Autism is a heterogeneous disorder with genetic and environmental factors likely contributing to its origins. Examination of hazardous pollutants has suggested the importance of air toxics in the ...etiology of autism, yet little research has examined its association with local levels of air pollution using residence-specific exposure assignments.
To examine the relationship between traffic-related air pollution, air quality, and autism.
This population-based case-control study includes data obtained from children with autism and control children with typical development who were enrolled in the Childhood Autism Risks from Genetics and the Environment study in California. The mother's address from the birth certificate and addresses reported from a residential history questionnaire were used to estimate exposure for each trimester of pregnancy and first year of life. Traffic-related air pollution was assigned to each location using a line-source air-quality dispersion model. Regional air pollutant measures were based on the Environmental Protection Agency's Air Quality System data. Logistic regression models compared estimated and measured pollutant levels for children with autism and for control children with typical development.
Case-control study from California.
A total of 279 children with autism and a total of 245 control children with typical development.
Crude and multivariable adjusted odds ratios (AORs) for autism.
Children with autism were more likely to live at residences that had the highest quartile of exposure to traffic-related air pollution, during gestation (AOR, 1.98 95% CI, 1.20-3.31) and during the first year of life (AOR, 3.10 95% CI, 1.76-5.57), compared with control children. Regional exposure measures of nitrogen dioxide and particulate matter less than 2.5 and 10 μm in diameter (PM2.5 and PM10) were also associated with autism during gestation (exposure to nitrogen dioxide: AOR, 1.81 95% CI, 1.37-3.09; exposure to PM2.5: AOR, 2.08 95% CI, 1.93-2.25; exposure to PM10: AOR, 2.17 95% CI, 1.49-3.16) and during the first year of life (exposure to nitrogen dioxide: AOR, 2.06 95% CI, 1.37-3.09; exposure to PM2.5: AOR, 2.12 95% CI, 1.45-3.10; exposure to PM10: AOR, 2.14 95% CI, 1.46-3.12). All regional pollutant estimates were scaled to twice the standard deviation of the distribution for all pregnancy estimates.
Exposure to traffic-related air pollution, nitrogen dioxide, PM2.5, and PM10 during pregnancy and during the first year of life was associated with autism. Further epidemiological and toxicological examinations of likely biological pathways will help determine whether these associations are causal.
Aptamer-related technologies represent a revolutionary advancement in the capacity to rapidly develop new classes of targeting ligands. Structurally distinct RNA and DNA oligonucleotides, aptamers ...mimic small, protein-binding molecules and exhibit high binding affinity and selectivity. Although their molecular weight is relatively small-approximately one-tenth that of monoclonal antibodies-their complex tertiary folded structures create sufficient recognition surface area for tight interaction with target molecules. Additionally, unlike antibodies, aptamers can be readily chemically synthesized and modified. In addition, aptamers' long storage period and low immunogenicity are favorable properties for clinical utility. Due to their flexibility of chemical modification, aptamers are conjugated to other chemical entities including chemotherapeutic agents, siRNA, nanoparticles, and solid phase surfaces for therapeutic and diagnostic applications. However, as relatively small sized oligonucleotides, aptamers present several challenges for successful clinical translation. Their short plasma half-lives due to nuclease degradation and rapid renal excretion necessitate further structural modification of aptamers for clinical application. Since the US Food and Drug Administration (FDA) approval of the first aptamer drug, Macugen
(pegaptanib), which treats wet-age-related macular degeneration, several aptamer therapeutics for oncology have followed and shown promise in pre-clinical models as well as clinical trials. This review discusses the advantages and challenges of aptamers and introduces therapeutic aptamers under investigation and in clinical trials for cancer treatments.
Background: Little is known about environmental causes and contributing factors for autism. Basic science and epidemiologic research suggest that oxidative stress and inflammation may play a role in ...disease development. Traffic-related air pollution, a common exposure with established effects on these pathways, contains substances found to have adverse prenatal effects. Objectives: We examined the association between autism and proximity of residence to freeways and major roadways during pregnancy and near the time of delivery, as a surrogate for air pollution exposure. Methods: Data were from 304 autism cases and 259 typically developing controls enrolled in the Childhood Autism Risks from Genetics and the Environment (CHARGE) study. The mother's address recorded on the birth certificate and trimester-specific addresses derived from a residential history obtained by questionnaire were geocoded, and measures of distance to freeways and major roads were calculated using ArcGIS software. Logistic regression models compared residential proximity to freeways and major roads for autism cases and typically developing controls. Results: Adjusting for sociodemographic factors and maternal smoking, maternal residence at the time of delivery was more likely be near a freeway (< 309 m) for cases than for controls odds ratio (OR) = 1.86; 95% confidence interval (CI), 1.04-3.45. Autism was also associated with residential proximity to a freeway during the third trimester (OR = 2.22; CI, 1.16–4.42). After adjustment for socioeconomic and sociodemographic characteristics, these associations were unchanged. Living near other major roads at birth was not associated with autism. Conclusions: Living near a freeway was associated with autism. Examination of associations with measured air pollutants is needed.
To determine the diagnostic and prognostic performance of serum neurofilament light chain (NFL) in amyotrophic lateral sclerosis (ALS).
This single-centre, prospective, longitudinal study included ...the following patients: 124 patients with ALS; 50 patients without neurodegenerative diseases; 44 patients with conditions included in the differential diagnosis of ALS (disease controls); 65 patients with other neurodegenerative diseases (20 with frontotemporal dementia, 20 with Alzheimer's disease, 19 with Parkinson's disease, 6 with Creutzfeldt-Jakob disease (CJD)). Serum NFL levels were measured using the ultrasensitive single molecule array (Simoa) technology.
Serum NFL levels were higher in ALS in comparison to all other categories except for CJD. A cut-off level of 62 pg/mL discriminated between ALS and all other conditions with 85.5% sensitivity (95% CI 78% to 91.2%) and 81.8% specificity (95% CI 74.9% to 87.4%). Among patients with ALS, serum NFL correlated positively with disease progression rate (r
=0.336, 95% CI 0.14 to 0.506, p=0.0008), and higher levels were associated with shorter survival (p=0.0054). Serum NFL did not differ among patients in different ALS pathological stages as evaluated by diffusion-tensor imaging, and in single patients NFL levels were stable over time.
Serum NFL is increased in ALS in comparison to other conditions and can serve as diagnostic and prognostic biomarker. We established a cut-off level for the diagnosis of ALS.
Neurofilaments are elevated in the cerebrospinal fluid (CSF) and serum of amyotrophic lateral sclerosis (ALS) patients. However, timing of this increase is unknown. To characterize the premanifest ...disease phase, we performed a cross‐sectional study on asymptomatic (n = 12) and symptomatic (n = 64) ALS mutation carriers and family controls (n = 19). Neurofilaments NF‐L (neurofilament–light chain) and pNF‐H (phosphorylated neurofilament–heavy chain) are normal before symptom onset and increased by at least an order of magnitude at early symptom onset in CSF (pNF‐H) or serum and CSF (NF‐L). Thus, blood and CSF neurofilament levels are linked to the symptomatic phase of ALS and might serve as objective markers of structural damage to the nervous system. ANN NEUROL 2016;79:152–158
Prenatal exposure to air pollution has been associated with childhood respiratory disease and other adverse outcomes. Epigenetics is a suggested link between exposures and health outcomes.
We aimed ...to investigate associations between prenatal exposure to particulate matter (PM) with diameter Formula: see text (Formula: see text) or Formula: see text (Formula: see text) and DNA methylation in newborns and children.
We meta-analyzed associations between exposure to Formula: see text (Formula: see text) and Formula: see text (Formula: see text) at maternal home addresses during pregnancy and newborn DNA methylation assessed by Illumina Infinium HumanMethylation450K BeadChip in nine European and American studies, with replication in 688 independent newborns and look-up analyses in 2,118 older children. We used two approaches, one focusing on single cytosine-phosphate-guanine (CpG) sites and another on differentially methylated regions (DMRs). We also related PM exposures to blood mRNA expression.
Six CpGs were significantly associated false discovery rate (FDR) Formula: see text with prenatal Formula: see text and 14 with Formula: see text exposure. Two of the Formula: see text CpGs mapped to FAM13A (cg00905156) and NOTCH4 (cg06849931) previously associated with lung function and asthma. Although these associations did not replicate in the smaller newborn sample, both CpGs were significant (Formula: see text) in 7- to 9-y-olds. For cg06849931, however, the direction of the association was inconsistent. Concurrent Formula: see text exposure was associated with a significantly higher NOTCH4 expression at age 16 y. We also identified several DMRs associated with either prenatal Formula: see text and or Formula: see text exposure, of which two Formula: see text DMRs, including H19 and MARCH11, replicated in newborns.
Several differentially methylated CpGs and DMRs associated with prenatal PM exposure were identified in newborns, with annotation to genes previously implicated in lung-related outcomes. https://doi.org/10.1289/EHP4522.
Biomarkers for the diagnosis of motoneuron diseases (MND) are urgently needed to improve the diagnostic pathway, patient stratification and monitoring. The aim of this study was to validate candidate ...markers for MND in cerebrospinal fluid (CSF) and specify cut-offs based on large patient cohorts by especially considering patients who were seen under the initial differential diagnosis (MND mimics).
In a prospective study, we investigated CSF of 455 patients for neurofilament light chain (NfL), phosphorylated heavy chain (pNfH), tau protein (Tau) and phospho-tau protein (pTau). Analysed cohorts included patients with apparently sporadic and familial amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS) (MND, n=253), MND mimics (n=85) and neurological control groups. Cut-off values were specified, and diagnostic performance and correlation with progression were analysed.
Nfs were significantly higher in the MND group compared to the control groups, whereas Tau and pTau did not differ. At a cut-off level of 2200 pg/mL for NfL, a 77% diagnostic sensitivity (CI 71% to 82%), 85% specificity (CI 79% to 90%) and 87% positive predictive value (PPV) (CI 81% to 91%) were achieved. For pNfH, we calculated 83% sensitivity (CI 78% to 88%), 77% specificity (CI 71% to 83%) and 82% PPV (CI 77% to 86%) at 560 pg/mL. There were no significant differences between sporadic and genetic ALS or PLS. Nf levels were elevated at early disease stage, and correlated moderately with MND progression and duration.
Neurofilaments in CSF have a high relevance for the differential diagnosis of MNDs and should be included in the diagnostic work-up of patients. Their value as prognostic markers should be investigated further.
Information on circulating miRNAs in frontotemporal lobar degeneration is very limited and conflicting results have complicated an interpretation in Alzheimer's disease thus far. In the present study ...we I) collected samples from multiple clinical centers across Germany, II) defined 3 homogenous patient groups with high sample sizes (bvFTD n = 48, AD n = 48 and cognitively healthy controls n = 44), III) compared expression levels in both CSF and serum samples and IV) detected a limited set of miRNAs by using a MIQE compliant protocol based on SYBR-green miRCURY assays that have proven reliable to generate reproducible results. We included several quality controls that identified and reduced technical variation to increase the reliability of our data. We showed that the expression levels of circulating miRNAs measured in CSF did not correlate with levels in serum. Using cluster analysis we found expression pattern in serum that, in part, reflects the genomic organization and affiliation to a specific miRNA family and that were specifically altered in bvFTD, AD, and control groups. Applying factor analysis we identified a 3-factor model characterized by a miRNA signature that explained 80% of the variance classifying healthy controls with 97%, bvFTD with 77% and AD with 72% accuracy. MANOVA confirmed signals like miR-320a and miR-26b-5p at BH corrected significance that contributed most to discriminate bvFTD cases with 96% sensitivity and 90% specificity and AD cases with 89% sensitivity and specificity compared to healthy controls, respectively. Correlation analysis revealed that miRNAs from the 3-factor model also correlated with levels of protein biomarker amyloid-beta1-42 and phosphorylated neurofilament heavy chain, indicating their potential role in the monitoring of progressive neuronal degeneration. Our data show that miRNAs can be reproducibly measured in serum and CSF without pre-amplification and that serum includes higher expressed signals that demonstrate an overall better ability to classify bvFTD, AD and healthy controls compared to signals detected in CSF.
There is a need to consider paternal contributions to autism spectrum disorder (ASD) more strongly. Autism etiology is complex, and heritability is not explained by genetics alone. Understanding ...paternal gametic epigenetic contributions to autism could help fill this knowledge gap. In the present study, we explored whether paternal autistic traits, and the sperm epigenome, were associated with autistic traits in children at 36 months enrolled in the Early Autism Risk Longitudinal Investigation (EARLI) cohort. EARLI is a pregnancy cohort that recruited and enrolled pregnant women in the first half of pregnancy who already had a child with ASD. After maternal enrollment, EARLI fathers were approached and asked to provide a semen specimen. Participants were included in the present study if they had genotyping, sperm methylation data, and Social Responsiveness Scale (SRS) score data available. Using the CHARM array, we performed genome-scale methylation analyses on DNA from semen samples contributed by EARLI fathers. The SRS-a 65-item questionnaire measuring social communication deficits on a quantitative scale-was used to evaluate autistic traits in EARLI fathers (n = 45) and children (n = 31). We identified 94 significant child SRS-associated differentially methylated regions (DMRs), and 14 significant paternal SRS-associated DMRs (fwer p < 0.05). Many child SRS-associated DMRs were annotated to genes implicated in ASD and neurodevelopment. Six DMRs overlapped across the two outcomes (fwer p < 0.1), and, 16 DMRs overlapped with previous child autistic trait findings at 12 months of age (fwer p < 0.05). Child SRS-associated DMRs contained CpG sites independently found to be differentially methylated in postmortem brains of individuals with and without autism. These findings suggest paternal germline methylation is associated with autistic traits in 3-year-old offspring. These prospective results for autism-associated traits, in a cohort with a family history of ASD, highlight the potential importance of sperm epigenetic mechanisms in autism.
PDF
