  • How come I find it so easy to reflexively post on forums, but so hard to put together Really Important, official, organised pages for my website that I desperately need to do?
  • How come sometimes I can’t even post on this blog when it’s a Really Important post I really need to make? I must have two dozen Really Important posts I’m being totally impotent about.
  • How come sometimes I can’t even face replying to people’s comments and emails? I have Really Important emails I need to write to friends that have been outstanding for six months or more.
  • How come I used to be able to design websites until I had to do it for a living and it became Really Important, and then it all dried up? Now I can’t even design a simple logo for a friend. I actually dread it when friends ask for design help because I simply can’t do things for other people.
  • How come I used to be able to write pages and pages of creative work until it became Really Important and I wanted to properly publish a book and imagined other people reading it?

I’m sorry – I do owe a lot of people replies to their emails and comments and I just can’t handle them right now because the length of time people have been waiting has bumped them up to Really Important status. In fact, as soon as anyone else asks me to do something for them, it becomes Really Important in my head, and I turn into a gibbering fuckwit who wants to grasp her head and groan and rock back and forth.

This is writer’s block. I’ve had it for years but I never really thought about how totally it permeates the way I behave and the decisions I make and the life I am leading today.

Yet here I am being tremendously prolific writing this blog. Until recently – when I started to realise how many Really Important posts I desperately need to make to explain everything, and I started to not want to write this blog anymore.

Tonight I came across a rather enlightening article in the BBC H2G2 DNA project. The article is about hypergraphia – being driven in a frenzy to write and write. Sort of like what happened with this blog. It’s caused by writer’s block.

The inability to communicate one’s ideas causes depression and anxiety, which in turn causes an inability to communicate and decreased activity in the frontal lobe where ideas are organised and edited – which is what writer’s block is all about. However, writer’s block is often genre-specific and the people who suffer from this condition often turn to other outlets for release – be it pouring one’s soul into poetry, chronicling one’s life in painful detail, writing lengthy letters or, in the age of electronics, marathon emails. Indeed, it has become a technique employed by writers in the rut – escaping from the block by writing about it, which is apparently what Coleridge and Wordsworth were famous for. Hypergraphia

So what I can say is that I have too much going on in the temporal lobes, too little going on in the frontal lobes? My writing tutor used to call this kind of behaviour a ‘displacement activity’ – doing anything and everything to put off doing real writing. I knew however, that I wasn’t doing it to put off real writing, but because I was totally incapable of doing any real writing and really frustrated about it.

According to the article, hypergraphia is a trait associated with temporal lobe epilepsy, bipolar disorder, and (you guessed it), asperger’s syndrome. It’s also a trait that runs in my family – my father and my sister both have it. They are both disorganised and are unable to do stuff that is Really Important like paying bills. My sister has been a total fuckwit about music ever since she left Hepburn. These are traits that are governed by dopamine levels. Says the article:

In cases where hypergraphia results as a consequence of genre-specific writer’s block, there are educational and psychotherapeutic treatments available. Alice Flaherty and Harvard psychologist Shelly Carson are now experimenting with ways to break writing blocks using light to relieve Seasonal Affective Disorder (SAD)-related blocks (SAD is a form of depression that affects people when the days get darker and colder).

SAD lights actually raise serotonin levels – serotonin tends to lower dopamine and vice versa, though SAD lights tend to raise neurotransmitters overall. However I actually tend to write better during the winter, and half of my problem is a lack of concentration, which indicates low dopamine – ADD. Sigh. But if I didn’t have those traits at all, I probably wouldn’t even want to be a writer.

Now I am going back into hibernation. I’m very sorry I’m not answering communications, especially not ones that ask questions. If I don’t do some Really Important writing soon I will never do it at all.

Written by alienrobotgirl

6 January, 2008 at 11:07 pm

Posted in Personal Diary