Low end-tidal CO2 as a real-time severity marker of intra-anaesthetic acute hypersensitivity reactions.

BACKGROUND: Prompt diagnosis of intra-anaesthetic acute hypersensitivity reactions (AHR) is challenging because of the possible absence and/or difficulty in detecting the usual clinical signs and because of the higher prevalence of alternative diagnoses. Delayed epinephrine administration during AHR, because of incorrect/delayed diagnosis, can be associated with poor prognosis. Low end-tidal CO2 (etCO2) is known to be linked to low cardiac output. Yet, its clinical utility during suspected intra-anaesthetic AHR is not well documented. METHODS: Clinical data from the 86 patients of the Neutrophil Activation in Systemic Anaphylaxis (NASA) multicentre study were analysed. Consenting patients with clinical signs consistent with intra-anaesthetic AHR to a neuromuscular blocking agent were included. Severe AHR was defined as a Grade 3-4 of the Ring and Messmer classification. Causes of AHR were explored following recommended guidelines. RESULTS: Among the 86 patients, 50% had severe AHR and 69% had a confirmed/suspected IgE-mediated event. Occurrence and minimum values of arterial hypotension, hypocapnia and hypoxaemia increased significantly with the severity of AHR. Low etCO2 was the only factor able to distinguish mild [median 3.5 (3.2;3.9) kPa] from severe AHR [median 2.4 (1.6;3.0) kPa], without overlap in inter-quartile range values, with an area under the receiver operator characteristic curve of 0.92 [95% confidence interval: 0.79-1.00]. Among the 41% of patients who received epinephrine, only half received it as first-line therapy despite international guidelines. CONCLUSIONS: An etCO2 value below 2.6 kPa (20 mm Hg) could be useful for prompt diagnosis of severe intra-anaesthetic AHR, and could facilitate early treatment with titrated doses of epinephrine. CLINICAL TRIAL REGISTRATION: NCT01637220.

Mucosal mast cells are indispensable for the timely termination of Strongyloides ratti infection.

Mast cells and basophils are innate immune cells with overlapping functions that contribute to anti-helminth immunity. Mast cell function during helminth infection was previously studied using mast cell-deficient Kit-mutant mice that display additional mast cell-unrelated immune deficiencies. Here, we use mice that lack basophils or mucosal and connective tissue mast cells in a Kit-independent manner to re-evaluate the impact of each cell type during helminth infection. Neither mast cells nor basophils participated in the immune response to tissue-migrating Strongyloides ratti third-stage larvae, but both cell types contributed to the early expulsion of parasitic adults from the intestine. The termination of S. ratti infection required the presence of mucosal mast cells: Cpa3Cre mice, which lack mucosal and connective tissue mast cells, remained infected for more than 150 days. Mcpt5Cre R-DTA mice, which lack connective tissue mast cells only, and basophil-deficient Mcpt8Cre mice terminated the infection after 1 month with wild-type kinetics despite their initial increase in intestinal parasite burden. Because Cpa3Cre mice showed intact Th2 polarization and efficiently developed protective immunity after vaccination, we hypothesize that mucosal mast cells are non-redundant terminal effector cells in the intestinal epithelium that execute anti-helminth immunity but do not orchestrate it.

Patients presenting at the emergency department with acute abdominal pain are less likely to be admitted to inpatient wards at times of access block: a registry study.

BACKGROUND: Also known as access block, shortage of inpatient beds is a common cause of emergency department (ED) boarding and overcrowding, which are both associated with impaired quality of care. Recent studies have suggested that access block not simply causes boarding in EDs, but may also result in that patients are less likely to be admitted to the hospital from the ED. The present study's aim was to investigate whether this effect remained for patients with acute abdominal pain, for which different management strategies have emerged. Access block was defined in terms of hospital occupancy and the appropriateness of ED discharges addressed as 72 h revisits to the ED. METHODS: As a registry study of ED administrative data, the study examined a population of patients who presented with acute abdominal pain at the ED of a 420-bed hospital in southern Sweden during 2011-2013. Associations between exposure and outcomes were addressed in contingency tables and by logistic regression models. RESULTS: Crude analysis revealed a negative association between access block and the probability of inpatient admission (38.6 % admitted at 0-95 % occupancy, 37.8 % at 95-100 % occupancy, and 35.0 % at ≥ 100 % occupancy) (p < .001). No significant associations between exposure and 72 h revisits emerged. Multivariable models indicated an odds ratio of inpatient admission of 0.992 (95 % CI: 0.986-0.997) per percentage increase in hospital occupancy. CONCLUSIONS: Study findings indicate that patients with acute abdominal pain are less likely to be admitted to the hospital from the ED at times of access block and that other management strategies are employed instead. No association with 72 h revisits was seen, but future studies need to address more granular outcomes in order to clarify the safety aspects of the effect.

A Tumor Growth Inhibition Model Based on M-Protein Levels in Subjects With Relapsed/Refractory Multiple Myeloma Following Single-Agent Carfilzomib Use.

Change in tumor size estimated using longitudinal tumor growth inhibition (TGI) modeling is an early predictive biomarker of clinical outcomes for multiple cancer types. We present the application of TGI modeling for subjects with multiple myeloma (MM). Longitudinal time course changes in M-protein data from relapsed and/or refractory MM subjects who received single-agent carfilzomib in phase II studies (n = 456) were fit to a TGI model. The tumor growth rate estimate was similar to that of other anti-myeloma agents, indicating that the model is robust and treatment-independent. An overall survival model was subsequently developed, which showed that early change in tumor size (ECTS) at week 4, Eastern Cooperative Oncology Group performance status (ECOG PS), hemoglobin, sex, percent bone marrow cell involvement, and number of prior regimens were significant independent predictors for overall survival (P < 0.001). ECTS based on M-protein modeling could be an early biomarker for survival in MM following exposure to single-agent carfilzomib.

Low-dose aspirin use and cancer characteristics: a population-based cohort study.

BACKGROUND: Long-term daily use of aspirin has been associated with reduced cancer mortality. To explore this association, we compared tumour TNM characteristics among aspirin users with those among non-users. METHODS: From the Swedish Cancer Register, we identified patients diagnosed with colorectal, lung, prostate and breast cancers between 2006 and 2009 and matched them to the Swedish Prescribed Drug Register to obtain information on low-dose aspirin use prior to diagnosis. Contingency table and logistic regression analyses were used to test for association and obtain odds ratios (ORs). RESULTS: We identified 17,041 colorectal, 9766 lung, 29,770 prostate and 20,299 breast cancer patients. The proportion of low-dose aspirin users was ~26% among colorectal, lung and prostate cancer patients and ~14% among breast cancer patients. Adjusted for age, gender, education level and place of residence, low-dose aspirin use was associated with lower tumour extent (T) for colorectal and lung cancers (P<0.0001) but not for prostate and breast cancers. The adjusted OR of aspirin use for the T4 vs T1 categories was ~0.7 (95% confidence interval (CI) 0.6-0.8). For all cancers, we found no evidence of association of aspirin use with nodal involvement (N). Except for a borderline result in prostate cancer (OR ~0.9; 95% CI 0.8-1.0), aspirin use was associated with a lower rate of metastatic disease (ORs ~0.6-0.8). Among the histological subgroups of lung cancer, significant differences in tumour extent were observed most clearly within the adenocarcinoma subgroup (OR ~0.6, 95% CI 0.5-0.8), although numbers of other subtypes were more limited; and there was a significant reduction of ~20-30% in the odds of metastasis among the aspirin users across the subgroups. CONCLUSION: Use of low-dose aspirin in the year prior to diagnosis was found to be associated with lower tumour extent and fewer metastatic disease for colorectal and lung cancers. For these cancers, the benefit of aspirin use appears to be during both early and late cancer progression.

Occupational exposure to UV light and mortality from multiple sclerosis.

BACKGROUND: The etiology of multiple sclerosis (MS) is largely unknown; low exposure to ultraviolet (UV) light has been a suggested risk factor. The aim of this study was to investigate whether occupational exposure to UV light reduces the risk of death from MS. METHODS: The cohort was based on all individuals in the Swedish census in 1980. All MS-related deaths were identified in the national registry of causes of death. A job-exposure matrix was developed to classify the occupational exposure to UV light. RESULTS: MS was recorded as a cause of the death for 839 individuals. The risk of MS-related death decreased with increasing occupational exposure to UV light. The relative risk adjusted for age, sex, and socioeconomic status was 0.48 (95% CI 0.28-0.80) in the high-exposure group and 0.88 (95% CI 0.73-1.06) in the intermediate-exposure group. CONCLUSIONS: Occupational exposure to UV light was associated with a reduced risk of MS. Our findings are corroborated by previous observations that UV light has a preventive role in the development of MS, although the possibility of reversed causality cannot be completely ruled out.

Hyperspectral imaging of plasmonic nanostructures with nanoscale resolution.

We report on the first realization of a hyperspectral imaging technique for surface plasmon polaritons on metallic nanostructures. The technique uses a scanning electron beam and allows for simple visualization of light emission from decoupled plasmons, providing information on decay lengths and feature sizes with nanometer resolution.

Generation of traveling surface plasmon waves by free-electron impact.

The injection of a beam of free 50 keV electrons into an unstructured gold surface creates a highly localized source of traveling surface plasmons with spectra centered below the surface plasmon resonance frequency. The plasmons were detected by a controlled decoupling into light with a grating at a distance from the excitation point. The dominant contribution to the plasmon generation appears to come from the recombination of d-band holes created by the electron beam excitation.

Polymorphic nanoparticles as all-optical memory elements.

A nanoparticle undergoing light-induced transformations between structural phases with different optical properties is an inheritably bistable structure and this bistability can be used to create a resonator-free optical memory element, operating at very low power levels. We experimentally demonstrate this memory functionality using a film of gallium nanoparticles, and we present a method for differentially accessing the logic state of the memory using a modulated optical probe beam.

National character does not reflect mean personality trait levels in 49 cultures.

Most people hold beliefs about personality characteristics typical of members of their own and others' cultures. These perceptions of national character may be generalizations from personal experience, stereotypes with a "kernel of truth," or inaccurate stereotypes. We obtained national character ratings of 3989 people from 49 cultures and compared them with the average personality scores of culture members assessed by observer ratings and self-reports. National character ratings were reliable but did not converge with assessed traits. Perceptions of national character thus appear to be unfounded stereotypes that may serve the function of maintaining a national identity.

Thermal radiation from C(N)+ and La@C(N)+.

The radiative cooling of positively charged fullerene and endohedral fullerene fragments of C60, C70, C84, and La@C82 has been measured in a time-of-flight mass spectrometer. The radiative cooling is measured via its influence on the metastable decay. The emissivity extracted from the data is between 4x10(-4) and 13x10(-4). These values agree fairly well with the emissivity calculated from considering the low-energy tail of the surface plasmon. No major difference is found in the emission behavior of empty and endohedral fullerenes.

Assessing the reliability of PBPK models using data from methyl chloride-exposed, non-conjugating human subjects.

Physiologically based pharmacokinetic (PBPK) models are often optimized by adjusting metabolic parameters so as to fit experimental toxicokinetic data. The estimates of the metabolic parameters are then conditional on the assumed values for all other parameters. Meanwhile, the reliability of other parameters, or the structural model, is usually not questioned. Inhalation exposures with human volunteers in our laboratory show that non-conjugators lack metabolic capacity for methyl chloride entirely, and that elimination in these subjects takes place via exhalation only. Therefore, data from these methyl chloride exposures provide an excellent opportunity to assess the general reliability of standard inhalation PBPK models for humans. A hierarchical population PBPK model for methyl chloride was developed. The model was fit to the experimental data in a Bayesian framework using Markov chain Monte Carlo (MCMC) simulation. In a Bayesian analysis, it is possible to merge a priori knowledge of the physiological, anatomical and physicochemical parameters with the information embedded in the experimental toxicokinetic data obtained in vivo. The resulting estimates are both statistically and physiologically plausible. Model deviations suggest that a pulmonary sub-compartment may be needed in order to describe the inhalation and exhalation of volatile adequately. The results also indicate that there may be significant intra-individual variability in the model parameters. To our knowledge, this is the first time that the toxicokinetics of a non-metabolized chemical is used to assess population PBPK parameters. This approach holds promise for more elaborate experiments in order to assess the reliability of PBPK models in general.

A Bayesian analysis of the influence of GSTT1 polymorphism on the cancer risk estimate for dichloromethane.

The carcinogenicity of dichloromethane (DCM) is related to metabolic activation mediated by glutathione transferase theta 1 (GSTT1), whereas oxidation serves as a detoxification pathway. The aim of this study was to calculate the excess cancer risk from DCM, using Bayesian statistics. In a first step, a previously developed population physiologically based pharmacokinetic (PBPK) model for DCM was simultaneously fitted to extensive human toxicokinetic data from 27 male volunteers exposed to 250-1000 ppm DCM (Astrand et al. Scand. J. Work Environ. Health 1, 78-94, 1975; Engström and Bjurström, Scand. J. Work Environ. Health 7, 215-224, 1977) using Markov chain Monte Carlo simulation. Improved population estimates were obtained for the PBPK model parameters. In a second step, excess cancer risk was calculated for lifelong exposure to 1-1000 ppm DCM by Monte Carlo simulation. Data on GSTT1 gene frequencies in the Swedish population were used, including all three genotypes. Estimated mean and median excess risks were in general agreement with those previously derived (El-Masri et al. Toxicol. Appl. Pharmacol. 158, 221-230, 1999). However, we estimate higher excess risks at the upper confidence limits. Furthermore, our simulations suggest that 1% of the Swedish population is not covered by a factor 4.2-7.1 away from the mean target dose. The majority of the fraction of the population not covered was classified as GSTT1 homozygote. This indicates that a higher uncertainty factor than the commonly used 3.16 should be considered in noncancer risk assessment for substances with polymorphic bioactivation.

Association of the telomere-telomere-binding protein complex of hypotrichous ciliates with the nuclear matrix and dissociation during replication.

Telomeric interactions with the nuclear matrix have been described in a variety of eukaryotic cells and seem to be essential for specific nuclear localization. Macronuclear DNA of hypotrichous ciliates occurs in small gene-sized DNA molecules, each being terminated by telomeres. Each macronucleus contains over 10(8 )individual DNA molecules. Owing to the high number of telomeres present in this nucleus it provides an excellent model to study telomere behaviour throughout the cell cycle. In this study we provide experimental evidence that the telomere-telomere-binding protein (TEBP) complex specifically interacts with components of the nuclear matrix in vivo. In the course of replication the specific interaction of the TEBP with components of the nuclear matrix is resolved and an attachment of the telomeres to the matrix no longer occurs.

Both subtelomeric regions are required and sufficient for specific DNA fragmentation during macronuclear development in Stylonychia lemnae.

BACKGROUND: Programmed DNA-reorganization and DNA-elimination events take place frequently during cellular differentiation. An extreme form of such processes, involving DNA reorganization, DNA elimination and DNA fragmentation, is found during macronuclear differentiation in hypotrichous ciliates. Ciliated protozoa can therefore serve as a model system to analyze the molecular basis of these processes during cellular differentiation in eukaryotic cells. RESULTS: Using a biological approach to identify cis-acting sequences involved in DNA fragmentation, we show that in the hypotrichous ciliate Stylonychia lemnae sequences required for specific DNA processing are localized in the 3'- and the 5'-subtelomeric regions of the macronuclear precursor sequence. They can be present at various positions in the two subtelomeric regions, and an interaction between the two regions seems to occur. Sequence comparison revealed a consensus inverted repeat in both subtelomeric regions that is almost identical to the putative Euplotes chromosome breakage sequence (E-Cbs), also identified by sequence comparison. When this sequence was mutagenized, a processed product could no longer be detected, demonstrating that the sequence plays a crucial role in DNA processing. By injecting a construct into the developing macronucleus, which exclusively contains the subtelomeric regions of the Stylonychia alphal-tubulin gene, we show that subtelomeric regions are not only required but are also sufficient for DNA processing in Stylonychia. CONCLUSIONS: Our results indicate that an inverted repeat with the core sequence 5'-TGAA present in both subtelomeric regions acts as a Cbs in Stylonychia. The results allow us to propose a mechanistic model for DNA processing in this ciliate.

Physiologically based pharmacokinetic modeling of inhalation exposure of humans to dichloromethane during moderate to heavy exercise.

Dichloromethane (methylene chloride, DCM) is metabolized via two pathways in humans: mixed-function oxidases (MFO) and glutathione-S:-transferase (GST). Most likely, the carcinogenicity for DCM is related to metabolic activation of DCM via the GST pathway. However, as the two pathways are competing, the metabolic capacity for the MFO pathway in vivo is also of interest in risk assessment for DCM. Past estimates of MFO metabolism are based on the in vitro activity of tissue samples. The aim of the present study was to develop a population model for DCM in order to gain more knowledge on the variability of DCM inhalation toxicokinetics in humans, with main emphasis on the MFO metabolic pathway. This was done by merging published in vitro data on DCM metabolism and partitioning with inhalation toxicokinetic data (Astrand et al., 1975, Scand. J. Work.Environ. Health 1, 78-94) from five human volunteers, using the MCMC technique within a population PBPK model. Our results indicate that the metabolic capacity for the MFO pathway in humans is slightly larger than previously estimated from four human liver samples. Furthermore, the interindividual variability of the MFO pathway in vivo is smaller among our five subjects than indicated by the in vitro samples. We also derive a Bayesian estimate of the population distribution of the MFO metabolism (median maximum metabolic rate 28, 95% confidence interval 12-66 micromol/min) that is a compromise between the information from the in vitro data and the toxicokinetic information present in the experimental data.

Bayesian estimation of variability in adipose tissue blood flow in man by physiologically based pharmacokinetic modeling of inhalation exposure to toluene.

Due to the lipophilicity of many xenobiotics, the perfusion of fat tissue is of special interest in physiologically based pharmacokinetic (PBPK) modeling. In order to estimate inter- and intra-individual variability in fat tissue blood flow with exercise, a population PBPK model for toluene was fitted to experimental data from subjects exposed to toluene vapors (Carlsson, A., 1982. Exposure to toluene: uptake, distribution and elimination in man. Scand. J. Work Environ. Health 8, 43-55). Six male volunteers were exposed to 80 ppm toluene for two hours during rest and moderate to heavy exercise (50-150 W). Extensive data collection was made, including sampling of arterial blood, exhaled breath and subcutaneous fat tissue. The model was simultaneously fitted to the time courses of toluene in arterial blood, exhaled breath, and subcutaneous fat in the six individuals by Markov chain Monte Carlo (MCMC) simulation. In order to describe the experimental observations in subcutaneous fat accurately, the fat compartment was split in two. According to the analysis, the increased perfusion of perirenal fat associated with physical workload was best described if it was set to the same, elevated, level during all exercise levels, rather than scaled directly to the increase in oxygen uptake. No increase in subcutaneous fat perfusion could be detected at these exposure conditions.

Mercury uptake and kinetics after ingestion of dental amalgam.

The aim of the present study was to investigate the G-1 uptake of mercury (Hg) after intake of a single dose of amalgam-Hg, followed by pharmacokinetic analysis of the data. Eleven volunteers without amalgam fillings ingested 1.00 g amalgam powder. Hg in plasma vs. time was analyzed with a two-compartment model by means of mixed-effects modeling. A fraction of the absorption rate of Hg to the central compartment was inversely proportional to the plasma ferritin levels. The population mean half-life of the terminal phase of Hg in plasma was 37 days, with a considerable standard deviation in the population. The absorbed fraction of the administered dose was estimated to be about 0.04%. It is concluded that the G-1 uptake of Hg is of quantitative importance during dental treatment.

Parental divorce: long-term effects on mental health, family relations and adult sexual behavior.

Specific long term effects of parental divorce were examined in a sample of 179 Icelanders, 20 to 30 years of age. The participants answered the Borromean Family Index, the Affect Balance Scale and a number of questions on sexual behavior and attitudes towards marriage and divorce. Results showed that compared to adults whose parents remained married, those of divorced parents reported more negative emotional experiences at the time of the study and had looser family ties. They also had greater number of short love affairs, had their first love affair at a younger age, had a greater number of sexual partners, and were younger at the time of their first sexual intercourse than adults whose parents remained married.

Icelandic norms for the Snodgrass and Vanderwart (1980) pictures: name and image agreement, familiarity, and age of acquisition.

This paper presents Icelandic norms for the widely used pictorial stimuli of Snodgrass and Vanderwart (1980). Norms are presented for name agreement, familiarity, imageability, rated and objective age-of-acquisition (AoA) of vocabulary, and word frequency. The ratings were collected from 103 adult participants while the objective AoA values were collected from 279 children, 2.5-11 years of age. The present norms are in many respects similar to those already collected for other language groups indicating that the stimuli will be useful for further psychological studies in Iceland. The rated AoA values show a high correlation with objective AoA (r = 0.718) thus confirming previous studies conducted with English speaking participants that rated AoA is a relatively valid measure of objective AoA. However, word frequency and familiarity are more closely correlated with rated AoA than with objective AoA indicating that these factors play some role in the ratings. Objective AoA norms are therefore to be preferred in studies of cognitive processes.