Study: Acetaminophen Use for Fever in Children Associated with Autism Spectrum

Study: Acetaminophen Use for Fever in Children Associated with Autism Spectrum Disorder
Autism Spectrum Disorder (ASD) is characterized by persistent deficits in social communication and restrictive behavior, interests, and activities. Our previous case-control study showed that use of acetaminophen at age 12–18 months is associated with increased likelihood for ASD (OR 8.37, 95% CI 2.08–33.7). In this study, we again show that acetaminophen use is associated with ASD (p = 0.013). Because these children are older than in our first study, the association is reversed; fewer children with ASD vs. non-ASD children use acetaminophen as a “first choice” compared to “never use” (OR 0.165, 95% CI 0.045, 0.599). We found significantly more children with ASD vs. non- ASD children change to the use of ibuprofen when acetaminophen is not effective at reducing fever (p = 0.033) and theorize this change in use is due to endocannabinoid system dysfunction. We also found that children with ASD vs. non-ASD children are significantly more likely to show an increase in sociability when they have a fever (p = 0.037) and theorize that this increase is due to anandamide activation of the endocannabinoid system in ASD children with low endocannabinoid tone from early acetaminophen use. In light of this we recommend that acetaminophen use be reviewed for safety in children.

Study – Effect of gluten free diet on gastrointestinal and behavioral indices for children with autism spectrum disorders: a randomized clinical trial

Effect of gluten free diet on gastrointestinal and behavioral indices for children with autism spectrum disorders: a randomized clinical trial.
Of the 80 children, 53.9% had gastrointestinal abnormalities. In the GFD group, the prevalence of gastrointestinal symptoms decreased significantly (P<0.05) after intake of GFD (40.57% vs. 17.10%) but increased insignificantly in the RD group (42.45% vs. 44.05%). GFD intervention resulted in a significant decrease in behavioral disorders (80.03±14.07 vs. 75.82±15.37, P<0.05) but an insignificant increase in the RD group (79.92±15.49 vs. 80.92±16.24).
This study suggested that GFD may be effective in controlling gastrointestinal symptoms and ASD behaviors.

The Alkaline Diet: Is There Evidence That an Alkaline pH Diet Benefits Health?
This review looks at the role of an alkaline diet in health. Pubmed was searched looking for articles on pH, potential renal acid loads, bone health, muscle, growth hormone, back pain, vitamin D and chemotherapy. Many books written in the lay literature on the alkaline diet were also reviewed and evaluated in light of the published medical literature. There may be some value in considering an alkaline diet in reducing morbidity and mortality from chronic diseases and further studies are warranted in this area of medicine

Oral Contraceptives and Autism

Oral Contraceptives and Autism
The mechanisms by which oral contraceptives instigate neurodevelopmental changes is slowly emerging. It appears that in addition to preventing pregnancy, synthetic hormones like ethinylestradiol, used in most birth control formulations, initiate epigenetic alterations in the oocytes (eggs) causing persistent changes in expression of the estrogen receptor beta gene (ERβ). When those eggs become fertilized and conception ensues, the changes in the estrogen receptor gene impact the expression of autism and other neurodevelopmental disorders.
Ethinylestradiol is an Endocrine Disruptor
Ethinylestradiol is a known endocrine disruptor. Anything that disrupts endogenous hormones can be considered an endocrine disruptor. Evidence is emerging that ethinylestradiol may trigger what is called DNA methylation of the estrogen receptor gene. This then causes decreased messenger RNA resulting in impaired brain estrogen signaling in offspring [2]. Let’s think more deeply about this.
Methylation means that, by way of a chemical process, a gene is turned on (hypomethylation) or turned off (methylation) by an enzyme or protein. Researchers believe that methylation is one of a number of mechanisms by which environmental interactions influence genetic activity. In this case, ethinylestradiol silences or turns off some important processes that are associated with estrogen signaling, namely receptor activity.
Methylation and other epigenetic reactions influence health and disease processes across generations. This is called transgenerational transmission. So, I suspect that the deleterious effects of ethinylestradiol on the estrogen receptor gene are transgenerational. This is possible because the estrogen receptor gene may be an imprinted gene. Imprinting is a dynamic epigenetic phenomenon by which certain genes are expressed in a parent-of-origin manner. If the allele, an alternative form of the same gene, inherited from the father is imprinted, it is thereby silenced, and only the allele from the mother is expressed. If the allele from the mother is imprinted, then only the allele from the father is expressed.

Study: The link between oral contraceptive use and prevalence in autism spectrum disorder
Autism spectrum disorder (ASD) is a group of developmental disabilities that include full syndrome
autism, Asperger’s syndrome, and other pervasive developmental disorders. The identified prevalence of ASD has increased in a short time period across multiple studies causing some to conclude that it has reached epidemic proportions in the U.S.
Many possible explanations for the rise in numbers of individuals diagnosed with ASD have been offered and yet, causes and contributing factors for ASD are inadequately understood. Current evidence suggests that both genetics and environment play a part in causing ASD.
One possible risk factor for the increase in prevalence has been profoundly overlooked in the existing biomedical and epidemiologic literature. As the prevalence of ASD has risen in the last sixty years, so has the prevalence of the usage of the oral contraceptives and other modern hormonal delivery methods. In 1960 about one million American women were using oral contraceptives, today close to 11 million women in the U.S. use oral contraceptives. Eighty-two percent of sexually active women in the U.S. have used oral contraceptives at some point during their reproductive years. Thus, the growth in use of progesterone/estrogen-based contraceptives in the United State has reached near-ubiquitous levels among women in the child-bearing age range.
The suppression of ovulation produced by estrogen–progesterone is an indisputable abnormality. It is logical to consider the outcome of the ovum that would have been normally released from the ovary during ovulation. To date there is no comprehensive research into the potential neurodevelopmental effects of oral contraceptive use on progeny. The issue has been only sparsely considered in the biomedical literature. This article hypothesizes that the compounds, estrogen and progesterone, used in oral contraceptives modify the condition of the oocyte and give rise to a potent risk factor that helps explain the recent increase in the prevalence of ASD’s.
This hypothesis does not propose to delineate the cause of autism. Rather, it attempts to explain the recent dramatic increase in prevalence and point the way for further study that will lead to causal examination

Study: An epigenetic basis for autism spectrum disorder risk and oral contraceptive use
In the United States 1 in 68 children are diagnosed with autism spectrum disorder (ASD). Although the etiology is unknown, many scientists believe ASD is caused by a combination of genetic and environmental factors and/or epigenetic factors. The widespread use of oral contraceptives is one environmental risk factor that has been greatly overlooked in the biomedical literature. Oral contraceptives, synthetic hormones created to imitate natural human hormones and disrupt endogenous endocrine function to inhibit pregnancy, may be causing the harmful neurodevelopmental effects that result in the increased prevalence of ASD.
It is conceivable that the synthetic hormones repeatedly assault the oocyte causing persistent changes in expression of the estrogen receptor beta gene. Ethinylestradiol, a known endocrine
disruptor, may trigger DNA methylation of the estrogen receptor beta gene causing decreased mRNA resulting in impaired brain estrogen signaling in progeny. In addition, it is possible the deleterious effects are transgenerational as the estrogen receptor gene and many of its targets may be imprinted and the methylation marks protected from global demethylation and preserved through fertilization and beyond to progeny generations. This article will delineate the hypothesis that ethinylestradiol activates DNA methylation of the estrogen receptor beta gene causing decreased mRNA resulting in diminished brain estrogen signaling in offspring of mothers exposed to oral contraceptives. Considering the detrimental epigenetic and transgenerational effects proposed, it calls for further study.

Potential Link between Oral Contraceptives and Autism
Oral Contraceptives are Endocrine Disruptors
One of the compounds found in oral contraceptives is the synthetic estrogen called Ethinylestradiol (EE2). EE2 is a known endocrine disrupting compound (EDC) capable of causing harm to the endocrine system and to progeny. Studies show that EDCs have the potential to do harm by adversely affecting the sensitive hormonal pathways that regulate reproductive function in a variety of species including humans. The National Institute for Environmental Health Sciences (NIEHS) reports that EDCs may disturb the endocrine system and produce adverse developmental, reproductive, neurological, and immune effects in humans and wildlife. The NIEHS indicates that research also shows that the highest risk of endocrine disruption occurs during prenatal and early postnatal development. Humans might be exposed to EDCs through foods, beverages, pesticides, and cosmetics, but the case with EE2 is particularly striking because EE2 exposure in female humans occurs at a pharmacologically effective dose, administered every day, for extended periods of time.
Hormones and their signaling pathways are essential to normal functioning of all tissues and organs in invertebrate and vertebrate species. Normal communication of the endocrine system can be disrupted by exogenous substances like EDCs, which have the same attributes as endogenous hormones. EDCs possess the ability to be active at low concentrations and like endogenous hormones, they are able to bind to receptors at very low concentrations. Therefore, endocrine disruption can occur from low-dose exogenous hormone exposure or from hormonally active substances that interfere with receptors for other hormonally assisted processes. In addition, some EDCs are able to interact with multiple hormone receptors concurrently. They can work simultaneously to create additive or synergistic effects not observed with the individual compounds. EDCs can act on a number of physiological processes in a tissue specific manner. And, as with endogenous hormones, it is often not feasible to extrapolate low-dose effects from the high-dose effects of EDCs. Thus the mimicry of estradiol (E2) and the information that such compounds can cause harmful effects on reproduction and the endocrine system provide mechanistic evidence that EE2 found in oral contraceptives may adversely affect the oocyte or developing embryo.

Update: Oral Contraceptive Use and Autism
In the realm of environmental risk factors, the oral contraceptive hypothesis I first proposed is compelling. As a group of agents, there are explicit documented mechanisms through which oral contraceptives can impact the oocyte and/or the developing embryo. Additional reasons for considering the role of oral contraceptives and autism include:

The exposure concentration is directly administered and pharmacologically effective.
The exposure to the endocrine disruptor may be of larger magnitude than other environmental exposures that mostly occur through passive secondary means.
A temporal correlation exists between the increased prevalence of oral contraceptive use and the increased prevalence of autism spectrum disorders over the last fifty years.
The possibility exists that the effects of EE2 could intensify over generations due to transgenerational transmission of altered epigenetic programming.
Continued exposure across generations could possibly impart sensitivity to developing autism spectrum disorders.

Do We Really Understand Oral Contraceptives?
While researching my hypothesis linking oral contraceptive use to the development of autism in children, I wondered about why so many women are still using a drug that has dangerous side-effect and could cause neurodevelopmental disorders in offspring. The simple answer seems to be lack of accurate medical information. Not only do individual women lack critical information about the pill, but the support systems women depend on for advice and help with decision-making also seem to lack information about the pill.
All health choices are complex and influenced by multiple variables that all interact. There are multiple levels, underlying determinants of health behaviors, which are relevant for understanding why oral contraceptives are still the primary method of choice in the United States. The following influencing factors are not exhaustive, but do shed light on why pill use is so prevalent in the U.S. Simply put, we don’t know better.

Autism related studies

Autism related studies
Fever plus mitochondrial disease could be risk factors for autistic regression.

Autistic spectrum disorders encompass etiologically heterogeneous persons, with many genetic causes. A subgroup of these individuals has mitochondrial disease. Because a variety of metabolic disorders, including mitochondrial disease show regression with fever, a retrospective chart review was performed and identified 28 patients who met diagnostic criteria for autistic spectrum disorders and mitochondrial disease. Autistic regression occurred in 60.7% (17 of 28), a statistically significant increase over the general autistic spectrum disorder population (P < .0001). Of the 17 individuals with autistic regression, 70.6% (12 of 17) regressed with fever and 29.4% (5 of 17) regressed without identifiable linkage to fever or vaccinations. None showed regression with vaccination unless a febrile response was present. Although the study is small, a subgroup of patients with mitochondrial disease may be at risk of autistic regression with fever. Although recommended vaccinations schedules are appropriate in mitochondrial disease, fever management appears important for decreasing regression risk.

Is fever a predictive factor in the autism spectrum disorders?

If it is confirmed that autistic children with high fevers are of higher functionality, it is possible for preventive intervention programs to be developed where children are exposed to the least possible chemical drugs intervention (antipyretics, antibiotics, etc.) or even selective vaccination. Further experimental, epidemiological and clinical studies are necessary to investigate the above.

Prevalence of autism spectrum disorders–Autism and Developmental Disabilities Monitoring Network, 14 sites, United States, 2008.

For 2008, the overall estimated prevalence of ASDs among the 14 ADDM sites was 11.3 per 1,000 (one in 88) children aged 8 years who were living in these communities during 2008. Overall ASD prevalence estimates varied widely across all sites (range: 4.8-21.2 per 1,000 children aged 8 years). ASD prevalence estimates also varied widely by sex and by racial/ethnic group. Approximately one in 54 boys and one in 252 girls living in the ADDM Network communities were identified as having ASDs. Comparison of 2008 findings with those for earlier surveillance years indicated an increase in estimated ASD prevalence of 23% when the 2008 data were compared with the data for 2006 (from 9.0 per 1,000 children aged 8 years in 2006 to 11.0 in 2008 for the 11 sites that provided data for both surveillance years) and an estimated increase of 78% when the 2008 data were compared with the data for 2002 (from 6.4 per 1,000 children aged 8 years in 2002 to 11.4 in 2008 for the 13 sites that provided data for both surveillance years). Because the ADDM Network sites do not make up a nationally representative sample, these combined prevalence estimates should not be generalized to the United States as a whole.

Bactericidal Antibiotics Induce Mitochondrial Dysfunction and Oxidative Damage in Mammalian Cells

Prolonged antibiotic treatment can lead to detrimental side effects in patients, including ototoxicity, nephrotoxicity, and tendinopathy, yet the mechanisms underlying the effects of antibiotics in mammalian systems remain unclear. It has been suggested that bactericidal antibiotics induce the formation of toxic reactive oxygen species (ROS) in bacteria. We show that clinically relevant doses of bactericidal antibiotics—quinolones, aminoglycosides, and β-lactams—cause mitochondrial dysfunction and ROS overproduction in mammalian cells. We demonstrate that these bactericidal antibiotic–induced effects lead to oxidative damage to DNA, proteins, and membrane lipids. Mice treated with bactericidal antibiotics exhibited elevated oxidative stress markers in the blood, oxidative tissue damage, and up-regulated expression of key genes involved in antioxidant defense mechanisms, which points to the potential physiological relevance of these antibiotic effects. The deleterious effects of bactericidal antibiotics were alleviated in cell culture and in mice by the administration of the antioxidant N-acetyl-L-cysteine or prevented by preferential use of bacteriostatic antibiotics. This work highlights the role of antibiotics in the production of oxidative tissue damage in mammalian cells and presents strategies to mitigate or prevent the resulting damage, with the goal of improving the safety of antibiotic treatment in people.