Is loneliness associated with cancellation of medical appointments during the COVID-19 pandemic? Evidence from the Hamburg City Health Study (HCHS).

BACKGROUND: The COVID-19 pandemic engendered numerous societal and economic challenges in addition to health-related concerns. Maintenance of healthcare utilization assumed immense significance during this period. However, few studies have examined the association between loneliness and cancelled medical appointments during the COVID-19 pandemic. This study aimed to examine whether medical appointments are less likely to be cancelled with increased loneliness during a pandemic. We analyzed the association between loneliness and both patient- and provider-initiated appointment cancellations. METHODS: Cross-sectional data from the Hamburg City Health Study (HCHS) were collected during April 2020-November 2021. The analytical sample included 1,840 participants with an average age of 55.1 years (standard deviation: 6.5, range 45-76 years). Medical appointments cancelled by individuals-medical appointments in general, and GP, specialist, and dentist appointments-and appointments cancelled by healthcare providers served as outcome measures. Loneliness was quantified using a single item ranging from 0 to 10. Accordingly, we created empirical loneliness tertiles. Covariates were selected based on the Andersen model. Several penalized maximum likelihood logistic regressions were utilized to examine the association between loneliness and cancellation of medical appointments during the COVID-19 pandemic. RESULTS: The penalized maximum likelihood logistic regressions showed that, compared to individuals in the lowest loneliness tertiles, individuals in the other two tertiles reported a higher chance of medical appointments cancellation by individuals, particularly driven by cancelled GP appointments. Except for age and sex, none of the covariates were comparably associated with the outcomes. When appointments cancelled by healthcare providers served as outcomes, only a higher number of chronic conditions was significantly positively associated with it. CONCLUSIONS: Individuals scoring higher in loneliness had a greater chance of cancelling medical (particularly GP) appointments. This may contribute to a potential cascade of loneliness and skipped medical appointments in the future, resulting in adverse health outcomes over the medium-to-long term. Future research should examine whether lonely people are more likely to lack the social motivation to visit the doctor.

Lifestyle behaviour and prevalence of cardiovascular risk factors - a pilot study comparing Kiribati and European seafarers.

BACKGROUND: According to internal observations within a German shipping company, obvious risk-behaviour persists among the crew members coming from the Pacific Island State of Kiribati and representing a large part of the crew aboard merchant vessels of this company. These observations were related to excessive eating habits. This study aims to assess the cardiovascular risk among seafarers and to compare lifestyle factors between Kiribati and European crew members. METHODS: In the present maritime field study 81 sailors (48 Kiribati, 33 European, average age at 38.9 and 36.8 years respectively) were examined from April until August 2014 aboard four container ships crossing the Atlantic Ocean (participation rate of 90.9%). RESULTS: Based on the number of established risk factors, 35.4% of the Kiribati and 16.7% of the European crew members were regarded as a high risk group for cardiovascular diseases. The HDL-values of Kiribati were found to be considerably lower (34.9 mg/dl) than the references values given by the WHO and in comparison to the European crew members (44.8 mg/dl) (p = 0.002). 91.7% of Kiribati and 51.5% of European participants were found to be overweight according to WHO-criteria - with a mean Body Mass Index (BMI) of 30.3 kg/m2 and 25.6 kg/m2 (p <  0.001). Regarding lifestyle factors Kiribati often claimed to eat significantly larger amounts of food aboard while most European sailors stated to eat less or about the same during their shipboard stay (p = 0.017). Daily sleeping hours were slight on both sides; however with a mean of 5.2 h a day Kiribati crew members had significant fewer sleep (p = 0.038). The examined Kiribati sailors had a mean increase in weight of 6 kg over a 12 months period of observation. CONCLUSIONS: In total the compiled data points towards a higher risk of cardiovascular diseases particularly due to alimentary habits within the Kiribati crew members. The distinct weight-gain measured among the Kiribati in spite of higher energy consumption levels at sea is alarming. Thus, the results of this study confirm the necessity of health-improving interventions aboard cargo vessels.

Content of Asthmagen Natural Rubber Latex Allergens in Commercial Disposable Gloves.

The use of natural rubber latex (NRL) gloves in many occupations may lead to latex sensitization, allergic asthma, and skin reactions. Due to their good properties and environmental safety NRL gloves are still being used in the healthcare setting, but also in the food industry, by hairdressers, cleaners, etc. The aim of our study was to assess the protein and NRL allergen content in commercial gloves by different methods, including a new assay. Twenty commercially available NRL gloves were analyzed. Protein extraction was performed according to the international standard ASTM D-5712. Total protein content was measured with a modified Lowry method, NRL content with the CAP Inhibition Assay, the Beezhold ELISA Inhibition Assay, and an innovative ELISA with IgY-antibodies extracted from eggs of NRL-immunized hens (IgY Inhibition Assay). We found a high protein content in a range of 215.0-1304.7 µg/g in 8 out of the 20 NRL gloves. Seven of the 20 gloves were powdered, four of them with a high protein content. In gloves with high protein content, the immunological tests detected congruently high levels of NRL allergen. We conclude that a high percentage of commercially available NRL gloves still represent a risk for NRL allergy, including asthma. The modified Lowry Method allows to infer on the latex allergen content.

IgE Reactivity, Work Related Allergic Symptoms, Asthma Severity, and Quality of Life in Bakers with Occupational Asthma.

In Germany, bakers with occupational asthma willing to stay in their job are included in an interdisciplinary program of the Social Accident Insurance for Foodstuff and Catering Industry (BGN). The primary aim is to reduce flour dust exposure, and to provide adequate medical treatment. Our aim was to evaluate the program's effect on the disease's course using routinely collected data. Forty three bakers with allergic occupational asthma and with the available baseline level of IgE (f4, f5) were investigated. Changes in IgE related to wheat and rye flour exposure were measured by ImmunoCAP test during follow-up visits. A questionnaire on work-related allergic complaints (WRAC), the Asthma Control Test (ACT), a 10-point scale of asthma severity grade, and quality of life instruments (EQ-5D-5L, Mini-AQLQ) were administered. We found an improvement of asthma severity in 88.4 % of the bakers. WRAC were reported by 65 %; 77 % had good asthma control (ACT ≥ 20); and 81 % had regular asthma medication. A relevant reduction of ≥2 CAP-classes for both allergens was seen in 12 % of the subjects. Health-related and asthma-specific quality of life was high. We conclude that satisfactory asthma control is probably the result of adequate medical management. In a subgroup of bakers with decreased specific IgE, it may also be attributed to reduced allergen exposure.

Content of Asthmagen Natural Rubber Latex Allergens in Commercial Disposable Gloves.

The use of natural rubber latex (NRL) gloves in many occupations may lead to latex sensitization, allergic asthma, and skin reactions. Due to their good properties and environmental safety NRL gloves are still being used in the healthcare setting, but also in the food industry, by hairdressers, cleaners, etc. The aim of our study was to assess the protein and NRL allergen content in commercial gloves by different methods, including a new assay. Twenty commercially available NRL gloves were analyzed. Protein extraction was performed according to the international standard ASTM D-5712. Total protein content was measured with a modified Lowry method, NRL content with the CAP Inhibition Assay, the Beezhold ELISA Inhibition Assay, and an innovative ELISA with IgY-antibodies extracted from eggs of NRL-immunized hens (IgY Inhibition Assay). We found a high protein content in a range of 215.0-1304.7 µg/g in 8 out of the 20 NRL gloves. Seven of the 20 gloves were powdered, four of them with a high protein content. In gloves with high protein content, the immunological tests detected congruently high levels of NRL allergen. We conclude that a high percentage of commercially available NRL gloves still represent a risk for NRL allergy, including asthma. The modified Lowry Method allows to infer on the latex allergen content.

Seafarer deaths at sea: a German mortality study.

BACKGROUND: Seafarers face numerous hazards during their work at sea. AIMS: To demonstrate the frequency and causes of mortality in German seafarers. METHODS: The deaths of all German seafarers from 1998 to 2008 were counted and evaluated using the German central civil register in Berlin. RESULTS: The study cohort comprised a total of 159588 seafarer-years. During the 11 year period, 68 male seafarers died on board. The average age was 48.5 years (SD 12.7 years) and comprised 35 deck officers, 16 engine officers and 17 general crew members (i.e. non-officers from the deck and engine room crew and galley staff). Cause of death was documented in 45 cases (66%): 26 were due to unnatural causes (occupational accidents, suicides) and 19 due to natural causes (particularly, ischaemic heart disease). The crude annual mortality rate for German seamen was 65 per 100000 seafarer-years. For cardiac causes, this rate was significantly higher among deck and engine officers (24 and 38) than among crew ranks (7 per 100000 seafarer-years) (P < 0.05). Deck and engine offi-cers also showed a higher mortality rate for accidents (28 and 22) than crew ranks (15) (P < 0.05). The age-stratified fatal accident rate of German seafarers aboard was 10 times higher than the mortality of the German general population on shore. CONCLUSIONS: Seafaring constitutes an occupation with a high risk for serious accidents. Due to the unexpectedly high mortality rate among officers associated with work-related accidents, this occupational group should receive more effective education on safety behaviour on board.

Comparison of hospitalization among German coastal and deep sea fishermen.

PURPOSE: This study aims to compare the hospitalization of German fishermen employed on German-flagged fishing vessels with that of the general German population in consideration of differences between coastal and deep sea fishery. METHODS: By means of a database from the health insurance company for seafarers, diagnoses of German fishermen treated in German hospitals were determined from January 1997 to December 2007. Compared with the general German population, the fishermen's risk for specific diseases leading to hospitalization was calculated as standardized hospitalization ratio (SHR). RESULTS: Compared with the German reference population, German fishermen showed a considerably high SHR for malignant neoplasms at all sites (SHR 1.46; 95% CI 1.37-1.56), for respiratory cancer, and for non-Hodgkin lymphoma (NHL). Furthermore, they had more often been hospitalized due to diabetes mellitus, diseases of the respiratory and digestive systems as well as due to injury and poisoning. The risk for respiratory cancer and NHL among coastal fishermen exceeded that of deep sea fishermen, whereas the latter displayed a considerably higher SHR for diabetes mellitus, diseases of the respiratory system and metabolic and nutritional disorders. In contrast, the SHR for hypertensive and ischemic heart diseases was decreased among deep sea fishermen. Less qualified deep sea fishermen displayed a considerably higher SHR for malignant neoplasms at all sites than more highly qualified ones. CONCLUSIONS: Fishery is still an occupation which poses a high risk for malignant neoplasms and injuries. This is likely due to lifestyle and work-related factors. Further studies are needed to evaluate the different working and living conditions of coastal and deep sea fishermen.

Diffusion limitations of the lung - comparison of different measurement methods.

Pulmonary fibrosis leads to a decrease of oxygen diffusion, in particular during exercise. Bronchial obstruction also could decrease the partial pressure of oxygen (P(a)O(2)). In this study we investigated the validity of blood gas content, especially P(a)O(2) and P(a)O(2) affected by hyperventilation (P(a)O(2corr)) and alveolo-arterial oxygen gradient (P(A-a)O(2)) in comparison with the CO diffusion capacity (DLCO) in different lung diseases. A total of 250 subjects were studied (52.3 ± 12.5 year; F/M 40/210), among which there were 162 subjects with different lung disorders and 88 healthy controls. Pearson's correlation coefficients (r) of DLCO with P(a)O(2), P(a)O(2corr), and PA-aO(2) were analyzed in each group. The results show that the diagnostic power of P(A-a)O(2) against P(a)O(2corr) was equivalent, especially during exercise (r = -0.89 and -0.92, respectively). DLCO showed only weak correlations with P(a)O(2corr) and P(A-a)O(2) (r = 0.17 and -0.19, respectively). In conclusion, DLCO shows a better match with blood gas content during exercise than at rest during which it is routinely tested. Thus, the exercise test is advisable. The P(A-a)O(2) takes into account the level of ventilation, which makes it correlate better with DLCO rather than with blood gas content. The most significant problems in clinical evaluation of blood gas parameters during exercise are the insufficiently defined limits of normal-to-pathological range.

Gradual versus continuous increase of load in ergometric tests: are the results comparable?

Standard exercise testing (ET) comprises progressive exercise provocation with cardiovascular monitoring. Exercise tolerance is estimated by workload. Cardiopulmonary exercise testing (CPX) is a non-invasive measurement of ventilatory gas exchange which provides more accurate quantifications of cardiorespiratory fitness (CRF). Workload is usually increased stepwise in ET and continuously (ramp) in CPX. Our aim was to examine the comparability of the results. Thirty two healthy volunteers (17 females/15 males, age 26.8±6.1 years, BMI 24.5±3.0) underwent exercise testing on a bicycle ergometer up to maximum physical exhaustion; under ramp protocol (CPX) and 2-7 days later with a stepwise increase of workload (ET). We compared the physical work capacity under both methods at maximum workload, at heart rate of 150 and 170 beats/min (PWC150 and PWC170), and the exercise duration. We found that there were no statistically significant differences in the maximum heart rate (CPX: 177.1±11.7/min vs. ET: 178.5±11.2/min) or maximal workload (CPX: 219.8±50.6 vs. ET: 209.4±42.5). PWC150 and PWC150/kg were higher with CPX than those with ET (156.6±51 vs. 146.4±42.3, p<0.001 and 2.1±0.5 vs. 1.9±0.4, respectively, p<0.001). Exercise duration was almost equal (12.1 vs. 11.3 min). We conclude that overall physical performance was higher with CPX. Since the results are similar, we recommend the CPX: wattage and other parameters in performance assessment are to be determined directly, interpolations are obsolete.

Effects of Exposure to Welding Fume on Lung Function: Results from the German WELDOX Study.

The association between exposure to welding fume and chronic obstructive pulmonary disease (COPD) has been insufficiently clarified. In this study we assessed the influence of exposure to welding fume on lung function parameters. We investigated forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC, and expiratory flow rates in 219 welders. We measured current exposure to respirable particles and estimated a worker's lifetime exposure considering welding techniques, working conditions and protective measures at current and former workplaces. Multiple regression models were applied to estimate the influence of exposure to welding fume, age, and smoking on lung function. We additionally investigated the duration of working as a welder and the predominant welding technique. The findings were that age- and smoking-adjusted lung function parameters showed no decline with increasing duration, current exposure level, and lifetime exposure to welding fume. However, 15% of the welders had FEV1/FVC below the lower limit of normal, but we could not substantiate the presence of an association with the measures of exposure. Adverse effects of cigarette smoking were confirmed. In conclusion, the study did not support the notion of a possible detrimental effect of exposure to welding fume on lung function in welders.

[Epidemiological and occupational medicine aspects of pleural mesothelioma]. / Epidemiologie und arbeitsmedizinische Aspekte des Pleuramesothelioms.

Malignant mesothelioma of the pleura represents a signal tumour for (occupational) exposure to asbestos. Almost 20 years after the ban of asbestos in Germany, incident cases are still occurring due to the long latency period between the initial exposure to asbestos and the onset of the tumour. Of particular interest is the development of mesothelioma epidemiology. In Germany, it is extensively discussed whether the incidence of malignant pleura mesothelioma continues to rise, has already reached a plateau or is expected to decline in the next few years. The development is predominantly caused by the total asbestos use, its application and the gradual substitution of asbestos. The prevention of asbestos-related diseases due to former exposures, but also due to existing asbestos contaminations and their restoration is still a hot topic in occupational medicine. It is thus of major importance to ensure an adequate occupational safety and to care for asbestos-exposed workers - even after cessation of their exposure - with effective and efficient measures of early detection. New technologies, such as nanotechnology with carbon nanotubes, represent new potential health hazards.

A straightforward method for determination of the sevoflurane metabolite hexafluoroisopropanol in urinary occupational medical samples by headspace-gas chromatography mass spectrometry.

Biological monitoring of the unmodified sevoflurane and its metabolite hexafluoroisopropanol (HFIP) in urine samples was proposed to determine the individual exposure levels of the medical staff. In this study, a method for simultaneous determination of both compounds in urine using static headspace-gas chromatography-mass spectrometry (HS-GC-MS) was developed. The method is linear over a broad concentration range from 1 to 1000 µg/L (r2 > 0.999) and shows high precision. Limits of quantification (LOQ) are 0.6 µg/L for sevoflurane and 3 µg/L for HFIP, representing an excellent sensitivity without the necessity of analyte enrichment. The method was successfully applied in a German pilot-study to monitor both compounds in samples from medical personnel working in operating theatres. Urinary concentrations of HFIP ranged between < LOQ and 145 µg/L, while sevoflurane was below the LOD in all samples.

Di-n-butyl phthalate (DnBP) and diisobutyl phthalate (DiBP) metabolism in a human volunteer after single oral doses.

An individual (male, 36 years, 87 kg) ingested two separate doses of di-n-butyl phthalate (DnBP) and diisobutyl phthalate (DiBP) at a rate of ~60 µg/kg. Key monoester and oxidized metabolites were identified and quantified in urine continuously collected until 48 h post-dose. For both DnBP and DiBP, the majority of the dose was excreted in the first 24 h (92.2 % of DnBP, 90.3 % of DiBP), while only <1 % of the dose was excreted in urine on day 2. In each case, the simple monoesters were the major metabolites (MnBP, 84 %; MiBP, 71 %). For DnBP, ~8 % was excreted as various side chain oxidized metabolites. For DiBP, approximately 20 % was excreted mainly as the oxidized side chain metabolite 2OH-MiBP, indicating that the extent of oxidative modification is around 2.5 times higher for DiBP than for DnBP. All DnBP and DiBP metabolites reached peak concentrations between 2 and 4 h post-exposure, followed by a monotonic decline. For DnBP metabolites, the elimination halftime of MnBP was 2.6 h; longer elimination halftimes were estimated for the oxidized metabolites (2.9-6.9 h). For DiBP metabolites, MiBP had the shortest halftime (3.9 h), and the oxidized metabolites had somewhat longer halftimes (4.1 and 4.2 h). Together with the simple monoesters, secondary oxidized metabolites are additional and valuable biomarkers of phthalate exposure. This study provides basic human metabolism and toxicokinetic data for two phthalates that have to be considered human reproductive toxicants and that have been shown to be omnipresent in humans.

Effects of a multi-behavioral health promotion program at worksite on smoking patterns and quit behavior.

BACKGROUND: Tobacco use is associated with various severe health risks. Therefore, the need to decrease smoking rates is a great public health concern. The workplace has capability as a setting through which large groups of smokers can be reached to encourage smoking cessation. OBJECTIVE: The aim of the present study was to evaluate effects of a multi behavioral worksite health promotion intervention. The primary outcome was the change of smoking rate. Secondary outcomes were changes in smoking attitudes and readiness to stop smoking among employees over an intervention period of 12 months. METHOD: 112 and 110 employees were enrolled in the intervention and control arm respectively. The intervention group received a 12-month multicomponent health promotion intervention. One of the main elements of the multicomponent intervention was a smoking cessation and counseling program. During the pilot year, participants completed a self-evaluation questionnaire at baseline and again after 12 months to related outcomes and changes. RESULTS: Results showed that participants' quit behavior and smoking behavior changed over time in the intervention group (IG). Readiness to quit smoking also increased in the IG compared to the comparison group (CG). Some positive intervention effects were observed for cognitive factors (e.g., changes attitudes towards smoking). Baseline willingness to change smoking behavior was significantly improved over time. CONCLUSIONS: This study showed initial results of a long-term multicomponent worksite health promotion program with regard to changes in smoking behavior, attitudes towards smoking and readiness to quit smoking. The evaluation suggests that a worksite health promotion program may lead to improvements in smoking behavior for a number of workers.

German Environmental Specimen Bank: 24-hour urine samples from 1999 to 2017 reveal rapid increase in exposure to the para-phthalate plasticizer di(2-ethylhexyl) terephthalate (DEHTP).

The worldwide plasticizer markets are facing constant substitution processes. Many classic ortho-phthalate plasticizers like di(2-ethylhexyl) phthalate (DEHP) are phased out, due to their proven toxicity to reproduction. Assumedly less critical, less regulated plasticizers such as di(2-ethylhexyl) terephthalate (DEHTP) are increasingly applied in consumer near products like toys, food contact materials, and medical devices. With the increasing use of DEHTP, increasing exposures of the general population have to be expected likewise. Human biomonitoring is a well-established tool to determine population exposures. In the present study we investigate the time trend of exposure to DEHTP using 24-hour urine samples of the German Environmental Specimen Bank (ESB) collected from 1999 to 2017. In these samples (60 per odd-numbered year, 600 samples in total) collected from young German adults (20-29 years, equal gender distribution) we determined four specific urinary metabolites as biomarkers of DEHTP exposure. From 1999 to 2009, the main specific urinary metabolite 5cx-MEPTP was quantifiable in <10% of the samples. Thereafter, detection rates and levels constantly increased, in line with rapidly increasing DEHTP consumption volumes. In 2017, all samples had 5cx-MEPTP levels above the limit of quantification (LOQ) with a median concentration of 3.35 µg/L (95th percentile: 12.8 µg/L). The other metabolites were detected less frequently and at lower levels but correlated well with 5cx-MEPTP robustly confirming the increasing DEHTP exposure. All 5cx-MEPTP concentrations were well below the German health based guidance value (HBM-I) of 2800 µg/L for adults. Likewise, the median calculated daily intake, based on 5cx-MEPTP measured in 2017, was 0.74 µg/kg bw∗d (95th percentile: 3.86 µg/kg bw∗d), still well below the tolerable daily intake (TDI) of 1000 µg/kg bw∗d. Based on current toxicological knowledge we can hence conclude that for the population investigated, DEHTP exposure gives no reason for immediate concern. However, the steep ongoing increase of DEHTP exposure warrants further close monitoring in the future, preferably also in sub-populations with known higher exposures to plasticizers, especially children.

Exhaled breath condensate analysis: evaluation of a methodological setting for epidemiological field studies.

The analysis of exhaled breath condensate (EBC) is a noninvasive method to determine airway inflammation. There is accumulating evidence that pH, nitrogen oxides (NOx), and leukotriene B4 (LTB4) are suitable markers of inflammatory airway diseases. It was the aim of the present pilot study to evaluate a protocol of EBC sampling and processing for epidemiologic field studies. EBC samples were repeatedly obtained by 16 healthy adults on each of four days over two consecutive weeks. The effects of sample collection (volume vs. time, with vs. without nose-clip) and sample processing on volume, pH, NOx, and LTB4 as well as within-day, between-day, and between-week reproducibility were assessed. We found that wearing a nose-clip had no significant effects on mediators. Sampling time was the major determinant of the volume. Reproducibility was fairly good. Storage at 4-6 degrees C for 24 h had no significant effects on NOx and LTB4 concentrations, but resulted in an increase of pH. In conclusion, wearing a nose-clip during EBC collection is not recommended in terms of convenience and compliance for repeated investigations. Samples for the analyses of NOx and LTB4 can be transported under usual conditions, but pH should preferably be determined at the workplace.

Association of CYP1B1 codon 432 mutant allele in head and neck squamous cell cancer is reflected by somatic mutations of p53 in tumor tissue.

Tobacco use is causally associated with head and neck squamous cell cancer (HNSCC). Here, we present the results of a case-control study that investigated the effects that the genetic variants of the cytochrome (CYP)1A1, CYP1B1, glutathione-S-transferase (GST)M1, GSTT1, and GSTP1 genes have on modifying the risk of smoking-related HNSCC. Allelisms of the CYP1A1, GSTT1, GSTM1, and GSTT1 genes alone were not associated with an increased risk. CYP1B1 codon 432 polymorphism was found to be a putative susceptibility factor in smoking-related HNSCC. The frequency of CYP1B1 polymorphism was significantly higher (P < 0.001) in the group of smoking cases when compared with smoking controls. Additionally, an odds ratio (OR) of 4.53 (2.62-7.98) was discovered when investigating smoking and nonsmoking cases for the susceptible genotype CYP1B1*2/*2, when compared with the presence of the genotype wild type. In combination with polymorphic variants of the GST genes, a synergistic-effect OR was observed. The calculated OR for the combined genotype CYP1B1*2/*2 and GSTM1*2/*2 was 12.8 (4.09-49.7). The calculated OR for the combined genotype was 13.4 (2.92-97.7) for CYP1B1*2/*2 and GSTT1*2/*2, and 24.1 (9.36-70.5) for the combination of CYP1B1*2/*2 and GSTT1-expressors. The impact of the polymorphic variants of the CYP1B1 gene on HNSCC risk is reflected by the strong association with the frequency of somatic mutations of the p53 gene. Smokers with susceptible genotype CYP1B1*2/*2 were 20 times more likely to show evidence of p53 mutations than were those with CYP1B1 wild type. Combined genotype analysis of CYP1B1 and GSTM1 or GSTT1 revealed interactive effects on the occurrence of p53 gene mutations. The results of the present study indicate that polymorphic variants of CYP1B1 relate significantly to the individual susceptibility of smokers to HNSCC.

Cholesterol enhances platelet-derived growth factor-BB-induced [Ca2+]i and DNA synthesis in rat aortic smooth muscle cells.

In the present study, we describe possible mechanisms by which hypercholesterolemia may contribute to the development of cardiovascular diseases. Treatment of rat aortic smooth muscle cells for 20 hours with cholesterol-rich liposomes (500 micrograms/mL cholesterol, 100 micrograms/mL low-density lipoprotein) resulted in a 76 +/- 12% increase in total cholesterol content. The effects of cholesterol enrichment were examined by determination of changes in cell membrane fluidity. Fluidity of the cholesterol-enriched cell membranes was decreased at all temperatures between 15 degrees C and 40 degrees C. Changes in membrane fluidity in whole cell membranes represented changes in fluidity of microsomal membranes isolated by Percoll gradient ultracentrifugation. The basal [Ca2+]i and the maximal platelet-derived growth factor (PDGF)-BB-induced [Ca2+]i was elevated by 30% and 90% in cholesterol-enriched cells, respectively. In contrast, the resting pH, and the PDGF-BB-induced stimulation of the Na+/H+ exchange were not affected in cholesterol-enriched cells. The effect of PDGF-BB on [3H]thymidine incorporation in cholesterol-enriched cells was elevated by 40% in comparison with untreated cells. Our findings show that cellular cholesterol may be involved in the development of vascular diseases via modulation of the PDGF-induced increase in [Ca2+]i and DNA synthesis in vascular smooth muscle cells.

Inhibition of glycosphingolipid synthesis by threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) and the modulation of IL-1beta-stimulated expression of inducible nitric oxide synthase in rat aortic smooth muscle cells.

1. The composition of glycosphingolipids is altered in atherosclerotic tissue. In order to study the possible modulation of interleukin-1beta (IL-1beta)-induced expression of inducible nitric oxide synthase (iNOS) by endogenously synthesized glycosphingolipids, we investigated rat aortic vascular smooth muscle cells (VSMC) grown in the presence of the inhibitor of glycosphingolipid synthesis, threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP). 2. Depletion of glycosphingolipids by PDMP (20-30 microM) was demonstrated by thin-layer chromatography of D-[1-(14)C]-galactose- or L-[-U14C]-serine-labelled glycosphingolipids. Nitrite generation was measured by the diaminonaphthalene assay, nitric oxide was determined by the oxyhaemoglobin technique and iNOS protein was detected by immunocytochemistry. 3. In VSMC grown in the presence of PDMP, the glycosphingolipid content was reduced by 30-50%. In PDMP-treated VSMC, IL-1beta (3 micro ml[-1])-stimulated release of nitrite (135 +/- 4 nmol mg(-1) protein 48 h[-1]) was significantly increased as compared to IL-1beta-stimulated control cells (40 +/- 3 nmol mg(-1) protein 48 h(-1); n = 6, P < 0.001). Similarly, IL-1beta (3 micro ml(-1), 36 h)-stimulated release of nitric oxide was higher in PDMP-treated VSMC (6.1 +/- 0.5 nmol mg(-1) protein h[-1]) as compared to untreated cells (2.0 +/- 0.6 nmol mg(-1) protein h(-1); n = 3, P < 0.01). These findings were confirmed by the demonstration of increased expression of iNOS protein (14.9 +/- 1.2% vs 6.4 +/- 0.2%; n = 4, P < 0.001), as shown by immunocytochemistry. 4. Evidence is presented that endogenous glycosphingolipids are important modulators of cytokine-induced iNOS expression. In view of an altered glycosphingolipid profile in atherosclerotic arteries, these mechanisms might be of relevance for the pathogenesis of atherosclerosis and restenosis subsequent to vessel injury.

Challenges to environmental toxicology and epidemiology: where do we stand and which way do we go?

Modern toxicology investigates a wide array of both old and new health hazards. Priority setting is needed to select agents for research from the plethora of exposure circumstances. The changing societies and a growing fraction of the aged have to be taken into consideration. A precise exposure assessment is of importance for risk estimation and regulation. Toxicology contributes to the exploration of pathomechanisms to specify the exposure metrics for risk estimation. Combined effects of co-existing agents are not yet sufficiently understood. Animal experiments allow a separate administration of agents which can not be disentangled by epidemiological means, but their value is limited for low exposure levels in many of today's settings. As an experimental science, toxicology has to keep pace with the rapidly growing knowledge about the language of the genome and the changing paradigms in cancer development. During the pioneer era of assembling a working draft of the human genome, toxicogenomics has been developed. Gene and pathway complexity have to be considered when investigating gene-environment interactions. For a best conduct of studies, modern toxicology needs a close liaison with many other disciplines like epidemiology and bioinformatics.