Autism with intellectual disability is associated with increased levels of maternal cytokines and chemokines during gestation.

Immune abnormalities have been described in some individuals with autism spectrum disorders (ASDs) as well as their family members. However, few studies have directly investigated the role of prenatal cytokine and chemokine profiles on neurodevelopmental outcomes in humans. In the current study, we characterized mid-gestational serum profiles of 22 cytokines and chemokines in mothers of children with ASD (N=415), developmental delay (DD) without ASD (N=188), and general population (GP) controls (N=428) using a bead-based multiplex technology. The ASD group was further divided into those with intellectual disabilities (developmental/cognitive and adaptive composite score<70) (ASD+ID, N=184) and those without (composite score⩾70) (ASD-noID, N=201). Levels of cytokines and chemokines were compared between groups using multivariate logistic regression analyses, adjusting for maternal age, ethnicity, birth country and weight, as well as infant gender, birth year and birth month. Mothers of children with ASD+ID had significantly elevated mid-gestational levels of numerous cytokines and chemokines, such as granulocyte macrophage colony-stimulating factor, interferon-γ, interleukin-1α (IL-1α) and IL-6, compared with mothers of children with either ASD-noID, those with DD, or GP controls. Conversely, mothers of children with either ASD-noID or with DD had significantly lower levels of the chemokines IL-8 and monocyte chemotactic protein-1 compared with mothers of GP controls. This observed immunologic distinction between mothers of children with ASD+ID from mothers of children with ASD-noID or DD suggests that the intellectual disability associated with ASD might be etiologically distinct from DD without ASD. These findings contribute to the ongoing efforts toward identification of early biological markers specific to subphenotypes of ASD.

Increased female autosomal burden of rare copy number variants in human populations and in autism families.

Autosomal genetic variation is presumed equivalent in males and females and makes a major contribution to disease risk. We set out to identify whether maternal copy number variants (CNVs) contribute to autism spectrum disorders (ASDs). Surprisingly, we observed a higher autosomal burden of large, rare CNVs in females in the population, reflected in, but not unique to, ASD families. Meta-analysis across control data sets confirms female excess in CNV number (P=2.1 × 10(-5)) and gene content (P=4.1 × 10(-3)). We additionally observed CNV enrichment in ASD mothers compared with control mothers (P=0.03). We speculate that tolerance for CNV burden contributes to decreased female fetal loss in the population and that ASD-specific maternal CNV burden may contribute to high sibling recurrence. These data emphasize the need for study of familial CNV risk factors in ASDs and the requirement of sex-matched comparisons.

CFTR mutation analysis and haplotype associations in CF patients.

Most newborn screening (NBS) laboratories use second-tier molecular tests for cystic fibrosis (CF) using dried blood spots (DBS). The Centers for Disease Control and Prevention's NBS Quality Assurance Program offers proficiency testing (PT) in DBS for CF transmembrane conductance regulator (CFTR) gene mutation detection. Extensive molecular characterization on 76 CF patients, family members or screen positive newborns was performed for quality assurance. The coding, regulatory regions and portions of all introns were sequenced and large insertions/deletions were characterized as well as two intronic di-nucleotide microsatellites. For CF patient samples, at least two mutations were identified/verified and four specimens contained three likely CF-associated mutations. Thirty-four sequence variations in 152 chromosomes were identified, five of which were not previously reported. Twenty-seven of these variants were used to predict haplotypes from the major haplotype block defined by HapMap data that spans the promoter through intron 19. Chromosomes containing the F508del (p.Phe508del), G542X (p.Gly542X) and N1303K (p.Asn1303Lys) mutations shared a common haplotype subgroup, consistent with a common ancient European founder. Understanding the haplotype background of CF-associated mutations in the U.S. population provides a framework for future phenotype/genotype studies and will assist in determining a likely cis/trans phase of the mutations without need for parent studies.

Hormonal evidence supports the theory of selection in utero.

OBJECTIVES: Antagonists in the debate over whether the maternal stress response during pregnancy damages or culls fetuses have invoked the theory of selection in utero to support opposing positions. We describe how these opposing arguments arise from the same theory and offer a novel test to discriminate between them. Our test, rooted in reports from population endocrinology that human chorionic gonadotropin (hCG) signals fetal fitness, contributes not only to the debate over the fetal origins of illness, but also to the more basic literature concerned with whether and how natural selection in utero affects contemporary human populations. METHODS: We linked maternal serum hCG measurements from prenatal screening tests with data from the California Department of Public Health birth registry for the years 2001-2007. We used time series analysis to test the association between the number of live-born male singletons and median hCG concentration among males in monthly gestational cohorts. RESULTS: Among the 1.56 million gestations in our analysis, we find that median hCG levels among male survivors of monthly conception cohorts rise as the number of male survivors falls. RESULTS: Elevated median hCG among relatively small male birth cohorts supports the theory of selection in utero and suggests that the maternal stress response culls cohorts in gestation by raising the fitness criterion for survival to birth.

Identification and sequence analysis of grain softness protein in selected wheat, rye and triticale.

Grain softness protein (GSP) is an important protein for overcoming milling and grain defenses in the innate immunity systems of cereals. The objective of this study was to evaluate and understand GSP sequences in selected wheat, rye and triticale. Using sequences for this gene from a sequence database, we performed clustering analysis to compare the sequences obtained from 3 germplasms with other studied sequences for GSP. The maximum difference between the Hirmand GSP genotype in wheat and the database sequences was 23% in EF109396 and EF109399. Most amino acid variation between the GSP sequences involved the same amino acids. The Nikita rye GSP gene showed 64% identity with DQ269918 and AY667063. The isoelectric point in the GSP of wheat and Lasko triticale was significantly higher than that of rye GSP. In addition, parameters such as optical density, grand average of hydrophobicity, percentage of hydrophobicity and hydrophilic amino acids, and number of alpha helices and beta sheets in GSP were similar in wheat and triticale but not in wheat and rye.

Graphene on insulating crystalline substrates.

We show that it is possible to prepare and identify ultra-thin sheets of graphene on crystalline substrates such as SrTiO(3), TiO(2), Al(2)O(3) and CaF(2) by standard techniques (mechanical exfoliation, optical and atomic force microscopy). On the substrates under consideration we find a similar distribution of single layer, bilayer and few-layer graphene and graphite flakes as with conventional SiO(2) substrates. The optical contrast C of a single graphene layer on any of those substrates is determined by calculating the optical properties of a two-dimensional metallic sheet on the surface of a dielectric, which yields values between C = -1.5% (G/TiO(2)) and C = -8.8% (G/CaF(2)). This contrast is in reasonable agreement with experimental data and is sufficient to make identification by an optical microscope possible. The graphene layers cover the crystalline substrate in a carpet-like mode and the height of single layer graphene on any of the crystalline substrates as determined by atomic force microscopy is d(SLG) = 0.34 nm and thus much smaller than on SiO(2).

Maternal mid-pregnancy C-reactive protein and risk of autism spectrum disorders: the early markers for autism study.

Maternal pregnancy levels of the inflammatory marker C-reactive protein (CRP) has been previously associated with autism spectrum disorder (ASD) in the offspring. We conducted a population-based nested case-control study with 500 children with ASD, 235 with developmental delay (DD) and 580 general population (GP) controls to further investigate whether elevated CRP during pregnancy increases the risk of ASD. Maternal CRP concentration was measured in archived serum collected during 15-19 weeks of pregnancy and genome-wide single-nucleotide polymorphism (SNP) data were generated. The levels of CRP were compared between ASD vs GP and DD vs GP. The genetic associations with CRP were assessed via linear regression. Maternal CRP levels in mid-pregnancy were lower in mothers of ASD compared with controls. The maternal CRP levels in the upper third and fourth quartiles were associated with a 45 and 44% decreased risk of ASD, respectively. Two SNPs at the CRP locus showed strong association with CRP levels but they were not associated with ASD. No difference was found between maternal CRP levels of DD and controls. The reasons for the lower levels of CRP in mothers of ASD are not known with certainty but may be related to alterations in the immune response to infectious agents. The biological mechanisms underlying this association remain to be clarified.

Banking of human tissue for biomonitoring and exposure assessment: utility for environmental epidemiology and surveillance.

Human tissue banking could provide a tool to address a number of public health concerns. We can potentially use it to monitor trends in human exposures, serve as an early warning system for new environmental exposures, assess low-level exposures around hazardous waste and other point sources of pollutants, evaluate the effectiveness of regulatory programs, and study etiologies of diseases (e.g., childhood cancer and birth defects) that are likely to be related to the environment. This article discusses opportunities to establish human tissue banks in connection with pre-existing public health surveillance programs for cancer and adverse reproductive outcomes. This is a cost-effective way to conduct surveillance and enhances the ability to carry out epidemiologic studies. The article also discusses ethical issues that are particularly important for public health practice. One is the issue of risk communication and the need to explain risks in a way that provides people with the information they need to determine appropriate action on the individual and community levels. Second is the issue of environmental justice. We recommend early involvement of communities that are likely to be involved in tissue-banking projects and full explanation of individual and group social risks from their participation.

Evaluation of four maternal smoking questions.

OBJECTIVE: The authors evaluated four questions about maternal smoking during pregnancy for use on birth certificates. METHODS: Question 1 (yes/no format) and Question 2 (trimester-specific design) were tested among 1171 women who delivered at two Kaiser Permanente medical centers in northern California. Responses to Questions 1 and 2 were compared with smoking information provided by participants in telephone interviews conducted during pregnancy. Question 3 (multiple choice format) and Question 4 (month- and grouped month-specific design) were tested among 900 women who enrolled in a statewide prenatal screening program and who delivered in 20 hospitals in four Central Valley counties. Responses to Questions 3 and 4 were compared with mid-pregnancy serum cotinine levels. The authors evaluated the four questions in terms of conciseness, response rate, data accuracy, and type of data requested. RESULTS: Questions 1 and 2 were the most concise. Response rates could not be calculated for Questions 1 and 2. Response rates were 86.0% for Question 3 and 74.2% for Question 4. Sensitivity was 47.3% for Question 1, 62.1% for Question 2, 83.8% for Question 3, and 86.7% for Question 4. The types of data requested by Questions 2 and 4 seem to best satisfy the needs of the broad audience of birth certificate users. CONCLUSIONS: No single question was clearly superior. The authors propose a combination of Questions 2 and 4, which asks about average number of cigarettes smoked per day in the three months before pregnancy and in each trimester of pregnancy.

Pregnancy outcomes and risk factors in Mexican Americans: the effect of language use and mother's birthplace.

Effects of acculturation have been thought to contribute adversely to poor reproductive health in Mexican immigrants, and a traditional Mexican orientation has been hypothesized to be protective against poor birth outcomes. A population-based cross-sectional study of 4404 births of Mexico-born and U.S.-born Mexican-American women was conducted in California in 1992 to examine the effect of language use (as a proxy measure of acculturation) on reproductive outcomes. Utilizing birth certificates, supplemental questionnaires, and 1990 U.S. Census data, the study analyzed differences in the proportions of pregnancy risk factors, low birth weight infants, and preterm deliveries in six nativity/language subgroups. Compared to U.S.-born English-speakers, U.S.-born Spanish-speakers had a higher risk profile and Mexico-born English-speakers had a lower risk profile for adverse pregnancy outcomes. After controlling for covariates, U.S.-born Spanish-speakers had the highest odds for low birth weight (OR = 1.98, 95% C.I. = 1.00, 3.93) and Mexico-born English-speakers had the lowest odds for preterm delivery (OR = 0.70, 95% C.I. = 0.35, 1.40) compared to U.S.-born English-speakers. These nativity/language differences in risk profiles and pregnancy outcomes suggest that Mexican Americans do not experience a simple negative mode of adaptation to U.S. society, but rather a complex process of positive and negative acculturation, which may be dependent on socio-economic conditions or selection factors related to immigration.

Graphene on Si(111)7×7.

We demonstrate that it is possible to mechanically exfoliate graphene under ultrahigh vacuum conditions on the atomically well defined surface of single crystalline silicon. The flakes are several hundred nanometers in lateral size and their optical contrast is very faint, in agreement with calculated data. Single-layer graphene is investigated by Raman mapping. The graphene and 2D peaks are shifted and narrowed compared to undoped graphene. With spatially resolved Kelvin probe measurements we show that this is due to p-type doping with hole densities of n(h) ~/= 6 × 10(12) cm(-2). The in vacuo preparation technique presented here should open up new possibilities to influence the properties of graphene by introducing adsorbates in a controlled way.

HPLC analysis of eluted monomers from two composite resins cured with LED and halogen curing lights.

This study investigated the leaching of monomers (Bis-GMA and TEGDMA) from nano-hybrid (Filtek Supreme) and flowable (Filtek Flow) dental composite resins cured with LED or conventional halogen curing lights, and immersed in saliva or water for 24 h. Nine disc specimens were made for each experimental group. After the polymerization process, the specimens were immersed in either water or saliva and incubated at 37 degrees C for 24 h. Eluted Bis-GMA and TEGDMA monomers were detected using high performance liquid chromatography (HPLC). The data were analyzed using three-way ANOVA (p = 0.05) and the independent samples t test. TEGDMA (53.15-1 microg/L) was leached from the resins at a higher level than Bis-GMA (28-0.5 microg/L) (p < 0.01), regardless of the affecting factors: composite type, solvent (media) and type of curing light. In general, Filtek Flow resin released more TEGDMA than Filtek Supreme (p < 0.05), but the Supreme resin released more Bis-GMA than TEGDMA (p < 0.05). Halogen light induced greater monomer elution than LED light immersion in water. Saliva released more TEGDMA than water (p < 0.05). We conclude that (1) total leached TEGDMA was higher than total Bis-GMA, (2) saliva and halogen light (lower intensity than LED) leached more monomers from the resins, and (3) the flowable composite resin leached more TEGDMA than the nano-hybrid.

Anesthesia for carotid stent procedures.

PURPOSE: To present the techniques of anesthesia management used during percutaneous carotid interventions involving balloon dilation and stent deployment. METHODS AND RESULTS: Two access routes may be used for carotid angioplasty, and the anesthesia techniques for each are different. In the conventional common femoral artery approach, the patient is sedated, heparinized, and ventilated by mask with 100% oxygen; the groin site is anesthetized locally with lidocaine. When the procedure reaches the point of balloon inflation, the patient is awakened, and atropine is administered to block the baroreceptor response. The heparin is not reversed after the procedure. General anesthesia with short-acting nonopioid intravenous anesthetics is preferred for patients undergoing direct puncture of the common carotid artery. The patient is intubated and ventilated with 100% oxygen. Here the patient is awakened after completion of the procedure, at which time protamine sulfate is used if needed to restore coagulation time to normal prior to sheath removal. The anesthesiologist must be vigilant in monitoring hemodynamic and neurological status throughout these carotid interventions, particularly during balloon inflations and after the sheath removal for the cervical approach. CONCLUSIONS: Anesthesia for percutaneous carotid interventions differs from that used for carotid surgery. Protection of the brain from ischemic insult is paramount, and scrupulous attention to physiological factors influencing cerebral blood flow is mandatory. The anesthesiologist plays a crucial role in maintaining hemodynamic stability, adjusting anticoagulation, and monitoring neurological status.

Cystic fibrosis screening in newborns: results from existing programs.

Newborn screening for cystic fibrosis (CF) provides early identification and initiation of treatment to infants with this fatal and often misdiagnosed genetic disease. Although reports of health benefits continue to mount from decade-old screening programs in Wisconsin, France, and Australia, newborn screening for CF is still a highly debated topic in genetic policy development. This article summarizes the literature published between May 2000 and April 2001 regarding the health benefits, risks, cost-effectiveness, and programmatic issues of newborn screening for CF. The literature consistently shows evidence of benefits and lack of harm from newborn screening for CF.

Associations between maternal decaffeinated and caffeinated coffee consumption and fetal growth and gestational duration.

Because of concern about the potential adverse effects of consuming caffeinated beverages during pregnancy, pregnant women may choose to replace caffeinated with decaffeinated coffee. In a population-based study of 7,855 livebirths in California's San Joaquin Valley, we examined the relation of maternal decaffeinated and caffeinated coffee consumption during pregnancy to measures of fetal growth and gestational duration. Mothers answered a questionnaire in the hospital at the time of completing the birth certificate. Compared with women who drank neither decaffeinated nor caffeinated coffee, those who consumed only decaffeinated coffee showed no increased odds of small-for-gestational age birth, low birth weight, or preterm delivery, nor lowered mean birth weight or shortened mean gestational age. Women who consumed caffeinated coffee alone had an adjusted odds ratio of 1.3 [95% confidence limits (CL) = 1.0, 1.7] for preterm delivery, whereas those who consumed both caffeinated and decaffeinated coffee had an adjusted odds of 2.3 (95% CL = 1.3, 4.0). When caffeinated and decaffeinated coffee were considered as continuous variables, we found a reduction in adjusted mean birth weight of -3.0 gm per cup per week (95% CL = -5.9, -0.6) for caffeinated coffee and an increase of +0.4 gm per cup per week (95% CL = -3.7, 4.5) for decaffeinated coffee.