In utero and lactational exposure to PCB 118 and PCB 153 alter ovarian follicular dynamics and GnRH-induced luteinizing hormone secretion in female lambs

The effects of in utero and lactational exposure to two structurally different polychlorinated biphenyl (PCB) congeners on follicular dynamics and the pituitary-gonadal axis in female lambs were investigated. Pregnant ewes received corn oil, PCB 118, or PCB 153, and offspring was maintained until 60 days postpartum. Ovarian follicles were quantified using stereology. Plasma luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were measured using radioimmunoassay before and after administration of a gonadotropin releasing hormone (GnRH) analog. PCB 118 exposure increased numbers of transitional, secondary, and the sum of secondary, early antral, and antral (Σsecondary-antral) follicles, PCB 153 exposure only increased the number of primary follicles. GnRH-induced LH levels were significantly elevated in the PCB 153 exposure group. We conclude that PCB 153 and PCB 118 alter follicular dynamics in lambs and modulate the responsiveness of the pituitary gland to GnRH.     

Studying psychoactive substance use in injured patients: Does exclusion of late arriving patients bias the results?

BackgroundMost studies of the prevalence of psychoactive substances in injured emergency department patients have excluded those who arrive more than 6 h after injury. This may cause a selection bias. The aim of this study was: (1) to describe the characteristics of patients who arrive more than 6 h after injury, compared to patients who arrive sooner (2) to examine whether self-report can add to the assessment of alcohol use when the patient is assessed more than 6 h after injury.MethodsBlood sample analysis and self-report data were used to assess the prevalence of psychoactive substances in injured patients admitted to an emergency department within 48 h of injury (n = 1611). Discriminant function analysis was used to assess group differences.ResultsThe patients who arrived more than 6 h after injury differed significantly from those who arrived earlier in several respects. They more often screened positive for hypnotics; they were older, they were more likely to have had a fall and they were more often injured at home and at night. Self reported use of alcohol showed good consistency with blood sample screening within 6 h of injury and could therefore be used to assess alcohol use more than 6 h after injury.ConclusionsPatients who arrive more than 6 h after injury differ significantly from those who arrive earlier. Future studies on the prevalence of psychoactive substances in emergency departments could expand the inclusion window.     

Involvement of NADPH Oxidase and iNOS in Rodent Pulmonary Cytokine Responses to Urban Air and Mineral Particles

We have investigated the potential of two complex mineral particles (feldspar and mylonite), quartz (Min-U-Sil), and suspended particulate matter (SRM-1648) (SPM) from urban air to induce inflammatory cytokine responses in primary rat alveolar type 2 cells and alveolar macrophages, and the involvement of cellular formation of free radicals in these responses. All particle types induced an increased release of interleukin (IL)-6 and macrophage inflammatory protein (MIP)-2 from type 2 cells. Diphenyleneiodonium chloride (DPI), a selective inhibitor of NADPH-oxidase, reduced the IL-6 and MIP-2 responses to quartz, SPM and mylonite. N-(3-[Aminomethyl] benzyl) acetamidine (1400W), a selective inhibitor of inducible nitric oxide synthase (iNOS), significantly reduced the Il-6 response to SPM and feldspar in the type 2 cells. The macrophages displayed significantly increased TNF-α and MIP-2 release upon exposure to quartz or SPM. Here, DPI significantly reduced the tumor necrosis factor (TNF)-α and MIP-2 responses to quartz, and the MIP-2 response to SPM. No significant effect of 1400 W was detected in the alveolar macrophages. The role of particle-induced cellular generation of free radicals in lung cytokine responses was further elucidated in mice that lacked either NADPH-oxidase or iNOS as well as in wild-type (wt) mice. All particles were able to elicit increased cytokine levels in the bronchoalveolar lavage (BAL) fluid of the mice, although the levels depended on particle type. The NADPH-oxidase knockout (KO) mice demonstrated a significantly lower IL-6 and MIP-2 responses to SPM compared to their respective wt mice. The iNOS KO mice displayed significantly reduced IL-6, TNF-α, and MIP-2 responses to SPM. The overall results indicate the involvement of cellular free-radical formation in the pulmonary cytokine responses to particles of varying composition.     

The Protein Toxins Ricin and Shiga Toxin as Tools to Explore Cellular Mechanisms of Internalization and Intracellular Transport

Protein toxins secreted by bacteria and found in plants can be threats to human health. However, their extreme toxicity can also be exploited in different ways, e.g., to produce hybrid toxins directed against cancer cells and to study transport mechanisms in cells. Investigations during the last decades have shown how powerful these molecules are as tools in cell biological research. Here, we first present a partly historical overview, with emphasis on Shiga toxin and ricin, of how such toxins have been used to characterize processes and proteins of importance for their trafficking. In the second half of the article, we describe how one can now use toxins to investigate the role of lipid classes for intracellular transport. In recent years, it has become possible to quantify hundreds of lipid species using mass spectrometry analysis. Thus, it is also now possible to explore the importance of lipid species in intracellular transport. The detailed analyses of changes in lipids seen under conditions of inhibited toxin transport reveal previously unknown connections between syntheses of lipid classes and demonstrate the ability of cells to compensate under given conditions.     

Work-home interface stress: an important predictor of emotional exhaustion 15 years into a medical career

The importance of work-home interface stress can vary throughout a medical career and between genders. We studied changes in work-home interface stress over 5 yr, and their prediction of emotional exhaustion (main dimension of burn-out), controlled for other variables. A nationwide doctor cohort (NORDOC; n=293) completed questionnaires at 10 and 15 yr after graduation. Changes over the period were examined and predictors of emotional exhaustion analyzed using linear regression. Levels of work-home interface stress declined, whereas emotional exhaustion stayed on the same level. Lack of reduction in work-home interface stress was an independent predictor of emotional exhaustion in year 15 (β=−0.21, p=0.001). Additional independent predictors were reduction in support from colleagues (β=0.11, p=0.04) and emotional exhaustion at baseline (β=0.62, p<0.001). Collegial support was a more important predictor for men than for women. In separate analyses, significant adjusted predictors were lack of reduction in work-home interface stress among women, and reduction of collegial support and lack of reduction in working hours among men. Thus, change in work-home interface stress is a key independent predictor of emotional exhaustion among doctors 15 yr after graduation. Some gender differences in predictors of emotional exhaustion were found.     

The effect of variable cigarette consumption on the interaction with clozapine and olanzapine

Objective Cigarette smoking has been shown in several studies to induce the metabolism of the cytochrome P4501A2 (CYP1A2) substrates clozapine and olanzapine. The aim of the present study was to investigate the dose-dependent effect of cigarette smoking on serum concentrations of these drugs in a naturalistic setting.Methods In 73 schizophrenic patients recruited from psychiatric nursing homes, patient characteristics, smoking habits, drug dosing and serum concentrations of clozapine (n=33) and olanzapine (n=40) were registered. Concentration to dose (C/D) ratios of clozapine and olanzapine in non-smokers and subgroups of smokers were compared.Results Fifty-nine patients (80%) were smokers and these were stratified into the following groups according to smoking habits: 1–6 (n=0), 7–12 (n=13), 13–19 (n=18) and ≥20 (n=28) cigarettes daily. While the mean ratio was twice as high in non-smokers compared to smokers for both drugs (p<0.01), the C/D ratios of clozapine and olanzapine were not significantly different between the subgroups of smokers (p >0.15). Absolute serum concentrations were also higher in non-smokers compared to smokers: 50% for clozapine (p=0.058) and 67% for olanzapine (p<0.01).Conclusion A daily consumption of 7–12 cigarettes is probably sufficient for maximum induction of clozapine and olanzapine metabolism. A 50% lower starting dose of both drugs in non-smokers seems rational to avoid side effects.     

Residence near power lines and the risk of birth defects

BACKGROUND: There has been some concern that exposure to electromagnetic fields may cause birth defects. We studied risks of birth defects by residential exposure to 50-Hz magnetic fields from power lines. METHODS: We estimated the distance between residence and power lines for 161,844 Norwegian residences, and their corresponding magnetic fields in the period 1980 to 1997. Risks of 24 categories of birth defects were compared across exposure levels, adjusting for social and demographic variables. RESULTS: Among those living near power lines, the greatest reductions in risk were for cardiac defects (odds ratio = 0.5; 95% confidence interval = 0.3-0.9) and respiratory defects (0.4; 0.2-0.9). The largest increase in risk was for esophageal defects (2.5; 1.0-5.9). Other associations were weaker and had wide confidence intervals. CONCLUSIONS: There was little evidence that residence near power lines affected the risk of birth defects. The observed decreased risks of cardiac and respiratory defects and the increased risk of esophageal defects should be interpreted with caution given the number of endpoints, the imprecision in the calculations of the distance from the residence to the power line, and the limited information on pregnant women's change of residence.     

A respiration-metabolism chamber system and a GC-MS method developed for studying exhalation of perfluorobutane in rats after intravenous injection of the ultrasound contrast agent Sonazoid

Sonazoid is a new contrast agent for ultrasound imaging comprising an aqueous suspension of lipid-stabilised perfluorobutane (PFB) gas microbubbles. A respiration-metabolism chamber system was developed to collect exhaled air following intravenous administration of Sonazoid to rats. Analysis of PFB in the exhaled rat air was performed using a modified version of an earlier published method for blood samples, i.e. an automatic headspace gas chromatographic mass spectrometric (GC-MS) method using electron impact ionisation. The calibration standards were PFB diluted in air (2.5-1800 pg/ml). Perfluoropentane (PFP) was used as an internal standard and the MS detector was set to single ion monitoring of the base fragment ions of PFB (m/z 69 and 119) and PFP (m/z 69). The calibration curve, made by plotting the peak area ratios of PFB (m/z 69) to PFP (m/z 69) against the theoretical concentration of PFB, was fitted to a linear equation with weighting 1/y2 and found to be reproducible. The lower limit of quantification (LLOQ) was 2.5 pg PFB/ml. The between-day variation of the method was below 2.6% relative standard deviation (R.S.D.) and the within-day variation of the method was below 6.4% R.S.D. The accuracy of the method was evaluated and showed a relative error less than 5.2%. PFB was found to be stable for 14 days when stored in Tedlar sample bags at room temperature. An even lower detection limit may be obtained by using the more time-consuming process of solid-phase micro extraction; thus, by concentrating PFB on carboxen-PDMS fibres an LLOQ of 0.5 pg PFB/ml was obtained. When five rats were given an i.v. bolus injection of Sonazoid at a dose of 8 microl microbubbles/kg a mean recovery of 96% (range, 81-110%) was found during 24 h; more than 50% was exhaled during the first 30 min after injection.     

From cure to palliation: agreement, timing, and decision making within the staff

Important issues in the transition from curative treatment to palliative care are agreement, timing, and decision making. A survey of 309 nurses and 415 physicians in Sweden showed that 61% of the nurses and 83% of the physicians thought agreement was current practice. None said that the decisions were made too early, but 19% of the nurses and 14% of the physicians thought that they often were made too late. Very few respondents stated that such decisions are changed, 0% and 1%, respectively. More than half of the informants made detailed comments on such transitions indicating that awareness and flexibility are desirable to make well-informed decisions. Three themes that emerged from the analysis concerning the decision to stop curative treatment and focus on palliative care were that the staff members should (if possible) make such decisions in agreement and should sometimes make the decisions earlier and that well-based reasons are required to make changes.     

Proteomic strategies for individualizing therapy of acute myeloid leukemia (AML)

Acute myeloid leukemia (AML) is an aggressive hematological malignancy characterized by accumulating myeloid precursor cells in the bone marrow, with approximately 2-3 months 50% survival if left untreated. With current treatment modalities the five years overall survival hardly exceeds 50%. Cytogenetics and molecular diagnostics guide the clinician to select individualized therapy in certain subsets of AML, achieving long-term survival above 70% of these cases. However, approximately half of the AML patients have no risk stratifying features, and early reports indicate that proteomic approaches may be utilized for disease classification as well as development of novel biomarkers related to prognosis, diagnosis, and choice of therapeutic regimen. Proteomics, here defined as the analysis of all proteins in a cell, in a cell compartment or in a signaling pathway, has probably its greatest potential in investigating pathways that are easily targeted by small molecules or therapeutic antibodies. The major methodological challenges include detection sensitivity in a limited clinical material, a problem that in some cases can be solved through designated multiplexed protein assays based on single cells or cell extracts. In this review we will discuss pharmacoproteomic studies of drugs regulating leukemia specific targets like all-trans retinoic acid, histone deacetylase inhibitors, proteasome inhibitors and tyrosine kinase inhibitors, as well as studies on drug resistance and graft-versus-host studies during stem cell transplantations. These studies indicate new avenues in AML diagnostics, individualized therapy design and therapy response surveillance for the clinician.