Allopregnenolone (synthesized from 5AR) may prevent neurodegeneration

Kofi kofi at anon.un
Wed Aug 11 19:26:31 EST 2004


The latest research in mice raises a disturbing question about the 
safety of FDA approved 5AR inhibitors like finasteride 
(Proscar/Propecia) and especially dutasteride (Avodart) when it comes to 
managing long-term risk for neurodegenerative diseases like Alzheimer's.  
This is because these drugs not only reduce levels of DHT but also wound 
allopregnanolone production in the process.

To summarize the new findings on allopregnanolone  (see attached below), 
Niemann-Pick type C is a rare lysosomal storage disorder/childhood 
neurodegenerative disease in which brain cells accumulate fat and die 
due in part to severely disrupted neurosteroidogenesis.  A mutant gene 
for lysosomal acid sphingomyelinase disturbs cholesterol synthesis 
throughout the body and results in the accumulation of sphingomyelin.  
Progressive loss of neurosteroid synthesis may contribute to 
neurodegeneration.  Replacing lost allopregnanolone substantially 
increases the survival of mice with this type of disease by mitigating 
the damage and delaying the onset of symptoms.  Results were best when 
administered as early as possible in the animal¹s life.  
Allopregnanolone may be effective with managing other neurodegenerative 
disorders.  Other important neurosteroids like pregnenolone are also 
diminished in Niemann-Pick type C but what's interesting here is how 
valuable allopregnanolone is by itself.   
<http://www.sciencedaily.com/releases/2004/07/040713082347.htm>.  NPC 
model mice may have amyloid-beta accumulations similar to those in 
Alzheimer's [PMID 14982851, 14982829] and may represent a good model for 
studying general aspects of neurodegeneration.

5 alpha reductase (5AR) is an enzyme which comes in two forms, type I 
and type II.  It not only converts testosterone (T) to 
dihydrotestosterone (DHT, a ketone), it also converts progesterone to 
allopregnanolone and deoxycorticosterone (DOC) to tetrahydroDOC (THDOC), 
both allosteric enhancers of the GABA(a) receptor (e.g., they increase 
the effectiveness of inhibition signals relayed along GABA channels in 
nerves).  The second stage of this conversion is performed by 
3alpha-hydroxysteroid oxidoreductase.

This pathway has widespread influence in the body.  Progesterone is the 
precursor to allopregnanolone.  Monthly drops in women¹s progesterone 
prior to their periods is a factor in PMS and epileptic seizure.  
Progesterone lozenges ameliorate seizures.  Both estrogen and 
progesterone are important for TMJ remodeling [PMID 10670598].  Men with 
epilepsy can benefit from aromatase inhibitors which block the 
conversion of testosterone to estrogen via aromatase [PMID 15123030].  
Allopregnanolone can block cocaine induced seizures [PMID 12921865].  
Complete 5AR inhibition shortens inhibitory currents in GABA(A) channels 
both via allopregnanolone [PMID 12559121] and 
5alpha-dihydrocoticosterone (THDOC) [PMID 11978855].

SSRIs (antidepressants like Zoloft) have been shown to upregulate levels 
of progesterone and allopregnanolone (THP) [PMID 12957330] as well as 
neurogenesis [PMID 14872203, 15001810, 14512209].  In animal models it¹s 
the hippocampal neurogenesis that accounts for the behavioral effects of 
SSRIs [PMID 12907793].  Conversely, inescapable stress which reduces 
hippocampal neurogenesis also causes depression [PMID 12838272].

Levels of allopregnanolone can also be regulated by 3alpha-HSDs 
(3alpha-hydroxysteroid dehydrogenase) - enzymes which are identical in 
function to 5AR, except they convert T back from DHT instead of the 
other way around.  3alpha-HSDs are responsible for downregulating levels 
of DHT in the prostate and unusual inhibition of 3alpha-HSD would 
increase DHT levels, decrease allopregnanolone and incline a male toward 
impaired GABA functioning, acne, baldness, BHP and prostate cancer.  
Stimulating 3alpha-HSD might be more effective than 5AR inhibition for 
treating androgen disorders (although elevated exposure to either 
progesterone or allopregnanolone can become anxiety-provoking instead of 
calming; there are gender differences to this effect [PMID 12606703]).

Certain synthetic progesterones may interfere with allopregnanolone 
synthesis.  Medroxyprogesterone acetate (MPA), an ingredient in some 
birth control pills and hormone replacement therapies, doesn¹t convert 
into allopregnanolone and causes anxiety, aggression and depressed sex 
drive in mice compared to combinations of natural hormones 
<http://www.sciencedaily.com/releases/2004/06/040608065645.htm>.

This overview should drive home just how important allopregnanolone may 
be to human health.  Finasteride is a 5AR type II inhibitor which 
reduces DHT levels by up to 70%.  Dutasteride inhibits both type I and 
type II 5AR achieving a reduction of up to 94% of DHT.  Type I is the 
only 5AR expressed in the brain.  Its long term inhibition was never 
studied when dutasteride was approved by the FDA.  Blocking DHT 
synthesis in the brain like this also blocks allopregnanolone production 
there.  While other tissues like bone also express 5AR, finasteride has 
been specifically studied on bone growth and has had no effect.  Will 
this also be true for neurodegenerative disorders which take decades to 
develop?  Will 5AR inhibitors be safe for individuals with epilepsy, 
TMJ, neuropathy, alcoholism, tinnitus, metals poisoning or other 
GABAergic illnesses?

If it's true that dramatic 5AR inhibition contributes to long term 
neurodegeneration then what other therapeutic agents are available for 
dealing with excessive DHT?

Understanding why male hormonal disorders like BHP, prostate cancer and 
baldness have become common in "advanced" economies is important to 
answering this question.  One contributing factor is the bad mix of fats 
consumed in the American diet (high in trans-fats, hydrogenated oils, 
bad omega-6 and -9's and low in omega-3).  Another factor is high 
glycemic index diets which contribute to insulin resistance and androgen 
signaling disorders like polycystic ovarian syndrome.  High levels of 
insulin lower levels of sex hormone-binding globulin, a substance which 
binds to testosterone and lowers the amount of "free" androgens 
available to bind to the receptor (see [PMID 14527633], 
<http://www.thepaleodiet.com/articles/acne vulgaris.pdf>).  These 
androgen driven disorders are all complex genetic disorders which can 
develop from many different angles.  For instance, in a small study, 
prematurely balding men could be divided into two groups: the first 
group (about a third of the men) had a hormonal/insulin profile similar 
to women with polycycstic ovarian syndrome (low SHBG, hyperinsulemia, 
high free androgens and insulin resistance) whereas the second group had 
no similarities or only lower SHBG [PMID 15209536].  How you react to 
pathologically elevated levels of DHT is determined by your genetic risk 
and your environment. 

While dietary factors like fat and sugar consumption are important , the 
major actor on DHT throughout our evolutionary history has been a 
substance called equol.  Equol is a derivative of the soy metabolite 
daidzein produced by bifidus bacteria in the gut.  It directly binds to 
dihydrotestosterone and deactivates it [PMID 14681200].  Most male 
mammals produce ample amounts of equol to regulate excessive DHT 
production.  High levels of equol in men lowers the risk for prostate 
cancer [PMID 14681200, 14720329] and improves blood cholesterol [PMID 
14679315].

By taking antibiotics, you usually increase your risk for chronic 
inflammatory disorders.  In this case, killing your gut bacteria leaves 
abnormally high levels of free DHT floating around in your blood 
stimulating your androgen receptors beyond what your body is used to.  
Over a lifetime, this brings out your genetic risk for androgen-driven 
disorders like the ones I keep mentioning.  Destroying your gut bacteria 
with antibiotics probably also increases the risk for allergies, asthma, 
arthritis and other inflammatory disorders (see 
<http://www.sciencedaily.com/releases/2004/07/040723091648.htm>, 
<http://www.newscientist.com/news/news.jsp?id=ns99995047>, PMID 
15120189) - not to mention it can give you a bad yeast infection like 
you see in chronic sinusitis.

How can you obtain equol if you no longer make your own?

That's the problem.  You can't.  The only versions manufactured and sold 
today are racemic - meaning both the left and right isomers of the 
molecule are produced in a mixture.  Only one form is naturally made and 
used in the human body.  The other is not well studied.  Another 
limiting factor is that finasteride and dutasteride are patented while 
equol can't be - it's a natural product which has been around too long.  
Contact manufacturers and let them know there is a market for this 
therapeutic substance and that it's worth conducting clinical trials.

If 5AR inhibitors do pose long term risks and you absolutely have to 
take them, it may be possible to lessen the neurological damage with 
things like acetyl-l-carnitine, minocycline, l-theanine, taurine, 
curcumin, green tea (EGCG), CoQ10, nicotinamide/niacinamide, creatine, 
ketogenic diets, so on and so forth (each of which carries with it its 
own complicating factors).

If this information has in any way improved your medical care, please 
consider voting for John Kerry.

- Your amazing one and only crime-fighting/medical-spelunking UN 
secretary general Kofi Anon


(Relevant NIH abstracts are denoted by PMID ### reference.  To look it 
up, type 
<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&lis
t_uids=###&dopt=Abstract> in your browser or simply type the abstract ID 
into the NIH search engine.)


http://www.sciencedaily.com/releases/2004/07/040713082347.htm

Source:  
   University Of California, San Francisco

Date:  
   2004-07-13  
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Neurodegenerative Disease In Children Might Respond To Neurosteroids

Scientists studying mice have identified a possible strategy for slowing 
a rare, fatal childhood neurodegenerative disease known as Niemann-Pick 
type C, in which brain cells accumulate fat and die. The finding could 
also have implications for treating other neurodegenerative disease, 
they say.

In their study, published in the July issue of Nature Medicine, the team 
discovered that the synthesis of neurosteroid hormones in the brain -- a 
process known as neurosteroidogenesis -- is severely disrupted in mice 
that naturally develop the disease. They then determined that 
replenishing the depleted neurosteroid hormone allopregnanolone, the 
prime casualty of the disruption, significantly delayed the onset of 
some of the animals' neurological deficits, and doubled their lifespan. 
The treatment was particularly potent when administered early in the 
animals' life.

"The results were astounding," says senior author Synthia Mellon, PhD, 
professor of obstetrics, gynecology and reproductive sciences at 
University of California, San Francisco.

While the treatment did not target the cause of the disease -- a 
mutation in one of two genes that disrupts the transport of cholesterol 
within all cells of the body -- nor cure it, the therapy substantially 
delayed the onset of weight loss, motor coordination, mobility -- and 
death. It also significantly delayed the accumulation of fats in 
cortical cells, and the death of some neurons in the cortex and 
cerebellum. The study was not designed to test intellectual function, 
another component of the disease.

LOSS OF NEUROSTEROIDS IN NEURODEGENERATION

"The finding suggests that the progressive loss of neurosteroids 
contributes to neuronal degeneration in NP-C mice," says Mellon. "We 
didn't cure the problem. There's still a big clog in the cell, but we've 
circumvented it. We've treated downstream consequences of that clog."

Scientists do not know if neurosteroid synthesis is disrupted in 
children with the disease, so the potential efficacy of allopregnanolone 
in children with NP-C cannot be predicted, says Mellon. However, 
allopregnanolone is produced naturally in humans, and provoked no 
evident side effects when administered to the NP-C mice. Thus, if the 
neurosteroid hormone is depleted in patients, it could prove a tactic 
for delaying the onset or progression of some symptoms of the disease.

To determine neurosteroidogenesis activity in children with NP-C, 
scientists could compare brain tissue from autopsied NP-C patients with 
that from children who died from unrelated causes. Mellon says she and 
colleagues hope to be able to initiate pre-clinical studies aimed at 
determining safety, safe dosage and any possible side effects of 
allopregnanolone, with an eye to optimizing dosage and carrying out a 
clinical trial.

If the therapy worked, it would signify a major advance, as scientists 
have not made headway in repairing the culprit gene, discovered in 1997, 
or the protein it synthesizes. Although clinical manifestations are 
varied and can present at any time from intrauterine life to adulthood, 
patients often begin demonstrating motor and intellectual decline during 
late childhood, and die between the ages of eight and eighteen. The 
disease, which also causes enlargement of the liver, occurs in about 1 
in 150,000 children.

ILLUMINATING THE ROLE OF NEUROSTEROIDS

The finding, in broader terms, provides some of the strongest evidence 
to date that neurosteroids may play an important role in neurological 
function in humans, says Mellon. If synthesis of these steroid hormones 
is found to be disrupted in other neurodegenerative diseases -- a 
question that has just begun to be investigated -- neurosteroid therapy 
could prove effective in stalling them, she says.

Like most other steroid hormones, neurosteroids are derived from 
cholesterol, a lipid that plays an important role in the formation of 
cell membranes. But while much is known about the role of other steroid 
hormones, such as testosterone, scientists are only beginning to 
understand the role of those that function in the brain. Neurosteroids 
are known to affect neuronal growth and differentiation and to modulate 
various moods and reactions via neurotransmitter receptors, including 
GABA. However, says Mellon, scientists generally have presumed that 
neurosteroids play a supportive, rather than an essential, role in 
neurological function.

The research team, whose scientific interest is illuminating the role of 
neurosteroids, suspected that neurosteroid synthesis would be disturbed 
in NP-C, due to disruption of cholesterol transport within cells, which 
leads to the accumulation of cholesterol and other lipids in cellular 
compartments. Their theory was bolstered by the fact that mice with NP-C 
have below normal concentrations of testosterone and underdeveloped 
reproductive organs, suggesting that, at least, the synthesis of sex 
steroid hormones in the testes is disrupted in the disease.

To test their hypothesis, the scientists compared the brains of normal, 
so-called "wild type," mice, with those of animals with NP-C. The 
results were dramatic. While neurosteroidogenesis was not affected in 
NP-C mice prenatally, the impact began at birth and increased over time. 
The quantity of pregnenolone, the first steroid produced from 
cholesterol, was significantly decreased. The quantity of 
allopregnanolone, which is converted from pregnenolone, was diminished 
even further.

Supporting this finding, the two enzymes that synthesize 
allopregnanolone, 3a-hydroxysteroid dehydrogenase and 5a-reductase, were 
significantly depleted in all principal brain regions (the cortex, the 
midbrain and the hindbrain) by birth, and were reduced to irrelevant 
quantities by 10 weeks.

The team then examined the impact of administering allopregnanolone to 
the brains of NP-C mice. The effect was equally pronounced. In a series 
of experiments, the drug was given progressively early in the animals' 
lives, at 21 to 23 days of age in the first mice examined, at 7 days of 
age in the last mice evaluated. The response, in terms of stalled 
neurological deficits, cellular damage and death, was greater the 
earlier the administration of the neurosteroid.

DRAMATIC RESULTS

The most dramatic results reported were in mice treated with a single 
injection at seven days of age. They gained weight steadily until age 86 
days, and lived to a mean age of 124 days. In contrast, untreated NP-C 
mice had a mean survival of 67 days.

In still more notable results, the researchers cited, but did not 
report, in their published paper that several treatments beginning at 
day seven in the animals' lives extended their lifespan and delayed the 
onset of neurological impairment even further.

"The finding suggests that allopregnanolone may be involved in a 
neurodevelopmental process that occurs within or before the first week 
of life," says Mellon.

NP-C is an autosomal recessive disease, meaning both parents must 
contribute a copy of the mutated gene to cause the disease, and that 
there is a 25 percent chance their offspring will develop it. As infants 
suspected of having the disease can be tested to see if they carry the 
mutated gene, the disease can be detected early. Thus, if 
allopregnanolone proves effective in humans, it could be used to stall 
the disease from the outset.

The obvious next challenge for the researchers, however, will be 
determining how brain development of the mouse compares to that of the 
human.

Co-authors of the study were Lisa D. Griffin, MD, PhD, formerly UCSF 
assistant professor of neurology, Wenhui Gong, MD, PhD, a postdoctoral 
fellow in the Mellon lab, and Lucie Verot, PhD, graduate student in the 
laboratory of Marie T. Vanier, MD, PhD, of INSERM, U189 and Laboratoire 
Foundation Gillet-Merieux, Lyon-Sud Medical School and Hospital, 
Pierre-Benite, France.

The study was funded by the National Institutes of Health, the National 
Niemann Pick Disease Foundation, the March of Dimes Birth Defects 
Foundation, the Ara Parsaeghian Medical Research Foundation and Vaincre 
les Maladies Lyosomales.

Editor's Note: The original news release can be found here.


 Semin Cell Dev Biol. 2004 Aug;15(4):445-54. Related Articles, Links
    Click here to read 
    Cellular pathology of Niemann-Pick type C disease.

    Ikonen E, Holtta-Vuori M.

    Institute of Biotechnology, University of Helsinki, Helsinki, 
Finland.

    Niemann-Pick type C (NPC) is a lysosomal storage disorder that 
results in the accumulation of cholesterol and sphingolipids. Mutations 
in the NPC1 or NPC2 gene are responsible for the disease but the precise 
functions of the encoded proteins remain unresolved. Recent observations 
have challenged the traditional concept of NPC as a primary cholesterol 
transport defect. This review updates the recent NPC literature, 
summarizing the increasing insight into the cholesterol trafficking 
circuits and also addressing the contribution of other lipids in the 
cellular pathogenesis. The importance of NPC as a model for subcellular 
lipid imbalance in studying more common diseases, such as Alzheimer's 
and cardiovascular diseases, is discussed.

    PMID: 15207834 [PubMed - in process]

Am J Respir Cell Mol Biol. 2004 Jul 15 [Epub ahead of print] Related 
Articles, Links
    Click here to read 
    Mechanistic similarities between cultured cell models of cystic 
fibrosis and Niemann-Pick type C.

    White NM, Corey DA, Kelley TJ.

    Recent data demonstrate that inhibition of 
3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase restores normal 
signal transducer and activator of transcription-1 (STAT1) and inducible 
nitric oxide synthase expression (NOS2) regulation in CF cells through 
the modulation of RhoA function. These findings lead to the hypothesis 
that alterations in the cholesterol synthesis pathway may be an 
initiating factor in CF-related cell signaling regulation. A disease 
with a known lesion in the cholesterol synthesis pathway is Niemann-Pick 
type C (NPC). The hypothesis of this study is that CF cells and NPC 
fibroblasts share a common mechanistic lesion and should exhibit similar 
cell signaling alterations. NPC fibroblasts exhibit similar alterations 
in STAT1, RhoA, SMAD3, and NOS2 protein expression that characterize CF. 
Further comparison reveals NPC-like accumulation of free cholesterol in 
two cultured models of CF epithelial cells. These data identify novel 
signaling changes in NPC, demonstrate the cholesterol-synthesis pathway 
is a likely source of CF-related cell signaling changes, and that 
cultured CF cells exhibit impaired cholesterol processing.

    PMID: 15256387 [PubMed - as supplied by publisher]

Nat Med. 2004 Jul;10(7):704-11. Epub 2004 Jun 20. Related Articles, Links
    Click here to read 
    Niemann-Pick type C disease involves disrupted neurosteroidogenesis 
and responds to allopregnanolone.

    Griffin LD, Gong W, Verot L, Mellon SH.

    Department of Neurology, Center for Reproductive Sciences, 
University of California, San Francisco, 513 Parnassus Avenue, San 
Francisco, California 94143-0556, USA.

    Niemann-Pick type C (NP-C) disease is a fatal, autosomal recessive, 
childhood neurodegenerative disease. The NP-C mouse recapitulates the 
cholesterol and sphingolipid storage, onset of neurological deficits, 
histopathological lesions, Purkinje cell loss and early death typical of 
the most severe form of human NP-C. Neurosteroids, steroids made in the 
brain, affect neuronal growth and differentiation, and modulate 
neurotransmitter receptors. Disordered cholesterol trafficking might 
disrupt neurosteroidogenesis, thereby contributing to the NP-C 
phenotype. Here we show that NP-C mouse brain contains substantially 
less neurosteroid than wild-type brain and has an age-related decrease 
in the ability to synthesize 5alpha-dihydroprogesterone and 
allopregnanolone. Immunohistochemical assessment confirms a decrease in 
expression of 5alpha-reductase and 3alpha-hydroxysteroid dehydrogenase, 
especially in cerebellum. Neonatal administration of allopregnanolone 
delays the onset of neurological symptoms, increases Purkinje and 
granule cell survival, reduces cortical GM2 and GM3 ganglioside 
accumulation and doubles the lifespan of NP-C mice. Earlier 
administration increases effectiveness of treatment. Decreased 
production of allopregnanolone apparently contributes to the pathology 
of NP-C; thus, neurosteroid treatment may be useful in ameliorating 
progression of the disease.

    PMID: 15208706 [PubMed - in process]

 Biochem Biophys Res Commun. 2004 Mar 5;315(2):408-17. Related Articles, 
Links
    Click here to read 
    Chronic exposure to U18666A induces apoptosis in cultured murine 
cortical neurons.

    Cheung NS, Koh CH, Bay BH, Qi RZ, Choy MS, Li QT, Wong KP, Whiteman 
M.

    Department of Biochemistry, Faculty of Medicine, National University 
of Singapore, 8 Medical Drive, Singapore 117597, Singapore.

    Niemann-Pick disease type C (NPC) is a juvenile neurodegenerative 
disorder characterized by premature neuronal loss and altered 
cholesterol metabolism. Previous reports applying an 8-h exposure of 
U18666A, a cholesterol transport-inhibiting agent, demonstrated a 
dose-dependent reduction in beta-amyloid (Abeta) deposition and 
secretion in cortical neurons, with no significant cell injury. In the 
current study, we examined the chronic effect of 24-72h of U18666A 
treatment on primary cortical neurons and several cell lines. Our 
results showed caspase-3 activation and cellular injury in 
U18666A-treated cortical neurons but not in the cell lines, suggesting 
cell death by apoptosis only occurred in cortical neurons after chronic 
exposure to U18666A. We also demonstrated through filipin staining the 
accumulation of intracellular cholesterol in cortical neurons treated 
with U18666A, indicating the phenotypic mimic of NPC by U18666A. 
However, additions of 10 and 25microM pravastatin with 0.5microg/ml 
U18666A significantly attenuated toxicity. Taken together, these data 
showed for the first time that U18666A induces cell death by apoptosis 
and suggested an important in vitro model system to study NPC.

    PMID: 14766223 [PubMed - indexed for MEDLINE]

Exp Neurol. 2003 Dec;184(2):887-903. Related Articles, Links
    Click here to read 
    Postnatal development of inflammation in a murine model of 
Niemann-Pick type C disease: immunohistochemical observations of 
microglia and astroglia.

    Baudry M, Yao Y, Simmons D, Liu J, Bi X.

    Department of Psychiatry & Human Behavior, University of California 
Irvine, Irvine, CA 92612, USA.

    Niemann-Pick type C (NPC) is a rare and fatal neurovisceral storage 
disorder that is currently untreatable. In most cases, NPC is caused by 
mutations of the NPC1 gene, which encodes a glycoprotein playing an 
important role in cholesterol transport. Mice lacking the NPC1 gene 
exhibit several pathological features of NPC patients and have been 
widely used to provide insights into the mechanisms of the disease. In 
the present study, we analyzed the postnatal development of pathological 
manifestations of inflammation in several brain regions of NPC1-/- mice. 
Brain sections from NPC1-/- and wild-type (NPC1+/+) mice were 
immunostained with the MAC1 antibody, which recognizes microglia, with 
antibodies against glial fibrillary acidic protein (GFAP), which 
recognize astrocytes, and with antibodies against the cytokine 
interleukin-1beta (IL-1beta). Numbers of MAC1 immunopositive cells were 
markedly increased in several brain regions of NPC1-/- mice as early as 
2 weeks of age. This effect was particularly evident in globus pallidus, 
ventral lateral thalamus, medial geniculate nucleus, and cerebellum. 
MAC1-immunopositive cells had enlarged cell bodies and shorter 
processes, suggesting they were in an active state. By 4 weeks, most 
brain structures exhibited enhanced microglial activation in NPC1-/- 
mice, and this was maintained at 12 weeks. At 2 weeks, reactive 
astrocytes were only observed in the ventral lateral thalamus while they 
were present throughout the brain of NPC1-/- mice at 4 weeks of age. 
Moreover, the astroglial reaction coincided with up-regulation of the 
cytokine, interleukin-1beta, in most, but not all brain regions. In 
particular, no interleukin-1beta up-regulation was observed in regions 
devoid of neuronal degeneration. These results suggest that microglial 
activation precedes and might be causally related to neuronal 
degeneration, while astrocyte activation might be a consequence of 
neuronal degeneration.

    PMID: 14769381 [PubMed - indexed for MEDLINE]



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