Assessing the chemical anthropocene - Development of the legacy pollution fingerprint in the North Sea during the last century.

The North Sea and its coastal zones are heavily impacted by anthropogenic activities, which has resulted in significant chemical pollution ever since the beginning of the industrialization in Europe during the 19th century. In order to assess the chemical Anthropocene, natural archives, such as sediment cores, can serve as a valuable data source to reconstruct historical emission trends and to verify the effectiveness of changing environmental legislation. In this study, we investigated 90 contaminants covering inorganic and organic pollutant groups analyzed in a set of sediment cores taken in the North Seas' main sedimentation area (Skagerrak). We thereby develop a chemical pollution fingerprint that records the constant input of pollutants over time and illustrates their continued great relevance for the present. Additionally, samples were radiometrically dated and PAH and PCB levels in porewater were determined using equilibrium passive sampling. Furthermore, we elucidated the origin of lead (Pb) contamination utilizing non-traditional stable isotopic analysis. Our results reveal three main findings: 1. for all organic contaminant groups covered (PAHs, OCPs, PCBs, PBDEs and PFASs) as well as the elements lead (Pb) and titanium (Ti), determined concentrations decreased towards more recent deposited sediment. These decreasing trends could be linked to the time of introductions of restrictions and bans and therefor our results confirm, amongst possible other factors, the effectiveness of environmental legislation by revealing a successive change in contamination levels over the decades. 2. concentration trends for ΣPAH and ΣPCB measured in porewater correspond well with the ones found in sediment which suggests that this method can be a useful expansion to traditional bulk sediment analysis to determine the biologically available pollutant fraction. 3. Arsenic (As) concentrations were higher in younger sediment layers, potentially caused by emissions of corroded warfare material disposed in the study area after WW II.

Power, perspective, and privilege: The challenge of translating stakeholder theory from business management to environmental and natural resource management.

Stakeholder analysis and engagement is a central tenet for understanding and solving sustainability challenges, and is applied widely in environmental and natural resource management (ENRM). The practice in ENRM follows translation of stakeholder theory from its origins in business management to the sustainability sector. In this analytical essay we explore key concepts in ENRM research and practice to examine complexities that have accompanied this translation to ENRM. In particular, we consider the centrality of stakeholders' landscape perspectives in defining their stake in ENRM issues, and through this lens examine the limitations that are inherent in the classic 'hub-and-spoke' model of stakeholder analysis that is the theoretical underpinning for ENRM stakeholder analysis and engagement practice. We argue that unlike the traditional business context where both power and perspective are centred on the business entity that then defines other stakeholders in reference to itself, in ENRM, stakeholder relations are centred on an ENRM issue, typically a landscape or the implications of policy change on a landscape. As a consequence, decision-making power is decentred onto one of several stakeholders; often a government or other high power entity, implicitly conferring privilege to those powerful stakeholders' landscape perspectives over those held by low power stakeholders. We conclude with priorities for foregrounding power and explicating landscape perspectives to identify privilege in ENRM. We direct these insights especially to those ENRM actors who have the dual roles of adjudicator and privileged stakeholder such that they do not inadvertently perpetuate power imbalances through the privilege of aligning their decision-making power with their landscape perspectives.

High-Throughput Fluorescence Polarization Assay to Identify Ligands Using Purified G Protein-Coupled Receptor.

The development of cell-free high-throughput (HT) methods to screen and select novel lead compounds remains one of the key challenges in G protein-coupled receptor (GPCR) drug discovery. Mutational approaches have allowed the stabilization of GPCRs in a purified and ligand-free state. The increased intramolecular stability overcomes two major drawbacks for usage in in vitro screening, the low receptor density on cells and the low stability in micelles. Here, an HT fluorescence polarization (FP) assay for the neurotensin receptor type 1 (NTS1) was developed. The assay operates in a 384-well format and is tolerant to DMSO. From a library screen of 1272 compounds, 12 (~1%) were identified as primary hits. These compounds were validated in orthogonal assay formats using surface plasmon resonance (SPR), which confirmed binding of seven compounds (0.6%). One of these compounds showed a clear preference for the orthosteric binding pocket with submicromolar affinity. A second compound revealed binding at a nonorthosteric binding region and showed specific biological activity on NTS1-expressing cells. A search of analogs led to further enhancement of affinity, but at the expense of activity. The identification of GPCR ligands in a cell-free assay should allow the expansion of GPCR pharmaceuticals with antagonistic or agonistic activity.

[Hearing impairment and dementia]. / Hörstörung und Demenz.

The World Health Organization (WHO) burden of disease study identified dementia and hearing problems as leading causes of loss of quality of life in the industrial world. The prevalence of dementia and hearing problems increases in aging societies. Comorbidity of these two diseases causes increasing demands on healthcare systems. The similarity and possible interaction of symptoms renders diagnosis and therapy of dementia and hearing loss a challenge for neurologists, psychiatrists, ear, nose and throat (ENT) and hearing specialists. Knowledge of both diseases enables an early intervention and helps preserve participation in society and thereby reducing the risk of developing dementia. This paper focuses on the characteristics of the diagnosis and therapy of hearing problems and dementia.

[24-hour pH monitoring of the hypopharynx in 545 patients with special regard to a critical data evaluation]. / Ergebnisse der 24-Stunden-pH-Metrie des Hypopharynx von 545 Patienten unter besonderer Berücksichtigung einer kritischen Auswertung.

BACKGROUND: Although a number of reports exist on 24-hour pH monitoring of the hypopharynx, no consensus has been reached about evaluation standards. In particular the influence of food and beverages is still different estimated. The parameters which are used to analyze the data of pharyngeal pH monitoring are not consistent. PATIENTS AND METHODS: 545 patients underwent esophagopharyngeal 24-hour pH monitoring in the Department of Otorhinolaryngology at the University of Rostock from February 1996 to December 2003. A score was calculated by excluding technical artefacts and pH drop caused by ingestion. RESULTS: Pharyngeal acid exposure was detected in 228 patients. The values of the reflux score ranged between 0 - 62,4 with a median value of zero. The left skewed score distribution shows a high abundance of patients with a minimum score and a limited amount of patients with high score values. The results were compared to reports of other authors. CONCLUSIONS: Evaluation standards are necessary for a reproducible analysis of pharyngeal pH monitoring data and for the comparison of different reports. A qualified score for the analysis and the comparison of pharyngeal pH monitoring data is suggested.

[Active language development in children with severe hearing loss and deafness in relation to technical auditory management]. / Die aktive Sprachentwicklung hochgradig hörgeschädigter und gehörloser Kinder in Abhängigkeit von der hörtechnischen Versorgung.

The extent of vocabulary depends on the success of rehabilitation in hearing, language and speech. In hearing impaired and deaf children, it is important to select the optimum technical device-hearing aid or cochlear implant. This study was performed on 30 children with hearing aids or cochlear implants using the Test of Expressive Vocabulary for Children Aged 3-6 years (Kiese-Himmel and Kozielski). The development of vocabulary was recorded over 12 months. The results were analysed dependent on the degree of hearing loss, age at primary diagnosis, duration of treatment and kind of hearing aid used. These were compared with the reference data from a normally hearing population. Cochlear implant users had better language development than hearing aid users despite a lower grade of hearing loss in the hearing aid group. In general, the extent of the expressive vocabulary was less in hearing impaired children than in the reference population. However, in terms of hearing age, the language development of some cochlear implant users was similar to that of normal children.

Using fluffy layer material to study the fate of particle-bound organic pollutants in the southern Baltic Sea.

This paper examines the utility of fluffy layer material for studying and monitoring the environmental levels, transport, and fate of particle-bound contaminants in coastal ecosystems. Fluffy layer material is the very young and mobile layer of particulate matter that accumulates on the sediment surface under quiescent conditions. We used this material to study the behavior of polycyclic aromatic hydrocarbons (PAHs) that are discharged by the Oder River into the Baltic Sea. With the fluffy layer material, it was possible to (i) do fingerprint analysis to trace the sources of PAHs in the river discharge, (ii) follow the modification of the PAHs from the mouth of the river to the depositional basin and identify the responsible processes, (iii) monitor the seasonal variation in the PAH input, (iv) study the influence of a major flood event on the PAH loading to the coastal ecosystem, and (v) conduct a PAH mass balance to estimate the contribution of the Oder River source to PAH accumulation in the depositional basin. The fluffy layer material integrated the particle-bound contaminant signal over a period ranging from several days to several months, depending on the sampling location. As such, fluffy layer material is a valuable addition to the matrixes commonly used for studying particle-associated chemicals: SPM and sediment, which reflect time scales of hours and years, respectively.

Hypoalgesic effect of caffeine in normotensive men and women.

Evidence from both hypertensive and normotensive individuals indicate that elevated blood pressure is associated with decreased pain sensitivity. The current study sought to experimentally raise blood pressure using 250 mg caffeine, and investigate its effects on the cold pressor pain experiences of 25 men and 25 women. In a placebo-controlled repeated-measures experiment, caffeine increased systolic and diastolic blood pressure, as well as producing more clearheaded and energetic feelings. Caffeine produced higher pain threshold and pain tolerance levels compared to placebo, and women had a lower tolerance to pain than men. Finally, a significant association was found between caffeine-related increase in systolic blood pressure and caffeine-related increase in pain tolerance. Furthermore, this association was the strongest in women. These results are discussed in light of future directions for pain and hypertension research.

[Diagnosis and therapy of laryngitis gastrica]. / Diagnostik und Therapie der Laryngitis gastrica.

We treated 64 patients with the diagnosis of laryngitis gastrica with Antra (Omeprazol) in doses of 10, 20, and 40 mg. To determine the success of the therapy, pH monitoring of the esophagus and hypopharynx, the voice status and measurement of vocal penetrating capacity were used. The results prove that a 20-mg dose of Antra is suitable for the therapy of laryngitis gastrica with a high rate of success. Problems which arose during the investigation, consequent changes of the original concept of the project as well as new aspects and questions which resulted from this are discussed with respect to further investigation.

[Measuring therapy success in laryngeal paralysis based on voice parameters]. / Messung des Therapieerfolgs bei Larynxparesen anhand von Stimmparametern.

The clinical courses of vocal rehabilitation of patients with different degrees of laryngeal paralysis can proceed very differently, but usually do not correspond with the physical changes of glottic function seen on laryngoscopy and stroboscopy. In this study 43 patients with laryngeal paralyses were examined, of whom 28 had regeneration of nerve function. Fifteen did not show any improvement in glottal function. All patients were asked to describe their voices, after which subjective data were compared to objective findings concerning vocal penetrating capacity, voice attack, volume, and capacity. In particular, voice capacity, attack, and vocal penetrating capacity were found to be valid in reflecting therapeutic effects and for estimating voice capability.

[Voice signal analysis in laryngeal hyperreactivity]. / Stimmsignalanalysen bei laryngealer Hyperreagibilität.

Increased reactions of the laryngeal mucosal membrane can appear after acetylcholine (ACH) inhalation. A red mucous membrane, vocal cord edema, mucus formation, changes in the glottic configuration and (rarely) subglottic edema are visible to laryngoscopic observations. The influence on various voice parameters in patients with and without laryngeal hyperreactivity was researched in order to decide the reliability of voice parameter measurements in clinical practice. Significant variations of the soft phonation index (SPI), the fundamental frequency variation (vFo), the noise-to-harmonic ratio (NHR) and the voice turbulence index (VTI) were examined for their correlations with the observable features of laryngeal hyperreactivity. A single diagnosis of hyperreactivity with voice parameter analysis failed in 50% of the patients examined because of functional voice instability and irregularities seen. Only with both laryngoscopy for reliable discrimination and voice parameter analysis for quantitative registration were findings sufficient for assessing laryngeal hyperreactivity.

Dose-proportional pharmacokinetics of a new 5-lipoxygenase inhibitor, ABT-761, in healthy volunteers.

ABT-761, a new potent 5-lipoxygenase inhibitor, is under development for the treatment of asthma. The pharmacokinetics and dose proportionality of ABT-761 after single doses (10-160 mg) of ABT-761 in 24 healthy male volunteers were investigated in a double-blind, placebo-controlled study. The compound was well tolerated, with no clinically significant effects on vital sign measurements, hematological parameters, clinical chemistry, urinalysis, or electrocardiogram. The plasma concentration-time profile of ABT-761 indicates that the drug declines in a monoexponential fashion after moderately slow absorption, with a tmax value of approximately 4 h. The terminal elimination t1/2 averaged 15 h, and was dose independent. ABT-761 mean values of Cmax and AUC were linearly related to drug dose. ABT-761 is well tolerated in healthy volunteers and the pharmacokinetics are linear in the single-dose range between 10 and 160 mg.

Pharmacokinetics and pharmacodynamics of single and multiple oral doses of a novel 5-lipoxygenase inhibitor (ABT-761) in healthy volunteers.

OBJECTIVE: This study evaluated the safety, pharmacokinetics and pharmacodynamics of ABT-761 [R(+)-N-[3-[5-(4-fluorophenylmethyl)-2-thienyl]-1- methyl-2-propynyl]-N-hydroxyurea], a new N-hydroxyurea analog. METHODS: This was a randomized, double-blind, placebo-controlled, single- and multiple-dose (15-day) study of ABT-761 (50 to 200 mg/day) in healthy, nonsmoking adult male volunteers. The pharmacokinetics were evaluated by investigation of the time- and dose-dependent effects of ABT-761, and the pharmacologic selectivity of ABT-761 was evaluated based on calcium ionophore-stimulated leukotriene B4 (LTB4) and thromboxane B2 (TXB2) biosynthesis ex vivo in whole blood. RESULTS: After single and multiple doses, mean observed time to reach maximum concentration values of ABT-761 ranged from 4.0 to 7.5 hours. Mean values for maximum concentration and area under the plasma concentration-time curve from 0 to 24 hours increased approximately linearly with dose. Mean terminal half-life and apparent volume of distribution during the terminal elimination phase of ABT-761 ranged from 15.4 to 17.8 hours and 69.5 to 78.9 L, respectively, and was dose independent. Steady state was reached on day 11 after multiple dosing. Less than 0.05% of unchanged ABT-761 was recovered in urine within the 24-hour period after day 15 dosing. Population ABT-761 plasma concentration at which 50% of the maximum possible inhibition was observed for LTB4 inhibition was 0.24 microgram/ml. No differences in mean TXB2 inhibition were observed between the subjects receiving ABT-761 and placebo. CONCLUSIONS: These results indicate that ABT-761 is a potent and selective inhibitor of 5-lipoxygenase and the pharmacokinetics of ABT-761 are time and dose independent between 50 and 200 mg/day after single and multiple dosing.

Lack of a clinically significant pharmacokinetic drug interaction between tiagabine and valproate.

This single-center, open-label study examined the safety and potential effect of tiagabine on valproate pharmacokinetics under steady-state conditions. Twelve adult patients with seizures controlled by an individualized fixed dosage of valproate participated in the study. On day 1, the pharmacokinetics of valproic acid were determined. On days 2 through 14, tiagabine was titrated from 8 to 24 mg/d (or the maximum tolerated dose up to 24 mg/d), and the patients continued to take their usual fixed dosage of valproate. Valproic acid pharmacokinetics were assessed again on day 14. The mean maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve from time zero to the end of the dosing interval (AUC0-tau ) for valproic acid were reduced approximately 10% and 12%, respectively (p < or = 0.05), when valproate and tiagabine were administered concomitantly, compared with the mean values when valproate was administered alone. The concomitant administration of these drugs was generally well tolerated. Ten patients reported treatment-emergent adverse events during the study, the most common of which was dizziness(n = 8). Only one patient experienced events that were considered to be severe. There were no clinically important effects on laboratory values, vital signs, or physical exam findings. The small decreases in mean valproic acid Cmax and AUC0-tau observed during the concomitant administration of tiagabine and valproate are probably of limited clinical importance, given the broad therapeutic range of valproate (50-100 microg/mL).

Multiple-dose pharmacokinetics of ritonavir in human immunodeficiency virus-infected subjects.

The multiple-dose pharmacokinetics of ritonavir were investigated in four groups of human immunodeficiency virus-positive male subjects (with 16 subjects per group) under nonfasting conditions; a 3:1 ritonavir:placebo ratio was used. Ritonavir was given at 200 (group I), 300 (group II), 400 (group III), or 500 (group IV) mg every 12 h for 2 weeks. The multiple-dose pharmacokinetics of ritonavir were moderately dose dependent, with the clearance for group IV (6.8 +/- 2.7 liters/h) being an average of 32% lower than that for group I (10.0 +/- 3.2 liters/h). First-pass metabolism should be minimal for ritonavir. The functional half-life, estimated from peak and trough concentrations, were similar among the dosage groups, averaging 3.1 and 5.7 h after the morning and evening doses, respectively. The area under the concentration-time curve at 24 h (AUC24) and apparent terminal-phase elimination rate constant remained relatively time invariant, but predose concentrations decreased 30 to 70% over time. Concentration-dependent autoinduction is the most likely mechanism for the time-dependent pharmacokinetics. The Km and initial maximum rate of metabolism (Vmax) values estimated from population pharmacokinetic modeling (nonlinear mixed-effects models) were 3.43 microg/ml and 46.9 mg/h, respectively. The group IV Vmax increased to 68 mg/h after 2 weeks. The maximum concentration of ritonavir in serum (Cmax) and AUC after the evening doses were an average of 30 to 40% lower than the values after the morning doses, while the concentration at 12 h was an average of 32% lower than the predose concentration, probably due to protracted absorption. Less than 2% of the dose was eliminated unchanged in the urine. Triglyceride levels increased from the levels at the baseline, and the levels were correlated with baseline triglyceride levels and AUC, Cmax, or predose concentrations.

Effect of valproate on the pharmacokinetics and pharmacodynamics of lorazepam.

The pharmacokinetic-pharmacodynamic interaction between valproate and lorazepam was evaluated in this randomized, double-blind, placebo-controlled crossover study. Sixteen healthy male volunteers enrolled in the study to receive either divalproex sodium (500 mg every 12 hours) or matching placebo for 12 days in the first period, and then to receive the other regimen for an identical second 12-day period. In both periods, lorazepam (1 mg every 12 hours) was administered on days 6 through 9 and on the morning of day 10. Concomitant administration of divalproex sodium with lorazepam resulted in an 8%, 20%, and 31% increase in steady-state maximum plasma concentration, area under the concentration-time curve, and trough plasma concentrations of lorazepam, respectively. The apparent clearance of lorazepam through the formation of lorazepam glucuronide was reduced by 31% during coadministration of divalproex sodium. Pharmacokinetic properties of valproate did not change significantly in the ten available participants during coadministration of lorazepam. Sedation scales revealed no statistically significant differences in sedation between the two regimens. It is concluded that valproate increases plasma concentrations and reduces clearance of lorazepam, most likely by impairing hepatic glucuronidation, and that coadministration of lorazepam does not affect the steady-state pharmacokinetic properties of valproate.

Biospeciation, by potentiometry and computer simulation, of Sm-EDTMP, a bone tumor palliative agent.

153Sm-EDTMP (ethylenediaminetetra(methylenephosphonic) acid) is of considerable interest as a bone therapeutic radiopharmaceutical but its properties in solution are not yet well characterized. The protonation constants of EDTMP and the formation constants of the complexes of Sm-EDTMP have accordingly been measured potentiometrically by glass electrode titrations at 25 degrees C in 0.15 M NaCl. Six protonation constants (log beta 011 = 9.638, log beta 012 = 17.330, log beta 013 = 23.597, 10g beta 014 = 28.636, log beta 015 = 31.501, log beta 016 = 32.624) and the formation constants of the [Sm(EDTMP)H-1]6-(log beta 11-1 = 4.865), [SmEDTMP]5-(log beta 110 = 12.018), [Sm(EDTMP)H]4- (log beta 111 = 17.892) and [Sm(EDTMP)H2]3- (log beta 112 = 23.437) complexes were determined. Computer simulations indicate that the [SmEDTMP]5- and the hydroxy [Sm(EDTMP)H-1]6- species are the major Sm(III) complexes formed in blood plasma, which explains the high degree of localization in the kidney and urine observed in biodistribution studies. Calcium ions are probably the major competitor for EDTMP in blood plasma. As the presence of secondary skeletal metastases results in a high rate of bone turnover, it is possible that the high concentration of calcium at these sites encourages localization of 153Sm-EDTMP.

Pharmacokinetic interactions and side effects resulting from concomitant administration of lithium and divalproex sodium.

BACKGROUND: Valproic acid is added to the lithium regimens of many patients with bipolar disorder, especially those with mania refractory to lithium treatment. METHOD: We evaluated the pharmacokinetic effects and safety of coadministration of lithium and valproate in 16 healthy volunteers in this randomized, placebo-controlled, two-period (12 days each) crossover trial. Valproate or placebo was given twice daily. On Days 6-10, lithium was added. Blood samples drawn on Days 5 and 10 were analyzed for valproate by high-pressure liquid chromatography (HPLC) and for lithium by atomic absorption spectrophotometry. RESULTS: Lithium pharmacokinetics were unchanged by valproate, but valproate C(max), C(min), and AUC rose slightly during lithium coadministration. Adverse events did not change significantly. CONCLUSION: Concomitant administration of lithium and valproate appears to be safe in patients with bipolar disorder.

[Evaluation of nasal mucociliary clearance with a modified saccharin test]. / Zur Beurteilung der nasalen Mukoziliartätigkeit mit einem modifizierten Saccharintest.

To measure the complex nasal clearance we propose to perform our variation of the Andersen saccharin method as a saccharin liquid test (SLT). The application of 3 molar aqueous sodium saccharin solutions with a Wiretrol capillary on the concha nasalis inferior or media allows simple handling, exact dosage, minimal nasal irritation and an increase in reproducibility. Application of 1 microlitre is sufficient to carry out the test. In the present study 48 healthy volunteers without any nose disease or history of sinusitis showed a saccharin transport rate of 10.4 (SD 4.2) minutes.

Pharmacokinetic interactions between zileuton and prednisone.

A randomized double-blind placebo-controlled crossover study evaluated the effects of zileuton 600mg 4 time daily on the pharmacokinetics of prednisolone after a single 400mg oral dose of prednisone. the effects of the single prednisone dose on the steady-state pharmacokinetics of zileuton were also evaluated. Multiple doses of zileuton had no significant effects on mean peak plasma concentration (Cmax), time to Cmax(tmax), or area under the plasma concentration-time curve from 0 to infinity (AUC0-infinity) values for prednisolone after oral administration of prednisone 40mg. A slight but statistically significant increase in the mean half-life (t1/2) of prednisolone was detected with zileuton + prednisone administration compared with prednisone + placebo (from 2.8 to 2.9 hours); however, this change was of no clinical relevance. Mean Cmax values of zileuton after coadministration with prednisone were similar to those of zileuton alone. While the single 40mg dose of prednisone resulted in a slight but statistically significant decrease in the mean zileuton AUC value from 0 to 6 hours (AUC0-6) [from 23 to 20 mg/L/h] and a reduction in tMAX (from 2.3 to 1.7 hours), these results were not considered to be clinically significant. Therefore, it is considered that zileuton and prednisone may be coadministered with minimal risk of a clinically significant pharmacokinetic interaction.