VPA länkat till förhöjd risk/chans för autism.

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VPA länkat till förhöjd risk/chans för autism.

Inläggav Aspigare » 2019-11-06 11:03:22

Man har ju kunnat se att VPA, de som ingår som stabiliserande för bipolära drag, de preparatet ger en ökad risk för att barnet föds med autism om modern får i sig dessa under graviditeten, men hur är de med om pappan äter de? Kan inte de påverka bäbisarna i pungen så att säga.
Aspigare
 
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VPA länkat till förhöjd risk/chans för autism.

Inläggav Micke » 2019-11-06 12:03:08

Har man använt en kontrollgrupp tror du, alltså jämfört med andra bipolära kvinnor som då inte har tagit medicinen och fött barn? Jag sökte lite men hittade enbart experiment på råttor.

Du har ju tidigare hävdat att autism är geni-spektrumet, vad innebär detta för råttorna som uppvisade autism efter att dom utsatts för VPA? Och menar du att om en kvinna tar en medicin mot epilepsi så kommer barnen hon eventuellt föder att bli genier? Jag har säkert missuppfattat något här. :-)063
Micke
 
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VPA länkat till förhöjd risk/chans för autism.

Inläggav Aspigare » 2019-11-06 12:16:24

VPA and its Link to Autism
Valproic acid is widely used to treat epilepsy and bipolar disorder and is also a potent teratogen. It was first introduced in the 60s as an anticonvulsant and later as the mood-stabilizing drug for the treatment of bipolar disorder. Case reports started to appear in the 90s on children with Fetal Anticonvulsant Syndrome, which included autistic traits (Christianson et al., 1994; Williams and Hersh, 1997; Williams et al., 2001). Two independent follow-up population studies confirmed a strong link between VPA and autism with approximately 10% of exposed children exhibiting full blown autism and 80% with one or more autistic features (Moore et al., 2000; Rasalam et al., 2005). Overall, the autism prevalence in the prenatally VPA-exposed population is approximately 11–100 times higher than in the general population assuming prevalence rates of 10–91 cases per 10,000 in the general population (Fombonne, 2006; Autism Speaks).
The physical malformations caused by VPA, such as facial dysmorphy and ear abnormalities, indicate an early insult to the brainstem during embryogenesis and, more specifically, around the time of neural tube closure. Support for the so-called brain-stem hypothesis of autism (Stromland et al., 1994; Rodier et al., 1996, 1997; Arndt et al., 2005) originate from a study on the brain stem-related teratogenic effects of thalidomide (Stromland et al., 1994), another prescribed drug strongly associated with autism. This study was the first to reveal that the occurrence of autism is strikingly high (30%) and exclusively when thalidomide intake occurred during gestational days 20–24, which led to the conclusions that autism is associated with a brainstem injury at the time point of neural tube closure. This notion is supported by magnetic resonance imaging studies which revealed brainstem hypoplasia in autism (Hashimoto et al., 1995; Gaffney et al., 1988) as well as a post-mortem study on an autistic subject who exhibited severe morphological abnormalities and neuronal loss in the brain stem (Rodier et al., 1996).
While the early brainstem hypothesis of autism assumes that all other brain alterations observed in autism are a consequence of this “big bang” (Rodier et al., 1996) it is possible that traces of the impact of VPA exposure could be carried by progenitors into the whole brain (and body), and these effects would only manifest when these brain regions begin to develop and have to start performing their functions. Indeed, VPA is teratogenic at sub-lethal doses and enhances gene transcription induced by a variety of exogenous and endogenous promoters by inhibiting histone deacetylase (Phiel et al., 2001).
Valproic acid given continuously throughout pregnancy to rats, as for humans, has been known for some time to cause severe behavioral alterations (for review see Vorhees, 1987a,b; Wagner et al., 2006; Markram et al., 2007b). However, theses alterations could be confounded by the numerous other VPA-induced insults and cognitive and motor impairments, more associated with generalized Fetal Anticonvulsant Syndrome than with autism. To target the autism component of this anticonvulsant syndrome, Rodier et al. (1996) developed a rat model for autism by specifically administering VPA only during the time period of neural tube closure according to the neurological hypothesis that the brainstem is injured in autism (reviewed in Markram et al., 2007b). The administration of a single i.p. injection of VPA (350 mg/kg) administered to pregnant dams on embryonic days (ED) 12–13 results in a reduction of the trigeminal and hypoglossal motor nuclei, loss of neurons in the abducens nucleus and in the oculomotor nucleus (Rodier et al., 1996), which parallels losses found in the brainstem in autism (Hashimoto et al., 1995; Rodier et al., 1996; Gaffney et al., 1988). Follow-up anatomical studies in the rat showed that VPA exposure on ED12.5 also results in a loss of cerebellar neurons (Rodier et al., 1997; Ingram et al., 2000), one of the most prominent features in the autistic brain (Ritvo et al., 1986; Kemper and Bauman, 1998; Palmen et al., 2004). Abnormalities in the serotonergic system, one of the most indicative biochemical pathological markers in autism (Lam et al., 2006), were also found (Narita et al., 2002; Miyazaki et al., 2005; Tsujino et al., 2007). Behaviorally, prenatal exposure to VPA on ED12.5 produces the two cardinal symptoms of autism in the rat offspring: decreased social interactions and increased repetitive behaviors (Schneider and Przewlocki, 2005; Markram et al., 2008). In the emotional domain, the offspring also exhibit enhanced anxiety (Schneider and Przewlocki, 2005; Schneider et al., 2007; Markram et al., 2008), in the motor domain, locomotor hyperactivity (Schneider and Przewlocki, 2005), in the nociception domain, lower sensitivity to pain (Schneider et al., 2001; Schneider and Przewlocki, 2005; Markram et al., 2008), in the sensory domain, hyper-sensitivity to non-painful sensory stimulation and impaired pre-pulse inhibition (Schneider and Przewlocki, 2005; Markram et al., 2008), and in the memory domain, enhanced eye-blink conditioning (Stanton et al., 2007) – all of which are common features of autism described in the DSM-IV and/or in the autism literature (Sears et al., 1994; Muris et al., 1998; American Psychiatric Association, 2000; McAlonan et al., 2002; Perry et al., 2007).
It is often argued that “autism is a human disorder” which is based on the higher cognitive symptoms that are most commonly associated with autism such a theory of mind and language deficits as well as unusual human talents. Albeit in a far more rudimentary form, many of the high-level cognitive functions can also be observed and measured in much lower mammals such as rats and mice. The common thread is the neocortex, which is the source of mammalian higher brain functions. The microcircuitry of the mammalian neocortex is remarkably similar from mouse to man in terms of layering, types of neurons, interconnections, and long-range connectivity principles (Silberberg et al., 2002). It would be very difficult to argue that insults and predispositions are exclusive to human neocortex. One may also argue that such a model ignores the well-established heredity component of autism (for review see, e.g., Persico and Bourgeron, 2006), but then not all homozygote twins succumb to autism. A pure genetic argument also ignores the high incidence of autism reported with thalidomide and high doses of VPA in human offspring. The most parsimonious interpretation is that autism is a poly-genetically predisposed disorder that is triggered by an insult and that the pathology unfolds during development. The low incidence of VPA-linked autism today is another possible argument, but the doses used today (around 5–10 mg/kg) are about 5–10 times lower than doses used in the earlier times (40–50 mg/kg). The animal models however used even higher doses (300–500 mg/kg) primarily because it would not be possible to systematically study the alterations if only 5–10% of the offspring are affected as reported in the earlier times. The higher doses seem to bring the incidence more into the 70–80% range and doses above 800 mg/kg are lethal (unpublished data). It may also turn out that these doses could be significantly lowered if combined with animals genetically engineered with identified predisposing mutations. Nevertheless, high doses do limit the strength of conclusions drawn from this model and further validation in human autism is required.
Aspigare
 
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VPA länkat till förhöjd risk/chans för autism.

Inläggav Aspigare » 2019-11-06 12:21:40

Autism har en genetisk grund, men även giftigt ämne kan trigga. Sen är det miljön, helt, som avgör om du utvecklar autism eller inte. Vi har ju alla olika typer av autism kan vi säga, eftersom vi alla har olika starka sinnen. Dom som är non verbal har en vis typ av gen uppsättning osv. Autism har funnits i tusentals år i historien långt innan VPA, Ju starkare sinnen och känslor, desto högre upplösning kan du förstå världen i samt pussla i hop pixlar (minnas dom) för att skapa dig en förståelse.

Att man studerar djur hjärnor är för att man ska kunna göra experiment som man annars inte får göra på människor. Men en del experiment och studier kan man göra på mänskliga autistiska hjärnor för att identifiera likheter (korrelationer).

The original notion of an Intense World Syndrome in autism arose, because VPA-exposed animals exhibited amplified fear processing and memories (Markram et al., 2005, 2008), which indicated that fragments of the world could easily become emotionally aversive and be stored excessively. In strong support of this, we found that on the neural circuit level, VPA-exposed animals exhibited enhanced neuronal reactivity and plasticity across several brain regions, such as the amygdala and neocortex. This provided the potential cellular and circuit explanation for how an autistic brain could be easily trapped in a painfully intense world, potentially explaining a broad range of common autistic symptoms such as sensory sensitivity, withdrawal, repetitive behavior, idiosyncrasies, and even exceptional talents.
The experimentally based and common neuropathology proposed in the Intense World Theory is hyper-functioning of elementary brain modules, called local neural microcircuits, which are characterized by hyper-reactivity and hyper-plasticity, both of which seem to be caused by a tendency for excitatory neurons to dominate their neighbors. Such hyper-functional microcircuits are proposed to easily become autonomous, leading to runaway information processing, over-specialization in tasks and a hyper-preference syndrome. The proposed core cognitive consequences are hyper-perception, hyper-attention, hyper-memory, functions mediated by the neocortex, and hyper-emotionality, mediated by the hyper-functionality of the limbic system. These four dimensions could potentially explain the full spectrum of symptoms in autism, depending on the severity of the microcircuit pathology in different brain regions. The degree of hyper-functionality in different brain regions could vary in each child depending on genetic personality traits, on unique epigenetic conditions, and unique sequence of postnatal experiences.
This article begins by shortly reviewing the validity of the VPA rat model of autism as well as the experimental insights obtained from this model, before delving deeper into an a re-examination and re-interpretation of previous studies on human autism in the light of these experimental results from the animal model. We make the case for a unified Intense World Theory for autism that can potentially explain many of the varied past results and resolve many conflicting findings and views, and by making some falsifiable experimental predictions.

https://www.frontiersin.org/articles/10.3389/fnhum.2010.00224/full
Aspigare
 
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