Repeated Exposure Enhanced Toxicity of Clarithromycin on Microcystis aeruginosa Versus Single Exposure through Photosynthesis, Oxidative Stress, and Energy Metabolism Shift.

Antibiotics are being increasingly detected in aquatic environments, and their potential ecological risk is of great concern. However, most antibiotic toxicity studies involve single-exposure experiments. Herein, we studied the effects and mechanisms of repeated versus single clarithromycin (CLA) exposure on Microcystis aeruginosa. The 96 h effective concentration of CLA was 13.37 µg/L upon single exposure but it reduced to 6.90 µg/L upon repeated exposure. Single-exposure CLA inhibited algal photosynthesis by disrupting energy absorption, dissipation and trapping, reaction center activation, and electron transport, thereby inducing oxidative stress and ultrastructural damage. In addition, CLA upregulated glycolysis, pyruvate metabolism, and the tricarboxylic acid cycle. Repeated exposure caused stronger inhibition of algal growth via altering photosynthetic pigments, reaction center subunits biosynthesis, and electron transport, thereby inducing more substantial oxidative damage. Furthermore, repeated exposure reduced carbohydrate utilization by blocking the pentose phosphate pathway, consequently altering the characteristics of extracellular polymeric substances and eventually impairing the defense mechanisms of M. aeruginosa. Risk quotients calculated from repeated exposure were higher than 1, indicating significant ecological risks. This study elucidated the strong influence of repeated antibiotic exposure on algae, providing new insight into antibiotic risk assessment.

Exploring the mechanisms of organic fertilizers on Cd bioavailability in rice fields: Environmental behavior and effect factors.

The problem of paddy Cadmium (Cd) contamination is currently the focus of global research. Earlier researches have confirmed that utilization of organic fertilizers regulates Cd chemical fraction distribution by increases organic bound Cd. However, environmental behaviours of organic fertilizers in paddy are still lack exploration. Here, we critical reviewed previous publications and proposed a novel research concept to help us better understand it. Three potential impact pathways of utilization of organic fertilizers on the bioavailability of Cd are presented: (i) use of organic fertilizers changes soil physicochemical properties, which directly affects Cd bioavailability by changing chemical form of Cd(II); (ii) use of organic fertilizers increases soil nutrient content, which indirectly regulates Cd supply and bioaccumulation through ion adsorption and competition for ion-transport channels between nutrients and Cd; and (iii) use of organic fertilizers increases activity of microorganisms and efflux of rice root exudates, which indirectly affects Cd bioavailability of through complexation and sequestration of these organic materials with Cd. Meanwhile, dissolved organic matter (DOM) in the rhizosphere of rice is believed to be the key to revealing the effects of organic fertilizers on Cd. DOM is capable of adsorption and complexation-chelation reactions with Cd and the fractionation of Cd(II) is regulated by DOM. Molecular mass, chemical composition, major functional groups and reaction sequence of DOM determine the formation and solubilization of DOM-Cd complexes.

Examining drinking water quality: analysis of physico-chemical properties and bacterial contamination with health implications for Shangla district, Khyber Pakhtunkhwa, Pakistan.

A comprehensive understanding of water quality is essential for assessing the complex relationship between surface water and sources of pollution. Primarily, surface water pollution is linked to human and animal waste discharges. This study aimed to investigate the physico-chemical characteristics of drinking water under both dry and wet conditions, assess the extent of bacterial contamination in samples collected from various locations in District Shangla, and evaluate potential health risks associated with consuming contaminated water within local communities. For this purpose, 120 groundwater and surface water samples were randomly collected from various sources such as storage tanks, user sites, streams, ponds and rivers in the study area. The results revealed that in Bisham, lakes had the highest fecal coliform levels among seven tested sources, followed by protected wells, reservoirs, downstream sources, springs, rivers, and ditches; while in Alpuri, nearly 80% of samples from five sources contained fecal coliform bacteria. Similarly, it was observed that the turbidity level, total dissolved solids, electrical conductivity, biological oxygen demand, and dissolved oxygen in the surface drinking water sources of Bisham were significantly higher than those in the surface drinking water sources of Alpuri. Furthermore, the results showed that in the Alpuri region, 14% of the population suffers from dysentery, 27% from diarrhea, 22% from cholera, 13% from hepatitis A, and 16% and 8% from typhoid and kidney problems, respectively, while in the Bisham area, 24% of residents are affected by diarrhea, 17% by cholera and typhoid, 15% by hepatitis A, 14% by dysentery, and 13% by kidney problems. These findings underscore the urgent need for improved water quality management practices and public health interventions to mitigate the risks associated with contaminated drinking water. It is recommended to implement regular water quality monitoring programs, enhance sanitation infrastructure, and raise awareness among local communities about the importance of safe drinking water practices to safeguard public health.

Microcystins-Loaded Aged Nanoplastics Provoke a Metabolic Shift in Human Liver Cells.

Studies concerning the toxicity of pollutant-loaded nanoplastics (NPs) toward humans are still in their infancy. Here, we evaluated the adsorption of microcystins (MCs) by pristine and aged polystyrene nanoplastics (PSNPs), prepared MCs-loaded aged PSNPS (1, 5, 10, 15, and 19 µg/mg), and systematically mapped the key molecular changes induced by aged and MCs-loaded PSNPs to human hepatoblastoma (HepG2) cells. According to the results, MC-LR adsorption is increased 2.64-fold by aging, and PSNP accumulation is detected in HepG2 cells. The cytotoxicity of the MC-LR-loaded aged PSNPs showed a positive relationship with the MC-LR amount, as the cell viability in the 19 µg/mg loading treatment (aPS-MC19) was 10.84% lower than aged PSNPs; meanwhile, more severe oxidative damage was observed. Primary approaches involved stressing the endoplasmic reticulum and reducing protein synthesis that the aged PSNPs posed for HepG2 cells, while the aggravated cytotoxicity in aPS-MC19 treatment was a combined result of the metabolic energy disorder, oxidative damage, endoplasmic reticulum stress, and downregulation of the MC-LR target protein. Our results confirm that the aged PSNPs could bring more MC-LR into the HepG2 cells, significantly interfere with biological processes, and provide new insight into deciphering the risk of NPs to humans.

Potential disintegration and transport of biochar in the soil-water environment: A case study towards purple soil.

Biochar has been widely applied in soil and water. However, the fate and transport of biochar are not yet fully understood. Here, biochar's disintegration, transport, and the effect of temperature on biochar transport in soil (purple soil)-water systems were investigated. The results showed that the potentially transportable components (PTC) of biochar for corn straw, wheat straw, rice straw, rice husk and wood biochar reached 6.22-7.60%, 5.96-12.29%, 11.77-12.45%, 5.34-6.26% and 5.08-6.14% by mass, respectively. An external force (ultrasound exposure) intensified the physical disintegration, including colloidal and nanoparticles from larger particles, thereby increasing the transport potential. The mass recovery rates of PTC for rice straw biochar after penetrating through soil at 5, 20 and 35 °C reached 44.25%, 32.97% and 10.98%, respectively, which was supported by the Derjaguin-Landau-Verwey-Overbeek (DLVO) theory results. Elevated temperatures increased the hydrodynamic average diameter of PTC, and the Zeta potential of PTC and soil at 35 °C were less negative than those at 5 and 20 °C. As a result, biochar's transportability decreases with increasing temperature in the soil-water system, during which the enhanced PTC aggregation and the decreased electrostatic repulsion between biochar and soil particles played a crucial role. The increase in electrical conductivity in the soil-water system may be the main reason for the decrease in electrostatic repulsion at higher temperatures. The findings are helpful for an in-depth understanding of the environmental fate and managing the transport risk of biochar.

The competitive advantage of Microcystis aeruginosa over Scenedesmus obliquus weakened by exposure to polylactic acid microplastics.

Aquatic ecosystems are heavily affected by microplastics (MPs), and its impacts on aquatic life have received extensive attention. However, it is still unclear how biodegradable MPs influence the growth and competition of phytoplankton. In this study, the response of growth dynamics, alternation in algal cell morphology and toxin-producing capability, and changes in the extracellular process of Microcystis aeruginosa (M. aeruginosa) and Scenedesmus obliquus (S. obliquus) were systematically studied in monoculture and co-culture conditions with and without the presence of polylactic acid MPs (PLA-MPs). The results indicated that although the loss of cell integrity was observed, PLA-MPs addition (50 mg/L) caused a 1.40- and 1.36-fold increase in cell densities of M. aeruginosa and S. obliquus in monoculture systems, respectively. This suggests the PLA-MPs more favored the growth of M. aeruginosa. This effect was manifested in co-culture conditions, because the degradation of PLA-MPs provided additional inorganic carbon in the experimental systems and benefited the growth of both M. aeruginosa and S. obliquus. Meanwhile, the synthesis of microcystins from the toxic M. aeruginosa was substantially reduced upon PLA-MPs exposure, which reduced the competitive advantage of M. aeruginosa over S. obliquus. Thus; the cell density of M. aeruginosa and S. obliquus showed 1.15- and 1.88-folds increasing compared to that without PLA-MPs addition. This interaction between PLA-MPs and algae weakened the competitive advantage of M. aeruginosa over S. obliquus, but their competitive outcomes remained unchanged. The results provided new insights into understanding the potential ecological risks of biodegradable plastics in aquatic ecosystems.

Effects of micro(nano)plastics on soil nutrient cycling: State of the knowledge.

The ecological impacts of micro(nano)plastics (MNPs) have attracted attention worldwide because of their global occurrence, persistence, and environmental risks. Increasing evidence shows that MNPs can affect soil nutrient cycling, but the latest advances on this topic have not systematically reviewed. Here, we aim to present the state of knowledge about the effects of MNPs on soil nutrient cycling, particularly of C, N, and P. Using the latest data, the present review mainly focuses on three aspects, including (1) the effects and underlying mechanisms of MNPs on soil nutrient cycling, particularly of C, N and P, (2) the factors influencing the effects of MNPs on soil nutrient cycling, and (3) the knowledge gaps and future directions. We conclude that MNPs can alter soil nutrient cycling via mediating soil nutrient availability, soil enzyme activities, functional microbial communities, and their potential ecological functions. Furthermore, the effects of MNPs vary with MNPs characteristics (i.e., polymeric type, size, dosage, and shape), chemical additives, soil physicochemical conditions, and soil biota. Considering the complexity of MNP-soil interactions, multi-scale experiments using environmental relevant MNPs are required to shed light on the effects of MNPs on soil nutrients. By learning how MNPs influence soil nutrients cycles, this review can guide policy and management decisions to safeguard soil health and ensure sustainable agriculture and land use practices.

Sex differences in the developing brain impact stress-induced epileptogenicity following hyperthermia-induced seizures.

Febrile seizures (FS) are common, affecting 2-5% of children between the ages of 3 months and 6 years. Complex FS occur in 10% of patients with FS and are strongly associated with mesial temporal lobe epilepsy. Current research suggests that predisposing factors, such as genetic and anatomic abnormalities, may be necessary for complex FS to translate to mesial temporal lobe epilepsy. Sex hormones are known to influence seizure susceptibility and epileptogenesis, but whether sex-specific effects of early life stress play a role in epileptogenesis is unclear. Here, we investigate sex differences in the activity of the hypothalamic-pituitary-adrenal (HPA) axis following chronic stress and the underlying contributions of gonadal hormones to the susceptibility of hyperthermia-induced seizures (HS) in rat pups. Chronic stress consisted of daily injections of 40 mg/kg of corticosterone (CORT) subcutaneously from postnatal day (P) 1 to P9 in male and female rat pups followed by HS at P10. Body mass, plasma CORT levels, temperature threshold to HS, seizure characteristics, and electroencephalographic in vivo recordings were compared between CORT- and vehicle (VEH)-injected littermates during and after HS at P10. In juvenile rats (P18-P22), in vitro CA1 pyramidal cell recordings were recorded in males to investigate excitatory and inhibitory neuronal circuits. Results show that daily CORT injections increased basal plasma CORT levels before HS and significantly reduced weight gain and body temperature threshold of HS in both males and females. CORT also significantly lowered the generalized convulsions (GC) latency while increasing recovery time and the number of electrographic seizures (>10s), which had longer duration. Furthermore, sex-specific differences were found in response to chronic CORT injections. Compared to females, male pups had increased basal plasma CORT levels after HS, longer recovery time and a higher number of electrographic seizures (>10s), which also had longer duration. Sex-specific differences were also found at baseline conditions with lower latency to generalized convulsions and longer duration of electrographic seizures in males but not in females. In juvenile male rats, the amplitude of evoked excitatory postsynaptic potentials, as well as the amplitude of inhibitory postsynaptic currents, were significantly greater in CORT rats when compared to VEH littermates. These findings not only validate CORT injections as a stress model, but also show a sex difference in baseline conditions as well as a response to chronic CORT and an impact on seizure susceptibility, supporting a potential link between sustained early-life stress and complex FS. Overall, these effects also indicate a putatively less severe phenotype in female than male pups. Ultimately, studies investigating the biological underpinnings of sex differences as a determining factor in mental and neurologic problems are necessary to develop better diagnostic, preventative, and therapeutic approaches for all patients regardless of their sex.

"Crisis management in the hospitality sector SMEs in Pakistan during COVID-19″.

The COVID-19 pandemic has delivered one of the worst economic shocks in modern history and the hospitality sector has been severely affected. Since small businesses from the hospitality sector are known to be relatively more susceptible to the economic complications arising from a crisis, we explore the underlying factors and management practices that influence their continuity of operations as they continue to struggle with the on-going COVID-19 crisis in Pakistan. Using a phenomenological approach, in-depth interviews were conducted to comprehend the experiences of owners-managers. The findings show that government support, cordial relationships with stakeholders, self-determination of entrepreneurs and formal planning are the most crucial factors that shaped the immediate adjustments of operational activities in response to COVID-19. These resilient practices are hygiene concerns, increased promotion through social media, innovative marketing practices (e.g., revised offerings), operational cost-cutting and employee training to comply with changing standard operating procedures from the government and industry. The practical and theoretical implications are also discussed.

Preparation of composite adsorbents of activated carbon supported MgO/MnO2 and adsorption of Rhodamine B.

Activated carbon (AC) was modified by MgO and MnO2 through an impregnation-precipitation-calcination procedure. The batch experiments of adsorption of Rhodamine B (RB) by a modified adsorption material, an MgO-MnO2-AC composite, were carried out and the characteristics of the composite adsorbent were evaluated. The results showed that manganese/magnesium loading changed the surface area, pore volume and increased the number of active adsorption sites of AC. The highest Brunauer-Emmett-Teller (BET) surface area (1,036.18 m2·g-1) was obtained for MgO-MnO2-AC compared with AC. The content of AC loaded with magnesium and manganese was 34.24 and 5.51 mg·g-1 respectively. The adsorption of RB on MgO-MnO2-AC was significantly improved. The maximum adsorption capacity of RB on MgO-MnO2-AC was 16.19 mg·g-1 at 25 °C under the RB concentration of 50 mg·L-1. The adsorption of RB by AC and MgO-MnO2-AC increased with the initial concentration of RB. The adsorption of RB increased first and then decreased when pH was between 3 and 11. The results indicated that the pseudo-second-order kinetic equation and Langmuir equation can be used to describe the adsorption of RB on MgO-MnO2-AC.

Rising environmental degradation and impact of foreign direct investment: An empirical evidence from SAARC region.

The Pollution Haven Hypothesis is amongst the latest discussion in economics that investigates the contribution of Foreign Direct Investment in raising environmental degradation in the host countries. Whereas, the concept of the Environmental Kuznets Curve hypothesis had been in economics since 1991 and is extensively studied under the umbrella of environmental degradation. Our present study is focused upon the role of economic growth, Foreign Direct Investment and energy consumption in increasing concentration of Carbon Dioxide in the South Asian region by using panel data from 1986 to 2014. The nascent techniques, panel ARDL, and FMOLS have been applied. The results thus obtained confirmed the existence of Pollution Heaven Hypotheses and Environmental Kuznets Curve in the short run. However, long-run analysis of the panel data confirms the absence of Pollution Heaven Hypotheses and existence of Environment Kuznets Curve. Furthermore, energy consumption in the region significantly contributing to environmental degradation. Since a major portion of the energy in South Asian countries is being generated from non-renewable energy resources. In the future, these countries are planning to meet their energy requirements through non-renewable energy resources that will inject more Carbon Dioxide to the atmosphere. The pattern of Study further refers to South Asian nations for extended co-operation in environmental R&D to mitigate future challenges. The governments in the region need to initiate environment-friendly regulations to suppress environmental degradation. Keen efforts are required by the statistical/environmental institutions in the region to set up a data collection/distribution forum so that real-time analysis be complied with, in order to accelerate the progress towards projected goals and sustainability.

Effects of Childhood Asthma on the Development of Obesity among School-aged Children.

RATIONALE: Asthma and obesity often occur together in children. It is unknown whether asthma contributes to the childhood obesity epidemic. OBJECTIVES: We aimed to investigate the effects of asthma and asthma medication use on the development of childhood obesity. METHODS: The primary analysis was conducted among 2,171 nonobese children who were 5-8 years of age at study enrollment in the Southern California Children's Health Study (CHS) and were followed for up to 10 years. A replication analysis was performed in an independent sample of 2,684 CHS children followed from a mean age of 9.7 to 17.8 years. MEASUREMENTS AND MAIN RESULTS: Height and weight were measured annually to classify children into normal, overweight, and obese categories. Asthma status was ascertained by parent- or self-reported physician-diagnosed asthma. Cox proportional hazards models were fitted to assess associations of asthma history with obesity incidence during follow-up. We found that children with a diagnosis of asthma at cohort entry were at 51% increased risk of developing obesity during childhood and adolescence compared with children without asthma at baseline (hazard ratio, 1.51; 95% confidence interval, 1.08-2.10) after adjusting for confounders. Use of asthma rescue medications at cohort entry reduced the risk of developing obesity (hazard ratio, 0.57; 95% confidence interval, 0.33-0.96). In addition, the significant association between a history of asthma and an increased risk of developing obesity was replicated in an independent CHS sample. CONCLUSIONS: Children with asthma may be at higher risk of obesity. Asthma rescue medication use appeared to reduce obesity risk independent of physical activity.

Mortality with brainstem seizures from focal 4-aminopyridine-induced recurrent hippocampal seizures.

OBJECTIVE: Sudden unexplained death in epilepsy is the leading cause of death in young adult epilepsy patients, typically occurring during the early postictal period, presumably resulting from brainstem and cardiorespiratory dysfunction. We hypothesized that ictal discharges in the brainstem disrupt the cardiorespiratory network, causing mortality. To study this hypothesis, we chose an animal model comprising focal unilateral hippocampal injection of 4-aminopyridine (4-AP), which produced focal recurrent hippocampal seizures with secondary generalization in awake, behaving rats. METHODS: We studied ictal and interictal intracranial electrographic activity (iEEG) in 23 rats implanted with a custom electrode array into the hippocampus, the contralateral cortex, and brainstem. The hippocampal electrodes contained a cannula to administer the potassium channel blocker and convulsant (4-AP). iEEG was recorded continuously before, during, and after seizures induced by 4-AP infusion into the hippocampus. RESULTS: The control group (n = 5) was monitored for 2-3 months, and the weekly baseline iEEG recordings showed long-term stability. The low-dose group (1 µL 4-AP, 40 mm, n = 5) exhibited local electrographic seizures without spread to the contralateral cerebral cortex or brainstem. The high-dose group (5 µL 4-AP, 40 mm, n = 3) had several hippocampal electrographic seizures, which spread contralaterally and triggered brainstem discharges within 40 min, and were associated with violent motor seizures followed by dyspnea and respiratory arrest, with cortical and hippocampal iEEG flattening. The group that received high-dose 4-AP without brainstem implantation (n = 5) had similar seizure-related respiratory difficulties. Finally, five rats that received high-dose 4-AP without EEG recording also developed violent motor seizures with postictal respiratory arrest. Following visualized respiratory arrest in groups III, IV, and V, manual respiratory resuscitation was successful in five of 13 animals. SIGNIFICANCE: These studies show that hippocampal seizure activity can spread or trigger brainstem epileptiform discharges that may cause mortality, possibly mediated by respiratory network dysfunction.

Genetic and epigenetic susceptibility of airway inflammation to PM2.5 in school children: new insights from quantile regression.

BACKGROUND: The fractional concentration of exhaled nitric oxide (FeNO) is a biomarker of airway inflammation that has proved to be useful in investigations of genetic and epigenetic airway susceptibility to ambient air pollutants. For example, susceptibility to airway inflammation from exposure to particulate matter with aerodynamic diameter < =2.5 µm (PM2.5) varies by haplotypes and promoter region methylation in inducible nitric oxide synthase (iNOS encoded by NOS2). We hypothesized that PM2.5 susceptibility associated with these epigenetic and genetic variants may be greater in children with high FeNO from inflamed airways. In this study, we investigated genetic and epigenetic susceptibility to airborne particulate matter by examining whether the joint effects of PM2.5, NOS2 haplotypes and iNOS promoter methylation significantly vary across the distribution of FeNO in school children. METHODS: The study included 940 school children in the southern California Children's Health Study who provided concurrent buccal samples and FeNO measurements. We used quantile regression to examine susceptibility by estimating the quantile-specific joint effects of PM2.5, NOS2 haplotype and methylation on FeNO. RESULTS: We discovered striking differences in susceptibility to PM2.5 in school children. The joint effects of short-term PM2.5 exposure, NOS2 haplotypes and methylation across the FeNO distribution were significantly larger in the upper tail of the FeNO distribution, with little association in its lower tail, especially among children with asthma and Hispanic white children. CONCLUSION: School-aged children with higher FeNO have greater genetic and epigenetic susceptibility to PM2.5, highlighting the importance of investigating effects across the entire distribution of FeNO.

Genome-wide interaction studies reveal sex-specific asthma risk alleles.

Asthma is a complex disease with sex-specific differences in prevalence. Candidate gene studies have suggested that genotype-by-sex interaction effects on asthma risk exist, but this has not yet been explored at a genome-wide level. We aimed to identify sex-specific asthma risk alleles by performing a genome-wide scan for genotype-by-sex interactions in the ethnically diverse participants in the EVE Asthma Genetics Consortium. We performed male- and female-specific genome-wide association studies in 2653 male asthma cases, 2566 female asthma cases and 3830 non-asthma controls from European American, African American, African Caribbean and Latino populations. Association tests were conducted in each study sample, and the results were combined in ancestry-specific and cross-ancestry meta-analyses. Six sex-specific asthma risk loci had P-values < 1 × 10(-6), of which two were male specific and four were female specific; all were ancestry specific. The most significant sex-specific association in European Americans was at the interferon regulatory factor 1 (IRF1) locus on 5q31.1. We also identify a Latino female-specific association in RAP1GAP2. Both of these loci included single-nucleotide polymorphisms that are known expression quantitative trait loci and have been associated with asthma in independent studies. The IRF1 locus is a strong candidate region for male-specific asthma susceptibility due to the association and validation we demonstrate here, the known role of IRF1 in asthma-relevant immune pathways and prior reports of sex-specific differences in interferon responses.

Rapid brief feedback intracerebral stimulation based on real-time desynchronization detection preceding seizures stops the generation of convulsive paroxysms.

OBJECTIVE: To investigate the abortion of seizure generation using "minimal" intervention in hippocampi using two rat models of human temporal lobe epilepsy. METHODS: The recording or stimulation electrodes were implanted into both hippocampi (CA1 area). Using the kainic acid (chronic: experiment duration 24 days) and the 4-aminopyridine (acute: experiment duration 2 h) models of paroxysms in rats, a real-time feedback stimulation paradigm was implemented, which triggered a short periodic electrical stimulus (5 Hz for 5 s) upon detecting a seizure precursor. Our seizure precursor detection algorithm relied on the monitoring of the real-time phase synchronization analysis, and detected/anticipated electrographic seizures as early as a few seconds to a few minutes before the behavioral and electrographic seizure onset, with a very low false-positive rate of the detection. RESULTS: The baseline mean seizure frequencies were 5.39 seizures per day (chronic) and 13.2 seizures per hour (acute). The phase synchrony analysis detected 88% (434 of 494) of seizures with a mean false alarm of 0.67 per day (chronic) and 83% (86 of 104) of seizures with a mean false alarm of 0.47 per hour (acute). The feedback stimulation reduced the seizure frequencies to 0.41 seizures per day (chronic) and 2.4 seizures per hour (acute). Overall, the feedback stimulation paradigm reduced seizure frequency by a minimum of 80% to a maximum of 100% in 10 rats, with 83% of the animals rendered seizure-free. SIGNIFICANCE: This approach represents a simple and efficient manner for stopping seizure development. Because of the short on-demand stimuli, few or no associated side effects are expected in clinical application in patients with epilepsy. Abnormal synchrony patterns are common features in epilepsy and other neurologic and psychiatric syndromes; therefore, this type of feedback stimulation paradigm could be a novel therapeutic modality for use in various neurologic and psychiatric disorders.

Spirometry effects on conventional and multiple flow exhaled nitric oxide in children.

OBJECTIVE: Clinical and research settings often require sequencing multiple respiratory tests in a brief visit. Guidelines recommend measuring the concentration of exhaled nitric oxide (FeNO) before spirometry, but evidence for a spirometry carryover effect on FeNO is mixed. Only one study has investigated spirometry carryover effects on multiple flow FeNO analysis. The objective of this study was to evaluate evidence for carryover effects of recent spirometry on three exhaled NO summary measures: FeNO at 50 ml/s, airway wall NO flux [J'awNO] and alveolar NO concentration [CANO] in a population-based sample of schoolchildren. METHODS: Participants were 1146 children (191 with asthma), ages 12-15, from the Southern California Children's Health Study who performed spirometry and multiple flow FeNO on the same day. Approximately, half the children performed spirometry first. Multiple linear regression was used to estimate differences in exhaled NO summary measures associated with recent spirometry testing, adjusting for potential confounders. RESULTS: In the population-based sample, we found no evidence of spirometry carryover effects. However, for children with asthma, there was a suggestion that exhaled NO summary measures assessed ≤6 min after spirometry were lower (FeNO: 25.8% lower, 95% CI: -6.2%, 48.2%; J'awNO: 15.1% lower 95% CI: -26.5%, 43.0%; and CANO 0.43 parts per billion lower, 95% CI: -0.12, 0.98). CONCLUSIONS: In clinical settings, it is prudent to assess multiple flow FeNO before spirometry. In studies of healthy subjects, it may not be necessary to assess FeNO first.

Fraction of exhaled nitric oxide values in childhood are associated with 17q11.2-q12 and 17q12-q21 variants.

BACKGROUND: The fraction of exhaled nitric oxide (Feno) value is a biomarker of eosinophilic airway inflammation and is associated with childhood asthma. Identification of common genetic variants associated with childhood Feno values might help to define biological mechanisms related to specific asthma phenotypes. OBJECTIVE: We sought to identify the genetic variants associated with childhood Feno values and their relation with asthma. METHODS: Feno values were measured in children age 5 to 15 years. In 14 genome-wide association studies (N = 8,858), we examined the associations of approximately 2.5 million single nucleotide polymorphisms (SNPs) with Feno values. Subsequently, we assessed whether significant SNPs were expression quantitative trait loci in genome-wide expression data sets of lymphoblastoid cell lines (n = 1,830) and were related to asthma in a previously published genome-wide association data set (cases, n = 10,365; control subjects: n = 16,110). RESULTS: We identified 3 SNPs associated with Feno values: rs3751972 in LYR motif containing 9 (LYRM9; P = 1.97 × 10(-10)) and rs944722 in inducible nitric oxide synthase 2 (NOS2; P = 1.28 × 10(-9)), both of which are located at 17q11.2-q12, and rs8069176 near gasdermin B (GSDMB; P = 1.88 × 10(-8)) at 17q12-q21. We found a cis expression quantitative trait locus for the transcript soluble galactoside-binding lectin 9 (LGALS9) that is in linkage disequilibrium with rs944722. rs8069176 was associated with GSDMB and ORM1-like 3 (ORMDL3) expression. rs8069176 at 17q12-q21, but not rs3751972 and rs944722 at 17q11.2-q12, were associated with physician-diagnosed asthma. CONCLUSION: This study identified 3 variants associated with Feno values, explaining 0.95% of the variance. Identification of functional SNPs and haplotypes in these regions might provide novel insight into the regulation of Feno values. This study highlights that both shared and distinct genetic factors affect Feno values and childhood asthma.

Longitudinal effects of air pollution on exhaled nitric oxide: the Children's Health Study.

OBJECTIVES: To assess the effects of long-term variations in ambient air pollutants on longitudinal changes in exhaled nitric oxide (FeNO), a potentially useful biomarker of eosinophilic airway inflammation, based on data from the southern California Children's Health Study. METHODS: Based on a cohort of 1211 schoolchildren from eight Southern California communities with FeNO measurements in 2006-2007 and 2007-2008, regression models adjusted for short-term effects of air pollution were fitted to assess the association between changes in annual long-term exposures and changes in FeNO. RESULTS: Increases in annual average concentrations of 24-h average NO2 and PM2.5 (scaled to the IQR of 1.8 ppb and 2.4 µg/m(3), respectively) were associated with a 2.29 ppb (CI 0.36 to 4.21; p=0.02) and a 4.94 ppb (CI 1.44 to 8.47; p=0.005) increase in FeNO, respectively, after adjustments for short-term effects of the respective pollutants. In contrast, changes in annual averages of PM10 and O3 were not significantly associated with changes in FeNO. These findings did not differ significantly by asthma status. CONCLUSIONS: Changes in annual average exposure to current levels of ambient air pollutants are significantly associated with changes in FeNO levels in children, independent of short-term exposures and asthma status. Use of this biomarker in population-based epidemiological research has great potential for assessing the impact of changing real world mixtures of ambient air pollutants on children's respiratory health.

Asthma epigenetics.

Asthma is the most common chronic disease of childhood, and a growing body of evidence indicates that epigenetic variations may mediate the effects of environmental exposures on the development and natural history of asthma. Epigenetics is the study of mitotically or meiotically heritable changes in gene expression that occur without directly altering the DNA sequence. DNA methylation, histone modifications and microRNAs are major epigenetic variations in humans that are currently being investigated for asthma etiology and natural history. DNA methylation results from addition of a methyl group to the 5 position of a cytosine ring and occurs almost exclusively on a cytosine in a CpG dinucleotide. Histone modifications involve posttranslational modifications such as acetylation, methylation, phosphorylation and ubiquitination on the tails of core histones. MicroRNAs are short ~22 nucleotide long, non-coding, single-stranded RNAs that binds to complementary sequences in the target mRNAs, usually resulting in gene silencing. While many studies have documented relationships of environmental exposures that have been implicated in asthma etiology with epigenetic alterations, to date, few studies have directly linked epigenetic variations with asthma development. There are several methodological challenges in studying the epigenetics of asthma. In this chapter, the influence of epigenetic variations on asthma pathophysiology, methodological concerns in conducting epigenetic research and future direction of asthma epigenetics research are discussed.