Next generation physiologically based kinetic (NG-PBK) models in support of regulatory decision making.

The fields of toxicology and chemical risk assessment seek to reduce, and eventually replace, the use of animals for the prediction of toxicity in humans. In this context, physiologically based kinetic (PBK) modelling based on in vitro and in silico kinetic data has the potential to a play significant role in reducing animal testing, by providing a methodology capable of incorporating in vitro human data to facilitate the development of in vitro to in vivo extrapolation of hazard information. In the present article, we discuss the challenges in: 1) applying PBK modelling to support regulatory decision making under the toxicology and risk-assessment paradigm shift towards animal replacement; 2) constructing PBK models without in vivo animal kinetic data, while relying solely on in vitro or in silico methods for model parameterization; and 3) assessing the validity and credibility of PBK models built largely using non-animal data. The strengths, uncertainties, and limitations of PBK models developed using in vitro or in silico data are discussed in an effort to establish a higher degree of confidence in the application of such models in a regulatory context. The article summarises the outcome of an expert workshop hosted by the European Commission Joint Research Centre (EC-JRC) - European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM), on "Physiologically-Based Kinetic modelling in risk assessment - reaching a whole new level in regulatory decision-making" held in Ispra, Italy, in November 2016, along with results from an international survey conducted in 2017 and recently reported activities occurring within the PBK modelling field. The discussions presented herein highlight the potential applications of next generation (NG)-PBK modelling, based on new data streams.

Blame It on the Metabolite: 3,5-Dichloroaniline Rather than the Parent Compound Is Responsible for the Decreasing Diversity and Function of Soil Microorganisms.

Pesticides are key stressors of soil microorganisms with reciprocal effects on ecosystem functioning. These effects have been mainly attributed to the parent compounds, while the impact of their transformation products (TPs) has been largely overlooked. We assessed in a meadow soil (soil A) the transformation of iprodione and its toxicity in relation to (i) the abundance of functional microbial groups, (ii) the activity of key microbial enzymes, and (iii) the diversity of bacteria, fungi, and ammonia-oxidizing microorganisms (AOM) using amplicon sequencing. 3,5-Dichloroaniline (3,5-DCA), the main iprodione TP, was identified as a key explanatory factor for the persistent reduction in enzymatic activities and potential nitrification (PN) and for the observed structural changes in the bacterial and fungal communities. The abundances of certain bacterial (Actinobacteria, Hyphomicrobiaceae, Ilumatobacter, and Solirubrobacter) and fungal (Pichiaceae) groups were negatively correlated with 3,5-DCA. A subsequent study in a fallow agricultural soil (soil B) showed limited formation of 3,5-DCA, which concurred with the lack of effects on nitrification. Direct 3,5-DCA application in soil B induced a dose-dependent reduction of PN and NO3--N, which recovered with time. In vitro assays with terrestrial AOM verified the greater toxicity of 3,5-DCA over iprodione. "Candidatus Nitrosotalea sinensis" Nd2 was the most sensitive AOM to both compounds. Our findings build on previous evidence on the sensitivity of AOM to pesticides, reinforcing their potential utilization as indicators of the soil microbial toxicity of pesticides in pesticide environmental risk analysis and stressing the need to consider the contribution of TPs in the toxicity of pesticides on the soil microbial community.IMPORTANCE Pesticide toxicity on soil microorganisms is an emerging issue in pesticide risk assessment, dictated by the pivotal role of soil microorganisms in ecosystem services. However, the focus has traditionally been on parent compounds, while transformation products (TPs) are largely overlooked. We tested the hypothesis that TPs can be major contributors to the soil microbial toxicity of pesticides using iprodione and its main TP, 3,5-dichloroaniline, as model compounds. We demonstrated, by measuring functional and structural endpoints, that 3,5-dichloroaniline and not iprodione was associated with adverse effects on soil microorganisms, with nitrification being mostly affected. Pioneering in vitro assays with relevant ammonia-oxidizing bacteria and archaea verified the greater toxicity of 3,5-dichloroaniline. Our findings are expected to advance environmental risk assessment, highlighting the potential of ammonia-oxidizing microorganisms as indicators of the soil microbial toxicity of pesticides and stressing the need to consider the contribution of TPs to pesticide soil microbial toxicity.

The etiopathogenesis of uterine fibromatosis.

Uterine fibroids or uterine leiomyomas are the most common benign tumors of the uterus among women of fertile age, while the etiology is still incompletely elucidated. The occurrence and development of the fibromatosis may be related to certain risk factors and genic mechanisms, although the exact causes are not yet fully known. The development of uterine fibroids is correlated not only with the metabolism and with the level of female sexual hormones, estrogen, and progesterone, but also with the number of these hormone receptors expressed on the surface of the myometrium. Proliferative effects of estrogen and progesterone may be exercised through proinflammatory factors (TNF alpha), growth factors (IGF1, IGF2, TGFbeta3 and betaFGF) or inhibitors of apoptosis (p53 suppression). A number of predisposing factors such as ethnicity - black skin, early menarche, nulliparity, caffeine and alcohol, chronic inflammation, obesity, were also identified. Approximately 40% of the uterine fibroids are caused by the same cytogenetic alterations found in the other tumor types such as kidney, lung, or leiomyosarcoma. As part of a system dysfunction, uterine fibromatosis was connected to other disorders such as AHT (arterial hypertension), endometrium adenocarcinoma, adenomyosis, endometriosis, diabetes mellitus, breast tumors, seemingly with a common causality. The action and effect of some hormonal imbalances over the various organs depend on the histological and local expression particularities of the various receptors, being the cause for many disorders, among which the uterine fibromatosis, coexisting or accompanying the later. This article examines and summarizes the latest data refreshed literature etiopathogenesis offering indicators of uterine fibroids.

Focal adenomyosis (intramural endometriotic cyst) in a very young patient - differential diagnosis with uterine fibromatosis.

Introduction. Adenomyosis is a widespread disease usually affecting the late reproductive years of the women's life, which has a great impact on their fertility. The most common form is diffuse adenomyosis, while focal adenomyosis, a cystic variant, is very rare, particularly in patients younger than 30 years old. Materials and methods. We reported a rare case of a 20-year-old Caucasian woman with cystic adenomyosis who was admitted in our service with severe chronic pelvic pain, dysmenorrhea, and menorrhagia, who had received conservative surgical treatment to preserve fertility and improve her obstetrical prognosis. Results and Discussions. Although the necrobiosis of a uterine fibroid was suspected preoperatively, the extemporaneous histopathological exam revealed adenomyosis associated with fibroleiomyoma with hyaline dystrophy and multiple foci of endometriosis of cystic formation in the wall of a young woman without any risk factors. Conclusion. Although a rare lesion in young patients, cystic adenomyosis should be considered when chronic pelvic pain is exacerbated during menstruation and is associated with a uterine tumor. In young patients, the differential diagnosis should be made with uterine malformations (hematometra), necrobiosis of uterine fibroids, pelvic endometriosis. The surgical treatment should be conservative with the excision of the lesion, always taking into account fertility preservation in young patients.

Modelling the exposure to chemicals for risk assessment: a comprehensive library of multimedia and PBPK models for integration, prediction, uncertainty and sensitivity analysis - the MERLIN-Expo tool.

MERLIN-Expo is a library of models that was developed in the frame of the FP7 EU project 4FUN in order to provide an integrated assessment tool for state-of-the-art exposure assessment for environment, biota and humans, allowing the detection of scientific uncertainties at each step of the exposure process. This paper describes the main features of the MERLIN-Expo tool. The main challenges in exposure modelling that MERLIN-Expo has tackled are: (i) the integration of multimedia (MM) models simulating the fate of chemicals in environmental media, and of physiologically based pharmacokinetic (PBPK) models simulating the fate of chemicals in human body. MERLIN-Expo thus allows the determination of internal effective chemical concentrations; (ii) the incorporation of a set of functionalities for uncertainty/sensitivity analysis, from screening to variance-based approaches. The availability of such tools for uncertainty and sensitivity analysis aimed to facilitate the incorporation of such issues in future decision making; (iii) the integration of human and wildlife biota targets with common fate modelling in the environment. MERLIN-Expo is composed of a library of fate models dedicated to non biological receptor media (surface waters, soils, outdoor air), biological media of concern for humans (several cultivated crops, mammals, milk, fish), as well as wildlife biota (primary producers in rivers, invertebrates, fish) and humans. These models can be linked together to create flexible scenarios relevant for both human and wildlife biota exposure. Standardized documentation for each model and training material were prepared to support an accurate use of the tool by end-users. One of the objectives of the 4FUN project was also to increase the confidence in the applicability of the MERLIN-Expo tool through targeted realistic case studies. In particular, we aimed at demonstrating the feasibility of building complex realistic exposure scenarios and the accuracy of the modelling predictions through a comparison with actual measurements.

Development of a standard documentation protocol for communicating exposure models.

An important step in building a computational model is its documentation; a comprehensive and structured documentation can improve the model applicability and transparency in science/research and for regulatory purposes. This is particularly crucial and challenging for environmental and/or human exposure models that aim to establish quantitative relationships between personal exposure levels and their determinants. Exposure models simulate the transport and fate of a contaminant from the source to the receptor and may involve a large set of entities (e.g. all the media the contaminants may pass though). Such complex models are difficult to be described in a comprehensive, unambiguous and accessible way. Bad communication of assumptions, theory, structure and/or parameterization can lead to lack of confidence by the user and it may be source of errors. The goal of this paper is to propose a standard documentation protocol (SDP) for exposure models, i.e. a generic format and a standard structure by which all exposure models could be documented. For this purpose, a CEN (European Committee for Standardisation) workshop was set up with objective to agree on minimum requirements for the amount and type of information to be provided on exposure models documentation along with guidelines for the structure and presentation of the information. The resulting CEN workshop agreement (CWA) was expected to facilitate a more rigorous formulation of exposure models description and the understanding by users. This paper intends to describe the process followed for defining the SDP, the standardisation approach, as well as the main components of the SDP resulting from a wide consultation of interested stakeholders. The main outcome is a CEN CWA which establishes terms and definitions for exposure models and their elements, specifies minimum requirements for the amount and type of information to be documented, and proposes a structure for communicating the documentation to different users.

IODINE STATUS IN PREGNANT WOMEN AFTER A DECADE OF UNIVERSAL SALT IODIZATION IN ROMANIA.

OBJECTIVE: To assess iodine status (median urinary iodine concentration) in 118 pregnant women during the third trimester from endemic or non-endemic areas, a decade after implementation of Universal Salt Iodization in Romania. SUBJECTS AND METHODS: One hundred and eighteen pregnant women in the third trimester were included in the study group (age range: 16 - 46 years, mean age: 28.78 years). Median urinary iodine concentration (UIC) and body mass index (BMI) were evaluated. Data regarding region of provenance, smoking habits during pregnancy, education level, iodized salt intake, bread intake, iodine supplements, comorbidities (iron deficiency anemia) and birth weight were assessed. Morning urine was collected to measure median UIC. The study was approved by the Local Ethics Committee. RESULTS: Median UIC in the study group was 206 mcg/L, reflecting iodine sufficiency during pregnancy. There is a statistically significant difference between pregnant women with and without iodine supplements from rural areas (281.5 versus 196.1 mcg/L, respectively, p=0.023). In the subgroup without iodine supplementation, there was a significant difference between overweight and obese subjects vs. normal weight subjects (232.5 versus 194 mcg/L, p=0.012). Only in the subgroup with a daily intake of less than 5 slices of bread (usually containing iodized salt) we found significant differences between those with and without iodine supplements (245.2 versus 128.3 mcg/L). Iron deficiency anemia was found in 29.66% and 19.49% were current smokers during pregnancy. CONCLUSIONS: Median UIC in the study group was 206 mcg/L, reflecting iodine sufficiency during pregnancy. The difference between the subgroup with iodine supplements and the subgroup without iodine supplements was not statistically significant, probably due to the excessive consumption of bread and other bakery products which is traditional in Romania.

Total Pelvic Exenteration for Recurrent Endometrial Sarcoma - A Case Report.

Endometrial stromal sarcomas are rare gynecologic malignancies characterized by the presence of cells that resemble those of the endometrial stroma during the prolipferative phase of the menstrual cycle. They are classified as low grade or high grade tumors depending on the mitotic index, the second one being usually associated with poor prognosis and high recurrence rate. We present the case of a 46-year-old patient who was previously submitted to surgery for an endometrial stromal sarcoma followed by adjuvant radiotherapy; 18 months later she was diagnosed with a pelvic recurrence invading the urinary bladder trigone and the rectosigmoid so she was submitted to a total pelvic exenteration.

Total Pelvic Exenteration for Recurrent Endometrial Sarcoma - A Case Report.

Endometrial stromal sarcomas are rare gynecologic malignancies characterized by the presence of cells that resemble those of the endometrial stroma during the prolipferative phase of the menstrual cycle. They are classified as low grade or high grade tumors depending on the mitotic index, the second one being usually associated with poor prognosis and high recurrence rate. We present the case of a 46-year-old patient who was previously submitted to surgery for an endometrial stromal sarcoma followed by adjuvant radiotherapy; 18 months later she was diagnosed with a pelvic recurrence invading the urinary bladder trigone and the rectosigmoid so she was submitted to a total pelvic exenteration.

Case report of fetal lingual tumor - perinatal care and neonatal surgical intervention.

Fetal tumors are rare and can be difficult to diagnose in utero. In this presentation, we report an infantile hemangiopericytoma of the tongue, and also review the clinical characteristics, imaging appearances, perinatal differential diagnosis, and potential treatments of this tumors. Prenatal diagnosis of lingual fetal tumors with two-dimensional (2D) ultrasound presents a challenge to sonographers and perinatologists because these lesions are rare, usually develop in the third trimester of pregnancy and need a multidisciplinary approach. We describe an lingual tumor and moderate polyhydramnios which were prenatally detected at 31 weeks of gestation with two- dimensional ultrasound. The application of the surface mode of three-dimensional ultrasound improved the visualization of this tumor. Fetal Magnetic resonance imaging was performed to help in prenatal differential diagnostic. The option of prenatal cytology gained by amniocentesis should also be considered. To our knowledge there are no prenatal reports of similar cases. However, in our experience every information provided during the pregnancy, a correct and early diagnose of fetal condition helps to cope with the demands of perinatal management and to explain to the parents and neonatologists the findings of the case.

Persistent memory of diffusing particles.

The variance of the advection-diffusion processes with variable coefficients is exactly decomposed as a sum of dispersion terms and memory terms consisting of correlations between velocity and initial positions. For random initial conditions, the memory terms quantify the departure of the preasymptotic variance from the time-linear diffusive behavior. For deterministic initial conditions, the memory terms account for the memory of the initial positions of the diffusing particles. Numerical simulations based on a global random walk algorithm show that the influence of the initial distribution of the cloud of particles is felt over hundreds of dimensionless times. In case of diffusion in random velocity fields with finite correlation range the particles forget the initial positions in the long-time limit and the variance is self-averaging, with clear tendency toward normal diffusion.

[Hemostatic hysterectomy in modern obstetrics]. / Histerectomia de hemostaza in obstetrica moderna.

UNLABELLED: Haemostatic hysterectomies have been performed for the first time in the XIXth century to reduce the increased maternal mortality and associated morbidity. In Romania the main cause of death through direct obstetrical risk (DOR) is the haemorrhagic syndrome, with a value of 45% of the total number of deaths in the last 15 -16 years, a lot higher then the world average of 25% as evaluated by OMS. Among the deaths due to hemorrhagic syndrome 43% is held by antepartum haemorrhage (placenta praevia, utero-placental apoplexy) and 42% by postpartum haemorrhage. RESULTS: In the past 15 years (1990 - 2005) there have been studied 53,870 births, out of which only 60 have had haemostatic hysterectomy, representing 0.11% of the total number of births. The prevalence of haemostatic hysterectomy is only 1 in every 883 births as a result of surgical teams' efforts to preserve the uterus. The placental pathology (30%) is responsible for most of haemostatic hysterectomy indications. Out of 60 cases under study, none ended with maternal death, while 11 cases ended with fetal death (intrapartum or postpartum). CONCLUSIONS: Morbidity and maternal death can be reduced by effective prenatal care, by identifying high risk patients and by the possibility of caesarean section. Haemostatic hysterectomy remains, in essence, a life saving procedure!