Biological Analysis of Endocrine-Disrupting Compounds in Tunisian Sewage Treatment Plants

Endocrin-disrupting compounds (EDCs) are frequently found in wastewater treatment plants (WWTPs). So far, research has been mainly focused on the detection of estrogenic compounds and very little work has been carried out on other receptors activators. In this study, we used reporter cell lines, which allow detecting the activity of estrogen (ERα), androgen (AR), pregnane X (PXR), glucocorticoid (GR), progesterone (PR), mineralocorticoid (MR), and aryl hydrocarbon (AhR) receptors, to characterise the endocrine-disrupting profile of the aqueous, suspended particulate matter, and sludge fractions from three Tunisian WWTPs. The aqueous fraction exhibited estrogenic and androgenic activities. Suspended particulate matter and sludge extracts showed estrogenic, aryl hydrocarbon and pregnane X receptor activities. No GR, MR, or PR (ant) agonistic activity was detected in the samples, suggesting that environmental compounds present in sewage might have a limited spectrum of activity. By performing competition experiments with recombinant ERα, we demonstrated that the estrogenic activity detected in the aqueous fraction was due to EDCs with a strong affinity for ERα. Conversely, in the sludge fraction, it was linked to the presence of EDCs with weak affinity. Moreover, by using different incubation times, we determined that the EDCs present in suspended particulate matter and sludge, which can activate AhR, are metabolically labile compounds. Finally, we showed in this study that environmental compounds are mainly ER, AR, PXR, and AhR activators. Concerning AR and PXR ligands, we do not to know the nature of the molecules. Concerning ER and AhR compounds, competition experiments with recombinant receptor and analysis at different times of exposure of the AhR activation gave some indications of the compound’s nature that need to be confirmed by chemical analysis.     

An inducible mouse model for skin cancer reveals distinct roles for gain- and loss-of-function p53 mutations

Mutations in ras and p53 are the most prevalent mutations found in human nonmelanoma skin cancers. Although some p53 mutations cause a loss of function, most result in expression of altered forms of p53, which may exhibit gain-of-function properties. Therefore, understanding the consequences of acquiring p53 gain-of-function versus loss-of-function mutations is critical for the generation of effective therapies for tumors harboring p53 mutations. Here we describe an inducible mouse model in which skin tumor formation is initiated by activation of an endogenous K-ras^G12D allele. Using this model we compared the consequences of activating the p53 gain-of-function mutation p53^R172H and of deleting the p53 gene. Activation of the p53^R172H allele resulted in increased skin tumor formation, accelerated tumor progression, and induction of metastasis compared with deletion of p53. Consistent with these observations, the p53^R172H tumors exhibited aneuploidy associated with centrosome amplification, which may underlie the mechanism by which p53^R172H exerts its oncogenic properties. These results clearly demonstrate that p53 gain-of-function mutations confer poorer prognosis than loss of p53 during skin carcinogenesis and have important implications for the future design of therapies for tumors that exhibit p53 gain-of-function mutations.     

Tissue factor: a link between C5a and neutrophil activation in antiphospholipid antibody induced fetal injury

Fetal loss in patients with antiphospholipid (aPL) antibodies has been ascribed to thrombosis of placental vessels. However, we have shown that inflammation, specifically activation of complement with generation of the anaphylotoxin C5a, is an essential trigger of fetal injury. In this study, we analyzed the role of the procoagulant molecule tissue factor (TF) in a mouse model of aPL antibody-induced pregnancy loss. We found that either blockade of TF with a monoclonal antibody in wild-type mice or a genetic reduction of TF prevented aPL antibody-induced inflammation and pregnancy loss. In response to aPL antibody-generated C5a, neutrophils express TF potentiating inflammation in the deciduas and leading to miscarriages. Importantly, we showed that TF in myeloid cells but not fetal-derived cells (trophoblasts) was associated with fetal injury, suggesting that the site for pathologic TF expression is neutrophils. We found that TF expression in neutrophils contributes to respiratory burst and subsequent trophoblast injury and pregnancy loss induced by aPL antibodies. The identification of TF as an important mediator of C5a-induced oxidative burst in neutrophils in aPL-induced fetal injury provides a new target for therapy to prevent pregnancy loss in the antiphospholipid syndrome.     

p38 Mitogen-Activated Protein Kinase Regulates Myelination

Most neurodegenerative disorders are characterised by deposits of aggregated proteins that are readily visualised by light microscopy. Although the presence of such a bulky structure inside the cell or in the extracellular space is likely not to be healthy, over recent years the idea has emerged that these end-stage aggregates are a relatively safe way to deposit harmful aberrant proteins. Protein quality control is a multi-level security system to safeguard cells from aberrant proteins and is therefore a protective response. However, protein quality control may turn destructive in case of impairment of protein quality control for example by aging or because of overflow of the quality control systems due to prolonged exposure. In many cases the medicine is worse than the cause and the “protective” response of the cell to aggregates kills the cell, rather than the aggregate itself. Here we review the role of protein quality control in neurodegeneration and aim to distinguish protective and destructive responses to aggregates in order to find targets for therapeutic intervention.     

Diabetes prevalence and treatment adherence in residents living in a colonia located on the West Texas, USA/Mexico border

Abstract   Little is known about how diabetes affects the health status of Hispanic people living in colonias located along the USA/Mexico border. The purpose of this report is to describe the demographic factors, prevalence of diabetes, and the health status of the residents living in a colonia on the border between El Paso, Texas, USA, and Juarez, Mexico, and to report the residents' adherence to the Behavioral Risk Factor Surveillance System (BRFSS) protocols for the management of type 2 diabetes. This study included 188 participants. The instruments used included a demographic questionnaire, the Short Acculturation Scale for Hispanics, "Cutting Down, Annoyance by Criticism, Guilty Feelings, and Eye-openers", BRFSS, and the Short Form-36 (v2). The prevalence of diabetes was 15.4% and 41.3% of the residents had a Body Mass Index score > 30. The rate of hypertension, elevated cholesterol, and depression for those reporting diabetes was significant. The SF-36 v2 physical score for the diabetic residents was 42.9 and it was 52.4 for the non-diabetic residents. The average resident of the colonia who reports diabetes has many health disadvantages when compared to those in other parts of Texas and the USA generally.     

Preparation and evaluation of 99mTc-EDDA/HYNIC-[Lys 3]-bombesin for imaging gastrin-releasing peptide receptor-positive tumours

BACKGROUND: Bombesin is a peptide that was initially isolated from frog skin and which belongs to a large group of neuropeptides with many biological functions. The human equivalent is gastrin-releasing peptide (GRP), whose receptors are over-expressed in a variety of malignant tumours. AIM: To prepare a HYNIC-[Lys 3]-bombesin analogue that could be easily labelled with 99mTc from lyophilized kit formulations and to evaluate its potential as an imaging agent for GRP receptor-positive tumours. METHODS: HYNIC was conjugated to the epsilon-amino group of Lys 3 residue at the N-terminal region of bombesin via succinimidyl-N-Boc-HYNIC at pH 9.0. 99mTc labelling was performed by addition of sodium pertechnetate solution and 0.2 M phosphate buffer pH 7.0 to a lyophilized formulation. Stability studies were carried out by reversed phase HPLC and ITLC-SG analyses in serum and cysteine solutions. In-vitro internalization was tested using human prostate cancer PC-3 cells with blocked and non-blocked receptors. Biodistribution and tumour uptake were determined in PC-3 tumour-bearing nude mice. RESULTS: 99mTc-EDDA/HYNIC-[Lys 3]-bombesin was obtained with radiochemical purities >93% and high specific activity ( approximately 0.1 GBq.nmol). Results of in-vitro studies demonstrated a high stability in serum and cysteine solutions, specific cell receptor binding and rapid internalization. Biodistribution data showed a rapid blood clearance, with predominantly renal excretion and specific binding towards GRP receptor-positive tissues such as pancreas and PC-3 tumours. CONCLUSION: 99mTc-EDDA/HYNIC-[Lys 3]-bombesin obtained from lyophilized kit formulations has promising characteristics for the diagnosis of malignant tumours that over-express the GRP receptor.     

Increased influenza severity in children in the wake of SARS-CoV-2

The SARS-CoV-2 pandemic and subsequent interruption of influenza circulation has lowered population immunity to influenza, especially among children with few prepandemic exposures. Using data from a prospective pediatric cohort study based in Managua, Nicaragua, we compared the incidence and severity of influenza A/H3N2 and influenza B/Victoria between 2022 and two prepandemic seasons. We found a higher incidence of A/H3N2 in older children in 2022 compared with pre-2020 and a higher proportion of severe influenza in 2022, primarily among children aged 0–4, suggesting an influence of the SARS-CoV-2 pandemic on influenza incidence and severity in children.     

¿Es útil el SPPB como método de screening de capacidad funcional en pacientes con enfermedad renal crónica avanzada?

Introduction and objectiveOne of the consequences of the CKD, is the deterioration of the functional capacity, being able to manifest from different stages of the disease, until renal replacement therapy.The objective of this study was to determine the functionality of patients with CKD through functional capacity test, valuing the usefulness of the SPPB as a screening test in parallel.Materials and methodsIt assessed the functional capacity of patients with CKD, using the test SPPB, 6MM, TUTG and STS. Also found the muscle strength with manual dynamometry.ResultsOf 121 patients who came to the CKD query, 118 presented a minimum functionality to perform tests of functional capacity, a 71.2% of the patients were able to perform 4 tests, a 28.8% only could make the SPPB test.To a 71.43% of patients who presented a low score in SPPB, not could follow assessed them with the rest of the test, while the 92.31% of which had a high score, continued with the rest of the evidence. To differentiate by age ranges, the majority of young patients have minimal limitations, finding higher rates of disability in older age ranges. A good score in SPPB meant to present good functional capacity and allowed to continue evaluating the patient, obtaining better results with the rest of test and more muscle strength. A good nutritional better status and body composition was a better functionality.ConclusionIn the absence of a consensus of what is the best method of determining the functional capacity of the kidney patient, and to assess all patients, propose to use the test SPPB as screening method, and depending on the result used as the rest of the test to more complete if it is necessary to study.