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Importance Gestational exposure to particulate matter (PM) air pollution may increase the risk of childhood obesity, but the impact of reducing air pollution during pregnancy on obesity-related outcomes in childhood has not been examined. Objective To assess the impact of reducing gestational PM exposure on body mass index (BMI) at two years of age. Methods In this single-blind, parallel group randomized controlled trial in Ulaanbaatar Mongolia, we randomly assigned 540 pregnant women to receive 1–2 portable high efficiency particulate air (HEPA) filter air cleaners or no air cleaners. We measured height and weight when children were a mean age of 23.8 months. Our primary outcome was age- and sex-specific BMI z-score based on the World Health Organization 2007 Growth Charts. Secondary outcomes included age- and sex-specific weight z score, overweight/obesity (defined as BMI z-score > 2.00), and catch-up growth (defined using various cut-offs to identify children with relatively low birth weight for sex and gestational age and relatively high age- and sex-specific weight in childhood). We imputed missing outcome data using multiple imputation with chained equations and our primary analysis was by intention to treat (ITT). We estimated intervention effects on continuous and binary outcomes using linear and logistic regression, respectively. Results After excluding known miscarriages, still births, and neonatal deaths our analysis included 480 children (235 control and 245 intervention). The mean (SD) child BMI z score was 0.79 (1.0); 9.8% of children were overweight or obese. The mean BMI z score of children who were randomly assigned to the intervention group was 0.16-units lower (95% CI: −0.35, 0.04) than children in the control group. The intervention was also associated with reductions in overweight/obesity (odds ratio = 0.59; 95% CI: 0.31, 1.12). Catch-up growth occurred less frequently in the intervention group, but effect estimates varied depending on the specific definition of catch-up growth and confidence intervals consistently spanned no effect. Conclusions We found that the use of portable air cleaners during pregnancy was associated with improvements in obesity-related outcomes, although some effect estimates lacked precision. Reducing PM exposure during pregnancy may lead to improvements in cardiometabolic health in childhood.

BACKGROUND AND AIM: Developmental exposure to fine particulate matter (PM2.5) may impair children’s behaviors; the timing of exposure may also play an important role. METHODS: In this single-blind ...

Background Developmental exposure to particulate matter (PM) air pollution may impair children’s behaviors. Our objectives were to quantify the impact of reducing indoor PM using portable HEPA filter air cleaners during pregnancy on behavioral problems in children and to assess associations between indoor fine PM (PM2.5) concentrations during pregnancy and children’s behavior. Methods This is a secondary analysis of a single-blind parallel-group randomized controlled trial in which we randomly assigned 540 non-smoking pregnant women to receive 1 or 2 HEPA filter air cleaners or no air cleaners. We administered the Behavior Assessment System for Children (BASC-3) to caregivers when children were a mean age of 23 months, and again at a mean age of 48 months. Primary outcomes were the four BASC-3 composite scales: externalizing problems, internalizing problems, adaptive skills, and the behavioral symptoms index. We imputed missing data using multiple imputation with chained equations. The primary analysis was by intention-to-treat. In a secondary analysis, we evaluated associations between BASC-3 composite indices and modeled trimester-specific PM2.5 concentrations inside residences. Results We enrolled participants at a median of 11 weeks gestation. After excluding miscarriages, still births and neonatal deaths, our analysis included 478 children (233 control and 245 intervention). We observed no differences in the mean BASC-3 scores between treatment groups. An interquartile increase (20.1 µg/m3) in first trimester PM2.5 concentration was associated with higher externalizing problem scores (2.4 units, 95% CI: 0.7, 4.1), higher internalizing problem scores (2.4 units, 95% CI: 0.7, 4.0), lower adaptive skills scores (-1.5 units, 95% CI: -3.0, 0.0), and higher behavior symptoms index scores (2.3 units, 95% CI: 0.7, 3.9). Third trimester PM2.5 concentrations were also associated with some behavioral indices at age 4, but effect estimates were smaller. No significant associations were observed with PM2.5 concentrations during the second trimester or for any of the BASC indices when children were 2 years old. Conclusion We found no benefit of reducing indoor particulate air pollution during pregnancy on parent-reported behaviors in children. Associations between indoor PM2.5 concentrations in the first trimester and behavioral scores among 4-year old children suggest that it may be necessary to intervene early in pregnancy to protect children, but these exploratory findings should be interpreted cautiously. Trial registration ClinicalTrials.gov: NCT01741051

Maintenance of axonal excitability relies on complex balance by multiple ion currents, but its evaluation is limited by in vitro single channel neurophysiological study on overall behavior. We sought to evaluate behaviors of multiple ion currents by pharmacological blockade. The threshold tracking technique was used to measure multiple excitability indices on tail sensory nerve of normal male mice before and after administration of either BaCl2 or ivabradine. Mathematical modeling was used to identify the interval changes of the channel parameters. After administration of BaCl2 and ivabradine, the following changes were present: greater threshold changes of both depolarizing and hyperpolarizing threshold electrotonus by both; additionally, reduced S2 accommodation, reduced late subexcitability and increased superexcitability by BaCl2, increased S3 accommodation by ivabradine. Mathematical modelling implied reduction of slow K+ conductance, along with reduction of H conductance (Ih) by BaCl2; and reduction of Ih while augmentation of K+ conductances by ivabradine. Pharmacological blockade of a selective ion channel may be compensated by other ion channels. Unintended effects by ion channel modification could be caused by secondary current alteration by multiple ion channels. J. Med. Invest. 64: 30-38, February, 2017.

Amyotrophic lateral sclerosis (ALS) is a multisystem neurodegenerative disease characterised by adult-onset degeneration of the upper and lower motor neuronal systems. The contribution of specific ALS disease genes differs between ethnic groups, at least partially due to founder effects. C9orf72 hexanucleotide repeat expansions (HRE) are the most frequent monogenic cause of ALS in the Western world, but extremely rare in Asian ALS populations, for example in China.1 This fact, together with a predominant C9orf72 risk haplotype in Europe, has fostered the hypothesis that one or very few founder events are responsible for the C9orf72 -linked ALS of European origin.2 However, more profound knowledge about the differences between ALS genetics in European and Asian populations is warranted. We thus set out to characterise ALS genetics in the genetically distinct and relatively homogeneous Mongolian population. Patients were recruited from the Department of Neurology, Institute of Medical Sciences of Mongolia, Ulaanbaatar, and neurologists throughout all provinces of Mongolia, from January 2015 to September 2018. All patients met the revised El Escorial criteria for ALS. Due to the lack of a validated neuropsychological test in Mongolian language, fronto-temporal dementia (FTD) diagnosis was established based on clinical impression by an experienced neurologist from the ALS/FTD centre in Ulm, Germany, who was always accompanied by an English-speaking Mongolian physician for translation. Analysis of the HRE in C9orf72 was performed by fragment analysis and repeat-primed PCR, confirmed by Southern blotting. For the SOD1 and FUS mutation screen, Sanger sequencing was employed (primer sequences available on request). For haplotype analysis of C9orf72- HRE positive cases and respective family members, the most conserved risk haplotypes consisting of 15 single nucleotide polymorphisms …

Charcot-Marie-Tooth disease (CMT) is a hereditary peripheral neuropathy characterised by length-dependent degeneration of the motor and sensory nerve fibres with consequent distal muscle weakness, atrophy and mild sensory loss, primarily in lower limbs. The historic prevalence of CMT in the general population is 1 in 2500 individuals,1 while the present prevalence is 1 in 1214 individuals.2 Missense mutations in the mitofusion 2 gene ( MFN2 ; OMIM*608506) have been found in most axonal forms (CMT type 2; CMT2) with autosomal dominant inheritance, and truncation mutations can be found in a few cases with seemingly autosomal recessive inheritance or sporadic cases. A dominant negative or toxic gain-of-function mechanism has been postulated in the autosomal dominant mode; however, the biological effect(s) by mutant MFN2 may vary depending on the nature of the mutations.3 This report describes a unique pathomechanism identified in a large Japanese MFN2 -CMT2A2 family. The currently living family members were examined by movement disorder specialists (TK, RM, HN, YN and YI). Neurological assessments, including the Charcot-Marie-Tooth disease neuropathy score V.2, electrophysiology of peripheral nerves and neuroimaging analyses, were carried out. Genetic analyses were conducted as described in online supplementary data, including targeted resequencing, Sanger sequencing, restriction fragment length polymorphism (RFLP) analysis and semiquantitative reverse-transcription (RT)-PCR. Peripheral T-cells were cultured with a nonsense-mediated decay (NMD) inhibitor, emetine, in order to evaluate the effect by NMD system. A bioinformatic analysis and literature review were also carried out. The details are described in online supplementary data. ### Supplementary data [jnnp-2015-312646supp.pdf] The family is composed of a three-generation kindred, with autosomal dominant inheritance (figure 1A). Nine individuals were diagnosed as ‘certainly affected’ and classified as having Charcot-Marie-Tooth disease. Clinical and laboratory features of all affected individuals are summarised in online supplementary tables S1 and S2, and figure S1. Age-at-onset was 5 or …

Maintenance of axonal excitability relies on complex balance by multiple ion currents, but its evaluation is limited by in vitro single channel neurophysiological study on overall behavior. We sought to evaluate behaviors of multiple ion currents by pharmacological blockade. The threshold tracking technique was used to measure multiple excitability indices on tail sensory nerve of normal male mice before and after administration of either BaCl

This study aimed to characterize the excitability changes in peripheral motor axons caused by hindlimb unloading, which is a model of disuse neuromuscular atrophy. Hindlimb unloading was performed in normal 6-week-old male mice by fixing the proximal tail by a clip connected to the top of the animal’s cage for 3 weeks. Axonal excitability studies were performed by stimulating the sciatic nerve at the ankle and recording the compound muscle action potential from the foot. The amplitudes of the motor responses of the unloading group were 51% of the control amplitudes (2.2 ± 1.3 mV [HLU] vs. 4.3 ± 1.2 mV [Control], P = 0.03). Multiple axonal excitability analysis showed that the unloading group had a smaller strength-duration time constant (SDTC) and late subexcitability (recovery cycle) than the controls (0.075 ± 0.01 [HLU] vs. 0.12 ± 0.01 [Control], P < 0.01; 5.4 ± 1.0 [HLU] vs. 10.0 ± 1.3 % [Control], P = 0.01, respectively). Three weeks after releasing from HLU, the SDTC became comparable to the control range. Using a modeling study, the observed differences in the waveforms could be explained by reduced persistent Na+ currents along with parameters related to current leakage. Quantification of RNA of a SCA1A gene coding a voltage-gated Na+ channel tended to be decreased in the sciatic nerve in HLU. The present study suggested that axonal ion currents are altered in vivo by hindlimb unloading. It is still undetermined whether the dysfunctional axonal ion currents have any pathogenicity on neuromuscular atrophy or are the results of neural plasticity by atrophy.

Serial recordings were performed to measure sensory excitability in peripheral nerves and elucidate age-dependent changes in neuronal ion currents in the peripheral sensory nervous system. The threshold tracking technique was used to measure multiple excitability indices in the tail sensory nerves of five normal male mice at four time points (6, 10, 14, and 19 weeks of age). A separate group of four mice was also measured at 43 weeks and at 60 weeks of age. Maturation was accompanied by an increase in early hyperpolarization and superexcitability at 10 weeks. At 60 weeks, the hyperpolarizing electrotonus shifted downward, while superexcitability became greater and subexcitability (double stimuli) decreased. Computer modeling showed that the most notable age-related interval changes in excitability parameters were Barrett-Barrett, H, and slow K(+) conductances. Understanding age-related changes in the excitability of sensory axons may provide a platform for understanding age-dependent sensory symptoms and developing age-specific channel-targeting therapies.

Objective The objective was to study the in vivo effects of anesthetic agents on peripheral nerve excitability. Methods Normal male mice were anesthetized by either isoflurane inhalation or a combination of medetomidine, midazolam, and butorphanol intraperitoneal injection (“triple agents”). Immediately after induction, the tail sensory nerve action potential was recorded and its excitability was monitored. Results Under both anesthetic protocols, there was an interval excitability change by long hyperpolarizing currents. There was greater threshold reduction approximately 30 min post induction, in comparison to immediately post induction. Other excitability parameters were stable over time. Modeling suggested interval suppression of internodal H conductance or leak current. Conclusions Anesthetic agents affected responses to long hyperpolarizing currents. Significance Axonal excitability during intraoperative monitoring may be affected by anesthetic agents. Interpretation of interval excitability changes under anesthesia requires caution, especially with long hyperpolarizing currents.

Objective To describe functional changes of axonal ion channels by a metabolic derivative of glucose, methylglyoxal (MGO), and its potential contribution to diabetic neuropathy. Methods (1) In wild-type male mice, multiple excitability measurements of sensory nerves were performed at baseline and 1week after serial administration of MGO (50mg/kg). (2) Excitability testing in patients with diabetic neuropathy ( N =17) and healthy controls ( N =12) were also conducted, and data were interpreted using mathematical modeling. Results In the animal study, there was a decrease in threshold changes by long hyperpolarization and in superexcitability after administration of MGO. In the preliminary human study, the threshold changes by long hyperpolarizing current were decreased in patients with diabetes. Mathematical modeling showed increased hyperpolarization-activated cation current ( I h) in the MGO-treated mice and in patients with diabetes. Conclusion I h was upregulated after MGO administration in normal mice. Significance MGO is associated with abnormal axonal excitability. Hyperexcitability in diabetic polyneuropathy may, at least in part, be caused by dysfunctional axonal hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. A future study with a large sample size of the diabetic patients would clarify this hypothesis.