Pesticide ecotoxicological effect factors and their uncertainties for freshwater ecosystems

Background, aim, and scope  Characterization factors for ecotoxicity in the Life Cycle Impact Assessment (LCIA) are used to convert emissions into ecotoxicological impacts. Deriving them involves a fate and an effect analysis step. The fate factor quantifies the change in environmental concentration per unit of emission, while the effect factor quantifies the change in impact on the ecosystem per unit of environmental concentration. This paper calculates freshwater ecotoxicological effect factors for 397 pesticides belonging to 11 pesticide-specific toxic modes of action (TMoA), such as acetylcholinesterase inhibition and photosynthesis inhibition. Moreover, uncertainties in the effect factors due to uncertain background concentrations and due to limited toxicity data are quantified. Methods  To calculate median ecotoxicological effect factors (EEFs), toxic pressure assessments were made, based on the species sensitivity distribution—and the multisubstance potentially affected fraction—concept. The EEF quantifies an estimate of the fraction of species that is probably affected due to a marginal change in concentration of a pesticide. EEFs were divided into a TMoA-specific and a chemical-specific part, which were calculated on the basis of physicochemical properties, emissions, and toxicity data. Propagation of parameter uncertainty in the EEFs and the TMoA- and chemical-specific parts was quantified by Monte Carlo simulation and results were reported as 90% confidence intervals. Results  Median EEFs range from 2·10⁻³ to 7·10⁶ l/g. Uncertainty in the TMoA-specific part is dominated by uncertainty in the TMoA-specific spread in species sensitivity and by uncertainty in the effective toxicity of a TMoA. Uncertainty in the chemical-specific part of the EEFs depends on the number of species for which toxicity data are available to calculate average toxicity (n _s) and ranges from a median uncertainty of 2.6 orders of magnitude for n _s = 2 to one order of magnitude for n _s ≥ 4. The TMoA-specific effect factor for systemic fungicides shows the largest uncertainty range. For seven TMoAs, uncertainty ranges of the TMoA-specific effect factor are less than two orders of magnitude. For the other four TMoAs, the EEF uncertainty range is between two and eight orders of magnitude. For the chemical-specific part of the EEFs, we found that variation in uncertainty readily decreases for pesticides for which toxicity data are available for at least three species. Discussion  The same parameters that contributed most to uncertainty were found for pesticides as were found before for high-production-volume chemicals. However, uncertainty in concentrations of pesticides was lower. TMoA-specific factors obtained with the applied nonlinear method differ up to nine orders of magnitude from the factor of 0.5, which is used in the linear method. With the applied method, a distinction in EEFs can be made among different TMoAs. Conclusions   Ecotoxicological effect factors are presented, including overviews of their uncertainty ranges and the main contributors to uncertainty. The applied nonlinear method provides the possibility to quantify parameter uncertainty in the TMoA-specific part of the ecotoxicological effect factor, which is helpful to get more insight in how uncertainty in ecotoxicological characterization factors can be reduced. Recommendations and perspectives  The calculated uncertainty ranges can be included in life cycle assessment (LCA) case studies, which allows for better interpretation of LCA results obtained with the EEFs. To put the uncertainty in effect factors into perspective within LCIA, more information on the uncertainty in fate factors should be derived. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

No difference in between-country variability in use of newly approved orphan and non- orphan medicinal products - a pilot study

Background

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, which rapidly leads to chronic respiratory failure requiring mechanical ventilation. Currently, forced vital capacity (FVC) < 50% is considered as physiologic marker for admitting patients to Noninvasive Positive Pressure Ventilation (NPPV) intervention, although it has been recently shown the median survival of patients with baseline FVC < 75% much shorter than median survival of patients with baseline FVC > 75%, independently by any treatment.

Aim

To assess the role of NPPV in improving outcome of ALS, a retrospective analysis was performed to investigate 1 year survival of ALS patients with FVC < 75% and nocturnal respiratory insufficiency, treated with NPPV, compared to a well-matched population of ALS patients, who refused or was intolerant to NPPV.

Methods

We investigated seventy-two consecutive ALS patients who underwent pulmonary function test. Forty-four presented a FVC > 75% and served as control group. Twenty-eight patients presented a FVC < 75% and showed, at polysomnography analysis, nocturnal respiratory insufficiency, requiring NPPV; sixteen were treated with NPPV, while twelve refused or were intolerant.

Results

Increased survival rate at 1 year in patients with FVC < 75% treated with NPPV, as compared to those who refused or could not tolerate NPPV (p = 0.02), was observed. The median rate of decline in FVC% was slower in NPPV patients than in patients who did not use NPPV (95% CI: 0.72 to 1.85; p < 0.0001).

Conclusion

This report demonstrates that early treatment with NPPV prolongs survival and reduces decline of FVC% in ALS.     

Therapeutic efficacy of alpha-1 antitrypsin augmentation therapy on the loss of lung tissue: an integrated analysis of 2 randomised clinical trials using computed tomography densitometry

Background

Two randomised, double-blind, placebo-controlled trials have investigated the efficacy of IV alpha-1 antitrypsin (AAT) augmentation therapy on emphysema progression using CT densitometry.

Methods

Data from these similar trials, a 2-center Danish-Dutch study (n = 54) and the 3-center EXAcerbations and CT scan as Lung Endpoints (EXACTLE) study (n = 65), were pooled to increase the statistical power. The change in 15^th percentile of lung density (PD15) measured by CT scan was obtained from both trials. All subjects had 1 CT scan at baseline and at least 1 CT scan after treatment. Densitometric data from 119 patients (AAT [Alfalastin^® or Prolastin^®], n = 60; placebo, n = 59) were analysed by a statistical/endpoint analysis method. To adjust for lung volume, volume correction was made by including the change in log-transformed total lung volume as a covariate in the statistical model.

Results

Mean follow-up was approximately 2.5 years. The mean change in lung density from baseline to last CT scan was -4.082 g/L for AAT and -6.379 g/L for placebo with a treatment difference of 2.297 (95% CI, 0.669 to 3.926; p = 0.006). The corresponding annual declines were -1.73 and -2.74 g/L/yr, respectively.

Conclusions

The overall results of the combined analysis of 2 separate trials of comparable design, and the only 2 controlled clinical trials completed to date, has confirmed that IV AAT augmentation therapy significantly reduces the decline in lung density and may therefore reduce the future risk of mortality in patients with AAT deficiency-related emphysema.

Trial registration

The EXACTLE study was registered in ClinicalTrials.gov as ''Antitrypsin (AAT) to Treat Emphysema in AAT-Deficient Patients''; ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT00263887","term_id":"NCT00263887"}}NCT00263887.     

PACSINs bind to the TRPV4 cation channel. PACSIN 3 modulates the subcellular localization of TRPV4

TRPV4 is a cation channel that responds to a variety of stimuli including mechanical forces, temperature, and ligand binding. We set out to identify TRPV4-interacting proteins by performing yeast two-hybrid screens, and we isolated with the avian TRPV4 amino terminus the chicken orthologues of mammalian PACSINs 1 and 3. The PACSINs are a protein family consisting of three members that have been implicated in synaptic vesicular membrane trafficking and regulation of dynamin-mediated endocytotic processes. In biochemical interaction assays we found that all three murine PACSIN isoforms can bind to the amino terminus of rodent TRPV4. No member of the PACSIN protein family was able to biochemically interact with TRPV1 and TRPV2. Co-expression of PACSIN 3, but not PACSINs 1 and 2, shifted the ratio of plasma membrane-associated versus cytosolic TRPV4 toward an apparent increase of plasma membrane-associated TRPV4 protein. A similar shift was also observable when we blocked dynamin-mediated endocytotic processes, suggesting that PACSIN 3 specifically affects the endocytosis of TRPV4, thereby modulating the subcellular localization of the ion channel. Mutational analysis shows that the interaction of the two proteins requires both a TRPV4-specific proline-rich domain upstream of the ankyrin repeats of the channel and the carboxyl-terminal Src homology 3 domain of PACSIN 3. Such a functional interaction could be important in cell types that show distribution of both proteins to the same subcellular regions such as renal tubule cells where the proteins are associated with the luminal plasma membrane.     

Ultrasound Measurements of Visceral and Subcutaneous Abdominal Thickness to Predict Abdominal Adiposity Among Older Men and Women

Accurate measures of visceral and abdominal subcutaneous fat are essential for investigating the pathophysiology of obesity. Classical anthropometric measures such as waist and hip circumference cannot distinguish between these two fat depots. Direct imaging methods such as computed tomography and magnetic resonance imaging (MRI) are restricted in large‐scale studies due to practical and ethical issues. We aimed to establish whether ultrasound is a valid alternative method to MRI for the quantitative assessment of abdominal fat depots in older individuals. The study population comprised 74 white individuals (41 men and 33 women, aged 67–76 years) participating in the Hertfordshire Birth Cohort Physical Activity trial. Anthropometry included height, weight, waist and hip circumferences. Abdominal fat was measured by ultrasound in two compartments: visceral fat defined as the depth from the peritoneum to the lumbar spine; and subcutaneous fat defined as the depth from the skin to the abdominal muscles and compared to reference measures by MRI (10‐mm single‐slice image). Ultrasound measures were positively correlated with MRI measures of visceral and subcutaneous fat (visceral: r = 0.82 and r = 0.80 in men and women, respectively; subcutaneous: r = 0.63 and 0.68 in men and women, respectively). In multiple regression models, the addition of ultrasound measures significantly improved the prediction of visceral fat and subcutaneous fat in both men and women over and above the contribution of standard anthropometric variables. In conclusion, ultrasound is a valid method to estimate visceral fat in epidemiological studies of older men and women when MRI and computed tomography are not feasible.     

Peroxisome reintroduction in Hansenula polymorpha requires Pex25 and Rho1

We identified two proteins, Pex25 and Rho1, which are involved in reintroduction of peroxisomes in peroxisome-deficient yeast cells. These are, together with Pex3, the first proteins identified as essential for this process. Of the three members of the Hansenula polymorpha Pex11 protein family-Pex11, Pex25, and Pex11C-only Pex25 was required for reintroduction of peroxisomes into a peroxisome-deficient mutant strain. In peroxisome-deficient pex3 cells, Pex25 localized to structures adjacent to the ER, whereas in wild-type cells it localized to peroxisomes. Pex25 cells were not themselves peroxisome deficient but instead contained a slightly increased number of peroxisomes. Interestingly, pex11 pex25 double deletion cells, in which both peroxisome fission (due to the deletion of PEX11) and reintroduction (due to deletion of PEX25) was blocked, did display a peroxisome-deficient phenotype. Peroxisomes reappeared in pex11 pex25 cells upon synthesis of Pex25, but not of Pex11. Reintroduction in the presence of Pex25 required the function of the GTPase Rho1. These data therefore provide new and detailed insight into factors important for de novo peroxisome formation in yeast.     

Comparing Leishman and Giemsa staining for the assessment of peripheral blood smear preparations in a malaria-endemic region in India

Background

The first phase of malaria infection occurs in the liver and is clinically silent. Inside hepatocytes each Plasmodium sporozoite replicate into thousands of erythrocyte-infectious merozoites that when released into the blood stream result in clinical symptoms of the disease. The time between sporozoite inoculation and the appearance of parasites in the blood is defined as the pre-patent period, which is classically analysed by time-consuming and labor-intensive techniques, such as microscopy and PCR.

Methods

Luciferase-expressing Plasmodium berghei parasites were used to measure pre-patent period of malaria infection in rodents using a bioluminescence assay that requires only one microliter of blood collected from the tail-vein. The accuracy and sensitivity of this new method was compared with conventional microscopy and PCR based techniques, and its capacity to measure the impact of anti-malarial interventions against the liver evaluated.

Results

The described method is very sensitive allowing the detection of parasites during the first cycles of blood stage replication. It accurately translates differences in liver load due to inoculation of different sporozoite doses as well as a result of treatment with different primaquine regimens.

Conclusions

A novel, simple, fast, and sensitive method to measure pre-patent period of malaria infection in rodents is described here. The sensitivity and accuracy of this new method is comparable to standard PCR and microscopy-based techniques, respectively.     

Same-Day Diagnosis Based on Histology for Women Suspected of Breast Cancer: High Diagnostic Accuracy and Favorable Impact on the Patient

Background

Same-day diagnosis based on histology is increasingly being offered to patients suspected of breast cancer. We evaluated to which extent same-day diagnosis affected diagnostic accuracy and patients'' anxiety levels during the diagnostic phase.

Patients and methods

All 759 women referred for same-day evaluation of suspicious breast lesions between November 2011–March 2013 were included. Diagnostic accuracy was assessed by linking all patients to the national pathology database to identify diagnostic discrepancies, in which case slides were reviewed. Patients'' anxiety was measured in 127 patients by the State Trait and Anxiety Inventory on six moments during the diagnostic workup and changes over time (< = 1 week) were analyzed by mixed effect models.

Results

Core-needle biopsy was indicated in 374/759 patients (49.3%) and in 205/759 (27%) patients, invasive or in situ cancer was found. Final diagnosis on the same day was provided for 606/759 (79.8%) patients. Overall, 3/759 (0.4%) discordant findings were identified. Anxiety levels decreased significantly over time from 45.2 to 30.0 (P = <0.001). Anxiety levels decreased from 44.4 to 25.9 (P = <0.001) for patients with benign disease, and remained unchanged for patients diagnosed with malignancies (48.6 to 46.7, P = 0.933). Time trends in anxiety were not affected by other patient or disease characteristics like age, education level or (family) history of breast cancer.

Conclusion

Same-day histological diagnosis is feasible in the vast majority of patients, without impairing diagnostic accuracy. Patients'' anxiety rapidly decreased in patients with a benign diagnosis and remained constant in patients with malignancy.