Re:Serena: Cerebral blood flow, SPECT, was: Are our kids tripping?

[Guest guest]

Really waiting for your paper...

Gayatri

> >

> > Thanks, Natasa. Interesting. I saw a picture elsewhere that

looked a

> whole lot like what you're talking about. I think it was a link off

> pathguy.com. Can't swear to it, but I think that one was from an MS

> patient. I by-passed it at the time because I was interested in

> something else just then.

> >

> > So do you think it's just the edema that interferes with

perfusion

> in the brain?

> >

> > Serena

> >

> > __________________________________________________

> >

[Guest guest]

Gayatri, yes to both! (not as in M Megson as cannot locate her original paper lol).

have a look at this

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search & DB=pubmed

they talk about VDR expression towards the bottom, although it is not

very clear (to me at least ) how VDR polymorphisms (as per

Yasko) would affect this. ...

re thyroid, it is a hormone and capable of directly regulating calcium

fluxes (the same as with estrogen, which IMO is behind the male/female

ratio in autism). I have not had time to sort these out yet, so here is

the whole lot of abstracts on this - enjoy! (would be nice if you could

sum them up and so contribute to the paper! only joking of course, but

volunteers welcome)

Natasa

Dev Med Child Neurol. 1991 Apr;33(4):313-9

Reduced thyroid-stimulating hormone response to thyrotropin-releasing hormone in autistic boys.

* Hashimoto T, Department of

Paediatrics, University of Tokushima, School of Medicine, Japan.

The thyroid-stimulating hormone (TSH) and prolactin

responses to thyrotropin-releasing hormone (TRH) were compared among

four groups of boys--41 autistic, 12 mentally retarded (MR), 12 with

minimal brain dysfunction (MBD) and five controls. The autistic boys

were divided into two groups: DQ(IQ) greater than or equal to 80 and

DQ(IQ) less than 80. Mean TSH basal and peak levels were significantly

lower in both autistic groups than in the MR, MBD and control groups.

Mean TSH peak value minus basal value (p- was significantly lower in

both autistic groups than in the control group. Mean prolactin levels

and p-b value did not differ among groups. It is suggested that there

may be enhanced dopaminergic and/or reduced serotonergic activity in

the central nervous system of autistic children, together with

hypothalamic dysfunction.

PMID: 1904373 [PubMed - indexed for MEDLINE]

Endocr Regul. 1992 Dec;26(4):163-70.

Blockade of potassium or calcium channels provokes

modifications in TRH-induced TSH release from rat perifused pituitaries.

* Roussel JP, Laboratoire de

Neurobiologie Endocrinologique, URA 1197 CNRS, Universite de

Montpellier 2, France.

The aim of the present study was to determine the

functional relationship between blockade of potassium or calcium

channel activity and the initial burst of TSH secretion in response to

TRH. Perifused rat pituitary fragments were stimulated by a 6-min pulse

of physiological concentration of TRH (10 nM) in the presence or

absence of pharmacological blockers of K+ or Ca2+ channels. Blockade of

Ca(2+)-activated K+ channels with TEA (10 mM and 30 mM), apamin (200

nM), or charybdotoxin (50 nM) completely or partially blunted

TRH-induced TSH release. By contrast, blockade of voltage-dependent K+

channels with 4-aminopyridine (4-AP) (500 microM) or with dendrotoxin

(DTX) (350 nM) significantly increased TSH response. Moreover, blockade

of T-type voltage-sensitive Ca2+ channels (VSCC) with NiCl (3 mM) or

with diphenylhydantoin (100 microM) significantly (P < 0.01) reduced

TSH response to TRH, whereas blockade of L-type Ca2+ channels with

verapamil (50 microM) was ineffective. Our results suggest that

secretion of TSH in response to nanomolar concentrations of TRH is

correlated with stimulation of Ca(2+)-activated K+ channels, and

inhibition of 4-AP-and DTX-sensitive voltage-dependent K+ channels;

furthermore TSH response seems to depend on the activation of T-type

VSCC.

PMID: 1284919 [PubMed - indexed for MEDLINE]

Eur J Pharmacol. 1990 Nov 6;190(1-2):135-45. Links

Involvement of dihydropyridine-sensitive calcium

channels in the GABAA potentiation of TRH-induced TSH release.

* Roussel JP,

* Astier H.

Laboratoire de Neurobiologie Endocrinologique, UA 1197 CNRS, Universite Montpellier II, France.

The effects of gamma-aminobutyric acid (GABA) and

isoguvacine on the thyrotropin (TSH) secretion stimulated by

thyrotropin releasing hormone (TRH), were investigated in vitro with

perifused rat pituitaries. At nanomolar concentrations the two agonists

induced potentiation of the TRH-induced TSH release. The potentiation

was blocked by SR 95531 a specific GABAA antagonist. The isoguvacine

potentiation of the TSH response to TRH failed to occur when cobalt

(Co2+) was added to the perifused medium. Nifedipine completely blocked

the GABA or isoguvacine potentiation of the TSH response while

omega-conotoxin did not modify it. Pre-perifusion of the pituitaries

with pertussis toxin did not change the TSH response to TRH but

completely inhibited the isoguvacine potentiation of the response. Our

results demonstrate that the GABA potentiation of TRH-induced TSH

release occurring through the stimulation of GABAA receptor sites is a

calcium (Ca2+)-dependent phenomenon, probably mediated by activation of

dihydropyridine (DHP)-sensitive, omega-conotoxin-insensitive Ca2+

channels involving a pertussis toxin-sensitive G protein.

PMID: 1706271 [PubMed - indexed for MEDLINE]

Eur J Endocrinol. 1995 Oct;133(4):489-98. Links

Dihydropyridine-like effects of amiodarone and

desethylamiodarone on thyrotropin secretion and intracellular calcium

concentration in rat pituitary.

* Roussel

JP, * Grazzini

E, * Guipponi

M, * Astier

H. Departement de Biologie-Sante Universite de

Montpellier, France.

Amiodarone (AM) and its major metabolite

desethylamiodarone (DEA) are structurally similar to biologically

active thyroid hormones. Amiodarone therapy is frequently associated

with impairment of thyrotropic function, whose mechanisms are still

controversial. Besides its effect on nuclear thyroid hormone binding.

AM is able to displace dihydropyridine (DH) binding on membrane

preparations from several tissues. By perifusing rat pituitary

fragments and measuring thyrotropin (TSH) release we examined: the

effect of AM on Ca(2+)-dependent and DHP-sensitive potentiation of the

TSH response to thyrotropin-releasing hormone (TRH) induced by either

triiodothyronine (T3, perifused for only 30 min before a TRH pulse) or

by the prepro-TRH peptide 160-169 (PS4); and the effect of DEA on

TRH-induced TSH response in the presence or absence of the DHP

nifedipine. We show that AM reverses T3 or PS4 potentiation of the TSH

response to TRH; this effect is specific because AM does not modify

ionomycin potentiation of that response. In contrast, DEA significantly

potentiates the TSH response to TRH and the DHP nifedipine reverses

that potentiation. We also tested whether AM would change the acute

T3-induced increase in intracellular Ca2+ concentration by measuring

intracellular Ca2+ ([Ca2+])i with fura-2 imaging on primary cultures of

pituitary cells. We show that AM reverses the effect of T3 on [Ca2+]i

as well as the PS4-induced increase in [Ca2+]i. In contrast, DEA

increases [Ca2+]i and nifedipine reverses this effect. Our results

suggest that AM and DEA display DHP-like effects on TRH-induced TSH

release, behaving either as a Ca2+ channel blocker (AM) or as a Ca2+

channel agonist (DEA).

PMID: 7581975 [PubMed - indexed for MEDLINE]

Toxicological Sciences 2005 85(1):647-656

Toxicological Sciences vol. 85 no. 1 Ù The Author 2005. Published by

Oxford University Press on behalf of the Society of Toxicology. All

rights reserved. For Permissions, please email:

journals.permissions@...

Impairment in Short-Term but Enhanced Long-Term Synaptic Potentiation

and ERK Activation in Adult Hippocampal Area CA1 Following

Developmental Thyroid Hormone Insufficiency*

L. Sui*, W. L. {dagger} and M. E.

Gilbert{dagger},{ddagger},National Research Council, Washington, DC

20001; {dagger} Neurotoxicology Division, U.S. Environmental Protection

Agency, Research Triangle Park, North Carolina 27711; and {ddagger}

Department of Psychology, University of North Carolina, North Carolina

27599

1 To whom correspondence should be addressed at Neurotoxicology

Division (MD-B105à05), National Health and Environmental Effects

Research Laboratory, U.S. Environmental Protection Agency, Research

Triangle Park, NC 27711. Fax: . E-mail:

gilbert.mary@....

Thyroid hormones are critical for the development and maturation of the

central nervous system. Insufficiency of thyroid hormones during

development impairs performance on tasks of learning and memory that

rely upon the hippocampus and impairs synaptic function in young

hypothyroid animals. The present study was designed to determine if

perturbations in synaptic function persist in adult euthyroid animals

exposed developmentally to insufficient levels of hormone. Pre- and

postnatal thyroid hormone insufficiency was induced by administration

of 3 or 10 ppm propylthiouracil (PTU) to pregnant and lactating dams

via the drinking water from gestation day (GD) 6 until postnatal day

(PN) 30. This regimen produced a graded level of hormonal insufficiency

in the dam and the offspring. Population spike and population

excitatory postsynaptic potentials (EPSP) were recorded at the

pyramidal cell layer and the stratum radiatum, respectively, in area

CA1 of hippocampal slices from adult male offspring. PTU exposure

increased baseline synaptic transmission, reduced paired-pulse

facilitation, and increased the magnitude of the population spike

long-term potentiation (LTP). Phosphorylation of the extracellular

signal-regulated kinases (ERK1 and ERK2) was increased as a function of

LTP stimulation in slices from PTU-exposed adult animals. On the other

hand, no differences in the basal levels of synaptic proteins

implicated in synaptic plasticity (total ERK, synapsin,

growth-associated protein-43, and neurogranin) were detected. These

results reinforce previous findings of persistent changes in synaptic

function and, importantly extend these observations to moderate levels

of thyroid hormone insufficiency that do not induce significant

toxicity to the dams or the offspring. Such alterations in hippocampal

synaptic function may contribute to persistent behavioral deficits

associated with developmental hypothyroidism.

Key Words: hypothyroidism; hippocampus; paired-pulse facilitation;

long-term potentiation; extracellular signal-regulated kinase; adult.

"É it is tempting to

speculate that augmented population spike LTP reflects enhanced calcium

influx through L-type calcium channels at the cell soma in slices from

developmentally thyroid-compromised animals.."

Mol Cell Endocrinol. 2001 Nov 26;184(1-2):143-50.

Effects of neonatal hypothyroidism on the

expressions of growth cone proteins and axon guidance molecules related

genes in the hippocampus.

Wong CC, Leung MS. Department of Physiology, The

Chinese University of Hong Kong, Shatin, N.T., Hong Kong.

ccwong@...

During critical periods of development,

hypothyroidism causes abnormalities of the central nervous system such

as incomplete maturation of neuronal and glial cells, reduction in

synaptic densities and myelin deficits. In this study expression of

development regulated genes, ie transcription of beta-actin, sema 3F,

CRMP 1 to 4, GAP-43, G alpha o1, G alpha o2 and translation of

beta-actin, G alpha o, G alpha o1, CRMP-2, CRMP-4 genes were examined

in the hippocampus of neonatal methimazole induced hypothyroid rats at

the age of day 16. All CRMPs mRNA levels were significantly higher in

the hypothyroid rats. Significant higher CRMP-2 protein but not CRMP-4

protein was found in the hypothyroid rats. The neonatal experimental

hypothyroid states did not affect the protein levels of beta-actin but

up-regulate its mRNA. Transcription of CRMP 1 to 4, GAP-43, G alpha o1

but not G alpha o2 and sema 3F was altered by the neonatal treatment.

The only sex difference in gene expression was found in the

transcription of CRMP-2 gene.

PMID: 11694350 [PubMed - indexed for MEDLINE]

CARDIAC:

Endocr Res. 2005;31(1):59-70.

Genomic and non-genomic regulation of L-type calcium channels in rat ventricle by thyroid hormone.

* Watanabe H, Division of

Cardiology, Niigata University Graduate School of Medical and Dental

Science, Niigata, Japan. hiroshi7@...

Hyperthyroidism is associated with low exercise

tolerance despite high cardiac output and sometimes with the

development of heart failure. L-type calcium channels may play a role

in the mechanism, but this has not been fully understood. We examined

the effects of thyroid hormone on gene expression and function of

L-type calcium channels in rat ventricles by the ribonuclease

protection assay and whole-cell patch-clamp technique, respectively.

The effects of bisoprolol, beta-blocking agent, on the regulation of

calcium channel by thyroid hormone was also studied. In hyperthyroid

animals, the mRNA of the calcium channel alpha1c subunit was reduced on

day 4, compared with that in euthyroid animals, and remained low on day

8. Bisoprolol did not affect the thyroid hormone mediated decrease in

alpha1c subunit mRNA. While L-type calcium current was greater in

hyperthyroid than euthyroid myocytes on day 4, it was smaller on day 8.

In addition, the isoproterenol-induced increase in calcium current in

euthyroid rats was attenuated in hyperthyroid rats. Acetylcholine

decreased calcium current in hyperthyroid myocytes, but not in

euthyroid myocytes. In conclusion, L-type calcium current was increased

by thyroid hormone in rat ventricular myocytes by the activation of the

adenylate cyclase cascade, despite a decreased calcium channel gene

expression. These genomic and non-genomic modifications may play an

important role in the association of high cardiac output with low

exercise tolerance, and in the development of heart failure in

hyperthyroidism.

PMID: 16238192 [PubMed - indexed for MEDLINE]

Effects of thyroid hormone on the calcium current and isoprenaline-induced background current in rabbit ventricular myocytes.

* Han J, Department of

Physiology and Biophysics, College of Medicine, Seoul National

University, Korea.

The majority of previous studies have been performed

to explain the effects of thyroid hormone on the heart in chronic

hyperthyroidism that was usually induced by eight to 10 daily

injections of thyroid hormones. However, it is unclear whether or not

the electrophysiological effects result from the chronic manifestations

of hyperthyroidism and whether thyroid hormone acts directly or

indirectly on cardiac myocytes to alter cardiac electrophysiological

properties. In order to examine the acute term electrophysiological

effects of thyroid hormone applied in vitro and the mechanisms

responsible for some of these effects, we investigated the modulatory

effects of thyroid hormone on the calcium current and

isoprenaline-induced background current in L-triiodothyronine-treated

ventricular myocytes of the rabbit. The major findings were as follows.

Over 5 h (range, 5-24 h) after treatment of L-triiodothyronine (1

microM) in vitro, the calcium current was increased significantly.

Isoprenaline (1 microM) and cyclic AMP (100 microM) caused an increase

in the calcium current in both euthyroid and hyperthyroid myocytes. The

hyperthyroid myocytes were more sensitive to the effect of

beta-adrenergic stimulation on the calcium current and

isoprenaline-activated background current. In euthyroid myocytes,

acetylcholine (1 microM) produced no or little changes in the amplitude

of the calcium current. In hyperthyroid myocytes, acetylcholine

markedly reduced the calcium current, however, acetylcholine was

ineffective in the presence of sufficient intracellular cyclic AMP (100

microM). Our results suggest that thyroid hormone can affect the

cardiac myocytes directly. Furthermore, our results demonstrate that

thyroid hormone affects the calcium current and isoprenaline-activated

background current. These electrophysiological changes may explain, at

least in part, the occurrence of positive inotropy and cardiac

arrhythmias that is associated with hyperthyroidism.

PMID: 7966361 [PubMed - indexed for MEDLINE]

Biochem Biophys Res Commun. 2003 Aug 29;308(3):439-44.

Thyroid hormone regulates mRNA expression and currents of ion channels in rat atrium.

* Watanabe H, Washizuka T,

Division of Cardiology, Niigata University Graduate School of Medical

and Dental Science, 1-754 Asahimachidori, Niigata, Japan.

hiroshi7@...

Atrial fibrillation is one of the common arrhythmias

associated with hyperthyroidism. This study examined the effects of

thyroid hormone (T3) on mRNA expression and currents of major ionic

channels determining the action potential duration (APD) in the rat

atrium using the RNase protection assay and the whole-cell patch-clamp

technique, respectively. T3 increased the Kv1.5 mRNA expression and

decreased the L-type calcium channel mRNA expression, while the Kv4.2

mRNA expression did not change. APD was shorter in hyperthyroid than in

euthyroid myocytes. The ultrarapid delayed rectifier potassium currents

were remarkably increased in hyperthyroid than in euthyroid myocytes,

whereas the transient outward potassium currents were unchanged. L-type

calcium currents were decreased in hyperthyroid than in euthyroid

myocytes. T3 shifted the current-voltage relationship for calcium

currents negatively. In conclusion, T3 increased the outward currents

and decreased the inward currents. The resultant changes of ionic

currents shortened APD, providing a substrate for atrial fibrillation.

PMID: 12914768 [PubMed - indexed for MEDLINE]

> >> > Natasa,> > > > I for one, am waiting with bated breath to read your paper. -> > > > > > > > > - I will be touching on most of these areas of> > impairment due to dysfunction of calcium conductances in my paper.> > > > VERY similar mechanisms seem to be at play in MS, as well as in > AIDS> > induced dementia, Alzheimer's, even Parkinsons to some extent, to > name> > but a few.> > > > Natasa> >>

[Guest guest]

Natasa - Actually, I had just been looking at some other info on the calcium problems, only related to CFS (Cheney). Cheney doesn't subclass CFS patients, so he tends to generalize a bit. And he concentrates on hypoperfusion because he's a heart transplant recipient now. He got a little dose of what that feels like, so he's applying his newfound knowledge to his other research. I'll look forward to reading your paper. I know my understanding in that area is very weak. I'm working on it. I did find some other scans - though not the ones Stan mentioned. Unfortunately, they are different than the ones I wanted to compare to, but these showed only the massive hyperperfusion in some areas without the wireframe representations mine have. It's somewhat a different pattern, but encompasses the same areas and surpasses them. I'm certainly no expert at reading these things, so it was a bit difficult to go back

and forth. I may have sounded before like I though hypoperfusion was the only game in town. I do get the two conditions coexist and have major impact, but I think when you say "edema" you're referring to generalized swelling as opposed to specific areas of hyperperfusion, right? __________________________________________________

[Guest guest]

"hen you say "edema" you're referring to generalized swelling as opposed to specific areas of hyperperfusion, right? "

Yes...

Here is something I emailed a while ago to someone else who was looking

at CFS/calcium links, in case might be of interest to you:

"...I have just come across some very interesting information re

possible involvement of dysfunctional ion (calcium) channels in CFS. I

really believe it all links nicely to what I observed might be

happening in autism :

http://www.phoenix-cfs.org/Neurological%20Channelopathy.htm

http://www.phoenix-cfs.org/The%20SITE/ChannelopathyCFS.htm

Natasa

>> Natasa - > >

Actually, I had just been looking at some other info on the calcium

problems, only related to CFS (Cheney). Cheney doesn't subclass CFS

patients, so he tends to generalize a bit. And he concentrates on

hypoperfusion because he's a heart transplant recipient now. He got a

little dose of what that feels like, so he's applying his newfound

knowledge to his other research. I'll look forward to reading your

paper. I know my understanding in that area is very weak. I'm working

on it.> > I did find some other scans - though not the

ones Stan mentioned. Unfortunately, they are different than the ones I

wanted to compare to, but these showed only the massive hyperperfusion

in some areas without the wireframe representations mine have. It's

somewhat a different pattern, but encompasses the same areas and

surpasses them. I'm certainly no expert at reading these things, so it

was a bit difficult to go back and forth. I may have sounded before

like I though hypoperfusion was the only game in town. I do get the two

conditions coexist and have major impact, but I think when you say

"edema" you're referring to generalized swelling as opposed to specific

areas of hyperperfusion, right? > > __________________________________________________>

[Guest guest]

Thanks for the links, Natasa. I already had those, but had forgotten them. (Main problem is the slowness with which I learn new material these days.) I did recall that one of those articles mentions Hokama's work on ciguatera - a neurotoxin from certain fish found in a high percentage of CFS patients. Shoemaker independently found genetic markers for that as well in patients who go chronic and do not recover normally - his work with mold patients actually began as work with fish toxins. The article's notion was that channelopathies occur as a consequence of various illnesses, rather than as a cause. I had avoided digging into this in the past, because I was so bent on resolving the cause (in this case, toxins). So I dug into the toxin issues instead. But I am beginning to think that it just may not be possible to separate these issues because of the long-term damage left behind by the toxins and the sheer

amount of time it can take to detox. __________________________________________________

[Guest guest]

I see your point, Serena, have been there myself... thinking if those

other factors are causing these mechanisms to go awry, then we should be

treating (getting rid) of those 'factors'... but then again if we can

identify the exact mechanism by which those factors do what they do,

then really it should be easier to:

1. stop those agents do whatever they are doing that does harm (before

we can actually get rid of them)

2. minimise the long-term effects, as you said yourself

and thirdly ... it just MAY be that by intercepting with the mechanisms

we are actually giving the factors less of a platform, which could work

towards actually getting rid of them... hopefully. I am refering here

specifically to viruses - one of the mechanisms through which they harm

the cell is through inducing excessive calcium influx, and there are

some indications that stopping those excessive fluxes we might be

actually harming viruses, (parallel to saving the cell from harm) ...

because once a virus is inside the host cell it needs all that excessive

calcium for many of its functions...

I hope to go into more detail on this soon..,

Natasa

>

> Thanks for the links, Natasa. I already had those, but had forgotten

them. (Main problem is the slowness with which I learn new material

these days.)

>

> I did recall that one of those articles mentions Hokama's work on

ciguatera - a neurotoxin from certain fish found in a high percentage of

CFS patients. Shoemaker independently found genetic markers for that as

well in patients who go chronic and do not recover normally - his work

with mold patients actually began as work with fish toxins. The

article's notion was that channelopathies occur as a consequence of

various illnesses, rather than as a cause. I had avoided digging into

this in the past, because I was so bent on resolving the cause (in this

case, toxins). So I dug into the toxin issues instead. But I am

beginning to think that it just may not be possible to separate these

issues because of the long-term damage left behind by the toxins and the

sheer amount of time it can take to detox.

>

> __________________________________________________

>