209 research outputs found
Elucidating membrane disruption mechanisms of peptide antibiotics
Antimicrobial peptides and proteins hold promise as a next generation of antibiotics. Whilst conventional antibiotics must cross the microbial membrane to target intracellular processes, many of these agents act by disrupting microbial lipid bilayers. This alternative mode of action attacks a conserved structural component of the cell and offers a promising alternative for treating infections caused by multi-resistant pathogens. To facilitate the translational development of antimicrobial peptides, it is beneficial to develop a fundamental understanding of their behaviour. However, resolving the interactions between antimicrobial peptides and lipid bilayers is challenging. Disruption to the lipid packing occurs at the nanoscale, is often dynamic and adapts under different environment conditions. Consequently, the rules linking peptide sequence to mechanisms of membrane disruption and biological activity remain largely unknown. The work presented here directly addresses this challenge. AFM imaging of model membrane systems is used to visualise disruption mechanisms with high temporal and spatial resolution. The findings are then compared to biological assays, and reveal new sequence-function relationships. Starting with a simplified α-helical template, we demonstrate that both the mode of lipid disruption and the biological selectivity of a sequence can be controlled at the single amino acid level. Next, we demonstrate that incorporating motifs from membrane-active but non-lytic peptide sequences into an α-helical design can confer auxiliary lipid interactions. Moving on from single α-helices, we provide the first evidence of membrane disruption by multi-helix bacteriocins, resolving a hitherto unknown multimodal mechanism. In addition we resolve the membrane interactions of supramolecular peptide structures, confirming that self-assembly can offer mechanistic advantage. Finally, preliminary data is presented that improves on the chemical and structural specificity of AFM, and therefore the insights into peptide-lipid interactions that it can provide
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Concentrations and potential health risks of metals in lip products.
BackgroundMetal content in lip products has been an issue of concern.ObjectivesWe measured lead and eight other metals in a convenience sample of 32 lip products used by young Asian women in Oakland, California, and assessed potential health risks related to estimated intakes of these metals.MethodsWe analyzed lip products by inductively coupled plasma optical emission spectrometry and used previous estimates of lip product usage rates to determine daily oral intakes. We derived acceptable daily intakes (ADIs) based on information used to determine public health goals for exposure, and compared ADIs with estimated intakes to assess potential risks.ResultsMost of the tested lip products contained high concentrations of titanium and aluminum. All examined products had detectable manganese. Lead was detected in 24 products (75%), with an average concentration of 0.36 ± 0.39 ppm, including one sample with 1.32 ppm. When used at the estimated average daily rate, estimated intakes were > 20% of ADIs derived for aluminum, cadmium, chromium, and manganese. In addition, average daily use of 10 products tested would result in chromium intake exceeding our estimated ADI for chromium. For high rates of product use (above the 95th percentile), the percentages of samples with estimated metal intakes exceeding ADIs were 3% for aluminum, 68% for chromium, and 22% for manganese. Estimated intakes of lead were < 20% of ADIs for average and high use.ConclusionsCosmetics safety should be assessed not only by the presence of hazardous contents, but also by comparing estimated exposures with health-based standards. In addition to lead, metals such as aluminum, cadmium, chromium, and manganese require further investigation
Particle Size Distribution in Aluminum Manufacturing Facilities.
As part of exposure assessment for an ongoing epidemiologic study of heart disease and fine particle exposures in aluminum industry, area particle samples were collected in production facilities to assess instrument reliability and particle size distribution at different process areas. Personal modular impactors (PMI) and Minimicro-orifice uniform deposition impactors (MiniMOUDI) were used. The coefficient of variation (CV) of co-located samples was used to evaluate the reproducibility of the samplers. PM2.5 measured by PMI was compared to PM2.5 calculated from MiniMOUDI data. Mass median aerodynamic diameter (MMAD) and concentrations of sub-micrometer (PM1.0) and quasi-ultrafine (PM0.56) particles were evaluated to characterize particle size distribution. Most of CVs were less than 30%. The slope of the linear regression of PMI_PM2.5 versus MiniMOUDI_PM2.5 was 1.03 mg/m3 per mg/m3 (± 0.05), with correlation coefficient of 0.97 (± 0.01). Particle size distribution varied substantively in smelters, whereas it was less variable in fabrication units with significantly smaller MMADs (arithmetic mean of MMADs: 2.59 μm in smelters vs. 1.31 μm in fabrication units, p = 0.001). Although the total particle concentration was more than two times higher in the smelters than in the fabrication units, the fraction of PM10 which was PM1.0 or PM0.56 was significantly lower in the smelters than in the fabrication units (p < 0.001). Consequently, the concentrations of sub-micrometer and quasi-ultrafine particles were similar in these two types of facilities. It would appear, studies evaluating ultrafine particle exposure in aluminum industry should focus on not only the smelters, but also the fabrication facilities
Ischemic Heart Disease Incidence in Relation to Fine versus Total Particulate Matter Exposure in a U.S. Aluminum Industry Cohort.
Ischemic heart disease (IHD) has been linked to exposures to airborne particles with an aerodynamic diameter <2.5 μm (PM2.5) in the ambient environment and in occupational settings. Routine industrial exposure monitoring, however, has traditionally focused on total particulate matter (TPM). To assess potential benefits of PM2.5 monitoring, we compared the exposure-response relationships between both PM2.5 and TPM and incidence of IHD in a cohort of active aluminum industry workers. To account for the presence of time varying confounding by health status we applied marginal structural Cox models in a cohort followed with medical claims data for IHD incidence from 1998 to 2012. Analyses were stratified by work process into smelters (n = 6,579) and fabrication (n = 7,432). Binary exposure was defined by the 10th-percentile cut-off from the respective TPM and PM2.5 exposure distributions for each work process. Hazard Ratios (HR) comparing always exposed above the exposure cut-off to always exposed below the cut-off were higher for PM2.5, with HRs of 1.70 (95% confidence interval (CI): 1.11-2.60) and 1.48 (95% CI: 1.02-2.13) in smelters and fabrication, respectively. For TPM, the HRs were 1.25 (95% CI: 0.89-1.77) and 1.25 (95% CI: 0.88-1.77) for smelters and fabrication respectively. Although TPM and PM2.5 were highly correlated in this work environment, results indicate that, consistent with biologic plausibility, PM2.5 is a stronger predictor of IHD risk than TPM. Cardiovascular risk management in the aluminum industry, and other similar work environments, could be better guided by exposure surveillance programs monitoring PM2.5
Paternal Smoking and Risk of Childhood Acute Lymphoblastic Leukemia: Systematic Review and Meta-Analysis
Objective. To investigate the association between paternal smoking and childhood acute lymphoblastic leukemia (ALL). Method. We identified 18 published epidemiologic studies that reported data on both paternal smoking and childhood ALL risk. We performed a meta-analysis and analyzed dose-response relationships on ALL risk for smoking during preconception, during pregnancy, after birth, and ever smoking. Results. The summary odds ratio (OR) of childhood ALL associated with paternal smoking was 1.11 (95% Confidence Interval (CI): 1.05–1.18, I2 = 18%) during any time period, 1.25 (95% CI: 1.08–1.46, I2 = 53%) preconception; 1.24 (95% CI: 1.07–1.43, I2 = 54%) during pregnancy, and 1.24 (95% CI: 0.96–1.60, I2 = 64%) after birth, with a dose-response relationship between childhood ALL and paternal smoking preconception or after birth. Conclusion. The evidence supports a positive association between childhood ALL and paternal ever smoking and at each exposure time period examined. Future epidemiologic studies should assess paternal smoking during well-defined exposure windows and should include biomarkers to assess smoking exposure and toxicological mechanisms
Incident Ischemic Heart Disease After Long-Term Occupational Exposure to Fine Particulate Matter: Accounting for 2 Forms of Survivor Bias.
Little is known about the heart disease risks associated with occupational, rather than traffic-related, exposure to particulate matter with aerodynamic diameter of 2.5 µm or less (PM2.5). We examined long-term exposure to PM2.5 in cohorts of aluminum smelters and fabrication workers in the United States who were followed for incident ischemic heart disease from 1998 to 2012, and we addressed 2 forms of survivor bias. Left truncation bias was addressed by restricting analyses to the subcohort hired after the start of follow up. Healthy worker survivor bias, which is characterized by time-varying confounding that is affected by prior exposure, was documented only in the smelters and required the use of marginal structural Cox models. When comparing always-exposed participants above the 10th percentile of annual exposure with those below, the hazard ratios were 1.67 (95% confidence interval (CI): 1.11, 2.52) and 3.95 (95% CI: 0.87, 18.00) in the full and restricted subcohorts of smelter workers, respectively. In the fabrication stratum, hazard ratios based on conditional Cox models were 0.98 (95% CI: 0.94, 1.02) and 1.17 (95% CI: 1.00, 1.37) per 1 mg/m(3)-year in the full and restricted subcohorts, respectively. Long-term exposure to occupational PM2.5 was associated with a higher risk of ischemic heart disease among aluminum manufacturing workers, particularly in smelters, after adjustment for survivor bias
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Workplace secondhand smoke exposure in the U.S. trucking industry.
BackgroundAlthough the smoking rate in the United States is declining because of an increase of smoke-free laws, among blue-collar workers it remains higher than that among many other occupational groups.ObjectivesWe evaluated the factors influencing workplace secondhand smoke (SHS) exposures in the U.S. unionized trucking industry.MethodsFrom 2003 through 2005, we measured workplace SHS exposure among 203 nonsmoking and 61 smoking workers in 25 trucking terminals. Workers in several job groups wore personal vapor-phase nicotine samplers on their lapels for two consecutive work shifts and completed a workplace SHS exposure questionnaire at the end of the personal sampling.ResultsMedian nicotine level was 0.87 microg/m3 for nonsmokers and 5.96 microg/m3 for smokers. As expected, smokers experienced higher SHS exposure duration and intensity than did nonsmokers. For nonsmokers, multiple regression analyses indicated that self-reported exposure duration combined with intensity, lack of a smoking policy as reported by workers, having a nondriver job, and lower educational level were independently associated with elevated personal nicotine levels (model R2 = 0.52). Nondriver job and amount of active smoking were associated with elevated personal nicotine level in smokers, but self-reported exposure, lack of a smoking policy, and lower educational level were not.ConclusionsDespite movements toward smoke-free laws, this population of blue-collar workers was still exposed to workplace SHS as recently as 2005. The perceived (reported by the workers), rather than the official (reported by the terminal managers), smoking policy was associated with measured SHS exposure levels among the nonsmokers. Job duties and educational level might also be important predictors of workplace SHS exposure
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Secondhand smoke exposure and inflammatory markers in nonsmokers in the trucking industry.
BackgroundFew studies have directly assessed the association of secondhand smoke (SHS) with cardiovascular disease-related inflammatory markers, and the findings are inconsistent.ObjectivesWe assessed the association between SHS exposure and the inflammatory markers high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and soluble intercellular adhesion molecule-1 (sICAM-1) in 199 nonsmoking U.S. trucking industry workers.MethodsParticipants provided blood samples either by mail (blood drawn at local health care provider near home) or at the work site (blood drawn by research staff on-site) and completed a health and work history questionnaire at the time of blood draw. Exposure to SHS was measured by plasma cotinine concentrations. We used multivariate regression analyses to assess the associations between levels of cotinine and inflammatory markers.ResultsThe median cotinine level was 0.10 ng/mL (interquartile range, 0.04-0.23 ng/mL). The odds ratios of elevated hs-CRP (above highest CRP tertile, 1.5 mg/L) were 2.85 [95% confidence interval (CI), 1.03-7.89] for the high-cotinine group (> 0.215 ng/mL) and 2.80 (95% CI, 1.11-7.10) for the moderate-cotinine group (0.05-0.215 ng/mL), compared with the low-cotinine group (< 0.05 ng/mL), adjusting for age, sex, race, educational level, obesity, previous smoking history, job title, and medical history. Plasma cotinine levels were not associated with IL-6 or sICAM-1.ConclusionsSHS exposure, as assessed by plasma cotinine, was positively associated with hs-CRP in this group of blue-collar workers. The strength of the association with hs-CRP depended on the cut points selected for analysis
A cross-sectional study of secondhand smoke exposure and respiratory symptoms in non-current smokers in the U.S. trucking industry: SHS exposure and respiratory symptoms
Background: Previous studies have suggested associations of adult exposures to secondhand smoke (SHS) with respiratory symptoms, but no study has focused on blue-collar industrial environments. We assessed the association between SHS and respiratory symptoms in 1,562 non-current smoking U.S. trucking industry workers. Methods: Information on SHS exposure and respiratory health was obtained by questionnaire. Multiple logistic regression analyses were used to assess the associations of recent and lifetime exposures to SHS with chronic phlegm, chronic cough, and any wheeze, defined by American Thoracic Society criteria. Results: In analyses adjusted for age, gender, race, childhood SHS exposure, former smoking, pack-years of smoking and years since quitting, body mass index, job title, region of the country, and urban residence, recent exposures to SHS were associated with all three respiratory symptoms (odds ratio (OR) = 1.46; 95% confidence interval (CI) = 1.00-2.13) for chronic cough, 1.55 (95% CI = 1.08-2.21) for chronic phlegm, and 1.76 (95% CI = 1.41-2.21) for any wheeze). Workplace exposure was the most important recent exposure. Childhood exposure to SHS was also associated with all three symptoms, but only statistically significantly for chronic phlegm (OR = 1.84; 95% CI = 1.24-2.75). Additional years of living with a smoker were associated with an increased risk, but there was no evidence of a dose–response, except for chronic phlegm. Conclusions: In this group of trucking industry workers, childhood and recent exposures to SHS were related to respiratory symptoms
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