A synthetic agent ameliorates polycystic kidney disease by promoting apoptosis of cystic cells through increased oxidative stress.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of chronic kidney disease and the fourth leading cause of end-stage kidney disease, accounting for over 50% of prevalent cases requiring renal replacement therapy. There is a pressing need for improved therapy for ADPKD. Recent insights into the pathophysiology of ADPKD revealed that cyst cells undergo metabolic changes that up-regulate aerobic glycolysis in lieu of mitochondrial respiration for energy production, a process that ostensibly fuels their increased proliferation. The present work leverages this metabolic disruption as a way to selectively target cyst cells for apoptosis. This small-molecule therapeutic strategy utilizes 11beta-dichloro, a repurposed DNA-damaging anti-tumor agent that induces apoptosis by exacerbating mitochondrial oxidative stress. Here, we demonstrate that 11beta-dichloro is effective in delaying cyst growth and its associated inflammatory and fibrotic events, thus preserving kidney function in perinatal and adult mouse models of ADPKD. In both models, the cyst cells with homozygous inactivation of Pkd1 show enhanced oxidative stress following treatment with 11beta-dichloro and undergo apoptosis. Co-administration of the antioxidant vitamin E negated the therapeutic benefit of 11beta-dichloro in vivo, supporting the conclusion that oxidative stress is a key component of the mechanism of action. As a preclinical development primer, we also synthesized and tested an 11beta-dichloro derivative that cannot directly alkylate DNA, while retaining pro-oxidant features. This derivative nonetheless maintains excellent anti-cystic properties in vivo and emerges as the lead candidate for development.

A Vocal Hygiene Program for Mitigating the Effects of Occupational Vocal Demand in Primary School Teachers.

PURPOSE: Teachers are occupational voice users with significant vocal demand. This study examined if a vocal hygiene program could mitigate the effects of occupational vocal demand in primary school teachers across 1 month. METHOD: Sixty female teachers participated, with 30 in an experimental group receiving vocal hygiene education plus daily home practice for 1 month and 30 in a control group with no intervention. Their vocal changes across the month were quantified with (a) acoustic measures on fundamental frequency (fo), vocal intensity, jitter and shimmer, harmonics-to-noise ratio, and smoothed cepstral peak prominence and (b) Voice Handicap Index (VHI-10) and Vocal Fatigue Index (VFI) scores. RESULTS: Analysis of covariance showed significantly larger changes (significant decreases) in conversational fo and in jitter for the experimental group relative to the control group. Post hoc pairwise comparisons following repeated-measures analysis of variance showed significant decreases in conversational fo and in jitter across the month for the experimental group. No significant differences in VHI-10 and VFI scores were found between the groups. CONCLUSIONS: Vocal demand-related changes in acoustic measures could be partially mitigated with the vocal hygiene program. Future studies with a more refined intervention program and more long-term follow-up are recommended to better understand the long-term benefits of vocal hygiene programs on primary school teachers.

Comparison of Human Antral Follicles of Xenograft versus Ovarian Origin Reveals Disparate Molecular Signatures.

The activation, growth, and maturation of oocytes to an ovulatory phase, termed folliculogenesis, is governed by the orchestrated activity of multiple specialized cell types within the ovary; yet, the mechanisms governing diversification and behavior of discrete cellular sub-populations within follicles are poorly understood. We use bulk and single-cell RNA sequencing to distinguish the transcriptional signature of prospectively isolated granulosa and theca/stroma cell subsets within human antral follicles derived from xenografts or ovaries. The analysis deconstructs phenotypic diversification within small (<4 mm) antral follicles, identifying secreted factors that are differentially enriched between mural and oophorus granulosa cells, and segregating stromal/support and steroidal activity between theca externa and interna, respectively. Multiple factors are differentially expressed in follicles of xenograft versus ovarian origin. These data capture a high-resolution transcriptional signature of granulosa and theca subpopulations and provide a systems-level portrait of cellular diversification in early antral human follicles.

Blocking cellular N-glycosylation suppresses human cytomegalovirus entry in human fibroblasts.

N-glycosylation plays an important role in the pathogenesis of viral infections. However, the role of host cell N-glycosylation in human cytomegalovirus (hCMV) infection remains to be elucidated. In this study, we found that blocking or removal of cellular N-glycosylation by tunicamycin, peptide-N-glycosidase F (PNGase F) treatment, or N-acetylglucosaminyltransferase I (MGAT1) knockdown resulted in suppression of hCMV infection in human fibroblasts. This suppression was reversed following N-glycosylation restoration. Immunofluorescence and flow cytometry analysis showed that blockade of cellular N-glycosylation interfered with hCMV entry rather than binding. Removal of N-glycosylation on epidermal growth factor (EGFR) and integrin ß3, two proposed hCMV receptors, blocked their interaction with hCMV glycoproteins B and H. It also suppressed activation of these receptors and downstream integrin ß3/Src signaling. Taken together, these results suggest that N-glycosylation of host cell glycoproteins including two proposed hCMV receptors is critical for hCMV entry rather than attachment. They provide novel insights into the biological process important for the early stage of hCMV infection with potential therapeutic implications.

Chronic Low-grade Inflammatory Phenotype (CLIP) and Senescent Immune Dysregulation.

PURPOSE: The aim was to provide an overview of chronic low-grade inflammatory phenotype (CLIP) and evidence for its role in the pathogenesis of frailty and other chronic conditions as well as potential causative factors and interventions. METHODS: We reviewed evidence from published clinical and laboratory studies and summarized the opinions of experts from published reviews. FINDINGS: CLIP is a low-grade, systemic, unresolved, and smoldering chronic inflammatory state clearly indicated by a 2- to 4-fold increase in serum levels of inflammatory mediators, such as interleukin-6 and C-reactive protein. It involves many other cellular and molecular inflammatory mediators. CLIP typically occurs during aging, also known as "inflammaging," and is an integral part of the spectrum of immunosenescence. Causative factors likely include persistent viral infections, particularly chronic cytomegalovirus infection, cellular senescence, failure to eliminate degraded materials and waste products, dysregulated microbiota and gut permeability, obesity, and others. Substantial evidence supports CLIP as a powerful contributing factor to frailty and many other chronic conditions and adverse health outcomes. Many of the inflammatory mediators and their regulatory mechanisms in CLIP may serve as potential targets for therapeutic intervention. However, development of new interventional strategies for CLIP and its associated chronic conditions should take the complexity of the inflammatory network into consideration. Nonpharmacologic interventions, such as caloric restriction and exercise, may have significant impact on CLIP and its causative factors, leading to substantial health benefits. Metformin and resveratrol have anti-inflammatory property and may serve as a promising therapeutic agent for treatment of CLIP and frailty. IMPLICATIONS: CLIP is a chronic inflammatory pathophysiologic process that plays an important role in the pathogenesis of frailty and many other chronic conditions. Improving our understanding of this phenotype may provide opportunities to identify potential targets of effective prevention and therapeutic strategies for frailty and other CLIP-associated conditions.

Prospective study of particulate air pollution exposures, subclinical atherosclerosis, and clinical cardiovascular disease: The Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air).

The Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air) was initiated in 2004 to investigate the relation between individual-level estimates of long-term air pollution exposure and the progression of subclinical atherosclerosis and the incidence of cardiovascular disease (CVD). MESA Air builds on a multicenter, community-based US study of CVD, supplementing that study with additional participants, outcome measurements, and state-of-the-art air pollution exposure assessments of fine particulate matter, oxides of nitrogen, and black carbon. More than 7,000 participants aged 45-84 years are being followed for over 10 years for the identification and characterization of CVD events, including acute myocardial infarction and other coronary artery disease, stroke, peripheral artery disease, and congestive heart failure; cardiac procedures; and mortality. Subcohorts undergo baseline and follow-up measurements of coronary artery calcium using computed tomography and carotid artery intima-medial wall thickness using ultrasonography. This cohort provides vast exposure heterogeneity in ranges currently experienced and permitted in most developed nations, and the air monitoring and modeling methods employed will provide individual estimates of exposure that incorporate residence-specific infiltration characteristics and participant-specific time-activity patterns. The overarching study aim is to understand and reduce uncertainty in health effect estimation regarding long-term exposure to air pollution and CVD.

Decreased PM10 exposure attenuates age-related lung function decline: genetic variants in p53, p21, and CCND1 modify this effect.

BACKGROUND: Decreasing exposure to airborne particulates was previously associated with reduced age-related decline in lung function. However, whether the benefit from improved air quality depends on genetic background is not known. Recent evidence points to the involvement of the genes p53 and p21 and of the cell cycle control gene cyclin D1 (CCND1) in the response of bronchial cells to air pollution. OBJECTIVE: We determined in 4,326 participants of the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA) whether four single-nucleotide polymorphisms in three genes [CCND1 (rs9344 [P242P], rs667515), p53 (rs1042522 [R72P]), and p21 (rs1801270 [S31R])] modified the previously observed attenuation of the decline in the forced expiratory flow between 25% and 75% of the forced vital capacity (FEF(25-75)) associated with improved air quality. METHODS: Subjects of the prospective population-based SAPALDIA cohort were assessed in 1991 and 2002 by spirometry, questionnaires, and biological sample collection for genotyping. We assigned spatially resolved concentrations of particulate matter with aerodynamic diameter < or = 10 microm (PM(10)) to each participant's residential history 12 months before the baseline and follow-up assessments. RESULTS: The effect of diminishing PM(10) exposure on FEF(25-75) decline appeared to be modified by p53 R72P, CCND1 P242P, and CCND1 rs667515. For example, a 10-microg/m(3) decline in average PM(10) exposure over an 11-year period attenuated the average annual decline in FEF(25-75) by 21.33 mL/year (95% confidence interval, 10.57-32.08) among participants homozygous for the CCND1 (P242P) GG genotype, by 13.72 mL/year (5.38-22.06) among GA genotypes, and by 6.00 mL/year (-4.54 to 16.54) among AA genotypes. CONCLUSIONS: Our results suggest that cell cycle control genes may modify the degree to which improved air quality may benefit respiratory function in adults.

Health risks of ozone from long-range transboundary air pollution

Ozone is a highly oxidative gas formed in the lower atmosphere (from gases originating to a large extent from anthropogenic sources) by photochemistry driven by solar radiation. Owing to its highly reactive chemical properties, ozone is harmful to vegetation, materials and human health. In the troposphere, ozone is also an efficient greenhouse gas. This report summarizes the results of a multidisciplinary analysis to assess the effects of ozone on health. The analysis indicates that ozone pollution affects the health of most of the populations of the WHO European Region, leading to a wide range of health problems. The effects include some 21 000 premature deaths each year in 25 countries in the European Union on and after days with high ozone levels. Current policies are not sufficient to reduce ozone levels in the Region or their impact in the next decade.

Time-variable simulation of soil vapor intrusion into a building with a combined crawl space and basement.

A time-variable one-dimensional model (called ViM for Vapor Intrusion Model)to predict indoor vapor concentrations in a dwelling with a combined basement and crawl space has been developed. ViM predicts vapor concentrations in each of the three compartments. Volatile chemicals that intrude into the dwelling are assumed to originate from soil, groundwater (where an attenuating plume is simulated), or ambient air. Processes included in the model are advection, diffusion, biodecay, and adsorption in the soil column; transport by diffusion and advection into individual crawl space and basement compartments; advection from each compartment into an overlying dwelling space; and exchange of ambient air and indoor air. The time-variable concentration fields are solved by first transforming the partial and ordinary differential equations into Laplace space, solving the resulting ordinary differential equations or algebraic equations, and numerically inverting those equations. This approach was an expedient way of handling the coupling between the subsurface and the dwelling. ViM was applied to a building (Building 20) located at the former Moffett Field Naval Air Station, in Mountain View, CA. The building is a former bachelor officer's quarters. The shallow groundwater beneath the building is contaminated with a number of volatile chemicals, including trichloroethene, cis-1,2-dichloroethene, and trans-1,2-dichloroethene, all of which were simulated. Using indoor air data collected in 2003-2004, and other field data collected prior to that time, the accuracy of the model's predictions was demonstrated. ViM's results were also compared against a version of the steady-state Johnson and Ettinger model (1) that was modified to accommodate a dwelling with a combined crawl space and basement (called the JEM model in this paper). The predictions from the JEM model were consistently higher than the predictions from ViM, but still near the upper range of the observed data.

A community study of the effect of particulate matter on blood measures of inflammation and thrombosis in an elderly population.

BACKGROUND: The mechanism behind the triggering effect of fine particulate matter (PM) air pollution on cardiovascular events remains elusive. We postulated that elevated levels of PM would be associated with increased blood levels of inflammatory and thrombotic markers in elderly individuals. We also hypothesized that elevated PM would increase levels of cytokines in individuals with heart disease. METHODS: We measured these blood markers in 47 elderly individuals with (23) and without (16 COPD and 8 healthy) cardiovascular disease (CVD) on 2 or 3 mornings over a 5 or 10-day period between February 2000 and March 2002. Blood measures were paired with residence level outdoor PM measured by nephelometry. Analyses determined the within-individual effect of 24-hour averaged outdoor PM on blood measures. RESULTS: Analyses found no statistically significant effect of a same day 10 ug/m3 increase in fine PM on log transformed levels of CRP 1.21 fold-rise [95% CI: 0.86, 1.70], fibrinogen 1.02 fold-rise [95% CI: 0.98, 1.06], or D-dimer 1.02 fold-rise [95% CI: 0.88, 1.17] in individuals with CVD. One-day lagged analyses in the CVD subgroup found similar null results. These same models found no change in these blood markers at the same-day or 1-day lag in the group without CVD. In 21 individuals with CVD, a 10 mug/m3 increase in same-day PM was associated with a 1.3 fold-rise [95% CI: 1.1, 1.7] in the level of monocyte chemoattractant protein-1. CONCLUSION: We did not find consistent effects of low ambient levels of PM on blood measures of inflammation or thrombosis in elderly individuals.

Validation of an objective scar pigmentation measurement by using a spectrocolorimeter.

Scar pigmentation changes throughout its maturation process and it is often used as one of the indicators for scar maturation, yet it is often rated subjectively. The purpose of this study was to investigate the application of a commercial spectrocolorimeter to produce a reliable measurement on scar pigmentation. Commission Internationale de l'Eclairage (CIE) model of color has been adopted in this study for measurement of scar pigmentation 24 patients with hypertrophic scars at different stages of maturation were selected for the study, were inspected by two therapists using the Vancouver scar scale (VSS) and then using spectrocolorimeter for inter-rater reliability. The measurements were taken after 30min by the same group of therapists (test-retest reliability). Results indicated that the inter-rater reliability among the three therapists was satisfactory, with intra-class correlation coefficient (ICC) (2, 2) from 0.50 to 0.99 in all the three color parameters. The test-retest reliability of the spectrocolorimeter was satisfactory with ICC (3, 6) ranged from 0.95 to 0.99. A significant difference was also noted between the measurements of normal skin and hypertrophic scar (P<0.00, t-values: from 2.78 to 0.05, d.f.: from 29.7 to 46.00) in all color parameters, except the chroma C(*). We also found a positive relationship between VSS scores and the spectrocolorimeter readings. The spectrocolorimeter is found to be a reliable instrument to quantify scar pigmentation and to differentiate normal skin and scar tissue. With further studies, the constructs of scar properties could further be explored using this spectrocolorimeter.

Application of a nutrient cycling model (NuCM) to a northern mixed hardwood and a southern coniferous forest.

The nutrient cycling model, NuCM, which incorporates state-of-the-art understanding of the biogeochemical and transport processes controlling nutrient cycles, simulates vegetation growth, litterfall and decay, soil biogeochemical processes, and movement of water. Output of the model includes the available nutrients in soil strata and vegetation pools and the fluxes between pools on a weekly, monthly or annual basis. Solution and adsorbed concentrations in the various soil layers can be plotted versus time. The model has been used to simulate effects of acidic deposition on nutrient status at two sites: Huntington Forest, New York and Smokies Tower, Tennessee. Model results show only minor changes in nutrient status at the sites over the next 65 years at current rates of acidic deposition. The results also show only small differences in soil nutrient status between two alternative scenarios for reduction of SO(x) emissions. Neither "threshold effects" nor abrupt changes in nutrient pool sizes occurred in either of the simulations.