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K. Ohno, MD, PhD, J. Brengman, S. T. Iannaccone, MD,
C. M. Harper, MD and A. G. Engel, MD
From the Department of Neurology (M.M., X.M.S., D.S.,
J.B., C.M.H., A.G.E.), Mayo Clinic, Rochester, MN;
Division of Neurogenetics (K.O.),
Center for Neurological Diseases and Cancer,
Nagoya University Graduate School of Medicine,
Nagoya, Japan; and Division of Pediatric
Neurology (S.T.I.), Children’s Medical Center,
University of Texas Southwestern
Medical Center, Dallas.

Address correspondence and reprint requests to
Dr. Margherita Milone, Department of Neurology,
Mayo Clinic, 200 First Street SW, Rochester,
MN 55905 Milone.Margher…@mayo.edu

Background: Pathogenic mutations in rapsyn result in
endplate acetylcholine receptor (AChR) deficiency and
are a common cause of postsynaptic congenital myasthenic
syndromes.

Methods: Clinical, electrophysiologic, pathologic, and
molecular studies were done in 39 patients.

Results: In all but one patient, the disease presented
in the first 2 years of life.
In 9 patients, the myasthenic symptoms included constant
or episodic ophthalmoparesis, and 1 patient had a pure
limb-girdle phenotype.
More than one-half of the patients experienced intermittent
exacerbations.
Long-term follow-up was available in 25 patients after
start of cholinergic therapy: 21 became stable or were
improved and 2 of these became asymptomatic; 3 had a
progressive course; and 1 died in infancy.
In 7 patients who had endplate studies, the average counts
of AChR per endplate and the synaptic response to ACh were
less reduced than in patients harboring low AChR expressor
mutations.
Eight patients were homozygous and 23 heterozygous for the
common p.N88K mutation.
Six mutations, comprising 3 missense mutations, an in-frame
deletion, a splice-site mutation, and a nonsense mutation,
are novel.
Homozygosity for p.N88K was associated with varying grades
of severity. No genotype-phenotype correlations were observed
except in 8 Near-Eastern patients homozygous for the promoter
mutation (c.-38A>G), who had a mild course.

Conclusions: All but 1 patient presented early in life and most
responded to cholinergic agonists.
With early diagnosis and therapy, rapsyn deficiency has a
benign course in most patients.
There was no consistent phenotype-genotype correlation except
for an E-box mutation associated with jaw deformities.

Abbreviations: 3,4-DAP = 3,4-diaminopyridine; -bgt = -bungarotoxin;
AChR = acetylcholine receptor; CMAP = compound muscle action
potential; CMS = congenital myasthenic syndrome; EP = endplate;
MEPC = miniature endplate currents; MEPP = miniature endplate
potentials; TPR = tetratricopeptide.

Supported by NIH grant 6277 and by a research grant from the
Muscular Dystrophy Association to Dr. Engel.

Disclosure: Author disclosures are provided at the end of the
article.

Received February 16, 2009. Accepted in final form April 13, 2009.

NEUROLOGY 2009;73:228-235
© 2009 American Academy of Neurology
——————-
"It was the double vision among other things that led to my mis-
diagnosis with myasthenia gravis before I was dx with ALS."

Isn’t this curious ..
The above was a snip from a person who was diagnosed with gravis
BEFORE .. ALS.
The recommended treatment to prevent .. gravis .. ?
Choline .. lecithin .. which makes .. ? .. acetylcholine ..

I .. JUST .. posted that in BOTH models of ALS diseased mice they are
unable to produce .. ? .. acetylcholine ..
Isn’t that .. curious ..

"Choline and lecithin supplementation may be an effective means of
increasing the levels of acetylcholine in myasthenia gravis patients
and thus relieving symptoms or preventing myasthenic episodes."

http://www.lef.org/protocols/neurolo…_gravis_01.htm

Who loves ya.
Tom

Jesus Was A Vegetarian!
http://tinyurl.com/2r2nkh

Man Is A Herbivore!
http://tinyurl.com/a3cc3

DEAD PEOPLE WALKING
http://tinyurl.com/zk9fk

This would be the lecithin and steroid connection ..
Since sheer stress regulates acetylcholine .. one might wonder which
of the steroids would control that .. the estrogen which decreases
sheer stress or testosterone which increases sheer stress .. and
then .. bloodletting which would decrease sheer stress.

Neuroactive steroid regulation of neurotransmitter
release in the CNS: Action, mechanism and possible
significance.
Zheng P.
Prog Neurobiol. 2009 Jul 10.
State Key Laboratory of Medical Neurobiology,
Institutes of Brain Science, Shanghai Medical College,
Fudan University, 138 Yixueyuan Road, Shanghai 200032,
People’s Republic of China.

Neuroactive steroids refer to steroids that are capable
of regulating neuronal activities.
Neuroactive steroids, synthesized either de novo in the
nervous tissue or in the peripheral endocrine glands or
as synthetic steroids, have exhibited numerous important
modulatory effects on brain functions and brain diseases.
At the cellular level, in addition to the effect on
postsynaptic receptors, most neuroactive steroids,
including pregnenolone, pregnenolone sulfate, progesterone,
allopregnanolone, dehydroepiandrosterone,
dehydroepiandrosterone sulfate, testosterone and estradiol,
have modulatory effects on the release of multiple
neurotransmitters like glutamate, GABA, acetylcholine,
norepinephrine, dopamine and 5-HT.
Many of these effects occur in the brain regions involved
in learning and memory, emotion, motivation, motor and
cognition.
Moreover, the effects are rather complicated, may be
depending on many factors such as types of neuroactive
steroids, brain regions and presynaptic functional states.
The mechanisms are also complicated.
Many of them involve rapid non-genomic effects on
presynaptic receptors and ion channels like sigma-1
receptor, alpha(1) receptor, nicotine receptor, D1
receptor, NMDA receptor, GABA(A) receptor and L-type
C(2+) channels.
These effects have made neuroactive steroids important
regulators of synaptic transmission in the central nervous
system and constitute the major basis for many important
actions of neuroactive steroids on brain functions and brain
diseases.

PMID: 19595736

Who loves ya.
Tom

Jesus Was A Vegetarian!
http://tinyurl.com/2r2nkh

Man Is A Herbivore!
http://tinyurl.com/a3cc3

DEAD PEOPLE WALKING
http://tinyurl.com/zk9fk

Dumbed down .. Peter Jackson .. or maybe Camels ..

"Inhaled delivery"

Bioorganic & Medicinal Chemistry Letters
Volume 19, Issue 16, 15 August 2009, Pages 4560-4562
Discovery of (3-endo)-3-(2-cyano-2,2-diphenylethyl)-8,8-dimethyl-8-
azoniabicyclo[3.2.1]octane bromide as an efficacious inhaled
muscarinic acetylcholine receptor antagonist for the treatment of
COPD
Zehong Wan, a, , Dramane I. Lainea, Hongxing Yana, Chongjie Zhua,
Katherine L. Widdowsona, Peter T. Buckleya, Miriam Burmana, James J.
Foleya, Henry M. Saraua, Dulcie B. Schmidta, Edward F. Webba, Kristen
E. Belmontea and Michael Palovicha

aRespiratory Centre of Excellence for Drug Discovery, Research and
Development, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, PO
Box 1539, King of Prussia, PA 19406, USA

Received 17 March 2009;  revised 26 June 2009;  accepted 2 July 2009.
Available online 8 July 2009.

Abstract
Design and syntheses of a novel series of muscarinic
antagonists are reported.
These efforts have culminated in the discovery of
(3-endo)-3-(2-cyano-2,2-diphenylethyl)-8,
8-dimethyl-8-azoniabicyclo[3.2.1]octane bromide (4a)
as a potent and pan-active muscarinic antagonist as
well as a functionally active compound in a murine
model of bronchoconstriction.
The compound has also displayed pharmacokinetic
characteristics suitable for inhaled delivery.

Who loves ya.
Tom

Jesus Was A Vegetarian!
http://tinyurl.com/2r2nkh

Man Is A Herbivore!
http://tinyurl.com/a3cc3

DEAD PEOPLE WALKING
http://tinyurl.com/zk9fk

Medical Calculators
http://med-videos.blogspot.com/2009/07/medical-calculators.html

Pregnancy Due-Dates and other medical Calculators
http://med-videos.blogspot.com/2009/07/pregnancy-due-dates-and-other-…

Common laboratory test values
http://med-videos.blogspot.com/2009/07/common-laboratory-values.html

Deletion of the 7 Nicotinic Acetylcholine Receptor Gene
Improves Cognitive Deficits and Synaptic Pathology in a
Mouse Model of Alzheimer’s Disease
Neurobiology of Disease
Gustavo Dziewczapolski,1 Carolina M. Glogowski,
1 Eliezer Masliah,2,3 and Stephen F. Heinemann1
The Journal of Neuroscience, July 8, 2009,
29(271Molecular Neurobiology Laboratory,
The Salk Institute for Biological Studies,
La Jolla, California 92037, and
Departments of 2Neurosciences and 3Pathology,
University of California at San Diego,
La Jolla, California 92037

Correspondence should be addressed to Dr. Gustavo Dziewczapolski,
Molecular Neurobiology Laboratory, The Salk Institute for
Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA
92037.
Email: gust…@salk.edu

It has been recently shown that the Alzheimer’s disease (AD)
pathogenic peptide amyloid β1–42 (Aβ1–42) binds to the 7
nicotinic acetylcholine receptor (7nAChR) with high affinity
and the 7nAChR and Aβ1–42 are both found colocalized in neuritic
plaques of human brains with AD.
Moreover, the intraneuronal accumulation of Aβ1–42 was shown to
be facilitated by its high-affinity binding to the 7nAChR, and
7nAChR activation mediates Aβ-induced tau protein phosphorylation.
To test the hypothesis that 7nAChRs are involved in AD pathogenesis,
we used a transgenic mouse model of AD overexpressing a mutated form
of the human amyloid precursor protein (APP) and lacking the 7nAChR
gene (APP7KO).
We have shown that, despite the presence of high amounts of APP and
amyloid deposits, deleting the 7nAChR subunit in the mouse model of
AD leads to a protection from the dysfunction in synaptic integrity
(pathology and plasticity) and learning and memory behavior.
Specifically, APP7KO mice express APP and Aβ at levels similar to
APP mice, and yet they were able to solve a cognitive challenge such
as the Morris water maze test significantly better than APP, with
performances comparable to control groups.
Moreover, deleting the 7nAChR subunit protected the brain from loss
of the synaptic markers synaptophysin and MAP2, reduced the gliosis,
and preserved the capacity to elicit long-term potentiation otherwise
deficient in APP mice.
These results are consistent with the hypothesis that the 7nAChR
plays a role in AD and suggest that interrupting 7nAChR function
could
be beneficial in the treatment of AD.

Received Dec. 26, 2008; revised May 6, 2009; accepted June 1, 2009.

Correspondence should be addressed to Dr. Gustavo Dziewczapolski,
Molecular Neurobiology Laboratory,
The Salk Institute for Biological Studies,
10010 North Torrey Pines Road, La Jolla, CA 92037.
Email: gust…@salk.edu

————–

Human Molecular Genetics Advance Access originally published online on
May 9, 2009
Human Molecular Genetics 2009 18(15):2922-2927; doi:10.1093/hmg/
ddp216
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© 2009 The Author(s)
This is an Open Access article distributed under the terms of the
Creative Commons Attribution Non-Commercial License (http://
creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted
non-commercial use, distribution, and reproduction in any medium,
provided the original work is properly cited.

A common genetic variant in the 15q24 nicotinic acetylcholine receptor
gene cluster (CHRNA5–CHRNA3–CHRNB4) is associated with a reduced
ability of women to quit smoking in pregnancy
Rachel M. Freathy1, Susan M. Ring2, Beverley Shields3, Bruna
Galobardes2, Beatrice Knight3, Michael N. Weedon1, George Davey
Smith2,4, Timothy M. Frayling1 and Andrew T. Hattersley3,*
1 Genetics of Complex Traits, Peninsula Medical School, Institute of
Biomedical and Clinical Science, Magdalen Road, Exeter EX1 2LU, UK 2
Department of Social Medicine, University of Bristol, Oakfield House,
Oakfield Grove, Bristol BS8 2BN, UK 3 Peninsula National Institute for
Health Research Clinical Research Facility, Peninsula Medical School,
Barrack Road, Exeter EX2 5DW, UK 4 MRC Centre for Causal Analyses in
Translational Epidemiology, University of Bristol, Oakfield House,
Oakfield Grove, Bristol BS8 2BN, UK

* To whom correspondence should be addressed. Tel: +44 1392406806;
Fax: +44 1392406767; Email: andrew.hatters…@pms.ac.uk

Received March 1, 2009; Accepted May 5, 2009

Maternal smoking during pregnancy is associated with low birth weight
and adverse pregnancy outcomes. Women are more likely to quit smoking
during pregnancy than at any other time in their lives, but some
pregnant women continue to smoke. A recent genome-wide association
study demonstrated an association between a common polymorphism
(rs1051730) in the nicotinic acetylcholine receptor gene cluster
(CHRNA5–CHRNA3–CHRNB4) and both smoking quantity and nicotine
dependence. We aimed to test whether the same polymorphism that
predisposes to greater cigarette consumption would also reduce the
likelihood of smoking cessation in pregnancy. We studied 7845 pregnant
women of European descent from the South-West of England. Using 2474
women who smoked regularly immediately pre-pregnancy, we analysed the
association between the rs1051730 risk allele and both smoking
cessation during pregnancy and smoking quantity. Each additional copy
of the risk allele was associated with a 1.27-fold higher odds (95% CI
1.11–1.45) of continued smoking during pregnancy (P = 0.0006).
Adjustment for pre-pregnancy smoking quantity weakened, but did not
remove this association [odds ratio (OR) 1.20 (95% CI 1.03–1.39); P =
0.018]. The same risk allele was also associated with heavier smoking
before pregnancy and in the first, but not the last, trimester [OR for
smoking 10+ cigarettes/day versus 1–9/day in first trimester = 1.30
(95% CI 1.13–1.50); P = 0.0003]. To conclude, we have found strong
evidence of association between the rs1051730 variant and an increased
likelihood of continued smoking in pregnancy and have confirmed the
previously observed association with smoking quantity. Our data
support the role of genetic factors in influencing smoking cessation
during pregnancy.

Who loves ya.
Tom

Jesus Was A Vegetarian!
http://tinyurl.com/2r2nkh

Man Is A Herbivore!
http://tinyurl.com/a3cc3

DEAD PEOPLE WALKING
http://tinyurl.com/zk9fk

Excuse me!!
Would you stop for a moment?!
Haven’t you thought-one day- about yourself ?
Who has made it?
Have you seen a design which hasn’t a designer ?!
Have you seen a wonderful,delicate work without a worker ?!
It’s you and the whole universe!..
Who has made them all ?!!
You know who ?.. It’s "ALLAH",prise be to him.
Just think for a moment.
How are you going to be after death ?!
Can you believe that this exact system of the universe and all of
these great creation will end in nothing…just after death!
Have you thought, for a second, How to save your soul from Allah’s
punishment?!
Haven’t you thought about what is the right religion?!
Here you will get the answer http://www.ISLAMTOMORROW.com/

http://www.quranexplorer.com/quran/