Radon and lung cancer in the pooled uranium miners analysis (PUMA): highly exposed early miners and all miners.

OBJECTIVES: Radon is a ubiquitous occupational and environmental lung carcinogen. We aim to quantify the association between radon progeny and lung cancer mortality in the largest and most up-to-date pooled study of uranium miners. METHODS: The pooled uranium miners analysis combines 7 cohorts of male uranium miners with 7754 lung cancer deaths and 4.3 million person-years of follow-up. Vital status and lung cancer deaths were ascertained between 1946 and 2014. The association between cumulative radon exposure in working level months (WLM) and lung cancer was modelled as the excess relative rate (ERR) per 100 WLM using Poisson regression; variation in the association by temporal and exposure factors was examined. We also examined analyses restricted to miners first hired before 1960 and with <100 WLM cumulative exposure. RESULTS: In a model that allows for variation by attained age, time since exposure and annual exposure rate, the ERR/100 WLM was 4.68 (95% CI 2.88 to 6.96) among miners who were less than 55 years of age and were exposed in the prior 5 to <15 years at annual exposure rates of <0.5 WL. This association decreased with older attained age, longer time since exposure and higher annual exposure rate. In analyses restricted to men first hired before 1960, we observed similar patterns of association but a slightly lower estimate of the ERR/100 WLM. CONCLUSIONS: This new large, pooled study confirms and supports a linear exposure-response relationship between cumulative radon exposure and lung cancer mortality which is jointly modified by temporal and exposure factors.

Effects of spatial variation in dose delivery: what can we learn from radon-related lung cancer studies?

Exposure to radon progeny results in heterogeneous dose distributions in many different spatial scales. The aim of this review is to provide an overview on the state of the art in epidemiology, clinical observations, cell biology, dosimetry, and modelling related to radon exposure and its association with lung cancer, along with priorities for future research. Particular attention is paid on the effects of spatial variation in dose delivery within the organs, a factor not considered in radiation protection. It is concluded that a multidisciplinary approach is required to improve risk assessment and mechanistic understanding of carcinogenesis related to radon exposure. To achieve these goals, important steps would be to clarify whether radon can cause other diseases than lung cancer, and to investigate radon-related health risks in children or persons at young ages. Also, a better understanding of the combined effects of radon and smoking is needed, which can be achieved by integrating epidemiological, clinical, pathological, and molecular oncology data to obtain a radon-associated signature. While in vitro models derived from primary human bronchial epithelial cells can help to identify new and corroborate existing biomarkers, they also allow to study the effects of heterogeneous dose distributions including the effects of locally high doses. These novel approaches can provide valuable input and validation data for mathematical models for risk assessment. These models can be applied to quantitatively translate the knowledge obtained from radon exposure to other exposures resulting in heterogeneous dose distributions within an organ to support radiation protection in general.

Lung Cancer and Radon: Pooled Analysis of Uranium Miners Hired in 1960 or Later.

BACKGROUND: Despite reductions in exposure for workers and the general public, radon remains a leading cause of lung cancer. Prior studies of underground miners depended heavily upon information on deaths among miners employed in the early years of mine operations when exposures were high and tended to be poorly estimated. OBJECTIVES: To strengthen the basis for radiation protection, we report on the follow-up of workers employed in the later periods of mine operations for whom we have more accurate exposure information and for whom exposures tended to be accrued at intensities that are more comparable to contemporary settings. METHODS: We conducted a pooled analysis of cohort studies of lung cancer mortality among 57,873 male uranium miners in Canada, Czech Republic, France, Germany, and the United States, who were first employed in 1960 or later (thereby excluding miners employed during the periods of highest exposure and focusing on miners who tend to have higher quality assessments of radon progeny exposures). We derived estimates of excess relative rate per 100 working level months (ERR/100 WLM) for mortality from lung cancer. RESULTS: The analysis included 1.9 million person-years of observation and 1,217 deaths due to lung cancer. The relative rate of lung cancer increased in a linear fashion with cumulative exposure to radon progeny (ERR/100 WLM=1.33; 95% CI: 0.89, 1.88). The association was modified by attained age, age at exposure, and annual exposure rate; for attained ages <55 y, the ERR/100 WLM was 8.38 (95% CI: 3.30, 18.99) among miners who were exposed at ≥35 years of age and at annual exposure rates of <0.5 working levels. This association decreased with older attained ages, younger ages at exposure, and higher exposure rates. DISCUSSION: Estimates of association between radon progeny exposure and lung cancer mortality among relatively contemporary miners are coherent with estimates used to inform current protection guidelines. https://doi.org/10.1289/EHP10669.

Mortality in Underground Miners in a Former Uranium Ore Mine­Results of a Cohort Study Among Former Employees of Wismut AG in Saxony and Thuringia.

BACKGROUND: From 1946 to 1990, more than 400 000 people were employed by Wismut AG, a Soviet/Soviet-German corporation (German abbreviation: SAG/ SDAG), in the East German states of Saxony and Thuringia. In the early years in particular, employees were exposed to large amounts of radon and respirable crystalline silica. METHODS: In a cohort of 35 204 former underground employees of Wismut AG, mortality was analyzed in comparison to the general male population of East Germany, and the pertaining standardized mortality ratios (SMRs) were calculated. RESULTS: 18 510 persons in the study cohort died in the follow-up period 1960-2013. Mortality from lung cancer was 2.36 higher in the study cohort than in the general population (95% confidence interval, [2.28; 2.45]); the associated SMRs rose markedly with increasing radon exposure. Mortality from silicosis and other types of pneumoconiosis was elevated by a factor of 22.62 [21.20; 24.11], and the associated SMRs rose exponentially with increasing exposure to respirable crystalline silica. Mortality from both of these causes was still markedly elevated more than 20 years after Wismut AG had ceased its activities. Mortality from a wide range of other diseases was elevated as well, with the following SMRs: stomach cancer, 1.28 [1.17; 1.40]; liver cancer, 1.34 [1.15; 1.55]; all tumors other than lung cancer, 1.06 [1.02; 1.09]; infections, 1.18 [1.01; 1.38]; cerebrovascular diseases, 1.33 [1.26; 1.41]; and influenza/pneumonia, 1.13 [1.01; 1.27]. Mortality from a small number of other causes was found to be markedly lowered in the study cohort (mental illness, renal diseases, and nervous system diseases). The role of occupational risk factors, lifestyle differences and other reasons for the latter results is unclear. CONCLUSION: Underground miners employed by Wismut AG displayed marked excess mortality due to silicosis/other pneumoconiosis and lung cancer. The contribution of individual occupational risk factors for these and other causes of death with increased SMR are being further investigated in analyses within the study cohort.

PUMA - pooled uranium miners analysis: cohort profile.

OBJECTIVES: Epidemiological studies of underground miners have provided clear evidence that inhalation of radon decay products causes lung cancer. Moreover, these studies have served as a quantitative basis for estimation of radon-associated excess lung cancer risk. However, questions remain regarding the effects of exposure to the low levels of radon decay products typically encountered in contemporary occupational and environmental settings on the risk of lung cancer and other diseases, and on the modifiers of these associations. These issues are of central importance for estimation of risks associated with residential and occupational radon exposures. METHODS: The Pooled Uranium Miner Analysis (PUMA) assembles information on cohorts of uranium miners in North America and Europe. Data available include individual annual estimates of exposure to radon decay products, demographic and employment history information on each worker and information on vital status, date of death and cause of death. Some, but not all, cohorts also have individual information on cigarette smoking, external gamma radiation exposure and non-radiological occupational exposures. RESULTS: The PUMA study represents the largest study of uranium miners conducted to date, encompassing 124 507 miners, 4.51 million person-years at risk and 54 462 deaths, including 7825 deaths due to lung cancer. Planned research topics include analyses of associations between radon exposure and mortality due to lung cancer, cancers other than lung, non-malignant disease, modifiers of these associations and characterisation of overall relative mortality excesses and lifetime risks. CONCLUSION: PUMA provides opportunities to evaluate new research questions and to conduct analyses to assess potential health risks associated with uranium mining that have greater statistical power than can be achieved with any single cohort.

Analysis of mortality in a pooled cohort of Canadian and German uranium processing workers with no mining experience.

PURPOSE: Long-term health risks of occupational exposures to uranium processing were examined to better understand potential differences with uranium underground miners and nuclear reactor workers. METHODS: A cohort study of mortality of workers from Port Hope, Canada (1950-1999) and Wismut, Germany (1946-2008) employed in uranium milling, refining, and processing was conducted. Poisson regression was used to evaluate the association between cumulative exposures to radon decay products (RDP) and gamma-rays and causes of death potentially related to uranium processing. RESULTS: The pooled cohort included 7431 workers (270,201 person-years of follow-up). Mean RDP exposures were lower than in miners while gamma-ray doses were higher than in reactor workers. Both exposures were highly correlated (weighted rho = 0.81). Radiation risks of lung cancer and cardiovascular diseases (CVD) in males were increased but not statistically significant and compatible with risks estimated for miners and reactor workers, respectively. Higher RDP-associated CVD risks were observed for exposures 5-14 years prior to diagnosis compared to later exposures and among those employed <5 years. Radiation risks of solid cancers excluding lung cancer were increased, but not statistically significant, both for males and females, while all other causes of death were not associated with exposures. CONCLUSIONS: In the largest study of uranium processing workers to systematically examine radiation risks of multiple outcomes from RDP exposures and gamma-rays, estimated radiation risks were compatible with risks reported for uranium miners and nuclear reactor workers. Continued follow-up and pooling with other cohorts of uranium processing workers are necessary for future comparisons with other workers of the nuclear fuel cycle.

Leukaemia mortality and low-dose ionising radiation in the WISMUT uranium miner cohort (1946-2013).

OBJECTIVES: To examine the risk of death from leukaemia in relation to occupational chronic low-level external and internal radiation exposure in a cohort of 58 972 former German uranium miners with mortality follow-up from 1946 to 2013. METHODS: The red bone marrow (RBM) dose from low-linear energy transfer (LET) (mainly external γ-radiation) and high-LET (mainly radon gas) radiation was estimated based on a job-exposure matrix and biokinetic/dosimetric models. Linear excess relative risks (ERR) and 95% CIs were estimated via Poisson regression for chronic lymphatic leukaemia (CLL) and non-CLL. RESULTS: The mean cumulative low-LET and high-LET RBM doses among the 86% radiation-exposed workers were 48 and 9 mGy, respectively. There was a positive non-significant dose-response for mortality from non-CLL (n=120) in relation to low-LET (ERR/Gy=2.18; 95% CI -0.41 to 6.37) and high-LET radiation (ERR/Gy=16.65; 95% -1.13 to 46.75). A statistically significant excess was found for the subgroup chronic myeloid leukaemia (n=31) in relation to low-LET radiation (ERR/Gy=7.20; 95% CI 0.48 to 24.54) and the subgroup myeloid leukaemia (n=99) (ERR/Gy=26.02; 95% CI 2.55 to 68.99) for high-LET radiation. The ERR/Gy tended to be about five to ten times higher for high-LET versus low-LET radiation; however, the CIs largely overlapped. Results indicate no association of death from CLL (n=70) with either type of radiation. CONCLUSIONS: Our findings indicate an increased risk of death for specific subtypes from non-CLL in relation to chronic low-LET and high-LET radiation, but no such relation for CLL.

On the potential of models for location and scale for genome-wide DNA methylation data.

BACKGROUND: With the help of epigenome-wide association studies (EWAS), increasing knowledge on the role of epigenetic mechanisms such as DNA methylation in disease processes is obtained. In addition, EWAS aid the understanding of behavioral and environmental effects on DNA methylation. In terms of statistical analysis, specific challenges arise from the characteristics of methylation data. First, methylation ß-values represent proportions with skewed and heteroscedastic distributions. Thus, traditional modeling strategies assuming a normally distributed response might not be appropriate. Second, recent evidence suggests that not only mean differences but also variability in site-specific DNA methylation associates with diseases, including cancer. The purpose of this study was to compare different modeling strategies for methylation data in terms of model performance and performance of downstream hypothesis tests. Specifically, we used the generalized additive models for location, scale and shape (GAMLSS) framework to compare beta regression with Gaussian regression on raw, binary logit and arcsine square root transformed methylation data, with and without modeling a covariate effect on the scale parameter. RESULTS: Using simulated and real data from a large population-based study and an independent sample of cancer patients and healthy controls, we show that beta regression does not outperform competing strategies in terms of model performance. In addition, Gaussian models for location and scale showed an improved performance as compared to models for location only. The best performance was observed for the Gaussian model on binary logit transformed ß-values, referred to as M-values. Our results further suggest that models for location and scale are specifically sensitive towards violations of the distribution assumption and towards outliers in the methylation data. Therefore, a resampling procedure is proposed as a mode of inference and shown to diminish type I error rate in practically relevant settings. We apply the proposed method in an EWAS of BMI and age and reveal strong associations of age with methylation variability that are validated in an independent sample. CONCLUSIONS: Models for location and scale are promising tools for EWAS that may help to understand the influence of environmental factors and disease-related phenotypes on methylation variability and its role during disease development.

Differences in BMI z-scores between offspring of smoking and nonsmoking mothers: a longitudinal study of German children from birth through 14 years of age.

BACKGROUND: Children of mothers who smoked during pregnancy have a lower birth weight but have a higher chance to become overweight during childhood. OBJECTIVES: We followed children longitudinally to assess the age when higher body mass index (BMI) z-scores became evident in the children of mothers who smoked during pregnancy, and to evaluate the trajectory of changes until adolescence. METHODS: We pooled data from two German cohort studies that included repeated anthropometric measurements until 14 years of age and information on smoking during pregnancy and other risk factors for overweight. We used longitudinal quantile regression to estimate age- and sex-specific associations between maternal smoking and the 10th, 25th, 50th, 75th, and 90th quantiles of the BMI z-score distribution in study participants from birth through 14 years of age, adjusted for potential confounders. We used additive mixed models to estimate associations with mean BMI z-scores. RESULTS: Mean and median (50th quantile) BMI z-scores at birth were smaller in the children of mothers who smoked during pregnancy compared with children of nonsmoking mothers, but BMI z-scores were significantly associated with maternal smoking beginning at the age of 4-5 years, and differences increased over time. For example, the difference in the median BMI z-score between the daughters of smokers versus nonsmokers was 0.12 (95% CI: 0.01, 0.21) at 5 years, and 0.30 (95% CI: 0.08, 0.39) at 14 years of age. For lower BMI z-score quantiles, the association with smoking was more pronounced in girls, whereas in boys the association was more pronounced for higher BMI z-score quantiles. CONCLUSIONS: A clear difference in BMI z-score (mean and median) between children of smoking and nonsmoking mothers emerged at 4-5 years of age. The shape and size of age-specific effect estimates for maternal smoking during pregnancy varied by age and sex across the BMI z-score distribution.

Understanding child stunting in India: a comprehensive analysis of socio-economic, nutritional and environmental determinants using additive quantile regression.

BACKGROUND: Most attempts to address undernutrition, responsible for one third of global child deaths, have fallen behind expectations. This suggests that the assumptions underlying current modelling and intervention practices should be revisited. OBJECTIVE: We undertook a comprehensive analysis of the determinants of child stunting in India, and explored whether the established focus on linear effects of single risks is appropriate. DESIGN: Using cross-sectional data for children aged 0-24 months from the Indian National Family Health Survey for 2005/2006, we populated an evidence-based diagram of immediate, intermediate and underlying determinants of stunting. We modelled linear, non-linear, spatial and age-varying effects of these determinants using additive quantile regression for four quantiles of the Z-score of standardized height-for-age and logistic regression for stunting and severe stunting. RESULTS: At least one variable within each of eleven groups of determinants was significantly associated with height-for-age in the 35% Z-score quantile regression. The non-modifiable risk factors child age and sex, and the protective factors household wealth, maternal education and BMI showed the largest effects. Being a twin or multiple birth was associated with dramatically decreased height-for-age. Maternal age, maternal BMI, birth order and number of antenatal visits influenced child stunting in non-linear ways. Findings across the four quantile and two logistic regression models were largely comparable. CONCLUSIONS: Our analysis confirms the multifactorial nature of child stunting. It emphasizes the need to pursue a systems-based approach and to consider non-linear effects, and suggests that differential effects across the height-for-age distribution do not play a major role.

Boosting structured additive quantile regression for longitudinal childhood obesity data.

Childhood obesity and the investigation of its risk factors has become an important public health issue. Our work is based on and motivated by a German longitudinal study including 2,226 children with up to ten measurements on their body mass index (BMI) and risk factors from birth to the age of 10 years. We introduce boosting of structured additive quantile regression as a novel distribution-free approach for longitudinal quantile regression. The quantile-specific predictors of our model include conventional linear population effects, smooth nonlinear functional effects, varying-coefficient terms, and individual-specific effects, such as intercepts and slopes. Estimation is based on boosting, a computer intensive inference method for highly complex models. We propose a component-wise functional gradient descent boosting algorithm that allows for penalized estimation of the large variety of different effects, particularly leading to individual-specific effects shrunken toward zero. This concept allows us to flexibly estimate the nonlinear age curves of upper quantiles of the BMI distribution, both on population and on individual-specific level, adjusted for further risk factors and to detect age-varying effects of categorical risk factors. Our model approach can be regarded as the quantile regression analog of Gaussian additive mixed models (or structured additive mean regression models), and we compare both model classes with respect to our obesity data.

Interactions of genetic and environmental risk factors with respect to body fat mass in children: results from the ALSPAC study.

OBJECTIVE: To evaluate if percentile-specific effects of genetic, environmental and lifestyle obesity risk factors on body mass index (BMI) might reflect gene-environment interactions with respect to the development of overweight. DESIGN AND METHODS: Retrospective study with data of 2,346 children from the Avon Longitudinal Study of Parents and Children (ALSPAC), using quantile regression with body fat mass index (FMI) for children at the age of 9 years as outcome variable. We assessed interactions of an "obesity-risk-allele-score" with environmental and nutritional factors. RESULTS: There was no evidence of interactions between the obesity-risk-allele score and the environmental variables except for maternal overweight. However, we found a significant interaction with respect to intake of mono- and polyunsaturated fatty acids at the age of 7. In children with low intake, genetic risk was associated with increasing effect sizes by FMI percentile. CONCLUSIONS: Our results suggest an interaction between a low dietary content of unsaturated fatty acids and genetic risk factors for overweight on FMI. This effect is likely to be stronger in children with higher FMI.

Boosted beta regression.

Regression analysis with a bounded outcome is a common problem in applied statistics. Typical examples include regression models for percentage outcomes and the analysis of ratings that are measured on a bounded scale. In this paper, we consider beta regression, which is a generalization of logit models to situations where the response is continuous on the interval (0,1). Consequently, beta regression is a convenient tool for analyzing percentage responses. The classical approach to fit a beta regression model is to use maximum likelihood estimation with subsequent AIC-based variable selection. As an alternative to this established - yet unstable - approach, we propose a new estimation technique called boosted beta regression. With boosted beta regression estimation and variable selection can be carried out simultaneously in a highly efficient way. Additionally, both the mean and the variance of a percentage response can be modeled using flexible nonlinear covariate effects. As a consequence, the new method accounts for common problems such as overdispersion and non-binomial variance structures.

Prediction intervals for future BMI values of individual children: a non-parametric approach by quantile boosting.

BACKGROUND: The construction of prediction intervals (PIs) for future body mass index (BMI) values of individual children based on a recent German birth cohort study with n = 2007 children is problematic for standard parametric approaches, as the BMI distribution in childhood is typically skewed depending on age. METHODS: We avoid distributional assumptions by directly modelling the borders of PIs by additive quantile regression, estimated by boosting. We point out the concept of conditional coverage to prove the accuracy of PIs. As conditional coverage can hardly be evaluated in practical applications, we conduct a simulation study before fitting child- and covariate-specific PIs for future BMI values and BMI patterns for the present data. RESULTS: The results of our simulation study suggest that PIs fitted by quantile boosting cover future observations with the predefined coverage probability and outperform the benchmark approach. For the prediction of future BMI values, quantile boosting automatically selects informative covariates and adapts to the age-specific skewness of the BMI distribution. The lengths of the estimated PIs are child-specific and increase, as expected, with the age of the child. CONCLUSIONS: Quantile boosting is a promising approach to construct PIs with correct conditional coverage in a non-parametric way. It is in particular suitable for the prediction of BMI patterns depending on covariates, since it provides an interpretable predictor structure, inherent variable selection properties and can even account for longitudinal data structures.

Period-specific growth, overweight and modification by breastfeeding in the GINI and LISA birth cohorts up to age 6 years.

Children's weight/growth development is age-specific and may be influenced by breastfeeding. We therefore assessed velocities of weight, length, body-mass-index and overweight/obesity development from birth up to age 6 years overall and in relation to breastfeeding. The method of this study is based on pooled data of the birth-cohorts GINI-plus and LISA-plus and follows 7,643 healthy full-term neonates in four study-centers in Germany. Up to nine anthropometric measurements are available. Overweight/obesity is percentile-defined according to WHO-Child-Growth-Standards. Fully-breastfed is defined as breastfed for at least 4 months. Piecewise-linear-random-coefficient-models were applied to assess growth trajectories and velocities between 0-3, 3-6, 6-12, 12-24 and beyond 24th months. Velocities for weight-, length- and BMI-development are highest in the first 3 months after birth and diminish, with differing pace, in the periods that follow. For overweight and obesity, peak-velocities are estimated in periods 6-12 and 3-6 months. The difference in the velocity of weight gain for breastfed vs. other children is -18 g/month in the first 3 month, -93 g/month between month 3 and 6, -14 g/month between month 6 and 12 and -3 g/month beyond the 24th month. Velocities in length are not different between breastfed and non-breastfed children. Over time, a slightly lower risk (difference < 2%) of being overweight was estimated for breastfed children, after adjustment for study-center, socio-economic-status and maternal smoking in pregnancy. Infants fully-breastfed gain less weight, but grow equally in length in the first 12 months of life versus mixed or formula-fed children. The protective effect of breastfeeding on becoming overweight is related to its weight-velocity-modifying-effect in early infancy.

Etiologic classification of seizures, signalment, clinical signs, and outcome in cats with seizure disorders: 91 cases (2000-2004).

OBJECTIVE: To evaluate associations among etiologic classifications of seizures and signalment, clinical signs, and outcome in cats with various seizure disorders. STUDY DESIGN: Retrospective case series. ANIMALS: 91 cats evaluated for seizure disorders at a veterinary teaching hospital from 2000 through 2004. PROCEDURES: Data regarding characteristics of the cats and their seizures were obtained from medical records. Seizures were classified as reactive, symptomatic, or idiopathic. Survival times were displayed as Kaplan-Meier curves, and differences between etiologic classifications were assessed by log-rank test. RESULTS: Over the 5-year period, the incidence of seizures among all cats evaluated at the hospital was 2.1%. Etiology was classified as reactive in 20 (22%) cats, symptomatic in 45 (50%), idiopathic or presumptive idiopathic in 23 (25%), and cardiac syncope in 3 (3%). Focal seizures with or without secondary generalization were recorded for 47 (52%) cats, and primary generalized seizures with or without status epilepticus were recorded for 44 (48%). Etiology was not associated with seizure type. However, mean age of cats with idiopathic seizures (3.5 years) was significantly lower than that of cats with reactive seizures (8.2 years) or symptomatic seizures (8.1 years). The 1-year survival rate for cats with idiopathic seizures (0.82) was longer than that for cats with reactive (0.50) or symptomatic (0.16) seizures. CONCLUSIONS AND CLINICAL RELEVANCE: Seizure etiology was symptomatic or reactive in most cats. Underlying disease was not associated with seizure type. Cats with idiopathic seizures lived longer than did cats with reactive or symptomatic seizures but were also younger.

Plasma interleukin-6 response is predictive for severity and mortality in canine systemic inflammatory response syndrome and sepsis.

BACKGROUND: Sepsis is still a major cause of death in both human and veterinary medicine. Early diagnosis is essential for appropriate treatment. Identification of patients at risk for developing sepsis is already possible in human medicine through the measurement of plasma interleukin-6 (IL-6) levels. In veterinary medicine, however, this has been investigated only in canine experimental models. OBJECTIVES: The purpose of this study was to measure IL-6 plasma levels in dogs with naturally occurring systemic inflammatory response syndrome (SIRS) and sepsis and to analyze the value of IL-6 as a predictive parameter for severity and mortality. METHODS: Included in the study were 79 dogs that had been admitted to the small animal clinics of Munich and Berlin from July 2004 to July 2005 and that satisfied the diagnostic criteria for SIRS and sepsis as defined using established parameters. Measurement of plasma IL-6 levels on days 0, 1, and 2 was performed by the use of a colorimetric bioassay based on IL-6-dependent cell growth. RESULTS: Septic foci were identified in 43 patients (septic group), and 36 patients were enrolled in the SIRS group. The frequency of positive blood cultures was 11%. The overall mortality rate was 48%. Higher plasma IL-6 levels on the day of admission were significantly correlated with a more severe degree of disease, increased mortality rate, and earlier fatality. CONCLUSIONS: Plasma IL-6 concentration is predictive of outcome in canine SIRS and sepsis and may be a valuable laboratory parameter for assessing critically ill dogs.

Combined otolith morphology and morphometry for assessing taxonomy and diversity in fossil and extant killifish (Aphanius, Prolebias).

Systematic assignment of fossil otoliths is virtually always based on studies of otolith morphology and subsequent comparisons with otoliths from collections and/or literature. Although this usually represents a practical method, comparisons and subsequent evaluation may be biased by subjective criteria used in the individual descriptions. Quantitative morphometric studies focusing on variations in the otolith morphology of extant fishes have been conducted in fisheries research, mostly based on Fourier shape analysis and related methods. However, with regard to fossil otoliths, these approaches are generally not suitable, mainly due to preservation-related problems. Here we present a new approach for quantifying otolith variation between species and populations of killifish (cyprinodontiforms) in the genera Aphanius Nardo and daggerProlebias Sauvage that can be used with both extant and fossil otoliths. Our new approach includes the definition of 10 variables from linear and angle measurements of an otolith and statistical analyses. Best results were obtained by presorting the otoliths into three groups based on sulcus shape (straight, bent, S-shaped). In this case, canonical discriminant analysis (CDA) with jackknifed cross-validation yielded an overall species classification success of 86-96%. The three groups based on sulcus shape separate according to zoogeographic patterns (i.e., Mediterranean Aphanius, Arabian Aphanius, European daggerProlebias) and probably reflect phylogenetic lineages. Application of CDA to compare otolith variation between populations resulted in an overall classification success (jackknifed) of 33-83%. High levels of variation were observed for Aphanius dispar and daggerProlebias malzi, but not for A. fasciatus and daggerP. weileri. We suggest that otolith variation between populations results predominantly from geographic separation. Combination of qualitative characters (sulcus morphology) with quantitative approaches (otolith morphometry) presents a new approach for obtaining a better understanding of the taxonomy, diversity, and zoogeography of both fossil and extant killifishes. Moreover, the method may also be suitable for assessing taxonomy and diversity in other species-rich groups like the atheriniforms and many perciforms because these groups display otolith Bauplans that are similar to those seen in killifishes.

Adjuvant immunotherapy of feline fibrosarcoma with recombinant feline interferon-omega.

BACKGROUND: Recombinant feline interferon-omega (rFeIFN-omega) was tested as a treatment option for cats with fibrosarcoma to assess safety and feasibility. HYPOTHESIS: Treatment with rFeIFN-omega in cats with fibrosarcoma is safe and feasible. ANIMALS: Twenty domestic cats. METHODS: In an open-labeled uncontrolled clinical trial 12 injections of 1 x 10(6) U/kg rFeIFN-omega were administered over a 5-week period: the 1st through 4th injections were given intratumorally, and the 5th through 12th injections were administered subcutaneously at the tumor excision site. Wide surgical excision of the tumors was carried out after the 4th injection and before the 5th injection of rFeIFN-omega. A Common Terminology Criteria for Adverse Events (CTCAE) analysis was conducted. Flow cytometry of fibrosarcoma cells after incubation with rFeIFN-omega and recombinant feline interferon-gamma was performed to assess the biological effect of rFeIFN-omega. RESULTS: Changes in blood cell count, increases in serum aspartate-amino-transferase activity, serum bilirubin concentration, serum creatinine and serum electrolyte concentrations, weight loss, anorexia, increased body temperature, and reduced general condition were observed but were mostly minor (grade 1 and 2) and self limiting. Eosinophilia (P = .025), neutropenia (P = .021), and weight loss (P < .001) were statistically correlated with rFeIFN-omega-treatment (analysis of parameters before treatment and after 3 injections of rFeIFN-omega). Flow cytometry of 5 unrelated feline fibrosarcoma cell lines showed increased expression of major histocompatibility complex (MHC) class I molecules (P = .026) in response to in vitro incubation with rFeIFN-omega, whereas expression of MHC class II molecules was not affected significantly. CONCLUSIONS AND CLINICAL IMPORTANCE: RFeIFN-omega for the treatment of feline fibrosarcoma is safe, well tolerated, and can be easily performed in practice. To assess the efficacy of the treatment, it should be tested in a placebo-controlled trial.