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Review July 2012 | Volume 120 | Issue 7
Tipping the Balance of Autism Risk: Potential Mechanisms Linking Pesticides and Autism
Janie F. Shelton,1 Irva Hertz-Picciotto,1,2 and Isaac N. Pessah2,3
Background: Autism spectrum disorders (ASDs) have been increasing in many parts of the world and a portion of cases are attributable to environmental exposures. Conclusive replicated findings have yet to appear on any specific exposure; however, mounting evidence suggests gestational pesticides exposures are strong candidates. Because multiple developmental processes are implicated in ASDs during gestation and early life, biological plausibility is more likely if these agents can be shown to affect core pathophysiological features.
Objectives: Our objectives were to examine shared mechanisms between autism pathophysiology and the effects of pesticide exposures, focusing on neuroexcitability, oxidative stress, and immune functions and to outline the biological correlates between pesticide exposure and autism risk.
Methods: We review and discuss previous research related to autism risk, developmental effects of early pesticide exposure, and basic biological mechanisms by which pesticides may induce or exacerbate pathophysiological features of autism.
Discussion: On the basis of experimental and observational research, certain pesticides may be capable of inducing core features of autism, but little is known about the timing or dose, or which of various mechanisms is sufficient to induce this condition.
Conclusions: In animal studies, we encourage more research on gene × environment interactions, as well as experimental exposure to mixtures of compounds. Similarly, epidemiologic studies in humans with exceptionally high exposures can identify which pesticide classes are of greatest concern, and studies focused on gene × environment are needed to determine if there are susceptible subpopulations at greater risk from pesticide exposures.
Citation: Shelton JF, Hertz-Picciotto I, Pessah IN. 2012. Tipping the Balance of Autism Risk: Potential Mechanisms Linking Pesticides and Autism. Environ Health Perspect 120:944–951; http://dx.doi.org/10.1289/ehp.1104553
Address correspondence to J.F. Shelton, Department of Public Health Sciences, Med Sci 1-C, University of California, Davis, One Shields Ave., Davis, CA 95616, USA. Telephone: (530) 752-7844. E-mail: firstname.lastname@example.com
Financial support for this work was provided by the U.S. Environmental Protection Agency [grants 2P01ES011269, 1R01ES015359 (STAR R829388 and R833292)], the Office of Graduate Studies, and the UC Davis Medical Investigations of Neurodevelopmental Disorders (MIND) Institute.
The authors declare they have no actual or potential competing financial interests.
Received: 29 September 2011
Accepted: 11 April 2012
Advance Publication: 25 April 2012
Final Publication: 1 July 2012
Causes for the recent rise in autism diagnoses throughout the United States remain largely unknown. In California, a 600% increased incidence in autism was observed among children up to 5 years of age for births from 1990 to 2001, yet only one-third of the rise could be explained by identified factors such as changing diagnostic criteria and a younger age at diagnosis (Hertz-Picciotto and Delwiche 2009). Across the United States, autism spectrum disorders (ASD) are now estimated to affect 1 in 88 eight-year-olds, with much higher prevalence in boys (1 in 54) than girls (1 in 252) (Centers for Disease Control and Prevention 2012). Autism is a heterogeneous, behaviorally defined condition often diagnosed in children prior to age 3 years. Although each individual diagnosis must meet specific criteria related to deficits in social interaction and language and to the presence of repetitive behaviors or restricted interests, autism phenotypes vary widely, even among concordant twins (Le Couteur et al. 1996).
Idiopathic autisms are diagnosed 4–5 times more often in boys than girls and frequently involve a wide range of genes that confer susceptibility as opposed to a singular heritable factor (Geschwind 2011). Genetic contributions to autism risks involve rare mutations, complex gene × gene interactions, and copy number variants (CNVs) including deletions and duplications (Stankiewicz and Lupski 2010). In a recent series of papers, rare de novo point mutations were associated with autism in parent–child trios with sporadic ASD (Neale et al. 2012; O'Roak et al. 2012; Sanders et al. 2012), and those mutations were more frequently derived from fathers, increasing with paternal age (O'Roak et al. 2012). Although twin studies have demonstrated evidence of heritability—a stronger concordance among monozygotic than dizygotic twins (Bailey et al. 1995; Rosenberg et al. 2009; Steffenburg et al. 1989)—in a recent twin study that parsed the contribution from genetics versus the environment, a larger component of the risk of autism was attributable to environmental factors than genetics alone (e.g., Hallmayer et al. 2011). The genetic and twin studies of autism point to variability unexplained by heritable factors and, in recent years, associations between gestational pesticide exposures and ASD or behaviors that are characteristic of pervasive developmental disorders have been reported.
Using exposure estimates from a historical pesticide use database, a study of mothers living in the California Central Valley showed that children born to mothers who had been exposed to organochlorine (OC) insecticides that were agriculturally applied within 500 m of the home between gestational days (GD) 26 and 81 (during neural tube closure) were 7.6 times more likely to be diagnosed with ASD than the children of mothers who lived in the lowest exposure quartile. Associations were also observed for the pyrethroid insecticide bifenthrin and for the organophosphate (OP) chemical class when comparing the cumulative exposure over the course of gestation among the highest versus lowest quartile (Roberts et al. 2007). Although Roberts et al. (2007) present provocative preliminary data and higher odds at closer proximity (a dose–response relationship), unmeasured confounding could have occurred for other exposures such as prenatal vitamin intake or occupational exposures. Additionally, because cases were obtained from the Department of Developmental Services (DDS) and controls from the birth certificate registry, misclassification of cases and controls may have occurred as children who receive an early diagnosis of autism are sometimes reclassified at a later date, and controls may include children who are on the autism spectrum but have not received a DDS diagnosis.
In a prospective cohort study also from the California Central Valley, a 230% increase in maternally reported symptoms of pervasive developmental disorders (PDD) was observed per 10-nM/L increase in prenatal maternal urinary levels of OP metabolites (Eskenazi et al. 2007). PDD is the greater diagnostic umbrella under which ASD falls, also encompassing Rett Syndrome, childhood disintegrative disorder (CDD), and pervasive developmental disorder–not otherwise specified (PDD-NOS). Although the prospective study design has the benefit of accuracy in exposure ascertainment from biospecimens collected during pregnancy, it is generally not feasible to obtain a cohort large enough to observe enough cases of full syndrome autism. Consequently the broader definition of borderline PDD increases the numbers but lacks specificity. Although these studies are by no means conclusive in establishing an autism–pesticide association, they do raise important questions regarding the health effects of these compounds on the developing fetus. In light of these findings and the current theories of autism pathophysiology, we review here potential pathways by which gestational pesticide exposure might contribute to autism, linking what is known about the origins of autism with information on biological effects of pesticides to generate clearer hypotheses that can help guide future research in this area.
Pesticide Exposure in the General Population
Pregnant women are exposed to pesticides through a wide variety of sources. Although many of the mechanisms of action outlined here have been observed in association with higher exposures than are likely to occur in the general population, it is difficult to estimate the direct dosage to a pregnant woman who may be applying pesticides in or around her home or to her pets, consuming food with residues of pesticides and pesticide metabolites, and inhaling air from agricultural or urban spraying near her home and workplace. Moreover, urine and blood levels indicate exposure to pregnant women is widespread. In the 2003–2004 National Health and Nutrition Examination Survey (NHANES), which recruits a representative sample of the U.S. adult population, 83% of pregnant women had detectable levels of urinary dimethylthiophosphate, an OP metabolite [geometric mean (GM), 2.43 µg/L urine]. DDE, the breakdown product of the persistent OC pesticide DDT, was detected in 100% of pregnant women with a GM of 140.4 ng/g lipid (Woodruff et al. 2011). Trends in pesticide use in the United States since 1964 have shown steep increases in the use of OPs, which make up the vast majority of pesticide sales, and rapid decreases in OC use following the 1972 ban on DDT (Figure 1). More recently, as OPs have been banned for residential uses, pyrethroid sales have increased rapidly (Williams et al. 2008).
Figure 1 – Agricultural pesticide trends in the United States by percent of sales, 1964–2000 (U.S. Department of Agriculture 2006).
The Quest for Animal Models of Autism and Environment
A variety of animal models have been developed that aid in understanding the mechanisms that may induce one or several of the core features of autism (Ey et al. 2011; Hamilton et al. 2011; Tabuchi et al. 2007). In particular, transgenic and knock-in mouse lines with targeted anomalies in genes associated with autism and the development of a comprehensive set of rodent assays to assess social interaction, communication, and repetitive behaviors, have greatly enhanced our ability to test hypotheses about the causes of autism (Silverman et al. 2010). However, implementations of these tools toward understanding gene × environment interactions that promote impairments in the three key behavioral domains have lagged. The Shank3 (SH3/ankyrin domain gene 3) (Peca et al. 2011) and oxytocin knockout mice (Crawley et al. 2007) are examples of monogenetic insults that disrupt all three domains. However, because only a small proportion of autism cases result from complete loss of a single gene, knockout animal models may not be as useful as models that carry mutations that impart partial gain or loss of gene function.
Functional impairments as seen in the reeler mouse (Laviola et al. 2009) and Timothy syndrome mouse models (Bader et al. 2011) are more relevant to the multi-gene and environment model of autism risk. In a subsection of a paper describing the paradoxical effects of acetylcholinesterase [AChE; the enzyme responsible for hydrolyzing the neurotransmitter acetylcholine (ACh)] in the reeler mouse, Laviola et al. (2006) describe the complexity of a gene × environment model whereupon exposure to chlorpyrifos restored behaviors to near normal that were initially impaired in the homozygous reeler mouse, and partially impaired in the heterozygous reeler mouse. It was shown that deficient cholinergic transmission in reeler mice could be restored by chlorpyrifos-mediated AChE inhibition. Subsequent studies found that perinatal estradiol levels influence the number of Purkinje cells and were regulated by reelin levels (Biamonte et al. 2009; Sigala et al. 2007). This sex × gene × environment interaction model serves more readily as a clue for further epidemiologic follow-up to understand autism etiology in humans (Halladay et al. 2009).
Several autism-associated genes are involved in Ca2+ signaling and regulation (Halladay et al. 2009; Pessah and Lein 2008). The Timothy syndrome mouse model of autism involves a single nucleotide mutation essential for proper voltage-dependent inactivation of the pore-forming subunit of the L-type calcium channel Cav1.2 (Splawski et al. 2004). Cav1.2 has been proposed to play direct roles in the development of synaptic plasticity (Morgan and Teyler 1999) and in gene translation and transcription (Dolmetsch 2003; Lenz and Avruch 2005; West et al. 2002).
Ca2+ signaling can be disrupted by polychlorinated biphenyls (PCBs, which are employed in a wide variety of industrial uses) (Pessah et al. 2010), the OC pesticides lindane and dieldrin (Heusinkveld and Westerink 2012), and several types of pyrethroid pesticides (Soderlund 2012). In a study comparing physiological effects of 11 pyrethroid compounds in rats, the type 2 pyrethroids strongly induced increased Ca2+ channel influx into the cell, whereas the type 1 pyrethroids did not (Breckenridge et al. 2009). It should be noted that these three exposure types induced calcium perturbations at levels below those described as having a toxic effect on the basis of primary mechanisms of action.
One could argue that mouse, rat, or zebrafish models may not demonstrate the core deficit that sets autism apart from other developmental disorders: a lack of social reciprocity. Recently, the prairie vole has been cited as a better model of autism due to its high degree of socialized behavior. For example, male prairie voles demonstrated social withdrawal after 10 days of dietary exposure to mercury, indicating a sex-specific effect of the exposure which induced a unique attribute of autism, social avoidance (Curtis et al. 2010).
Excitation/Inhibition Dysregulation of Neuronal Development
Rubenstein and Merzenich (2003) elegantly described a model of autism whereby the cortical networks that govern language and social behavior are skewed toward increased excitation (i.e., away from inhibition), resulting in an overall hyperexcitable state. Their hypothesis addresses both genomic and environmental factors influencing glutamate and GABA (γ-aminobutyric acid)–mediated neurotransmission, resulting in more noise in neural networks.
By poundage applied, the majority of pesticides inhibit AChE. Examples include two of the most frequently used pesticides worldwide, the OPs chlorpyrifos and diazinon, as well as the monomethyl carbamates (CBs), including propoxur and methomyl. Insecticides that target voltage-gated sodium channels (e.g., pyrethroids and DDT), the nicotinic ACh receptors (nAChR) themselves (e.g., imidacloprid), and GABAA receptors (e.g., OC and fipronil) are ranked next highest in use in overall poundage applied (Casida 2009). The levels of ACh- and GABA-mediated neurotransmission and the activity of voltage-dependent sodium channels are critical throughout prenatal and postnatal development, defining the ratio of excitatory and inhibitory neurotransmission in the brain, but also promoting and refining neural networks in the developing and adult brain (Belmonte and Bourgeron 2006).
GABA signaling pathways. GABA is critical for normal development and regulation of neurotransmission (Campbell 1996). GABA activates two major families of receptors expressed in the mammalian brain: a) GABAA and GABAC receptors that promote chloride fluxes, and b) GABAB receptors that are coupled to G-protein signaling. In adults, GABAA receptor activation promotes chloride influx and hyperpolarization of the membrane, decreasing neuronal excitability. However, during fetal development, the chloride gradients across the membrane are reversed, and therefore activation of GABAA receptors in the hippocampus and neocortex causes net chloride efflux and enhanced excitation (Watanabe et al. 2002). Thus, the temporal expression and spatial localization of GABA receptors within the brain can determine the patterns and activity of neural circuits. Numerous subunit isoforms for the GABAA receptor are developmentally regulated during the perinatal period and have distinct biophysical and pharmacological properties that contribute to their physiological (Cossart et al. 2005) and pathophysiological (Stafstrom et al. 2010) functions. GABA is known to regulate many aspects of neural stem cell proliferation, differentiation, migration, and elongation (Varju et al. 2001). Because of observed deficits in social and exploratory behavior, the GABAA receptor β3-gene–deficient mouse has been suggested as an animal model of autism spectrum disorder (DeLorey et al. 2008).
Disruptions in the GABA system have been reported to be associated with autism in studies of receptor density from brain tissue (Blatt et al. 2001) as well as in studies of genetic association (Buxbaum et al. 2002; Cook et al. 1998; McCauley et al. 2004). In postmortem cerebellar tissue samples from the brains of adults with autism, relative numbers of GABAA receptors were reduced in 4 cases as compared with 8 controls, and GABAB expression was altered in 5 cases as compared with 7 controls (Fatemi et al. 2009a, 2009b). Decreased expression of GABAA receptor β3 was shown to be associated with MECP2 (the gene for methyl CpG binding protein 2) impairment in brain tissue samples from cases of autism, Angelman syndrome, and Rett syndrome (Samaco et al. 2005). In a family-based study, single nucleotide polymorphisms were examined in 470 families with at least one case of autism (266 multiplex, 204 triads) for GABA subunits on 14 alleles. Findings showed significant associations for GABAA receptor polymorphisms, in particular the A4 subunit and gene × gene interaction between receptor subunits (Ma et al. 2005).
In rats, prenatal exposure to the OC pesticides dieldrin and lindane reduces GABAA receptor binding capabilities in the brainstem (Brannen et al. 1998). In another rat study, prenatal dieldrin exposure was found to alter mRNA expression and subunit composition of GABAA receptors (Liu et al. 1998). Results from in vitro cortical neuronal cultures have shown endosulfan and related OC pesticides to increase Akt phosphorylation, an effect mediated by the activation of ERβ, and to activate ERK1/2 through a mechanism involving GABAA and glutamate receptors (Briz et al. 2011). In humans, a diminished ability to bind GABA contributes to poor muscle tone, which is observed in over half of persons with autism (Ming et al. 2007), and induces hyperexcitable states as seen in epilepsy, a comorbidity in approximately 20% of autistic cases (Bolton et al. 2011; Tuchman and Cuccaro 2011).
PCBs are OCs that had broad industrial uses, including use as adjuvants in paints and pesticide formulations (U.S. Environmental Protection Agency 2011). Although banned approximately 40 years ago, PCB exposures remain a concern to human health because of their persistence in the environment. Developmental and in vitro studies in rodents and nonhuman primates have demonstrated the ability of non-coplanar PCBs to cause imbalances in excitatory and inhibitory neurotransmission within critical regions for language development (Kenet et al. 2007), social cognition (Nakagami et al. 2011), and seizures (Kim and Pessah 2011; Kim et al. 2009). A substantial body of epidemiologic literature has provided evidence that cognitive deficits are associated with elevated PCB exposures, and more recently, elevated prenatal exposures to mono-ortho PCBs were found to be predictive of lower scores on both the Mental Development Index (MDI) and the Psychomotor Development Index (PDI) of the Bayley Scales of Infant Development (Park et al. 2010). Furthermore, an analysis of seven hydroxylated metabolites of PCBs in cord blood revealed that the metabolite from mono-ortho substituted PCBs were the only ones associated with reduced MDI and PDI scores (Park et al. 2009). These findings underscore the complexity of toxicities within a compound class and, by the same principle, the critical need to characterize differences among, for example, OPs or pyrethroids.
ACh-signaling pathways. ACh-mediated neurotransmission is widely involved in the development of both the peripheral and the central nervous systems, and continues to play a critical role in regulating muscle movement, learning, attention, cognition, and memory throughout adulthood. ACh regulates aspects of nerve excitation and inhibition that influence brain plasticity, arousal, and reward. ACh increases excitation both directly and indirectly, and works through both nicotinic and muscarinic receptors to stimulate inhibitory interneurons, thereby modulating the activity of downstream effectors in a complex manner (Brown 2010; Scharf 2003).
Several cholinergic abnormalities have been reported in autism [Bauman and Kemper 2005; Perry et al. 2001; reviewed by Deutsch et al. (2010)]. In brief, studies of postmortem brain tissue have reported reduced nAChR binding in the frontal and parietal cortices (comparing 7 cases with 10 controls), reduced M1-muscarinic receptor binding in the parietal cortex (comparing 5 cases with 5 controls), and increased concentration of brain-derived neurotrophic factor (BDNF) (comparing 5 cases with 5 controls) (Deutsch et al. 2010). (BDNF is involved in the development and function of cholinergic neurons.) Although these studies involved small sample sizes, they suggest cholinergic abnormalities may be present in persons with autism.
OP insecticides irreversibly inhibit the active site of AChE, and while the severity of neurodevelopmental effects in animal studies correlate with AChE inhibition, additional neurotoxic effects have been observed at concentrations below the level sufficient to induce enzyme inhibition (Eddins et al. 2010; Levin et al. 2003; Slotkin et al. 2008). These effects include altered cell packing density, decreases in serotonin receptor and nAChR levels (Levin et al. 2010), altered Ca2+ and K+ ion concentrations (Harrison et al. 2002; Murgia 2004), and oxidative stress (Aluigi et al. 2005). Metabolism of OPs is mediated by the paraoxonase1 enzyme (PON1), whereby fast metabolizers suffer less AChE inhibition than slow metabolizers in response to the same level of exposure (Costa et al. 2005).
Pertinent to the male predominance observed in autism, sex selective developmental effects have been seen in animal models exposed to OPs. Chlorpyrifos exposure (1 mg/kg/day) in rats during postnatal days (PND) 1–4 decreased the number of errors in working and reference memory made by females, but increased the number of such errors made by males. These effects persisted into adolescence and adulthood, indicating a long-term consequence of exposure (Levin et al. 2001). Another study in rats showed that developmental exposures to low doses of the OP parathion induced greater developmental deficits in spatial navigation and working memory among males than females (Levin et al. 2009). Although these behaviors are not core features of autism, these findings provide evidence of different effects of early exposures between the sexes. In addition, parathion administration on PND1–4 at levels that barely inhibited cholinesterase was associated with deficits at 14–19 months of age, showing these deficits worsen with age (Levin et al. 2009).
The ability of OPs to inhibit AChE varies dramatically by chemical structure, which also determines reversibility. Aluigi et al. (2005) conducted a study examining the AChE-mediated developmental effects of OP exposure on chick embryos and discovered that 10–6 M chlorpyrifos was sufficient to inhibit head development. Even lower concentrations of chlorpyrifos-oxon disrupt axonal growth of rat dorsal root ganglia neurons (Yang et al. 2008), and sensory neuron development in zebrafish (Yang et al. 2011), indicating that exposure to very low levels of this OP has the potential to adversely influence development of neural networks (Yang et al. 2011). Persistent neurobehavioral consequences of chlorpyrifos exposure in zebrafish have also been demonstrated (Eddins et al. 2010; Levin et al. 2003). Although chlorpyrifos is still used worldwide in residential settings, residential use has been banned in the United States because of its neurotoxicity. However, no restrictions have been placed on its agricultural use.
Oxidative Stress and Mitochondrial Dysfunction
Cellular energy production through the degradation of ATP by mitochondria is necessary for muscle development and brain function. Mitochondrial dysfunction has three major consequences: a) decreased ATP production, b) increased production of reactive oxygen species (ROS) and oxidative damage, and c) induction of apoptosis (Rossignol and Frye 2012). These biochemical changes have been implicated in autism and can also be induced by exposure to OP, OC, and CB pesticides (Franco et al. 2009; Karami-Mohajeri and Abdollahi 2011; Rohlman et al. 2010). Although multiple modes of action have been described for specific organohalogens and halogenated insecticides, many induce dysregulation of Ca2+-mediated signaling and production of mitochondrial ROS (Mariussen and Fonnum 2006). A thorough mechanistic hypothesis of autism via genetic risk and oxidative stress has been described by Deth et al. (2008).
Nearly all insecticides discussed in this review induce oxidative stress. Permethrin, a pyrethroid used in agriculture and in topical creams for lice and scabies induces oxidative stress and apoptosis in the nervous system of zebrafish (Shi et al. 2011). Malathion, an OP commonly used in aerial spraying throughout the 1980s for the Mediterranean fruit fly and more recently to control mosquito vectors of West Nile Virus, induces mitochondrial dysfunction in liver cells at low concentrations and cytotoxicity at higher concentrations (Moore et al. 2010). The OC insecticide methoxychlor has been shown in mice to inhibit brain mitochondrial respiration (Schuh et al. 2005) and to cause mitochondrial dysfunction and oxidative damage in the mouse ovary (Gupta et al. 2006). More recently, methoxychlor-mediated mitochondrial dysfunction was found to cause oxidative damage and dysfunction of the dopamine system in brains of mice (Schuh et al. 2009). Another study examining the effect of the OP dichlorvos on rat brain mitochondria found that chronic, low-level exposure can cause mitochondrial disruption and apoptosis of neuronal cells via the release of cytochrome c and activation of caspase 3 after in vitro exposure (Kaur et al. 2007). Developmental exposure to the OP chlorpyrifos can permanently decrease dopamine levels in zebrafish into adulthood (Eddins et al. 2010), which is important to note in the context of an already disrupted dopamine system in autism (Muhle et al. 2004).
Several studies have shown that the toxicity of pyrethroid insecticides, many of which are organohalogen derivatives, is mediated by both the dysregulation of cytoplasmic Ca2+ signaling and the induction of oxidative stress (Cao et al. 2010; Kale et al. 1999; Soderlund 2012; Yan et al. 2011; Zhang et al. 2010). After the ban on residential uses of chlorpyrifos, household OP insecticides have been replaced with other insecticides, namely pyrethroids and fipronil, a phenylpyrazole insecticide. A comparative toxicity study was conducted on rat PC12 cells to evaluate the hypothesis that fipronil is less toxic than chlorpyrifos, but fipronil was found to induce higher oxidative stress than chlopyrifos, an effect that was not mediated by the GABAA pathway (Lassiter et al. 2009).
Although the role of mitochondrial function in the autistic phenotype is not fully understood, approximately 8% of ASD cases experience mitochondrial dysfunction, compared with 0.05% of the general population [reviewed by Haas (2010)]. Mitochondrial dysfunction and increased mtDNA over-replication and mtDNA deletions were reported more frequently in lymphocytes from 10 children with autism as compared with lymphocytes from 10 typically developing controls (Giulivi et al. 2010).
Immune Toxicity
Prenatal disruption of immune development can result in atopy, allergy, deficits in immune competence, and autoimmunity in early childhood (Hertz-Picciotto et al. 2008). Recent studies on intestinal flora have shown the immune system is highly involved and inextricably linked with neurodevelopment and subsequent behavior (Diamond et al. 2011; Heijtz et al. 2011). In turn, the immune response can also be strongly influenced by neurochemistry (Diamond et al. 2011). Children with autism experience a wide array of immune abnormalities. Recent reviews on this topic report altered cytokine profiles, altered cellular immunity, low levels of lymphocytes and T-cell mitogen responses, neuroinflammation, and autoantibodies directed at nuclear proteins (Ashwood et al. 2006; Goines and Van de Water 2010). Reduced levels of IgG and IgM have also been reported, which were correlated with a higher prevalence of aberrant behavioral symptoms in a study of 271 children with autism or developmental delay or who were typically functioning (Heuer et al. 2008). In a comparison of plasma cytokine levels from children with autism (n = 97) and typically developed controls (n = 87), cases had higher levels of proinflammatory cytokines compared with neurotypical children, and the concentrations of cytokines corresponded with impaired behavioral outcomes in a dose–response fashion (Ashwood et al. 2011).
Exposure to several types of pesticides may result in decreased immune competence, immune enhancement, and/or autoimmunity (Corsini et al. 2008). OPs are particularly immunotoxic (Galloway and Handy 2003) and have been shown to suppress natural killer cells, lymphokine-activated killer cells, and cytotoxic T lymphocytes by inhibiting granzymes, impairing the FasL/Fas pathways, and inducing apoptosis of immune cells (Li 2007). Pyrethroids have also been shown to be immunotoxic in animal models. Rats treated subchronically with permethrin showed large increases of superoxide anion production and hydrogen peroxide–myeloperoxidase activity in polymorphonuclear neutrophils (Gabbianelli et al. 2009). These effects were demonstrated not only for permethrin, but also for its major metabolites.
Insecticide exposures can induce inflammatory or suppressive immunological effects depending on the compound and the immunological outcome in question. Gestational exposure of rats to atrazine, an endocrine-disrupting triazine herbicide, demonstrated immunosuppressive effects [specifically, decreased delayed-type hypersensitivity (DTH) and antibody production] in male offspring only (Rooney et al. 2003). In a study of both male and female mice, gestational exposure to atrazine at nontoxic, environmentally relevant doses administered from GD14 to PND21, was associated with decreased socialization behaviors and changes in exploratory behavior, with males displaying feminized behavioral profiles (Belloni et al. 2011).
Neuroinflammation has been observed in the postmortem brain tissue of persons with autism across several age ranges (Li et al. 2009; Morgan et al. 2010; Vargas et al. 2005). Chlorpyrifos, an OP banned for residential use in 2002, and cyfluthrin, a type 2 pyrethroid used to replace chlorpyrifos, were compared for toxicological and toxicogenomic effects to primary human fetal astrocytes. Cyfluthrin had equivalent or more toxic effects in most assays, and up-regulated several insulin related genes and proinflammatory genes on the IFN-γ (interferon-γ) pathway, including IL6R (the gene for the interleukin 6 receptor) and GFAP (the gene for glial fibrillary acidic protein). Additionally, both compounds were found to promote inflammatory activation of astrocytes. The authors suggested that the combination of increased insulin production and inflammation could lead to a state of chronic brain inflammation that might significantly alter brain development (Mense et al. 2006).
Taken together, these studies indicate that gestational exposure to pesticides can induce immunological abnormalities as well as behavioral abnormalities. It is possible that the neurodevelopmental and the immune abnormalities observed in autism are downstream manifestations of the same underlying process given the tightly regulated interconnection between the developing systems in utero. The role of the immune phenomena as a cause, effect, or side effect of autism was recently reviewed and was postulated to be in part causal (Onore et al. 2012). In addition to autism, schizophrenia and major depressive disorders have also been noted to be accompanied by perturbations of the immune system, recently reviewed in an extensive monograph (Patterson 2011).
Parental Thyroid Hormone Levels and Brain Development
Adequate levels of in utero thyroid hormones are critical for brain development. Maternal thyroid impairment has been suggested as an underlying mechanism for developmental impairments resulting from exposures to environmental chemicals such as PCBs and polybrominated diphenyl ethers (PBDEs) used as flame retardants (Winneke 2011). Pesticides have been found to interfere with thyroid function by preventing iodine uptake [e.g., mancozeb, thiocyanates, 2,4-D (2,4-dichlorophenoxyacetic acid)] and peroxidation (e.g., aminotriazole, endosulfan, malathion), and by preventing the conversion of thyroxine (T4) to triiodothyronine (T3) (e.g., aminotriazole, dimethoate, fenvalerate) (Colborn 2004). In a review of the effects of mild-to-moderate iodine deficiency in humans, diminished maternal T4 was associated with disorders of mental and/or psychomotor development (Zimmermann 2007).
Roman (2007) hypothesized that even transient intrauterine deficits in thyroid hormones (as little as 3 days) at critical points in gestation could alter the cortical architecture, interfering with neuronal migration and Purkinje cell growth, indications of both of which have been observed in autopsy studies of autism (Fatemi et al. 2002; Wegiel et al. 2010). Because the human fetus does not start producing sufficient thyroid hormones until gestational week 18 (Burrow et al. 1994), adequate maternal thyroid hormones are critical to neurodevelopment in early fetal life, particularly for reelin-regulated neuronal migration (Pathak et al. 2011). Additionally, sex-mediated effects have been observed after exposure to chlorpyrifos on GD17–20, with the induction of increased levels of free T4 in female but not male mice (Haviland et al. 2009).
Vulnerable Genetic Subpopulations
The primary neurological targets of commonly used insecticides (Scharf 2003) can be paired with vulnerable genetic subpopulations that may be at increased risk for autism (Table 1). Because of both the large number of genetic alterations and gene × gene interactions that have been implicated in autism, and the phenotypic heterogeneity in cases, the notion that a single environmental exposure can be to blame for the majority of cases is unrealistic. Also, because the dosage of pesticides to nonoccupationally exposed women is likely to be lower than that required to induce the mechanisms of injury observed in many animal models, genetic susceptibility becomes a critical factor in this discussion.
Table 1 – Insecticide compounds with a generalized excitatory neurological effect.
In 2001, the reelin gene was implicated in autism risk when repeats (11+) in the 5´ untranslated region were associated with 72% transmission to affected siblings and only 32% transmission to unaffected siblings (Persico et al. 2001). The proteolytic activity of reelin on extracellular matrix proteins that control neuronal migration is significantly inhibited by OP pesticides (Sinagra et al. 2008), and OP metabolism efficiency is regulated by the gene for paraoxonase 1 (PON1) (Mackness et al. 1997). Interestingly, an association between less active forms of the PON1 gene and autism was observed in Caucasian families in North America, but not in Italian families, leading authors to hypothesize that the slow metabolizing polymorphism confers risk in areas with high levels of OPs but may not affect autism risk otherwise (D'Amelio et al. 2005).
We have reviewed several mechanisms by which pesticides may increase the risk of autism, summarized in Table 2. Pesticides may or may not, however, play a role in the trend of increasing autism prevalence, which itself is likely due to a confluence of multiple phenomena, including changes in diagnostic practices, physician and lay awareness, the availability of treatments, and the prevalence of a variety of environmental chemical, medical, and food-related exposures. While pesticide use patterns have changed, home and ambient environments also include other exposures that have changed over time as a result of regulatory and economic factors (e.g., flame retardants, plasticizers, solvents, stabilizers, antimicrobials).
Table 2 – Mechanisms by which gestational exposure to certain classes of pesticides may induce observed pathophysiologic symptoms of autism.
Pesticides are composed of a parent product, inert ingredients, and in some cases agonists that enhance the functionality of the parent compound, and all of these ingredients may be degraded to metabolites that also distribute throughout the body. Consequently, pesticide formulations represent a mixture of compounds that might contribute to observed effects. Difficulties in distinguishing the effects of metabolites versus parent compounds may have confounded associations observed in many studies of urinary metabolites and neurodevelopment, and very few studies have examined the main effects or effect modification of exposure to piperonyl butoxide, which slows the metabolism of several types of pesticides by inhibiting cytochrome P450 enzymes.
Although pesticides are a biologically plausible contributor to autism, research in several critical areas is needed to understand cognitive and behavioral consequences of gestational exposure in humans. First, animal studies suggest critical windows of exposure, yet in humans the window or windows of biologic susceptibility remain unknown, and would be expected to vary by mechanism. Second, studies of nontoxic, environmentally relevant doses are needed to understand the effects of developmental neurotoxicity in the context of a background of genetic susceptibilities. Third, the vast majority of exposures occur in combination with exposures to other ubiquitous and/or persistent compounds such as flame retardants, plasticizers, and other pesticides. More research on combinations of exposures may reveal interactions between environmental exposures, such as effect modification by chemical additives to pesticide compounds. In light of the recently revised prevalence estimates of autism (1 in 88), large birth cohorts, such as the National Children's Study (NCS), which aim to enroll women at pregnancy and follow the children over time, are well positioned to obtain enough cases and to examine prenatal exposures prospectively. Pending accurate and reliable exposure estimates in critical time windows, and enrollment of approximately 100,000 children resulting in 1,000 or more cases of autism, NCS can contribute greatly to our understanding of these associations. Finally, more case–control studies with large populations of participants with confirmed diagnoses of autism that examine environmental exposures in relation to severity of the core domains of language impairment, social avoidance, and repetitive behaviors or insistence on sameness may shed light on possible exposure-related endophenotypes.
Although we have described several possible avenues by which pesticide exposure may influence autism, the dearth of studies on large occupational and pregnancy cohorts with adequate exposure assessment impedes our understanding of a) whether pesticides are consistently associated with autism risk, and b) if so, which pesticide compounds and which components of those compounds might actually contribute to autism risk. Grandjean and Landrigan (2006) hypothesized that our exposure to chemicals that have not been adequately tested for developmental neurotoxicity has led to a silent pandemic. Further research is warranted to provide the evidence base that can ultimately lead to reducing or eliminating these potentially damaging exposures through changes to regulatory policy, consumer behavior, or dietary choices.
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West AE, Griffith EC, Greenberg ME. 2002. Regulation of transcription factors by neuronal activity. Nature Rev Neurosci 3(12):921–931.
Williams MK, Rundle A, Holmes D, Reyes M, Hoepner LA, Barr DB, et al. 2008. Changes in pest infestation levels, self-reported pesticide use, and permethrin exposure during pregnancy after the 2000–2001 U.S. Environmental Protection Agency restriction of organophosphates. Environ Health Perspect 116:1681–1688.
Winneke G. 2011. Developmental aspects of environmental neurotoxicology: lessons from lead and polychlorinated biphenyls. J Neurol Sci 308(1–2):9–15.
Woodruff TJ, Zota AR, Schwartz JM. 2011. Environmental chemicals in pregnant women in the United States: NHANES 2003–2004. Environ Health Perspect 119:878–885.
Yan Y, Yang Y, You J, Yang G, Xu Y, Huang N, et al. 2011. Permethrin modulates cholinergic mini-synaptic currents by partially blocking the calcium channel. Toxicol Lett 201(3):258–263.
Yang D, Howard A, Bruun D, Ajua-Alemanj M, Pickart C, Lein PJ. 2008. Chlorpyrifos and chlorpyrifos-oxon inhibit axonal growth by interfering with the morphogenic activity of acetylcholinesterase. Toxicol Appl Pharmacol 228(1):32–41.
Yang D, Lauridsen H, Buels K, Chi LH, La Du J, Bruun DA, et al. 2011. Chlorpyrifos-oxon disrupts zebrafish axonal growth and motor behavior. Toxicol Sci 121(1):146–159.
Zhang X, Daugherty SL, de Groat WC. 2010. Activation of CaMKII and ERK1/2 contributes to the time-dependent potentiation of Ca2+ response elicited by repeated application of capsaicin in rat DRG neurons. Am J Physiol Regul Integr Comp Physiol 300(3):R644–R654.
Zimmermann MB. 2007. The adverse effects of mild-to-moderate iodine deficiency during pregnancy and childhood: a review. Thyroid 17(9):829–835.
EHP is pleased to announce that "The Prevalence of Antibiotic-Resistant Staphylococcus aureus Nasal Carriage among Industrial Hog Operation Workers, Community Residents, and Children Living in Their Households: North Carolina, USA," published in EHP in the April 2017 issue, has been selected by the Children's Environmental Health Network (CEHN) as its October 2017 Article of the Month. (more…)
EHP is pleased to announce that "A Difference-in-Differences Approach to Assess the Effect of a Heat Action Plan on Heat-Related Mortality, and Differences in Effectiveness According to Sex, Age, and Socioeconomic Status (Montreal, Quebec)" has been awarded Honorable Mention as one of the Best Environmental Epidemiology Papers published in 2016. (more…)


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WITHDRAWING APPROVAL OF THE UNITED STATES FROM AGREEMENT ESTABLISHING THE WORLD TRADE ORGANIZATION -- (House of Representatives - June 09, 2005)
Mr. HOLT. Mr. Speaker, I rise today to express my concerns about H. Res. 27. H. Res. 27 would withdrawal the United States from participation in the World Trade Organization. I did not support a similar resolution five years ago, and I do not support this resolut ion today,
International trade is not just inevitable, it is a good thing. We live in a world today where more people can afford ever cheaper goods. But lowering the cost of goods and increasing their availability is not the single goal of trade. Trade done right helps lift the global standard of living and works to protect the irreplaceable environment we inherited. Trade is about values. I want to make sure the United States not only exports our-world class agriculture, but also our respect for the na tural environment and enforceable labor laws. We should make sure we export the goods we produce and not the workers who produce them.
That is why we must use the WTO to address these labor and environmental concerns. But if we walk away from the WTO, we won't be able to address any of these issues, Where else can we give voice to issues of child labor or environmentally destructive practices of some industries? The WTO-imperfect as it may be-is the forum that we, along with the other members of the int ernational community, established to enforce trade rules and more importantly allow for an open dialogue on the trade issues that concern us.
We need to realize that even if there are legitimate problems with the WTO, and I agree that some exist, the solution is not to unilaterally withdraw from the WTO. Withdrawing from the WTO would not help to solve any of these problems. Not one. We cannot stop trade, and we cannot end the global economy. What we can do is work within the World Trade Organization to address these concerns. We should not allow any others to dictate to us about what is in our national interest, but we must recognize that we cannot accomplish our national goals in isolation from the rest of the world. We can only work to protect American workers from anticompetitive practices of foreign countries from within the WTO, not by sitting on the sidelines. We should be working with our trade partners and with the WTO to enforce our existing trade rules. I urge my colleagues to vote against this resolution.

subset: commoncrawl


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ST. AUGUSTINE BEACH -- The owners of the Stumble In bar on State Road A1A face at least 11 counts of sign code violations, in part for flying pro-military flags after the start of the war in Iraq.
Despite spending thousands of dollars in legal fees and risking heavy fines, Richard and Tracey Whittaker are vowing to fight the St. Johns County sign ordinance.
County officials, meanwhile, are mulling over the definitions of a "patriotic flag."
"The flags are going to keep flying. And now it's become a constitutional thing," Richard Whittaker said.
The outside of the bar is lined with flags that are now attached to the building: U.S. Navy Seals, Rangers, Coast Guard and more. Between picnic tables, six American flags flap alongside Marine Corps, Army and POW flags. Other signs advertise charity work and the Ten Commandments.
The county sign ordinance limits the number of flags that can be flown to three, with the exception of American flags, which are not limited. Violating the ordinance can lead to fines of $108 per violation, according to the county code.
After a citation, the person is given a "reasonable" time to remove the flags, said St. Johns County Director of Development Services Michael Griffin. First comes a warning and a chance to comply. If the code isn't adhered to, the fine follows.
"We do enforce the flag ordinance and the banner ordinance. To my knowledge, this is as far as anyone's taken the flag issue," Griffin said.
Whittaker means to take it as far as he must to keep his military flags up. He and his wife feel like their right to freedom of speech has been trampled, he said. He said they feel Code Enforcement Officer Karen Bruner ignores other code violations and focuses unfairly on Stumble In.
Bruner declined to comment, deferring to Assistant County Attorney Laura Barrow. Barrow could not be reached for comment Wednesday afternoon.
The Whittakers also feel there's something wrong about being fined for posting a sign promoting charity work, like the Toys for Tots drop-off sign in front of their bar. Whittaker said his bar is now the headquarters for AmVet Post 0045, a group for military veterans who've been honorably discharged.
The two-month old post has already raised $1,200 for Billy Staley, a local veteran in a nursing home, according to finance officer Ken Osteen. They've also generated $200 for a local girl, and they hosted a Marine Corps ball this week, Osteen said.
"We live in America. We're supposed to be able to fly our flags and support our troops in the community. And help the needy," Osteen said. Getting fined for it is "not politically correct," he said.
Griffin agreed there is a "big sensitivity" to the subject now, given the troops overseas. He said the department is working with county attorneys to define or interpret a patriotic flag.
"It's very philosophical," Griffin said.
Meanwhile, Whittaker said he doesn't want to offend County Judge Charles Tinlin, who's hearing the cases -- which will be heard together -- at St. Johns County Courthouse.
But Whittaker wants to fly his flags. And he wants to fight the ordinance and the fines.
© 2017. All Rights Reserved. Contact Us


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Contact Information:
Jebel Ali Free Zone
PO Box 18022
United Arab Emirates
Danube Building Materials, the leader in construction, building materials and shop fitting industries, has revealed that the company posted a 31 per cent growth in revenue for the first two quarters of 2011 in the Kingdom of Bahrain, amidst the unrest that happened in early February. The figure reveals an increase in revenue for first half of 2011 as compared to same period in 2010. The company has reported that the country's move towards recovery is being bolstered by the entry of over BHD 614 million worth of new construction projects. Danube is aiming to take advantage of these new projects by leveraging its strong reputation as a premier provider of world class building materials across its rapidly growing customer base in the Kingdom.
According to recent performance reports, Danube suffered a key drop in business by 50 per cent during the unrest in February and March. However, strong government support and the move towards economic recovery helped the company bounce back in April to June, ultimately driving in the 31 per cent increase against the first half of 2010. The increase also complements a report from Research and Markets, a leading business research firm, showing that Bahrain's construction segment is likely to rebound soon with the emergence and influx of new projects across the country, The new projects are expected to help Bahrain regain its reputation as a key commercial and financial hub for the Middle East. The report further shows that Bahrain is one of the very few countries that have managed to key in positive economic growth despite the impact of the recent economic downturn.
"These are vibrant times for Bahrain, which is currently witnessing a key influx of construction projects that can ultimately give the country a needed push towards economic recovery, " said Rizwan Sajan, Founder & Chairman, Danube Building Materials. "We are looking to play a major role in this development by living up to our reputation as a premier provider of world class high quality building materials across these major projects."
Reports have also shown an upsurge in opportunities in the country's real estate segment. In fact, Bahrain's commercial rental rates have stabilized and are expected to track sideways for the duration of the current year. 2012 has been forecasted to drive in a five per cent increase in most of the sub-sectors in the Kingdom's three cities, except for retail space in Manama and Muharraq, which has been having a more delayed response to the downturn. Analysts have shared that the Bahraini government's move to introduce general reforms after the unrest has resulted in bringing back confidence to various institutions. To date, the introduced reforms are helping create a more competitive market atmosphere for Bahrain.
"Bahrain continues to be an important market for us and we are confident to key in more sustainable growth for the next half of 2011. Rest assured, we will remain true to our commitment of providing world class building materials and home interior products through our 2 branches in the country," concluded Rizwan Sajan.
Danube currently operates two BUILDMART retail showrooms in Bahrain, strategically located in Bahrain Mall and ٍSalmabad. The company will soon be opening a new Danube Building Materials Showroom in Bahrain which is set to open during the first week of October this year.


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Nebraska CPA Firms
Search for the Best CPA Firms in Nebraska
Find the best CPA in Nebraska quick and easy. Use our comprehensive search directories to get company and contact information for CPA firms in your area. Compare services and rates before deciding which CPA is the best fit for you. Choose a city from the list below to find reliable, affordable CPA firms in Nebraska.


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[photogallerylink id=24074]
There is a special place in my heart for[lastfm link_type="artist_info"] Kid Cudi[/lastfm] and his lost soul/psychedelic/punk rock ways, so his new music from his alternative pop effort, [lastfm link_type="artist_info"]WZRD[/lastfm], with producer [lastfm link_type="artist_info"]Dot Da Geniu[/lastfm]s is highly anticipated even if it's nothing like his old music.
[pullquote quote="WZRD is bringin Punk Rock back with a whole new energy and sound." credit="Kid Cudi"]Cudder gave away his first single from his debut album due to be released on Cudi's birthday, January 30th. The experimental Aquarius definitely lived up to the innovate nature of his star sign with the trippy "Brake."
According to Rap-Up, Cudi declared, "WZRD is bringin Punk Rock back with a whole new energy and sound…Tonight, you will all witness the new chapter, the new journey. Music will never be the same…"
If you want the song, Kid Cudi says it's yours for the taking.
- What do you think of WZRD? Let us know in the comments!
[Source: Rap-Up]


text: Hello, I'd just like to call attention to a few recent blog posts containing myself and my friend Creighton's entry into the ICFP '07 programming competition. Mainly because I'm looking to find someone who knows Haskell and the contest so they can tell me where my bug is :) Also, if anyone wants to see a Haskell approach towards the contest's DNA to RNA conversion, here you go. It's not always idiomatic HAskell, but that's what happens in a 72 hour contest. Any feedback would be appreciated. The bug (I believe) occurs somewhere in the implementation of "matchpattern", which is in the fourth URL. Bellow are the URLs of the Haskell source code (with comments included as blog posts). We only got as far as the DNA to RNA conversion algorithm. -Antoine http://panicsonic.blogspot.com/2007/07/icfp-07-post-mortem-i.html http://panicsonic.blogspot.com/2007/07/icfp-07-post-mortem-ii.html http://panicsonic.blogspot.com/2007/07/icfp-07-post-mortem-iii.html http://panicsonic.blogspot.com/2007/07/icfp-07-post-mortem-iv.html


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Inner and Outer Peace Through Meditation
Monday, Aug. 1, 2011, 3:48 p.m.Shepherd Park (Juanita E. Thornton) Library
Inner and Outer Peace Through Meditation
We have added a fourth meditation class, which will meet on August 6, at 1 p.m. in the activity room at Juanita E. Thornton/Shepherd Park Library.
David Newcomb will be discussing the importance of having a teacher, and we will practice meditation.
Please join us!


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NEW YORK --- Toyota recalled 1.33 million Corolla sedans and Matrix hatchbacks in the U.S. and Canada on Thursday because their engines might stall, the latest in a string of quality problems at the Japanese automaker.
The recall covers vehicles from the 2005-2008 model years sold in the U.S. and Canada. Three accidents and one minor injury have been reported, though Toyota said a link to the engine issue has not been confirmed.
Toyota's latest recall is one of its largest since it began recalling cars and trucks last October. The automaker has now recalled more than 10 million vehicles worldwide for problems ranging from faulty gas pedals and floor mats that can trap accelerators, to problems with its Prius hybrid.
Toyota said Corollas and Matrixes equipped with 1ZZ-FE engines might contain a defective engine control module, the computer that regulates the performance of the engine. In some cases, a crack might develop on the module's circuit board, which could prevent the engine from starting or could cause harsh shifting or an engine stall.
Separately, General Motors Co. is recalling 200,000 Pontiac Vibes in North America because of the same problem, GM spokesman Alan Adler said. The Vibe is similar to the Matrix and was built under a joint venture between Toyota and GM at a now-closed factory in Fremont, Calif.
Both automakers said they will replace the engine control modules on the recalled vehicles at no charge. The companies will begin mailing notifications to owners of the affected vehicles in mid-September.
The engine control module with the possible defect was manufactured by Delphi Corp., a large auto parts supplier headquartered in Troy, Mich., according to documents filed with federal regulators.
Toyota has been more aggressive in its pace of recalls in recent months. Its last recall was in late July, when the automaker said it would fix half a million cars, mostly Avalon sedans, over a steering issue.
U.S. regulators hit Toyota with a $16.4 million fine earlier this year for failing to promptly tell the government about its car defects. Toyota has been working to overhaul its quality controls and respond more aggressively to customer complaints in the fallout of its recall crisis.
The National Highway Traffic Safety Administration has been investigating the possibility of engine stalling in the Corolla and Matrix models since late November. On Tuesday, the traffic safety agency said it had intensified its investigation.


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Isn't great to get something for nothing! I just got 2 pieces of Vetbed for our 2 yorkies and they came in these very good quality thick plastic holdalls, zips & carryhandles. They will be ideal for transporting applique bits & pieces, storing strips, etc, etc. Cannot imagine what a craft shop here would charge for the like!
Have you got a good freebie in the sewing room?


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Donato Polignonewrote a review of La Sportiva Mantis Climbing Shoe on December 27, 2009
La Sportiva Mantis - Luv 'em
After learning how to climb with the La Sportiva Cliff shoe, the standard rental shoe in climbing gyms. i decided to upgrade my shoe. After trying on countless pairs of shoes i found the La Sportiva Mantis. Yes, they are a bit uncomfortable at first but break in quickly, maybe a few hours of wearing them. I have much better feel on smaller foot holds even though they come with a velcro fit system they seem to have molded to my feet even better than my old pair of Cliff shoes. I'm a 5.10 climber and working to get to 5.11's . I think this is the perfect shoe to get me there. Now, the rest is up to me. I highly recommend this shoe, it has all day wearing comfort and i don't have to take them off to belay!


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Sunrise from my flight's gate in Amsterdam.
After one very early flight from Cologne to Amsterdam, another flight from Amsterdam to Oslo, a four hour wait in Oslo and a five hour train ride through Norway, I finally arrived at the train station to be greeted by Sarah and her husband.
I was so happy to see them that the exhaustion from traveling over 14 hours was instantly wiped away.
Thursday was practically over by the time we arrived back at their home, but we made the most catching up over a traditional Norwegian evening meal before calling it a night.
Friday morning presented the opportunity to follow Sarah through her school day. We ate breakfast, she packed a lunch, then we met with her two neighbor boys to take the bus to school.
Want to know another example of what a great human being Sarah is? She learned and then taught Braille to the younger brother who has become blind. Yeah, she's awesome like that.
It was such a privilege to be welcomed into Sarah's schools and get to learn about the Norwegian school system. One of the interesting differences is that the children have a short break time between each and every lesson. I imagine every child I've ever taught could benefit from a short break between lessons.
I spent the first lesson of the day in Sarah's 4-5th grade English lesson before heading across the school yard to the preschool.
After playing in the preschool and gymnasium with the little kids, we all had a nearly identical lunch of bread or crackers with either cheese or sliced meat. Sarah got all fancy and even packed us vegetables and hard boiled eggs. Apparently, Norwegians like to eat alike.
The school day ends early in Norway so as Sarah carried on with after school supervision, I walked back to her home, taking photos along the way.
When I arrived Thursday night, it was too dark to see the landscape, but in the light of day, I felt absolutely dwarfed by the greatness of the surrounding mountains.
Sarah's school is probably about 1km away from her home. It was a bit drizzly and overcast on the walk back, but the atmosphere was peaceful and calming.
Lucky for Sarah and Aug, they were able to find a beautiful home right beside the water.
As if waking up every day to this amazing kitchen wasn't enough, check out the view!
Sarah and Aug have done such a wonderful job creating a warm, cozy, welcoming home. A lovely home to accompany their lovely personalities!
Once Sarah returned from school, we appropriately dressed for my first ever "real hike."
What I've been calling hiking all my life is a walk in the park compared to the hiking Sarah does in Norway.
See that big waterfall coming down from the mountain? That's called Haremdalen, and it was our first hike.
Did I mention that Sarah is 29 weeks pregnant? After working all day, this lady was hiking up mountains like a goat. As Sarah put it, she was active before she became pregnant so it has been easy to have an active pregnancy.
We climbed through mossy trails and even had to cross the rushing waterfall at one point, but Sarah expertly guided me along.
The trail was very steep, but she encouraged me the whole time.
A few times along the hike, I had to ask my pregnant friend to slow down so I could take a breather.
Sarah kindly obliged each and every time.
As we climbed higher and higher, the view became more and more amazing.
Before I knew it, we were able to look into the valley at the miniscule town below, and take in the massive mountains rising in every direction.
Although the sunlight started to fade and we needed to head back down before reaching the book at the tip-top, I still feel proud to say that on my 26th birthday, I climbed a mountain with the most fit soon-to-be-mama in Norway!
After our hike down the mountain, Sarah made a delicious traditional fish dish for my birthday dinner.
This baked dish was so yummy, I plan on making it with Sebastian later in the week!
After dinner, we relaxed in their hot tub, watched How I Met Your Mother, then ate cake. A great way to celebrate the day of my birth!


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Newron is becoming a leader in the development of innovative therapies for Central Nervous System (CNS) disorders and pain and is committed to improving the quality of life of patients around the world. Our team has a proven track record of bringing drugs to market in these areas and has built a well-balanced pipeline that embodies highly innovative compounds at different stages of development. Our search and development resources are focused on delivering novel therapies for rare CNS diseases.
Following the positive CHMP opinion in December 2014, the EU Commission approved Xadago® (safinamide) for mid-late stage PD patients on Februray 2015.
An MAA has been submitted to Swissmedic in March, 2014, by Zambon and obtained the approval for use in Parkinson's disease in November 2015.
The New Drug Application (NDA) to the U.S. FDA has been accepted for filing in early March 2015, after being re-submitted by Newron on Dec. 26, 2014.
Newron is working towards global approval of the compound, together with its partners.


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ServerSpyIRC is a Perl IRC bot (based on Net::IRC) which can retrieve information about Quake2, Quake3, and Halflife/CS online game servers. It supports many search functions, scanning of posted IP addresses, simple clanwar outputs, user management, bookable functions, and server lists.
Duke Nukem Forever is part four in a series of PC games featuring Duke Nukem as the hero. Parts one (Duke Nukem) and two (Duke Nukem 2) were sidescrollers/platform games, and part three, Duke Nukem 3D, was an FPS. Duke Nukem 3D became one of the top-selling games of all time, and is a very important part of FPS gaming history; it is one of the few "legendary" titles, together with Quake and Doom. The game is one of the most sophisticated FPS games ever. It features everything the Unreal engine has, but also features things like LOD, skeletal animation, and motion capture, for an optimal playing experience.
Excalibur: Morgana's Revenge (EMR) is a first-person shooter game with an epic and in-depth story line. The player travels through time in the Jurassic period, Camelot period, and into the future to chase down Morgana. Using the Aleph One engine, EMR creates an amazing new world, making it an entirely fun and unique gaming experience.
A free H.323 gatekeeper.
Structure parameter inference approach for endocrine feedback control.


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Three-year-old Pinker Pinker ($6.50) came from second-last in the Angus Armanaso Stakes to beat home Peter Moody's Sayahailmary ($9) by 1 ¼ while Sistine Angel ($8) finished off the trifecta the same distance away third.
Pinker Pinker won her first black-type in a blistering time of 1:21.46, just 0.26 of a second outside of the race record set by Exceed And Excel.
After the win, Pinker Pinker's third from eight starts, Eurell hinted at a trip to Sydney for his talented runner.
Pinker Pinker resumed for the season with a third behind Miss Gai Flyer in the Listed Kevin Hayes Stakes (1200m) at Caulfield on February 12.
Eurell may keep Pinker Pinker in Melbourne for her next start in the Group 3 Matron Stakes (1600m) at Flemington's Super Saturday of Racing on March 12.
Then a trip to Sydney is likely where she could target the Group 1 Coolmore Classic (1500m) at Rosehill on March 19.
If she continues to show form other options for Pinker Pinker include the Group 1 Storm Queen Stakes (2000m) at Rosehill on Golden Slipper Day, April 2 and the Group 1 Australian Oaks (2400m) at Randwick on April 16.
To get behind Pinker Pinker for her next start at the best possible prices, make sure you have an account open with premier online bookmaker Luxbet!
Photo courtesy (c) Taron Clarke Photography


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Education brings promise to Malaysia's remote interior
To celebrate the 20th anniversary of the Convention on the Rights of the Child, UNICEF features a series of stories about this landmark international agreement on the basic human rights of all children – including progress made and challenges that remain.
By Steve Nettleton
LONG LUTENG, Sarawak, 20 November 2009 – Meriam Anyie was born deep in the rainforest of Malaysian Borneo. As members of the Penan ethnic group, a nomadic indigenous people in the state of Sarawak, she and her family spent most of their life in the jungle, never living in a permanent home throughout her childhood.
Today, however, nearly all of the 10,000 Penans in Sarawak have abandoned their ancestral nomadic ways to live in towns and villages.
Ms. Anyie and her husband are raising four children in Long Luteng, a small village situated on rolling hills of ancient forest. They are hours from the nearest major city, Miri, by boat or four-wheel-drive vehicle.
And for the first time in her life, Ms. Anyie, who is in her thirties, is going to school.
Reaching the 'original people'
While Malaysia has succeeded in raising attendance and the quality of education nationwide, it is still tackling lower-than-average enrolment rates in remote rural areas, where children's education is generally dismissed in favour of earning money by working.
Ms. Anyie has enrolled in an adult literacy program called KEDAP. It is a pilot project of the Malaysian Ministry of Education to reach the remote Orang Asli and Penan communities of Malaysia.
By providing a basic education for parents, KEDAP aims to help them understand the value of schooling for their children.
"Now I know the alphabet and I can read, write and count to 10, to 20. Now I can help my children a little bit with their school work," says Ms. Anyie.
Education in demand
Long Luteng Primary School faces challenges unlike schools in many more accessible areas. Some students must travel hours on foot to attend class. Still, the adult literacy class is in such high demand in Long Luteng that many parents are on a waiting list.
Its success comes on the heels of a long-running effort, supported by UNICEF, to boost enrolment rates and educational achievement in rural areas – particularly among Orang Asli children in Peninsular Malaysia and indigenous children in distant areas of Malaysian Borneo's Sabah and Sarawak States.
The initiative is in keeping with the principles of the Convention on the Rights of the Child (CRC). Article 29 of the Convention establishes every child's right to an education that helps to develop his or her personality, talents and abilities to their fullest potential. Article 30 of the CRC protects the rights of minority and indigenous children – including the right to learn about and practice their own culture, language and religion.
'I want them to be successful'
Principal Edward Nullie Anggun boasts that the Long Luteng school has almost 100 per cent attendance. Under the government's incentive program to encourage educational opportunities for Penan children, the school provides its students with free education, including textbooks and school uniforms.
Principal Edwards describes his message to students: "You can only change through education, because with a good education you can get a better job. With a better job, then you can have a better life," he says.
As more parents like Ms. Anyie learn the importance of education, more children will be able to study and increase their potential.
"My hope is for my children to have ambition in their hearts," says Ms. Anyie. "I want them to be successful. Maybe my daughter can be a nurse … My son Andi can be a teacher, … I will be very happy."
Video: Penan Education
20 November 2009:
Programs to promote education for indigenous people in Malaysia.
All Children, Everywhere
Strategy for basic education and gender equality, 2009. Read
Education in Malaysia: Real Lives
20 November 2009:
2 September 2008:
31 August 2008:
29 February 2008:
Early boost for Orang Asli children
Newsline: Education
22 September 2010:
Raising the profile of education
8 September 2010:
Empowering children and communities
20 November 2009:
Without education, the future is dark
1 September 2009:
MPRN supports literacy for children
31 August 2009:
Education for every child, everywhere