Isolated and combined effects of prolonged exposures to noise and whole-body vibration on hearing,vision and strain

Summary This study was carried out in order: (1) to examine the effects of isolated and combined prolonged exposures to noise and whole-body vibration on hearing, vision and subjectively experienced strain, and (2) to check the combined effects with repeated exposures. Six male subjects were exposed twice to noise (N) at 92 dBA, whole-body vibration (V) in the Z-axis at 4 Hz and 1.0 ms^–2 rms, and noise and vibration (NV) for 90 min with each condition. Temporary threshold shifts of hearing (TTS) and their integrals (ITTS) were measured at 4, 6, 10, and 12 kHz. Visual acuity was examined by means of a very sensitive test. Cross-modality matching (CMM) of the handgrip force was used to judge the subjectively experienced strain. NV induced a clear tendency of higher TTS and ITTS than N, with several significant differences most pronounced at 10 kHz. With repeated exposures, the effect of NV decreased, while the reactions to N and V remained unchanged. The individual reactions to NV differed. The influence of the duration of exposures on vision depended on the condition; N caused time-dependent changes, whereas V did not. CMM-data increased with the duration of the exposure during V and NV. N was generally judged to be more straining than V; NV caused higher strain than V during the first 30 min of exposure only. Correlations between different effects suggest certain links between them. Additionally, less motivation — daily obtained by a questionnaire — often correlated with higher ITTS during N and NV. The results also illustrate the combined effects on the individual susceptibility, repetition of exposure, the kind of response, and, possibly, the actual psychic state.Abbreviations CMM cross-modality matching - MVC maximum voluntary contraction force - N exposure condition: noise level 92dBA, no whole-body vibration - NV exposure condition: combined exposure to noise with a level of 92 dBA and wholebody vibration with 4 Hz, 1 ms^–2 rms - V exposure condition: whole-body vibration with 4 Hz, 1 ms^–2 rms - TTS temporary threshold shift - ITTS integral of temporary threshold shift - WBV whole-body vibration in the common sense This work was done in the Temporary International Research Team on Combined Effects of Noise and Vibration of the Council of Mutual Economic Assistance of the Socialist Countries. The authors gratefully acknowledge the help and assistance of L.-M. Brumm, Y. Bening, M. Godau, G. Weber, and R. Vizcaino.     

A semimechanistic and mechanistic population PK-PD model for biomarker response to ibandronate, a new bisphosphonate for the treatment of osteoporosis

AIMS: Ibandronate, a highly potent nitrogen-containing bisphosphonate, is the subject of an ongoing clinical development programme that aims to maximize the potential of simplified, less frequent oral and intravenous (i.v.) administration in osteoporosis. A modelling and simulation project was undertaken to characterize further the clinical pharmacology of ibandronate and identify convenient intermittent oral and i.v. regimens for clinical evaluation. METHODS AND RESULTS: Using selected data from clinical studies involving 174 women with postmenopausal osteoporosis (PMO), a classical multicompartmental pharmacokinetic-pharmacodynamic (PK-PD) model was developed that accurately described the PK of i.v. ibandronate in plasma and urine and urinary excretion of the C-telopeptide of the alpha chain of type I collagen (uCTX), a sensitive biomarker of PD response to ibandronate. To reduce processing times, the classical PK-PD model was simplified using a "kinetics of drug action" or kinetic (K)-PD model (i.e. a dose-response model as opposed to a dose-concentration-response model). The performance of the K-PD model was evaluated by fitting data simulated with the PK-PD model under various dosing regimens. The simplified model produced a virtually indistinguishable fit of the data from that of the PK-PD model. The K-PD model was extended to consider the influence of supplemental therapy (calcium with or without vitamin D) on the PD response and validated by retrospectively simulating the uCTX response in a prior Phase III and Phase II/III study of i.v. ibandronate, given once every 3 months, in 3380 women with PMO. The observed median uCTX responses at the scheduled assessment points in the completed studies were within the distribution of the simulated responses. The K-PD model for i.v. ibandronate was extended further to allow simultaneous fitting of uCTX responses after i.v. and oral administration in 676 postmenopausal women with osteoporosis, and validated by retrospectively simulating the data observed in a Phase I study of oral daily ibandronate in 180 women with PMO. The K-PD model adequately described the uCTX response after oral dosing. CONCLUSIONS: This validated K-PD model is currently being used to evaluate a range of novel intermittent oral and i.v. ibandronate regimens in an ongoing clinical development programme.     

Effects of avasimibe on cytochrome P450 2C9 expression in vitro and in vivo.

Avasimibe, an acyl-CoA:cholesterol acyltransferase inhibitor, has been previously shown to be a potent inducer of CYP3A4 and multiple drug resistance protein 1. We have further characterized the drug interaction potential of avasimibe by studying the inductive and inhibitory effect of this compound on major drug-metabolizing enzymes. Enzymes known to be involved in the metabolism of drugs likely to be coadministered with avasimibe, such as CYP1A1/2, CYP2C, and CYP2B6, were evaluated further by microarray analysis, Western immunoblotting, and activity assays, using rifampicin and beta-naphthoflavone as positive controls. No change was observed in CYP1A1/2 mRNA or activity levels after avasimibe treatment. Differential induction of CYP2C9- and CYP2B6-immunoreactive protein and activity was observed depending on drug concentration and donor. Microarray analysis showed a similar increase in CYP2C and CYP2B6 mRNA levels. The inhibition potential of avasimibe on the major drug-metabolizing enzymes was assessed using pooled human liver microsomes. Avasimibe inhibited CYP2C9 (IC50 2.9 microM), CYP1A2 (IC50 13.9 microM), and CYP2C19 (IC50 26.5 microM). A clinical drug interaction study was conducted to determine whether avasimibe might interact with the CYP2C9 substrate warfarin. Volunteers received 750 mg of avasimibe and showed a 54.2% reduction in trough concentrations of S-warfarin and decreased prothrombin times by 12, 15, 19, and 21% on days 6 through 9, respectively. These results demonstrate that avasimibe's inductive spectrum resembles that of rifampin.     

Subchronic toxicity of ethylene glycol in Wistar and F-344 rats related to metabolism and clearance of metabolites.

Ethylene glycol (CAS RN 107-21-1) can cause kidney toxicity via the formation of calcium oxalate crystals in a variety of species, including humans. Numerous repeated dose studies conducted in rats have indicated that male rats are more susceptible than female rats. Furthermore, subchronic and chronic studies using different dietary exposure regimens have indicated that male Wistar rats may be more sensitive to renal toxicity than male Fischer-344 (F-344) rats. This study was conducted to compare the toxicity of ethylene glycol in the two strains of rats under identical exposure conditions and to evaluate the potential contribution of toxicokinetic differences to strain sensitivity. Ethylene glycol was mixed in the diet at concentrations to deliver constant target dosage levels of 0, 50, 150, 500, or 1000 mg/kg/day for 16 weeks to groups of 10 male Wistar and 10 male F-344 rats based on weekly group mean body weights and feed consumption. Kidneys were examined histologically for calcium oxalate crystals and pathology. Samples of blood, urine, and kidneys from satellite animals exposed to 0, 150, 500, or 1000 mg/kg/day for 1 or 16 weeks were analyzed for ethylene glycol, glycolic acid, and oxalic acid. Treatment of Wistar rats at 1000 mg/kg/day resulted in the death of two rats; in addition, at 500 and 1000 mg/kg/day, group mean body weights were decreased compared to control throughout the 16 weeks. In F-344 rats exposed at 1000 mg/kg/day and in Wistar rats receiving 500 and 1000 mg/kg/day, there were lower urine specific gravities, higher urine volumes, and increased absolute and relative kidney weights. In both strains of rats treated at 500 and 1000 mg/kg/day, some or all treated animals had increased calcium oxalate crystals in the kidney tubules and crystal nephropathy. The effect was more severe in Wistar rats than in F-344 rats. Accumulation of oxalic acid in the kidneys of both strains of rats was consistent with the dose-dependent and strain-dependent toxicity. As the nephrotoxicity progressed over the 16 weeks, the clearance of ethylene glycol and its metabolites decreased, exacerbating the toxicity. Benchmark dose analysis indicated a BMDL05 for kidney toxicity in Wistar rats of 71.5 mg/kg/day; nearly fourfold lower than in F-344 rats (285 mg/kg/day). This study confirms that the Wistar rat is more sensitive to ethylene glycol-induced renal toxicity than the F-344 rat and indicates that metabolism or clearance plays a role in the strain differences.     

Repeal of the Massachusetts seat belt law.

In November 1986, the Massachusetts mandatory seat belt use law repealed in a referendum by a 53 per cent to 47 per cent vote. In an anonymous random digit telephone survey of 1,046 adults in Massachusetts in summer 1986, while the law was in effect, 61 per cent of respondents had said they would vote in favor of the law. A post-repeal follow-up of 80 per cent of these persons revealed initial supporters and opponents of the law were equally likely to vote, but 15 per cent of the summer supporters switched their opinions and voted for repeal, compared to only 4 per cent of summer opponents who switched. In addition, a separate survey of 167 households that had refused to answer the summer survey indicated that survey nonrespondents were more likely to vote against the law than for it. Those opposing the law saw it as an infringement on personal liberty and believed it was not effective in reducing injury and death.     

Acute nonlymphatic leukemia among deck officers on coastal tankers: a report of two cases

Deck officers on coastal tankers may be exposed to high concentrations of cargo vapors during loading and tank-cleaning operations. Two cases of acute nonlymphatic leukemia are described. Both men had worked as chief officers on coastal tankers transporting benzene and other petroleum products.     

Statistical inference for decision curve analysis,with applications to cataract diagnosis

Statistical learning methods are widely used in medical literature for the purpose of diagnosis or prediction. Conventional accuracy assessment via sensitivity, specificity, and ROC curves does not fully account for clinical utility of a specific model. Decision curve analysis (DCA) becomes a novel complement as it incorporates a clinical judgment of the relative value of benefits (treating a true positive case) and harms (treating a false positive case) associated with prediction models. The preference of a patient or a policy-maker is formulated statistically as the underlying threshold probability, above which the patient would choose to be treated. Net benefit is then calculated for possible threshold probability, which places benefits and harms on the same scale. We consider the inference problems for DCA in this paper. Interval estimation procedure and inference methodology are provided after we derive the relevant asymptotic properties. Our formulation can accommodate the classification problems with multiple categories. We carry out numerical studies to assess the performance of the proposed methods. An eye disease dataset is analyzed to illustrate our proposals.     

Measures for evaluation of prognostic improvement under multivariate normality for nested and nonnested models

When comparing performances of two risk prediction models, several metrics exist to quantify prognostic improvement, including the change in the area under the Receiver Operating Characteristic curve, the Integrated Discrimination Improvement, the Net Reclassification Index at event rate, the change in Standardized Net Benefit, the change in Brier score, and the change in scaled Brier score. We explore the behavior and interrelationships between these metrics under multivariate normality in nested and nonnested model comparisons. We demonstrate that, within the framework of linear discriminant analysis, all six statistics are functions of squared Mahalanobis distance, a robust metric that properly measures discrimination by quantifying the separation between the risk scores of events and nonevents. These relationships are important for overall interpretability and clinical usefulness. Through simulation, we demonstrate that the performance of the theoretical estimators under normality is comparable or superior to empirical estimation methods typically used by investigators. In particular, the theoretical estimators for the Net Reclassification Index and the change in Standardized Net Benefit exhibit less variability in their estimates as compared to their empirically estimated counterparts. Finally, we explore how these metrics behave with potentially nonnormal data by applying these methods in a practical example based on the sex-specific cardiovascular disease risk models from the Framingham Heart Study. Our findings aim to give greater insight into the behavior of these measures and the connections existing among them and to provide additional estimation methods with less variability for the Net Reclassification Index and the change in Standardized Net Benefit.     

Development of a Toxicity Identification Evaluation Protocol Using Chlorophyll-<Emphasis Type="Italic">a</Emphasis> Fluorescence in a Marine Microalga

Growth inhibition bioassays with the microalga Nitzschia closterium have recently been applied in marine Toxicity Identification Evaluation (TIE) testing. However, the 48-h test duration can result in substantial loss of toxicants over time, which might lead to an underestimation of the sample toxicity. Although shorter-term microalgal bioassays can minimize such losses, there are few bioassays available and none are adapted for marine TIE testing. The acute (5-min) chlorophyll-a fluorescence bioassay is one alternative; however, this bioassay was developed for detecting herbicides in freshwater aquatic systems and its suitability for marine TIE testing was not known. In this study, a chlorophyll-a fluorescence bioassay using the marine microalga Isochrysis galbana was able to detect contaminants other than herbicides at environmentally relevant concentrations and tolerated the physical and chemical manipulations needed for a Phase I TIE. Phase I TIE procedures were successfully developed using this chlorophyll-a fluorescence bioassay and used to identify all classes of contaminants present in a synthetic mixture of known chemical composition. In addition, TIEs with both the acute fluorescence bioassay and the standard growth inhibition bioassay identified the same classes of toxicants in a sample of an unknown complex effluent. Even though the acute chlorophyll-a fluorescence end point was less sensitive than the chronic cell division end point, TIEs with the chlorophyll-a fluorescence bioassay provided a rapid and attractive alternative to longer-duration bioassays.     

The effect of community-level unemployment on preventive oral health care utilization

Objective. To test the hypothesis that high community-level unemployment is associated with reduced use of preventive dental care services by a dentally insured population.
Data. The study uses monthly data on population dental visits and unemployment in the Seattle and Spokane areas from 1995 to 2004. Utilization data come from Washington Dental Services. Unemployment data were obtained from the Bureau of Labor Statistics and Washington's Employment Security Department.
Study Design. The study uses a Box–Jenkins Autoregressive Integrated Moving Average (ARIMA) method to measure the association between the variables over time. The approach controls for the effects of autocorrelation, seasonality, and confounding variables.
Findings. In the Seattle area, an unexpected 10,000 unit increase in the number of unemployed individuals is associated with a 1.24 percent decrease in preventive visits during the month (  p =.0043). In the Spokane area, a similar increase in unemployment is associated with a 5.95 percent decrease in preventive visits (  p =.0326). The findings persist when the independent variable is the number of initial unemployment insurance claims.
Conclusions. The analysis suggests that utilization of preventive dental care declines during periods of high community-level unemployment. Community-level unemployment may impede or distract populations from utilizing preventive dental services. The study's findings have implications for insurers, dentists, policy makers, and researchers.