Homozygosity for a missense mutation in the 67 kDa isoform of glutamate decarboxylase in a family with autosomal recessive spastic cerebral palsy: parallels with Stiff-Person Syndrome and other movement disorders

Background Cerebral palsy (CP) is an heterogeneous group of neurological disorders of movement and/or posture, with an estimated incidence of 1 in 1000 live births. Non-progressive forms of symmetrical, spastic CP have been identified, which show a Mendelian autosomal recessive pattern of inheritance. We recently described the mapping of a recessive spastic CP locus to a 5 cM chromosomal region located at 2q24-31.1, in rare consanguineous families. Methods Here we present data that refine this locus to a 0.5 cM region, flanked by the microsatellite markers D2S2345 and D2S326. The minimal region contains the candidate gene GAD1, which encodes a glutamate decarboxylase isoform (GAD67), involved in conversion of the amino acid and excitatory neurotransmitter glutamate to the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Results A novel amino acid mis-sense mutation in GAD67 was detected, which segregated with CP in affected individuals. Conclusions This result is interesting because auto-antibodies to GAD67 and the more widely studied GAD65 homologue encoded by the GAD2 gene, are described in patients with Stiff-Person Syndrome (SPS), epilepsy, cerebellar ataxia and Batten disease. Further investigation seems merited of the possibility that variation in the GAD1 sequence, potentially affecting glutamate/GABA ratios, may underlie this form of spastic CP, given the presence of anti-GAD antibodies in SPS and the recognised excitotoxicity of glutamate in various contexts

Critical Review of Theoretical Models for Anomalous Effects (Cold Fusion) in Deuterated Metals

We briefly summarize the reported anomalous effects in deuterated metals at ambient temperature, commonly known as "Cold Fusion" (CF), with an emphasis on important experiments as well as the theoretical basis for the opposition to interpreting them as cold fusion. Then we critically examine more than 25 theoretical models for CF, including unusual nuclear and exotic chemical hypotheses. We conclude that they do not explain the data.Comment: 51 pages, 4 Figure

Pregnancy Recruitment for Population Research: the National Children's Study Vanguard Experience in W ayne C ounty, M ichigan

Background To obtain a probability sample of pregnancies, the N ational C hildren's S tudy conducted door‐to‐door recruitment in randomly selected neighbourhoods in randomly selected counties in 2009–10. In 2011, an experiment was conducted in 10 US counties, in which the two‐stage geographic sample was maintained, but participants were recruited in prenatal care provider offices. We describe our experience recruiting pregnant women this way in W ayne C ounty, M ichigan, a county where geographically eligible women attended 147 prenatal care settings, and comprised just 2% of total county pregnancies. Methods After screening for address eligibility in prenatal care offices, we used a three‐part recruitment process: (1) providers obtained permission for us to contact eligible patients, (2) clinical research staff described the study to women in clinical settings, and (3) survey research staff visited the home to consent and interview eligible women. Results We screened 34 065 addresses in 67 provider settings to find 215 eligible women. Providers obtained permission for research contact from 81.4% of eligible women, of whom 92.5% agreed to a home visit. All home‐visited women consented, giving a net enrolment of 75%. From birth certificates, we estimate that 30% of eligible county pregnancies were enrolled, reaching 40–50% in the final recruitment months. Conclusions We recruited a high fraction of pregnancies identified in a broad cross‐section of provider offices. Nonetheless, because of time and resource constraints, we could enrol only a fraction of geographically eligible pregnancies. Our experience suggests that the probability sampling of pregnancies for research could be more efficiently achieved through sampling of providers rather than households.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/97525/1/ppe12047.pd

Simpson's Paradox, Lord's Paradox, and Suppression Effects are the same phenomenon – the reversal paradox

This article discusses three statistical paradoxes that pervade epidemiological research: Simpson's paradox, Lord's paradox, and suppression. These paradoxes have important implications for the interpretation of evidence from observational studies. This article uses hypothetical scenarios to illustrate how the three paradoxes are different manifestations of one phenomenon – the reversal paradox – depending on whether the outcome and explanatory variables are categorical, continuous or a combination of both; this renders the issues and remedies for any one to be similar for all three. Although the three statistical paradoxes occur in different types of variables, they share the same characteristic: the association between two variables can be reversed, diminished, or enhanced when another variable is statistically controlled for. Understanding the concepts and theory behind these paradoxes provides insights into some controversial or contradictory research findings. These paradoxes show that prior knowledge and underlying causal theory play an important role in the statistical modelling of epidemiological data, where incorrect use of statistical models might produce consistent, replicable, yet erroneous results

RNA-inspired intramolecular transesterification accelerates the hydrolysis of polyethylene-like polyphosphoesters

To synthesize new (bio)degradable alternatives to commodity polymers, adapting natural motives can be a promising approach. We present the synthesis and characterization of degradable polyethylene (PE)-like polyphosphoesters, which exhibit increased degradation rates due to an intra-molecular transesterification similar to RNA. An α,ω-diene monomer was synthesized in three steps starting from readily available compounds. By acyclic diene metathesis (ADMET) polymerization, PE-like polymers with molecular weights up to 38 400 g mol(−1) were obtained. Post-polymerization functionalization gave fully saturated and semicrystalline polymers with a precise spacing of 20 CH(2) groups between each phosphate group carrying an ethoxy hydroxyl side chain. This side chain was capable of intramolecular transesterification with the main-chain similar to RNA-hydrolysis, mimicking the 2′-OH group of ribose. Thermal properties were characterized by differential scanning calorimetry (DSC (T(m)ca. 85 °C)) and the crystal structure was investigated by wide-angle X-ray scattering (WAXS). Polymer films immersed in aqueous solutions at different pH values proved an accelerated degradation compared to structurally similar polyphosphoesters without pendant ethoxy hydroxyl groups. Polymer degradation proceeded also in artificial seawater (pH = 8), while the polymer was stable at physiological pH of 7.4. The degradation mechanism followed the intra-molecular “RNA-inspired” transesterification which was detected by NMR spectroscopy as well as by monitoring the hydrolysis of a polymer blend of a polyphosphoester without pendant OH-group and the RNA-inspired polymer, proving selective hydrolysis of the latter. This mechanism has been further supported by the DFT calculations. The “RNA-inspired” degradation of polymers could play an important part in accelerating the hydrolysis of polymers and plastics in natural environments, e.g. seawater

Molecular origin of enhanced proton conductivity in anhydrous ionic systems

YesIonic systems with enhanced proton conductivity are widely viewed as promising electrolytes in fuel cells and batteries. Nevertheless, a major challenge toward their commercial applications is determination of the factors controlling the fast proton hopping in anhydrous conditions. To address this issue, we have studied novel proton-conducting materials formed via a chemical reaction of lidocaine base with a series of acids characterized by a various number of proton-active sites. From ambient and high pressure experimental data, we have found that there are fundamental differences in the conducting properties of the examined salts. On the other hand, DFT calculations revealed that the internal proton hopping within the cation structure strongly affects the pathways of mobility of the charge carrier. These findings offer a fresh look on the Grotthuss-type mechanism in protic ionic glasses as well as provide new ideas for the design of anhydrous materials with exceptionally high proton conductivity

Whether weather matters: Evidence of association between in utero meteorological exposures and foetal growth among Indigenous and non-Indigenous mothers in rural Uganda

Pregnancy and birth outcomes have been found to be sensitive to meteorological variation, yet few studies explore this relationship in sub-Saharan Africa where infant mortality rates are the highest in the world. We address this research gap by examining the association between meteorological factors and birth weight in a rural population in southwestern Uganda. Our study included hospital birth records (n = 3197) from 2012 to 2015, for which we extracted meteorological exposure data for the three trimesters preceding each birth. We used linear regression, controlling for key covariates, to estimate the timing, strength, and direction of meteorological effects on birth weight. Our results indicated that precipitation during the third trimester had a positive association with birth weight, with more frequent days of precipitation associated with higher birth weight: we observed a 3.1g (95% CI: 1.0–5.3g) increase in birth weight per additional day of exposure to rainfall over 5mm. Increases in average daily temperature during the third trimester were also associated with birth weight, with an increase of 41.8g (95% CI: 0.6–82.9g) per additional degree Celsius. When the sample was stratified by season of birth, only infants born between June and November experienced a significant associated between meteorological exposures and birth weight. The association of meteorological variation with foetal growth seemed to differ by ethnicity; effect sizes of meteorological were greater among an Indigenous subset of the population, in particular for variation in temperature. Effects in all populations in this study are higher than estimates of the African continental average, highlighting the heterogeneity in the vulnerability of infant health to meteorological variation in different contexts. Our results indicate that while there is an association between meteorological variation and birth weight, the magnitude of these associations may vary across ethnic groups with differential socioeconomic resources, with implications for interventions to reduce these gradients and offset the health impacts predicted under climate change

SPR Perspectives: scientific opportunities in the Environmental influences on Child Health Outcomes Program

Drawing upon extant data from existing pediatric cohorts and new follow-up of a diverse set of pediatric cohorts from across the United States, the Environmental influences on Child Health Outcomes (ECHO) Program creates the opportunity for novel and innovative investigations of many previously inaccessible scientific questions in the area of child health. We describe how the large sample size, diversity of participants, emphasis on team science, and infrastructure for improving research methodology make the ECHO Program a major research resource for improving our understanding of early life determinants of childhood health and well-being. Pediatric researchers leverage the unique features of the ECHO Program to address research questions with the potential to yield far-reaching and long-term impacts on child health. IMPACT: The ECHO Program unites pediatric cohorts from across the United States, allowing for investigations of compelling research questions that were previously infeasible due to limited sample sizes or lack of participant diversity. The focus of the ECHO Program on team science, solution-oriented research, and methodological innovation propels novel scientific investigations that are responsive to the needs of a wide range of stakeholders. Features of the ECHO program\u27s infrastructure poise its investigators to rapidly launch research endeavors that are responsive to time-sensitive and critical needs within the realm of pediatric research

Rare copy number variation in cerebral palsy

As per publisher: published online 22 May 2013Recent studies have established the role of rare copy number variants (CNVs) in several neurological disorders but the contribution of rare CNVs to cerebral palsy (CP) is not known. Fifty Caucasian families having children with CP were studied using two microarray designs. Potentially pathogenic, rare (<1% population frequency) CNVs were identified, and their frequency determined, by comparing the CNVs found in cases with 8329 adult controls with no known neurological disorders. Ten of the 50 cases (20%) had rare CNVs of potential relevance to CP; there were a total of 14 CNVs, which were observed in <0.1% (<8/8329) of the control population. Eight inherited from an unaffected mother: a 751-kb deletion including FSCB, a 1.5-Mb duplication of 7q21.13, a 534-kb duplication of 15q11.2, a 446-kb duplication including CTNND2, a 219-kb duplication including MCPH1, a 169-kb duplication of 22q13.33, a 64-kb duplication of MC2R, and a 135-bp exonic deletion of SLC06A1. Three inherited from an unaffected father: a 386-kb deletion of 12p12.2-p12.1, a 234-kb duplication of 10q26.13, and a 4-kb exonic deletion of COPS3. The inheritance was unknown for three CNVs: a 157-bp exonic deletion of ACOX1, a 693-kb duplication of 17q25.3, and a 265-kb duplication of DAAM1. This is the first systematic study of CNVs in CP, and although it did not identify de novo mutations, has shown inherited, rare CNVs involving potentially pathogenic genes and pathways requiring further investigation.Gai McMichael, Santhosh Girirajan, Andres Moreno-De-Luca, Jozef Gecz, Chloe Shard, Lam Son Nguyen, Jillian Nicholl, Catherine Gibson, Eric Haan, Evan Eichler, Christa Lese Martin and Alastair MacLenna