The Legacy of Redlining: Increasing Childhood Asthma Disparities Through Neighborhood Poverty.

RATIONALE: Identifying the root causes of racial disparities in childhood asthma is critical for health equity. OBJECTIVES: To determine if the 1930's racist policy of redlining led to present-day disparities in childhood asthma by increasing community-level poverty and decreasing neighborhood socioeconomic position (SEP). METHODS: We categorized census tracts at birth of participants from the Children's Respiratory and Environmental Workgroup birth cohort consortium into A, B, C, or D categories as defined by the Home Owners Loan Corporation (HOLC), with D being the highest perceived risk. Surrogates of present-day neighborhood-level SEP were determined for each tract including the percentage of low-income households, the CDC's social vulnerability index (SVI), and other tract-level variables. We performed causal mediation analysis, which, under the assumption of no unmeasured confounding, estimates the direct and mediated pathways by which redlining may cause asthma disparities through census tract-level mediators adjusting for individual-level covariates. MEASUREMENTS AND MAIN RESULTS: Of 4,849 children, the cumulative incidence of asthma through age 11 was 26.6% and 13.2% resided in census tracts with a HOLC grade of D. In mediation analyses, residing in grade D tracts (aOR = 1.03 [95%CI 1.01,1.05]) was significantly associated with childhood asthma, with 79% of this increased risk mediated by percentage of low-income households; results were similar for SVI and other tract-level variables. CONCLUSIONS: The historical structural racist policy of redlining led to present-day asthma disparities in part through decreased neighborhood SEP. Policies aimed at reversing the effects of structural racism should be considered to create more just, equitable, and healthy communities.

De novo mutations across 1,465 diverse genomes reveal mutational insights and reductions in the Amish founder population.

De novo mutations (DNMs), or mutations that appear in an individual despite not being seen in their parents, are an important source of genetic variation whose impact is relevant to studies of human evolution, genetics, and disease. Utilizing high-coverage whole-genome sequencing data as part of the Trans-Omics for Precision Medicine (TOPMed) Program, we called 93,325 single-nucleotide DNMs across 1,465 trios from an array of diverse human populations, and used them to directly estimate and analyze DNM counts, rates, and spectra. We find a significant positive correlation between local recombination rate and local DNM rate, and that DNM rate explains a substantial portion (8.98 to 34.92%, depending on the model) of the genome-wide variation in population-level genetic variation from 41K unrelated TOPMed samples. Genome-wide heterozygosity does correlate with DNM rate, but only explains <1% of variation. While we are underpowered to see small differences, we do not find significant differences in DNM rate between individuals of European, African, and Latino ancestry, nor across ancestrally distinct segments within admixed individuals. However, we did find significantly fewer DNMs in Amish individuals, even when compared with other Europeans, and even after accounting for parental age and sequencing center. Specifically, we found significant reductions in the number of C→A and T→C mutations in the Amish, which seem to underpin their overall reduction in DNMs. Finally, we calculated near-zero estimates of narrow sense heritability (h2), which suggest that variation in DNM rate is significantly shaped by nonadditive genetic effects and the environment.

Remission of persistent childhood asthma: Early predictors of adult outcomes.

BACKGROUND: Few data exist on the predictors of asthma remission by early adulthood in North America. OBJECTIVE: The predictors of adult asthma remission were determined in a multiethnic population of patients with mild-to-moderate persistent childhood asthma. METHODS: Asthma remission in early adulthood was measured by using 2 definitions: a clinical and a strict definition. Both included normal lung function and the absence of symptoms, exacerbations, and medication use. The strict definition also included normal airways responsiveness. Predictors were identified from 23 baseline measures by using multivariate logistic regression. The probability of remission was modeled by using decision tree analysis. RESULTS: In 879 subjects the mean ± SD baseline age was 8.8 ± 2.1 years, 59.4% were male, and 68.7% were white. By adulthood, 229 (26.0%) of 879 participants were in clinical remission, and 111 (15.0%) of 741 participants were in strict remission. The degree of FEV1/forced vital capacity (FVC) ratio impairment was the largest predictor of asthma remission. More than half of boys and two thirds of girls with baseline FEV1/FVC ratios of 90% or greater were in remission at adulthood. Decreased airways responsiveness was also a predictor for both remission definitions (clinical remission odds ratio, 1.23 [95% CI, 1.09-1.39]; strict remission odds ratio, 1.52 [95% CI, 1.26-1.84]). The combination of normal FEV1/FVC ratio, airways responsiveness, and serum eosinophil count at baseline yielded greater than 80% probability of remission by adulthood. CONCLUSION: A considerable minority of patients with persistent childhood asthma will have disease remission by adulthood. Clinical prognostic indicators of asthma remission, including baseline lung function, can be seen from an early age.

Primary Pancreatic Secretinoma: Further Evidence Supporting Secretin as a Diarrheogenic Hormone.

OBJECTIVES: To document the existence of primary pancreatic secretinoma in patients with watery diarrhea syndrome (WDS) and achlorhydria and establish secretin as a diarrheogenic hormone. BACKGROUND: Vasoactive intestinal peptide (VIP) has been widely accepted as the main mediator of WDS. However, in 1968, Zollinger et al reported 2 female patients with pancreatic neuroendocrine tumors, WDS, and achlorhydria. During surgery on the first, a 24-year-old patient, they noticed distended duodenum filled with fluid and a dilated gallbladder containing dilute bile with high bicarbonate concentration. After excision of the tumor, WDS ceased and gastric acid secretion returned. The second, a 47-year-old, patient's metastatic tumor extract given intravenously in dogs, produced significantly increased pancreatic and biliary fluid rich in bicarbonate. They suggested a secretin-like hormone of islet cell origin explains WDS and achlorhydria. These observations, however, predated radioimmunoassay, immunohistochemical staining, and other molecular studies. METHODS: The first patient's tumor tissue was investigated for secretin and VIP. Using both immunohistochemistry and laser microdissection and pressure catapulting technique for RNA isolation and subsequent reverse transcription polymerase chain reaction, the expression levels of secretin, and VIP were measured. RESULTS: Immunoreactive secretin and its mRNA were predominantly found in the tumor tissue whereas VIP and its mRNA were scarce. CONCLUSIONS: The findings strongly support that the WDS and achlorhydria in this patient may have been caused by secretin as originally proposed in 1968 and that secretin may act as a diarrheogenic hormone.

Bronchodilator response following methacholine-induced bronchoconstriction predicts acute asthma exacerbations.

Methacholine bronchial provocation test provides the concentration of methacholine causing a 20% decrease in forced expiratory volume in 1 s (FEV1) from baseline (PC20). The dose-response slope (DRS), and other continuous indices of responsiveness (CIR; the percentage decline from the post-diluent baseline FEV1 after the last dose of methacholine), and per cent recovery index (PRI; the percentage increase from the maximally reduced FEV1 after bronchodilator inhalation) are alternative measures. The clinical relevance of these indices in predicting acute asthma exacerbations has not been fully evaluated.In two prospective cohorts of childhood and elderly asthmatics, baseline PC20, DRS, CIR and PRI were measured and evaluated as predictors of acute asthma exacerbations.We found that PRI was significantly related to the presence of asthma exacerbations during the first year of follow-up in both cohorts of childhood (p=0.025) and elderly asthmatics (p=0.003). In addition, PRI showed a significant association with the total number of steroid bursts during 4.3 years of follow-up in the cohort of childhood asthmatics (p=0.04).We demonstrated that PRI, an index of reversibility following methacholine-induced bronchoconstriction, was a good clinical predictor of acute exacerbations of asthma in both childhood and elderly asthmatics.

Monocyte and macrophage plasticity in tissue repair and regeneration.

Heterogeneity and high versatility are the characteristic features of the cells of monocyte-macrophage lineage. The mononuclear phagocyte system, derived from the bone marrow progenitor cells, is primarily composed of monocytes, macrophages, and dendritic cells. In regenerative tissues, a central role of monocyte-derived macrophages and paracrine factors secreted by these cells is indisputable. Macrophages are highly plastic cells. On the basis of environmental cues and molecular mediators, these cells differentiate to proinflammatory type I macrophage (M1) or anti-inflammatory or proreparative type II macrophage (M2) phenotypes and transdifferentiate into other cell types. Given a central role in tissue repair and regeneration, the review focuses on the heterogeneity of monocytes and macrophages with current known mechanisms of differentiation and plasticity, including microenvironmental cues and molecular mediators, such as noncoding RNAs.

Synthesis, DNA binding affinity and anticancer activity of novel 4H-benzo[g][1,2,3]triazolo[5,1-c][1,4]oxazocines.

A new class of tricyclic heterocycles 4H-benzo[g][1,2,3]triazolo[5,1-c][1,4]oxazocines was synthesized through a Knoevenagel condensation/azide-alkyne cycloaddition reaction cascade in one-pot operation. These eight membered ring containing heterocycles exhibited moderately high anticancer activity against four cancer cell lines; human cervix cancer cell line (HeLa), human prostate cancer cell line (DU145), human breast cancer cell line (MCF-7) and human breast adenocarcinoma epithelial cell line (MDA-MB-231). Our results indicate that these compounds have a weak cytotoxic effect on normal human mammary epithelial cell line (MCF-10A). Cell cycle and apoptosis assay indicate that they inhibit the cell cycle at the G2/M phase and induce apoptosis. Through the RED100 assay, it is evident that they have potential to inhibit pBR 322 plasmid DNA cleavage by BamH1. UV-visible, fluorescence titration and viscosity studies suggested that these compounds possess DNA binding affinity.

Genomic screening and replication using the same data set in family-based association testing.

The Human Genome Project and its spin-offs are making it increasingly feasible to determine the genetic basis of complex traits using genome-wide association studies. The statistical challenge of analyzing such studies stems from the severe multiple-comparison problem resulting from the analysis of thousands of SNPs. Our methodology for genome-wide family-based association studies, using single SNPs or haplotypes, can identify associations that achieve genome-wide significance. In relation to developing guidelines for our screening tools, we determined lower bounds for the estimated power to detect the gene underlying the disease-susceptibility locus, which hold regardless of the linkage disequilibrium structure present in the data. We also assessed the power of our approach in the presence of multiple disease-susceptibility loci. Our screening tools accommodate genomic control and use the concept of haplotype-tagging SNPs. Our methods use the entire sample and do not require separate screening and validation samples to establish genome-wide significance, as population-based designs do.

Early-Life Exposure to Air Pollution and Childhood Asthma Cumulative Incidence in the ECHO CREW Consortium.

Importance: Exposure to outdoor air pollution contributes to childhood asthma development, but many studies lack the geographic, racial and ethnic, and socioeconomic diversity to evaluate susceptibility by individual-level and community-level contextual factors. Objective: To examine early life exposure to fine particulate matter (PM2.5) and nitrogen oxide (NO2) air pollution and asthma risk by early and middle childhood, and whether individual and community-level characteristics modify associations between air pollution exposure and asthma. Design, Setting, and Participants: This cohort study included children enrolled in cohorts participating in the Children's Respiratory and Environmental Workgroup consortium. The birth cohorts were located throughout the US, recruited between 1987 and 2007, and followed up through age 11 years. The survival analysis was adjusted for mother's education, parental asthma, smoking during pregnancy, child's race and ethnicity, sex, neighborhood characteristics, and cohort. Statistical analysis was performed from February 2022 to December 2023. Exposure: Early-life exposures to PM2.5 and NO2 according to participants' birth address. Main Outcomes and Measures: Caregiver report of physician-diagnosed asthma through early (age 4 years) and middle (age 11 years) childhood. Results: Among 5279 children included, 1659 (31.4%) were Black, 835 (15.8%) were Hispanic, 2555 (48.4%) where White, and 229 (4.3%) were other race or ethnicity; 2721 (51.5%) were male and 2596 (49.2%) were female; 1305 children (24.7%) had asthma by 11 years of age and 954 (18.1%) had asthma by 4 years of age. Mean values of pollutants over the first 3 years of life were associated with asthma incidence. A 1 IQR increase in NO2 (6.1 µg/m3) was associated with increased asthma incidence among children younger than 5 years (HR, 1.25 [95% CI, 1.03-1.52]) and children younger than 11 years (HR, 1.22 [95% CI, 1.04-1.44]). A 1 IQR increase in PM2.5 (3.4 µg/m3) was associated with increased asthma incidence among children younger than 5 years (HR, 1.31 [95% CI, 1.04-1.66]) and children younger than 11 years (OR, 1.23 [95% CI, 1.01-1.50]). Associations of PM2.5 or NO2 with asthma were increased when mothers had less than a high school diploma, among Black children, in communities with fewer child opportunities, and in census tracts with higher percentage Black population and population density; for example, there was a significantly higher association between PM2.5 and asthma incidence by younger than 5 years of age in Black children (HR, 1.60 [95% CI, 1.15-2.22]) compared with White children (HR, 1.17 [95% CI, 0.90-1.52]). Conclusions and Relevance: In this cohort study, early life air pollution was associated with increased asthma incidence by early and middle childhood, with higher risk among minoritized families living in urban communities characterized by fewer opportunities and resources and multiple environmental coexposures. Reducing asthma risk in the US requires air pollution regulation and reduction combined with greater environmental, educational, and health equity at the community level.

African ancestry and lung function in Puerto Rican children.

BACKGROUND: Puerto Rican and African American subjects share a significant proportion of African ancestry. Recent findings suggest that African ancestry influences lung function in African American adults. OBJECTIVE: We sought to examine whether a greater proportion of African ancestry is associated with lower FEV(1) and forced vital capacity (FVC) in Puerto Rican children independently of socioeconomic status, health care access, or key environmental/lifestyle factors. METHODS: We performed a cross-sectional case-control study of 943 Puerto Rican children aged 6 to 14 years with (n= 520) and without (n= 423) asthma (defined as physician-diagnosed asthma and wheeze in the prior year) living in Hartford, Connecticut (n= 383), and San Juan, Puerto Rico (n= 560). We estimated the percentage of African racial ancestry in study participants using genome-wide genotypic data. We tested whether African ancestry is associated with FEV(1) and FVC using linear regression. Multivariate models were adjusted for indicators of socioeconomic status and health care and selected environmental/lifestyle exposures. RESULTS: After adjustment for household income and other covariates, each 20% increment in African ancestry was significantly associated with lower prebronchodilator FEV(1) (-105 mL; 95% CI, -159 to -51 mL; P< .001) and FVC (-133 mL; 95% CI, -197 to -69 mL; P< .001) and postbronchodilator FEV(1) (-152 mL; 95% CI, -210 to -94 mL; P< .001) and FVC (-145 mL; 95% CI, -211 to -79 mL; P< .001) in children with asthma. Similar but weaker associations were found for prebronchodilator and postbronchodilator FEV(1) (change for each 20% increment in African ancestry, -78 mL; 95% CI, -131 to -25 mL; P= .004) and for postbronchodilator FVC among children without asthma. CONCLUSIONS: Genetic factors, environmental/lifestyle factors, or both correlated with African ancestry might influence childhood lung function in Puerto Rican subjects.

Effect of an online mindfulness program on stress in Indian adults during COVID-19 pandemic: A randomized controlled preliminary study.

Background: The Indian population is suffering from a high prevalence of mental stress and the situation has been worsened by the COVID-19 pandemic. Mindfulness, which can also be conducted online, has been used as a stress-relieving therapy in the Western world. There is not much experience with mindfulness in the Indian population. The COVID-19 pandemic demands the development of alternative therapies which can reach out to the masses at a minimal cost, avoiding direct personal contact. The researchers wanted to explore the potential of mindfulness as a stress-relieving therapy. Aim: To note any improvement in perceived stress of the participants compared to the controls. Methods: Ninety apparently healthy adults were randomized into group M (all of whom participated in an online mindfulness program) and group C (all of whom attended placebo sessions), with 45 participants each. Final sample size was n = 42 (group M) and n = 38 (group C). The perceived stress was measured using the perceived stress scale before and after the program. Qualitative data was collected in the form of written responses to the question "Which aspect of mindfulness meditation appealed to you the most for stress relief?" and some themes were formed. Results: There was a significant decrease in perceived stress scale scores on completion of the program in group M. "Positive mental state" and "non-judgmental" were the most prominent emergent themes suggested by the participants, as per the qualitative data analysis. Conclusion: This preliminary study sees potential in an online mindfulness program as an alternative stress-relieving therapy. Further research is suggested to substantiate the results and optimize the implementation.

Childhood Asthma Incidence, Early and Persistent Wheeze, and Neighborhood Socioeconomic Factors in the ECHO/CREW Consortium.

Importance: In the United States, Black and Hispanic children have higher rates of asthma and asthma-related morbidity compared with White children and disproportionately reside in communities with economic deprivation. Objective: To determine the extent to which neighborhood-level socioeconomic indicators explain racial and ethnic disparities in childhood wheezing and asthma. Design, Setting, and Participants: The study population comprised children in birth cohorts located throughout the United States that are part of the Children's Respiratory and Environmental Workgroup consortium. Cox proportional hazard models were used to estimate hazard ratios (HRs) of asthma incidence, and logistic regression was used to estimate odds ratios of early and persistent wheeze prevalence accounting for mother's education, parental asthma, smoking during pregnancy, child's race and ethnicity, sex, and region and decade of birth. Exposures: Neighborhood-level socioeconomic indicators defined by US census tracts calculated as z scores for multiple tract-level variables relative to the US average linked to participants' birth record address and decade of birth. The parent or caregiver reported the child's race and ethnicity. Main Outcomes and Measures: Prevalence of early and persistent childhood wheeze and asthma incidence. Results: Of 5809 children, 46% reported wheezing before age 2 years, and 26% reported persistent wheeze through age 11 years. Asthma prevalence by age 11 years varied by cohort, with an overall median prevalence of 25%. Black children (HR, 1.47; 95% CI, 1.26-1.73) and Hispanic children (HR, 1.29; 95% CI, 1.09-1.53) were at significantly increased risk for asthma incidence compared with White children, with onset occurring earlier in childhood. Children born in tracts with a greater proportion of low-income households, population density, and poverty had increased asthma incidence. Results for early and persistent wheeze were similar. In effect modification analysis, census variables did not significantly modify the association between race and ethnicity and risk for asthma incidence; Black and Hispanic children remained at higher risk for asthma compared with White children across census tracts socioeconomic levels. Conclusions and Relevance: Adjusting for individual-level characteristics, we observed neighborhood socioeconomic disparities in childhood wheeze and asthma. Black and Hispanic children had more asthma in neighborhoods of all income levels. Neighborhood- and individual-level characteristics and their root causes should be considered as sources of respiratory health inequities.

Identification of FGF7 as a novel susceptibility locus for chronic obstructive pulmonary disease.

RATIONALE: Traditional genome-wide association studies (GWASs) of large cohorts of subjects with chronic obstructive pulmonary disease (COPD) have successfully identified novel candidate genes, but several other plausible loci do not meet strict criteria for genome-wide significance after correction for multiple testing. OBJECTIVES: The authors hypothesise that by applying unbiased weights derived from unique populations we can identify additional COPD susceptibility loci. Methods The authors performed a homozygosity haplotype analysis on a group of subjects with and without COPD to identify regions of conserved homozygosity haplotype (RCHHs). Weights were constructed based on the frequency of these RCHHs in case versus controls, and used to adjust the p values from a large collaborative GWAS of COPD. RESULTS: The authors identified 2318 RCHHs, of which 576 were significantly (p<0.05) over-represented in cases. After applying the weights constructed from these regions to a collaborative GWAS of COPD, the authors identified two single nucleotide polymorphisms (SNPs) in a novel gene (fibroblast growth factor-7 (FGF7)) that gained genome-wide significance by the false discovery rate method. In a follow-up analysis, both SNPs (rs12591300 and rs4480740) were significantly associated with COPD in an independent population (combined p values of 7.9E-7 and 2.8E-6, respectively). In another independent population, increased lung tissue FGF7 expression was associated with worse measures of lung function. CONCLUSION: Weights constructed from a homozygosity haplotype analysis of an isolated population successfully identify novel genetic associations from a GWAS on a separate population. This method can be used to identify promising candidate genes that fail to meet strict correction for multiple testing.

Arsenic-induced alteration in intracellular calcium homeostasis induces head kidney macrophage apoptosis involving the activation of calpain-2 and ERK in Clarias batrachus.

We had earlier shown that exposure to arsenic (0.50 µM) caused caspase-3 mediated head kidney macrophage (HKM) apoptosis involving the p38-JNK pathway in Clarias batrachus. Here we examined the roles of calcium (Ca(2+)) and extra-cellular signal-regulated protein kinase (ERK), the other member of MAPK-pathway on arsenic-induced HKM apoptosis. Arsenic-induced HKM apoptosis involved increased expression of ERK and calpain-2. Nifedipine, verapamil and EGTA pre-treatment inhibited the activation of calpain-2, ERK and reduced arsenic-induced HKM apoptosis as evidenced from reduced caspase-3 activity, Annexin V-FITC-propidium iodide and Hoechst 33342 staining. Pre-incubation with ERK inhibitor U 0126 inhibited the activation of calpain-2 and interfered with arsenic-induced HKM apoptosis. Additionally, pre-incubation with calpain-2 inhibitor also interfered with the activation of ERK and inhibited arsenic-induced HKM apoptosis. The NADPH oxidase inhibitor apocynin and diphenyleneiodonium chloride also inhibited ERK activation indicating activation of ERK in arsenic-exposed HKM also depends on signals from NADPH oxidase pathway. Our study demonstrates the critical role of Ca(2+) homeostasis on arsenic-induced HKM apoptosis. We suggest that arsenic-induced alteration in intracellular Ca(2+) levels initiates pro-apoptotic ERK and calpain-2; the two pathways influence each other positively and induce caspase-3 mediated HKM apoptosis. Besides, our study also indicates the role of ROS in the activation of ERK pathway in arsenic-induced HKM apoptosis in C. batrachus.

Low concentration of arsenic could induce caspase-3 mediated head kidney macrophage apoptosis with JNK-p38 activation in Clarias batrachus.

We had earlier demonstrated that chronic exposure (30 days) to micro-molar concentration (0.50 microM) of arsenic induced head kidney macrophage (HKM) death in Clarias batrachus. The purpose of the present study is to characterize the nature of HKM death induced by arsenic and elucidate the signal transduction pathways involved in the process. Arsenic-induced HKM death was apoptotic in nature as evident from DNA gel, Annexin V-propidium iodide, Hoechst 33342 staining and TdT-mediated dUTP nick end labeling (TUNEL) assays. Inhibitor studies and immunoblot analyses further demonstrated that arsenic-induced HKM apoptosis involved activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase, a well-characterized caspase-3 substrate. Preincubation with antioxidants N-acetyl-cysteine or dimethyl sulfoxide significantly lowered reactive oxygen species (ROS) levels in arsenic-treated HKM and prevented caspase activation, malondialdehyde formation and HKM apoptosis. Arsenic induced membrane translocation of the NADPH oxidase subunit p47(phox). Preincubation with apocynin and diphenyleneiodonium chloride, both selective inhibitors of NADPH oxidases, prevented p47(phox) translocation, ROS production and HKM death. Exposure of HKM to arsenic induced the activation of mitogen-activated protein kinase family (MAPK) proteins including c-Jun NH(2)-terminal protein kinase (JNK) and p38 mitogen-activated protein kinase (p38). Preincubation of HKM with p38 inhibitor SB203580 and JNK inhibitor SP600125 protected the HKM against arsenic-induced apoptosis. We conclude that exposure to micro-molar concentration of arsenic induces ROS generation through the activation of NADPH oxidases, which in turn causes caspase-3 mediated HKM apoptosis. In addition, the study also indicates a role of p38-JNK pathway in arsenic-induced HKM apoptosis in C. batrachus.

A new model of wheezing severity in young children using the validated ISAAC wheezing module: A latent variable approach with validation in independent cohorts.

BACKGROUND: The International Study of Asthma and Allergies in Children (ISAAC) Wheezing Module is commonly used to characterize pediatric asthma in epidemiological studies, including nearly all airway cohorts participating in the Environmental Influences on Child Health Outcomes (ECHO) consortium. However, there is no consensus model for operationalizing wheezing severity with this instrument in explanatory research studies. Severity is typically measured using coarsely-defined categorical variables, reducing power and potentially underestimating etiological associations. More precise measurement approaches could improve testing of etiological theories of wheezing illness. METHODS: We evaluated a continuous latent variable model of pediatric wheezing severity based on four ISAAC Wheezing Module items. Analyses included subgroups of children from three independent cohorts whose parents reported past wheezing: infants ages 0-2 in the INSPIRE birth cohort study (Cohort 1; n = 657), 6-7-year-old North American children from Phase One of the ISAAC study (Cohort 2; n = 2,765), and 5-6-year-old children in the EHAAS birth cohort study (Cohort 3; n = 102). Models were estimated using structural equation modeling. RESULTS: In all cohorts, covariance patterns implied by the latent variable model were consistent with the observed data, as indicated by non-significant χ2 goodness of fit tests (no evidence of model misspecification). Cohort 1 analyses showed that the latent factor structure was stable across time points and child sexes. In both cohorts 1 and 3, the latent wheezing severity variable was prospectively associated with wheeze-related clinical outcomes, including physician asthma diagnosis, acute corticosteroid use, and wheeze-related outpatient medical visits when adjusting for confounders. CONCLUSION: We developed an easily applicable continuous latent variable model of pediatric wheezing severity based on items from the well-validated ISAAC Wheezing Module. This model prospectively associates with asthma morbidity, as demonstrated in two ECHO birth cohort studies, and provides a more statistically powerful method of testing etiologic hypotheses of childhood wheezing illness and asthma.

Novel mechanisms of Collagenase Santyl Ointment (CSO) in wound macrophage polarization and resolution of wound inflammation.

Collagenases are useful in enzymatic wound debridement. Clostridial collagenase, marketed as Collagenase Santyl Ointment (CSO), is FDA approved for such use. Building on the scientific premise that collagenases as well as collagen degradation products may regulate immune cell function, we sought to investigate the potential role of CSO in wound inflammation. We tested the hypothesis that in addition to enacting debridement, CSO contributes to the resolution of persistent wound inflammation. Wound macrophages were isolated from PVA sponges loaded with CSO or petrolatum and implanted in mice. Significant increase in pro-reparative and decrease in pro-inflammatory polarization was noted in macrophages of acute as well as diabetic wounds. Wound macrophages from CSO-treated group displayed increased production of anti-inflammatory cytokines IL-10 and TGF-ß, and decreased levels of pro-inflammatory cytokines TNF-α and IL-1ß. The active ingredient of CSO, CS-API, induced the expression of mϕheal /M(IL-4) polarization markers ex vivo. CS-API treatment attenuated transactivation of NF-κB and significantly induced STAT6 phosphorylation. A significant role of a novel PGE2-EP4 pathway in CS-API induced STAT6 activation and the mϕheal /M(IL-4) polarization was identified. Taken together, findings of this work reposition CSO as a potential agent that may be effective in resolving wound inflammation, including diabetic wounds.

Long-term exposure to arsenic affects head kidney and impairs humoral immune responses of Clarias batrachus.

The present study was aimed at determining the effects of long-term arsenic exposure on the head kidney (HK) and ensuing humoral immune responses in Clarias batrachus L. Long-term exposure (150 days) to non-lethal concentrations of arsenic (42.42 microM) resulted in significant time-dependent alterations in HK cell number eventually affecting the HK somatic index. Prolonged exposure to arsenic also suppressed HK-B cell proliferation and led to significant reduction in serum immunoglobulin levels and antigen-specific serum bacterial agglutinin titers. A decline in the number of antigen-specific plaque-forming cells with duration of arsenic exposure was noted in the HK. Enzyme linked immunosorbent assays further revealed that arsenic exposure inhibited the release of "IL-4 like factors" from HK-T cells. Histological studies documented time-dependent changes in the structure and cellular composition of HK characterized by extensive lymphocytopenia, decrease in melano-macrophage population and hemosiderin accumulation. From exposure-challenge studies with Aeromonas hydrophila it was evident that pathogens could efficiently disseminate and colonize distant host tissues in the exposed fish. Moreover, the ability to decrease the pathogen load was also significantly reduced in the arsenic-exposed fish. Thus long-term exposure to non-lethal concentrations of arsenic affects HK and interferes with the humoral immune system of C. batrachus rendering them immunocompromised and susceptible to pathogenic challenge.

Vibrational relaxation studies in methyl acetate: role of microenvironment and hydrodynamic forces.

The Raman spectra were recorded for the C=O stretching vibration of methyl acetate as solutions in various polar and non-polar solvents. The isotropic component was obtained and the vibrational relaxation rates were calculated. On the basis of dependence of isotropic Raman bandwidth on the hydrodynamic properties of the solute-solvent systems, the information was obtained on the microenvironment prevailing in the neighborhood of the C=O stretching mode. Significant correlation is observed between vibrational relaxation rate and solvent parameters namely viscosity, density, refractive index and molecular radius. Microviscosity, involving the size of solute and solvent molecules, is found to be crucial in determining the bandwidth, hence the relaxation rate. The microenvironment appears to play an important role in the vibrational relaxation process.

The Human Skeletal Muscle Transcriptome in Response to Oral Shilajit Supplementation.

UNLABELLED: The objective of the present study ( clinicaltrials.gov NCT02026414) was to observe the effects of oral supplementation of a purified and standardized Shilajit extract on skeletal muscle adaptation in adult overweight/class I obese human subjects from the U.S. POPULATION: Shilajit is a mineral pitch that oozes out of Himalayan rocks. The study design consisted of a baseline visit, followed by 8 weeks of 250 mg of oral Shilajit supplementation b.i.d., and additional 4 weeks of supplementation with exercise. At each visit, blood samples and muscle biopsies were collected for further analysis. Supplementation was well tolerated without any changes in blood glucose levels and lipid profile after 8 weeks of oral supplementation and the additional 4 weeks of oral supplementation with exercise. In addition, no changes were noted in creatine kinase and serum myoglobin levels after 8 weeks of oral supplementation and the additional 4 weeks of supplementation with exercise. Microarray analysis identified a cluster of 17 extracellular matrix (ECM)-related probe sets that were significantly upregulated in muscles following 8 weeks of oral supplementation compared with the expression at the baseline visit. This cluster included tenascin XB, decorin, myoferlin, collagen, elastin, fibrillin 1, and fibronectin 1. The differential expression of these genes was confirmed using quantitative real-time polymerase chain reaction (RT-PCR). The study provided maiden evidence that oral Shilajit supplementation in adult overweight/class I obese human subjects promoted skeletal muscle adaptation through upregulation of ECM-related genes that control muscle mechanotransduction properties, elasticity, repair, and regeneration.