Patterns of Growth and Decline in Lung Function in Persistent Childhood Asthma.

BACKGROUND: Tracking longitudinal measurements of growth and decline in lung function in patients with persistent childhood asthma may reveal links between asthma and subsequent chronic airflow obstruction. METHODS: We classified children with asthma according to four characteristic patterns of lung-function growth and decline on the basis of graphs showing forced expiratory volume in 1 second (FEV1), representing spirometric measurements performed from childhood into adulthood. Risk factors associated with abnormal patterns were also examined. To define normal values, we used FEV1 values from participants in the National Health and Nutrition Examination Survey who did not have asthma. RESULTS: Of the 684 study participants, 170 (25%) had a normal pattern of lung-function growth without early decline, and 514 (75%) had abnormal patterns: 176 (26%) had reduced growth and an early decline, 160 (23%) had reduced growth only, and 178 (26%) had normal growth and an early decline. Lower baseline values for FEV1, smaller bronchodilator response, airway hyperresponsiveness at baseline, and male sex were associated with reduced growth (P<0.001 for all comparisons). At the last spirometric measurement (mean [±SD] age, 26.0±1.8 years), 73 participants (11%) met Global Initiative for Chronic Obstructive Lung Disease spirometric criteria for lung-function impairment that was consistent with chronic obstructive pulmonary disease (COPD); these participants were more likely to have a reduced pattern of growth than a normal pattern (18% vs. 3%, P<0.001). CONCLUSIONS: Childhood impairment of lung function and male sex were the most significant predictors of abnormal longitudinal patterns of lung-function growth and decline. Children with persistent asthma and reduced growth of lung function are at increased risk for fixed airflow obstruction and possibly COPD in early adulthood. (Funded by the Parker B. Francis Foundation and others; ClinicalTrials.gov number, NCT00000575.).

Deficient autophagy in microglia impairs synaptic pruning and causes social behavioral defects.

Autism spectrum disorders (ASDs) are neurodevelopmental disorders caused by various genetic and environmental factors that result in synaptic abnormalities. ASD development is suggested to involve microglia, which have a role in synaptic refinement during development. Autophagy and related pathways are also suggested to be involved in ASDs. However, the precise roles of microglial autophagy in synapses and ASDs are unknown. Here, we show that microglial autophagy is involved in synaptic refinement and neurobehavior regulation. We found that deletion of atg7, which is vital for autophagy, from myeloid cell-specific lysozyme M-Cre mice resulted in social behavioral defects and repetitive behaviors, characteristic features of ASDs. These mice also had increases in dendritic spines and synaptic markers and altered connectivity between brain regions, indicating defects in synaptic refinement. Synaptosome degradation was impaired in atg7-deficient microglia and immature dendritic filopodia were increased in neurons co-cultured with atg7-deficient microglia. To our knowledge, our results are the first to show the role of microglial autophagy in the regulation of the synapse and neurobehaviors. We anticipate our results to be a starting point for more comprehensive studies of microglial autophagy in ASDs and the development of putative therapeutics.

Precision Control of the Electron Longitudinal Bunch Shape Using an Emittance-Exchange Beam Line.

We report on the experimental generation of relativistic electron bunches with a tunable longitudinal bunch shape. A longitudinal bunch-shaping (LBS) beam line, consisting of a transverse mask followed by a transverse-to-longitudinal emittance exchange (EEX) beam line, is used to tailor the longitudinal bunch shape (or current profile) of the electron bunch. The mask shapes the bunch's horizontal profile, and the EEX beam line converts it to a corresponding longitudinal profile. The Argonne wakefield accelerator rf photoinjector delivers electron bunches into a LBS beam line to generate a variety of longitudinal bunch shapes. The quality of the longitudinal bunch shape is limited by various perturbations in the exchange process. We develop a simple method, based on the incident slope of the bunch, to significantly suppress the perturbations.

Navigation programs, are they helpful for perioperative care with thyroid cancer patients?

The purpose of this study was to develop and evaluate a navigation program for patients with thyroid cancer. The navigation program was developed following an analysis of the unmet needs of patients who underwent surgery for thyroid cancer. Ninety-nine patients in the control group received usual care, and 95 in the navigation group were managed with a navigation program during the perioperative period. The effectiveness of the navigation program was assessed by administering a questionnaire to both groups. Overall satisfaction scores were significantly higher in the navigation than in the control group (p = .025), as were satisfaction scores on the continuity of information (p < .001), the continuity of management (p = .002), the continuity of relationships with healthcare providers (p<.001), and patient empowerment (p < .001). The newly developed navigation program for patients with thyroid cancer was effective in raising satisfaction levels and in actively managing the disease during the perioperative period.

A genome-wide analysis of the response to inhaled ß2-agonists in chronic obstructive pulmonary disease.

Short-acting ß2-agonist bronchodilators are the most common medications used in treating chronic obstructive pulmonary disease (COPD). Genetic variants determining bronchodilator responsiveness (BDR) in COPD have not been identified. We performed a genome-wide association study (GWAS) of BDR in 5789 current or former smokers with COPD in one African-American and four white populations. BDR was defined as the quantitative spirometric response to inhaled ß2-agonists. We combined results in a meta-analysis. In the meta-analysis, single-nucleotide polymorphisms (SNPs) in the genes KCNK1 (P=2.02 × 10(-7)) and KCNJ2 (P=1.79 × 10(-7)) were the top associations with BDR. Among African Americans, SNPs in CDH13 were significantly associated with BDR (P=5.1 × 10(-9)). A nominal association with CDH13 was identified in a gene-based analysis in all subjects. We identified suggestive association with BDR among COPD subjects for variants near two potassium channel genes (KCNK1 and KCNJ2). SNPs in CDH13 were significantly associated with BDR in African Americans.The Pharmacogenomics Journal advance online publication, 27 October 2015; doi:10.1038/tpj.2015.65.

Carrier Mobility Enhancement of Tensile Strained Si and SiGe Nanowires via Surface Defect Engineering.

Changes in the carrier mobility of tensile strained Si and SiGe nanowires (NWs) were examined using an electrical push-to-pull device (E-PTP, Hysitron). The changes were found to be closely related to the chemical structure at the surface, likely defect states. As tensile strain is increased, the resistivity of SiGe NWs deceases in a linear manner. However, the corresponding values for Si NWs increased with increasing tensile strain, which is closely related to broken bonds induced by defects at the NW surface. Broken bonds at the surface, which communicate with the defect state of Si are critically altered when Ge is incorporated in Si NW. In addition, the number of defects could be significantly decreased in Si NWs by incorporating a surface passivated Al2O3 layer, which removes broken bonds, resulting in a proportional decrease in the resistivity of Si NWs with increasing strain. Moreover, the presence of a passivation layer dramatically increases the extent of fracture strain in NWs, and a significant enhancement in mobility of about 2.6 times was observed for a tensile strain of 5.7%.

Coincidence of late-onset cytomegalovirus-induced myositis and gastritis in a pediatric renal transplant recipient.

An 8-year-old girl with a renal transplant was admitted for myalgia and muscle weakness in both legs over the previous 2 weeks. She also had fever and intermittent epigastric pain. Based on these clinical manifestations, and laboratory and histopathological findings, the diagnosis was coincidence of late-onset cytomegalovirus (CMV)-induced myositis and gastritis in an immunocompromised child with a renal transplant. After administration of intravenous ganciclovir for 3 weeks, her symptoms resolved, with normalization of abnormal muscle enzymes, including lactate dehydrogenase, creatine kinase, aspartate aminotransferase, and the disappearance of CMV viremia.

2-amino-N-(2,6-dichloropyridin-3-yl)acetamide derivatives as a novel class of HBV capsid assembly inhibitor.

Capsid structure is crucial for the maturation and maintenance of the stable hepatitis B virion. Therefore, chemicals that inhibit capsid assembly might potentially act as potent antiviral compounds. However, only a few chemicals are known to block the capsid assembly process and further viral proliferation. In this study, we present a novel family of capsid assembly inhibitors that act against hepatitis B virus (HBV). Based on X-ray crystallographic data of the HBV core protein (Cp), we built dimer and hexamer structural models to be used in library searches. Several chemicals in the 2-amino-N-(2,6-dichloropyridin-3-yl)acetamide family were predicted to have high affinity for the groove structure in Cp. Using in vitro assembly and the HepG2.2.15 cell culture test, we verified that these chemicals demonstrated inhibitory effects on capsid assembly. Furthermore, we investigated the combinatorial effects of these assembly inhibitor chemicals with lamivudine and revealed that, in combination, they have synergistic inhibitory effects on decreasing viral concentration. We propose that these inhibitors could be utilized as an effective combination treatment against HBV infection.

Effects of surface chemical structure on the mechanical properties of Si(1-x)Ge(x) nanowires.

The Young's modulus and fracture strength of Si(1-x)Ge(x) nanowires (NWs) as a function of Ge concentration were measured from tensile stress measurements. The Young's modulus of the NWs decreased linearly with increasing Ge content. No evidence was found for a linear relationship between the fracture strength of the NWs and Ge content, which is closely related to the quantity of interstitial Ge atoms contained in the wire. However, by removing some of the interstitial Ge atoms through rapid thermal annealing, a linear relationship could be produced. The discrepancy in the reported strength of Si and Ge NWs between calculated and experimented results could be related to SiO(2-x)/Si interfacial defects that are found in Si(1-x)Ge(x) NWs. It was also possible to significantly decrease the number of interfacial defects in the NWs by incorporating a surface passivated Al2O3 layer, which resulted in a substantial increase in fracture strength.

α-secretase cleaved amyloid precursor protein (APP) accumulates in cholinergic dystrophic neurites in normal, aged hippocampus.

AIMS: Dystrophic neurites are associated with ß-amyloid (Aß) plaques in the brains of Alzheimer's disease (AD) patients and are also found in some specific areas of normal, aged brains. This study assessed the molecular characteristics of dystrophic neurites in normal ageing and its difference from AD. METHODS: We compared the dystrophic neurites in normal aged human brains (age 20-70 years) and AD brains (Braak stage 4-6) by immunostaining against ChAT, synaptophysin, γ-tubulin, cathepsin-D, Aß1-16, Aß17-24, amyloid precursor protein (APP)-CT695 and APP-NT. We then tested the reproducibility in C57BL/6 mice neurone cultures. RESULTS: In normal, aged mice and humans, we found an increase in clustered dystrophic neurites of cholinergic neurones in CA1 regions of the hippocampus and layer II and III regions of the entorhinal cortex, which are the major and earliest affected areas in AD. These dystrophic neurites showed accumulation of sAPPα peptides cleaved from the amyloid precursor protein by α-secretase rather than Aß or C-terminal fragments. In contrast, Aß and APP-CTFs accumulated in the dystrophic neurites in and around Aß plaques of AD patients. Several experiments suggested that the accumulation of sAPPα resulted from ageing-related proteasomal dysfunction. CONCLUSIONS: Ageing-associated impairment of the proteasomal system and accumulation of sAPPα at cholinergic neurites in specific areas of brain regions associated with memory could be associated with the normal decline of memory in aged individuals. In addition, these age-related changes might be the most vulnerable targets of pathological insults that result in pathological accumulation of Aß and/or APP-CTFs and lead to neurodegenerative conditions such as AD.

Slewing Mirror Telescope optics for the early observation of UV/optical photons from Gamma-Ray Bursts.

We report on design, manufacture, and testing of a Slewing Mirror Telescope (SMT), the first of its kind and a part of Ultra-Fast Flash Observatory-pathfinder (UFFO-p) for space-based prompt measurement of early UV/optical light curves from Gamma-Ray Bursts (GRBs). Using a fast slewing mirror of 150 mm diameter mounted on a 2 axis gimbal stage, SMT can deliver the images of GRB optical counterparts to the intensified CCD detector within 1.5~1.8 s over ± 35 degrees in the slewing field of view. Its Ritchey-Chrétien telescope of 100 mm diameter provides a 17 × 17 arcmin² instantaneous field of view. Technical details of design, construction, the laboratory performance tests in space environments for this unique SMT are described in conjunction with the plan for in-orbit operation onboard the Lomonosov satellite in 2013.

Genetic association between human chitinases and lung function in COPD.

Two primary chitinases have been identified in humans--acid mammalian chitinase (AMCase) and chitotriosidase (CHIT1). Mammalian chitinases have been observed to affect the host's immune response. The aim of this study was to test for association between genetic variation in the chitinases and phenotypes related to chronic obstructive pulmonary disease (COPD). Polymorphisms in the chitinase genes were selected based on previous associations with respiratory diseases. Polymorphisms that were associated with lung function level or rate of decline in the Lung Health Study (LHS) cohort were analyzed for association with COPD affection status in four other COPD case-control populations. Chitinase activity and protein levels were also related to genotypes. In the caucasian LHS population, the baseline forced expiratory volume in one second (FEV(1)) was significantly different between the AA and GG genotypic groups of the AMCase rs3818822 polymorphism. Subjects with the GG genotype had higher AMCase protein and chitinase activity compared with AA homozygotes. For CHIT1 rs2494303, a significant association was observed between rate of decline in FEV(1) and the different genotypes. In the African American LHS population, CHIT1 rs2494303 and AMCase G339T genotypes were associated with rate of decline in FEV(1). Although a significant effect of chitinase gene alleles was found on lung function level and decline in the LHS, we were unable to replicate the associations with COPD affection status in the other COPD study groups.

Unique and shared systemic biomarkers for emphysema in Alpha-1 Antitrypsin deficiency and chronic obstructive pulmonary disease.

BACKGROUND: Alpha-1 Antitrypsin (AAT) deficiency (AATD), the most common genetic cause of emphysema presents with unexplained phenotypic heterogeneity in affected subjects. Our objectives to identify unique and shared AATD plasma biomarkers with chronic obstructive pulmonary disease (COPD) may explain AATD phenotypic heterogeneity. METHODS: The plasma or serum of 5,924 subjects from four AATD and COPD cohorts were analyzed on SomaScan V4.0 platform. Using multivariable linear regression, inverse variance random-effects meta-analysis, and Least Absolute Shrinkage and Selection Operator (LASSO) regression we tested the association between 4,720 individual proteins or combined in a protein score with emphysema measured by 15th percentile lung density (PD15) or diffusion capacity (DLCO) in distinct AATD genotypes (Pi*ZZ, Pi*SZ, Pi*MZ) and non-AATD, PiMM COPD subjects. AAT SOMAmer accuracy for identifying AATD was tested using receiver operating characteristic curve analysis. FINDINGS: In PiZZ AATD subjects, 2 unique proteins were associated with PD15 and 98 proteins with DLCO. Of those, 68 were also associated with DLCO in COPD also and enriched for three cellular component pathways: insulin-like growth factor, lipid droplet, and myosin complex. PiMZ AATD subjects shared similar proteins associated with DLCO as COPD subjects. Our emphysema protein score included 262 SOMAmers and predicted emphysema in AATD and COPD subjects. SOMAmer AAT level <7.99 relative fluorescence unit (RFU) had 100% sensitivity and specificity for identifying Pi*ZZ, but it was lower for other AATD genotypes. INTERPRETATION: Using SomaScan, we identified unique and shared plasma biomarkers between AATD and COPD subjects and generated a protein score that strongly associates with emphysema in COPD and AATD. Furthermore, we discovered unique biomarkers associated with DLCO and emphysema in PiZZ AATD. FUNDING: This work was supported by a grant from the Alpha-1 Foundation to RPB. COPDGene was supported by Award U01 HL089897 and U01 HL089856 from the National Heart, Lung, and Blood Institute. Proteomics for COPDGene was supported by NIH 1R01HL137995. GRADS was supported by Award U01HL112707, U01 HL112695 from the National Heart, Lung, and Blood Institute, and UL1TRR002535 to CCTSI; QUANTUM-1 was supported by the National Heart Lung and Blood Institute, the Office of Rare Diseases through the Rare Lung Disease Clinical Research Network (1 U54 RR019498-01, Trapnell PI), and the Alpha-1 Foundation. COPDGene is also supported by the COPD Foundation through contributions made to an Industry Advisory Board that has included AstraZeneca, Bayer Pharmaceuticals, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, and Sunovion.

Exposure to volatile organic compounds and loss of pulmonary function in the elderly.

Volatile organic compounds (VOCs) are reported to cause adverse effects on pulmonary function in occupationally exposed workers. However, evidence is lacking on the effect in the general population. We hypothesised that VOCs impair pulmonary function through enhancing oxidative stress, especially in the elderly population. A longitudinal panel study of 154 elderly people was performed in South Korea. Repeated spirometric tests were performed up to eight times on different days for each subject. We also measured urinary concentrations of metabolites of the VOC and markers of oxidative stress (malondialdehyde and 8-oxo-2'-deoxyguanosine) on the same day of spirometric tests. A mixed linear regression model was used to evaluate the association among the VOC metabolites, oxidative stress markers and spirometric tests. We found that the urinary levels of hippuric acid and methylhippuric acid, which are metabolites of toluene and xylene, respectively, were significantly associated with reduction of forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity (FVC), and forced expiratory flow at 25-75% of FVC. We also found significant associations between the metabolites of VOCs and the markers of oxidative stress. In addition, the oxidative stress markers were associated with pulmonary function parameters. This study suggests that exposure to toluene and xylene exert a harmful effect on pulmonary function by exacerbating oxidative stress in elderly people.

Molecular cloning and functional characterization of a sucrose isomerase (isomaltulose synthase) gene from Enterobacter sp. FMB-1.

AIMS: Isomaltulose (palatinose) is a slowly digestible sucrose isomer that can reduce both the glycemic and insulinemic response to foods. The aim of this study was to clone and express a sucrose isomerase (SIase) gene and characterize the protein that is responsible for the production of isomaltulose in the micro-organism Enterobacter sp. FMB-1. METHODS AND RESULTS: A cosmid clone containing c. 6 kbp region encoding an SIase gene was identified. The 5969-bp chromosomal DNA fragment covering the SIase (esi) gene in Enterobacter sp. FMB-1 was sequenced. Although this DNA fragment contained several open reading frames other than esi, only the presence of esi was sufficient to produce isomaltulose in recombinant Escherichia coli. The esi gene was expressed in E. coli, leading to the characterization of its SIase activity. CONCLUSIONS: The Enterobacter sp. FMB-1 esi gene was successfully cloned and expressed in E. coli. This gene encoded a functional SIase that produced isomaltulose from sucrose. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first molecular analysis of an SIase gene in an Enterobacter strain. The functional expression of the Enterobacter sp. FMB-1 esi gene in E. coli offers an alternative choice for the industrial production of isomaltulose.

Electronic and structural characteristics of Zr-incorporated Gd2O3 films on strained SiGe substrates.

Zr-incorporated Gd(2)O(3) films were grown on various substrates as a function of Zr content. The extent of interfacial reactions was found to be critically dependent on both the incorporated Zr content and the substrate type. Specifically, the silicide layer was suppressed and the Gd(2)O(3) phase was changed to ZrO(2) on a Si substrate with increasing Zr content. Crystalline Gd(2)Ge(2)O(7) was grown on a Ge substrate, as the result of interfacial reactions between Gd-oxide and the Ge substrate. However, interfacial reactions were not affected by the amount of Zr incorporated. On the SiGe/Si substrate, reactions between Gd-oxide and Si could be controlled effectively by the incorporation of Zr, while the extent of reactions with Ge was significantly enhanced as the Zr content increased. The formation of an interfacial layer between the film and the SiGe substrate resulted in a textured crystalline growth.

Differential control of clustering of the sodium channels Na(v)1.2 and Na(v)1.6 at developing CNS nodes of Ranvier.

Na(v)1.6 is the main sodium channel isoform at adult nodes of Ranvier. Here, we show that Na(v)1.2 and its beta2 subunit, but not Na(v)1.6 or beta1, are clustered in developing central nervous system nodes and that clustering of Na(v)1.2 and Na(v)1.6 is differentially controlled. Oligodendrocyte-conditioned medium is sufficient to induce clustering of Na(v)1.2 alpha and beta2 subunits along central nervous system axons in vitro. This clustering is regulated by electrical activity and requires an intact actin cytoskeleton and synthesis of a non-sodium channel protein. Neither soluble- or contact-mediated glial signals induce clustering of Na(v)1.6 or beta1 in a nonmyelinating culture system. These data reveal that the sequential clustering of Na(v)1.2 and Na(v)1.6 channels is differentially controlled and suggest that myelination induces Na(v)1.6 clustering.

Magneto-optical enhancement through gyrotropic gratings.

Diffracted magneto-optical (MO) effects are numerically investigated for one-dimensional lossy gyrotropic gratings in the zeroth and the first orders for the polar magnetization by utilizing the rigorous coupled-wave approach implemented as an Airy-like internal-reflection series. The simulated Kerr spectra agree well with the experimental ones. The dependence of the MO Kerr enhancement on the grating depth in the first-order diffraction, compared with that in the zeroth one, is illustrated, and the diffracted MO Faraday effect is theoretically investigated as well. Such a MO enhancement through the gyrotropic gratings is superior to the conventional MO devices and magneto-photonic crystals. The potential applications are also suggested.

Interactive effect of central obesity and hypertension on cognitive function in older out-patients with Type 2 diabetes.

AIM: Central obesity, hypertension and diabetes mellitus have been related individually to cognitive dysfunction. We aimed to study the interactive effects of these co-occurring risk factors on cognitive decline, which remain unclear in older patients with diabetes. METHODS: We assessed metabolic profiles and neuropsychological functions in 60 older out-patients with Type 2 diabetes to examine the associations of central obesity with cognitive functions, while controlling for other confounding factors in these subjects. RESULTS: Waist circumference was associated with poor performance in digits forward (r2 = 0.11, P = 0.02), choice reaction time (r2 = 0.08, P = 0.04) and cognitive reaction time (r2 = 0.07, P < 0.05) even after adjustment for potential confounders including age, gender, education and HbA1c. There were also significant interactions between central obesity and hypertension with respect to performance of digits forward (P = 0.04) and delayed verbal cued recall (P = 0.03). CONCLUSION: Our findings suggest that, in addition to glycaemic control, central obesity and hypertension influence cognitive functions, such as attention and psychomotor speed in older patients with Type 2 diabetes.

Band gap change and interfacial reaction in Hf-silicate film grown on Ge(001).

The interfacial reaction of hafnium-silicate [(HfO(2))(x)(SiO(2))(1-x), x=0.5,0.7] thin films grown on Ge(001) by atomic layer deposition was investigated using x-ray photoelectron spectroscopy and medium energy ion scattering spectroscopy. According to the peak changes in Hf 4f and Ge 3d, the Hf-silicate film reacted with the oxidized Ge surface forming Hf-germanate at the interface. The formation of Hf-germanate induced band bending of the Ge substrate at the interface and decreased band gap to 5.1 eV, which was lower than that of GeO(2) (5.6 eV). In particular, the interfacial reaction was dependent on the amount of SiO(2) in the Hf-silicate film, which resulted in more decrement in the band gap in the film with a high SiO(2) fraction.