Sea turtles are particularly vulnerable to plastic exposures, and the associated chemical additives, due to their feeding strategies. The species Caretta caretta is a proposed sentinel of plastic ...pollution worldwide. Thus, there is a need to find adequate biomarkers of plastic exposure through non-invasive protocols for this IUCN protected species. Plasmatic acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and carboxylesterase (CE) which participate in xenobiotic and endogenous metabolic reactions could all serve as biomarkers, as they are responsive to plasticizers and have already proved adequate for identifying organophosphorus esters exposures. Here we measured plasmatic B-esterases in wild specimens captured as accidental by-catch. Measurements were taken in each individual either at entry into the rehabilitation program or immediately before release after a recovery period. For CE measurements, 4 commercial substrates were used as potentially indicative of distinct enzyme isoforms. Increased activity was seen with the butyrate-derived substrates. Plasmatic CE activities were over one order of magnitude higher than AChE and BuChE substrates. Moreover, an in vitro protocol with the inclusion of plastic additives such as tetrabromobisphenol A (TBBPA), bisphenol A and some of its analogues was considered a proxy of enzymatic interactions. A clear inhibition by TBBPA was found when using commercially purified AChE and recombinant CE proteins. Overall, from in vitro and in vivo evidences, CEs in plasma are sensitive and easily measurable and have been shown to significantly increase after turtles have been rehabilitated in rescue centres. Nevertheless, the inclusion of plastic (or plasticizers) characterisation would help to confirm its association with plasmatic enzyme modifications before they can be adopted as biomarkers of plastic contamination.
•p-nitrophenyl butyrate is adequate for carboxylesterase measures in plasma.•Carboxylesterases are potential biomarkers of plastic pollution in sea turtles.•Plasmatic carboxylesterases increased in loggerhead turtle after a depuration period.•Plasmatic carboxylesterases are inhibited in vitro by TBBPA and some BPA analogues.•TBBPA affinity for albumin could compromise its physiological role in transport.
IntroductionPrevious studies have shown an association between high Body Mass Index (BMI) and worse cognitive performance in obese patients and the general population. Cognitive deficits and ...overweight are important challenges in the clinical treatment of psychosis but scarcity of studies have investigated this relationship. Moreover the effect of sex in the psychosis research has been neglected since recent years and there is still a lack of studies taking into account the sex differencesObjectivesTo determine the effect of overweight and its interaction with sex on cognitive performance in First Psychotic Episodes (FEP)MethodsWe included 159 FEP out-patients (mean age 23.1 years 33.3% females ) in their first year of antipsychotic treatment attending to the Early Intervention Program of the Institut Pere Mata, in Reus. At study entry participants underwent to a comprehensive clinical, biometric and cognitive assessment by standardized neurocognitive battery (MATRICS Consensus Cognitive Battery; MCCB). T scores were converted to standard equivalents (z-scores) based on data from a healthy control group from the same geographical area.Overweight was defined as BMI≥ 25 according to WHO standards. Two-way ANCOVAS were performed to determine the interaction effect between overweight and sex on the cognitive tests. Ethical approval was obtained by the Committee for Ethical Clinical and Pharmacological Investigation of the Pere Virgili Research InstituteResultsAt study entry 85% of participants were on antipsychotics for less than 6 months with a median dose of 300 (200-450) chlorpromazine equivalents (CPMZ) in mg/day. 37.7 % of participants were overweight without differences between men (41.5%) and women (30.2%) (X2 = 1.47; p = 0.22). There were no clinical and treatment differences between overweight and normal weight participants. With regards sex differences, females presented statistically significant higher scores in Calgary depression scale and lower doses of antipsychotics. No differences were found in cognitive performance regarding weight status but we found a significant interaction between sex and overweight in verbal learning memory ( F=6.09; p=0.01). When controlled for depressive symptoms and CPZM equivalents differences continued to be significant. Overweight females performed worse -1.09 ( SD 1.18) than normal weight females -0.23 (SD 1.10); (t= 2.57;p=0.02) in verbal learning memory whereas that difference was not found among overweight and normal weight males (t= -1.10; p=0.27)ConclusionsOur results provide evidence for sex-differences on cognitive function depending on weight status. Advances in the study of sex differences in FEP would help to target specific treatment strategiesDisclosure of InterestNone Declared
Although many more eyes of children with retinoblastoma are salvaged now compared to just 10 years ago, the control of vitreous seeding remains a challenge. The introduction of intravitreal injection ...of melphalan has enabled more eyes to be salvaged safely but with definite retinal toxicity. Intensive treatment with high-dose intravitreal topotecan may be a strategy to control tumor burden because of its cell cycle-dependent cytotoxicity and the proven safety in humans. Therefore, we evaluated the ocular and systemic safety of repeated high-dose intravitreal injections of topotecan in rabbits.
Systemic and ocular toxicity was assessed in non-tumor-bearing rabbits after four weekly injections of three doses of topotecan (10 μg, 25 μg, and 50 μg) or vehicle alone. Animals were evaluated weekly for general and ophthalmic clinical status. One week after the last injection, vitreous and plasma samples were collected for drug quantification and the enucleated eyes were subjected to histological assessment.
Weight, hair loss, or changes in hematologic values were absent during the study period across all animal groups. Eyes injected with all topotecan doses or vehicle showed no signs of anterior segment inflammation, clinical or histologic evidence of damage to the retina, and ERG parameters remained unaltered throughout the study. Vitreous and plasma topotecan lactone concentrations were undetectable.
Four weekly intravitreal injections of topotecan up to 50 μg in the animal model or a 100 μg human equivalent dose were not toxic for the rabbit eye. High doses of topotecan may show promising translation to the clinic for the management of difficult-to-treat retinoblastoma vitreous seeds.
A significant impediment to the success of cancer chemotherapy is the occurrence of multidrug resistance, which, in many cases, is attributable to overexpression of membrane transport proteins, such ...as the 170-kDa P-glycoprotein (P-gp). Also, upregulation of the phosphatidylinositol 3-kinase (PI3K)/Akt-signaling pathway is known to play an important role in drug resistance, and has been implicated in the aggressiveness of a number of different cancers, including T-acute lymphoblastic leukemia (T-ALL). We have investigated the therapeutic potential of the novel Akt inhibitor, perifosine (a synthetic alkylphospholipid), on human T-ALL CEM cells (CEM-R), characterized by both overexpression of P-gp and constitutive upregulation of the PI3K/Akt network. Perifosine treatment induced death by apoptosis in CEM-R cells. Apoptosis was characterized by caspase activation, Bid cleavage and cytochrome c release from mitochondria. The proapoptotic effect of perifosine was in part dependent on the Fas/FasL interactions and c-Jun NH(2)-terminal kinase (JNK) activation, as well as on the integrity of lipid rafts. Perifosine downregulated the expression of P-gp mRNA and protein and this effect required JNK activity. Our findings indicate that perifosine is a promising therapeutic agent for treatment of T-ALL cases characterized by both upregulation of the PI3K/Akt survival pathway and overexpression of P-gp.
The loggerhead sea turtle (Caretta caretta) has been selected as sentinel species by the Marine Strategy Framework Directive (MSFD) descriptor 10 in relation to marine litter. In this, and other ...protected species, there is a need to develop conservative pollution biomarkers equally informative of chemical exposures to those traditionally carried out in metabolic organs, such as the liver. With this aim, plasma from turtles undergoing rehabilitation at the Fundació Oceanogràfic rescue centre (Arca del Mar) were selected and tested for B-esterase measurements. Hydrolysis rates of acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and carboxylesterases (CEs) using four commercial substrates were undertaken on 191 plasma samples. Results indicated that acetylthiocholine was the most adequate substrate of cholinesterases and butyrate esters for CE measures. The correlation of these parameters with well-established blood biochemistry measurements was analysed. B-esterase measures in wild specimens were discussed in relation to age group, pathology on admission to the rescue centre and season; moreover, contrasts with long-term resident turtles were also made. Although this study provides baseline data on B-esterase measures in a large sample size for this species, more complementary information is still needed in terms of population genetics, chemical exposures, and in relation to other biochemical parameters before they can be confidently applied in wild specimens within the regulatory MSFD.
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•Plasmatic B-esterase hydrolysis rates are provided in loggerhead turtles.•Gas embolism does not modulate B-esterase responses.•Recovery centres can aid on the use of loggerheads as sentinels.•B-esterases are robust measures applicable to recently deceased individuals.
Olive mill wastes represent an important environmental problem. Their high phenol, lipid, and organic acid concentrations turn them into phytotoxic materials. Specifically, wet olive pomace (WOP) is ...the waste generated in the two-phase continuous extraction process. WOP is a paste with around 60% water. The total volume of WOP generated is around 0.25 L/kg of olives processed. Its current waste management practices result in environmental problems as soil contamination, underground seepage, water-bodies pollution, and foul odor emissions. Some valorization alternatives include composting, biological treatments, direct combustion for energy production, or direct land application. The leather industry is making great efforts to apply cleaner processes while substituting chemical products for natural products. In this way, different alternatives are being studied, such as the use of zeolites, triazine derivatives, grape seed extract, olive leaf extract, etc. In this work, the use of wet olive pomace is presented as a possible alternative to conventional vegetable tannins (mimosa, quebracho, chestnut, etc.). Although different projects and studies have been developed for the valorization of olive mill wastes, there is completely a new approach to the WOP application for tanning purposes. This study shows that WOP has a significant number of polyphenolic substances, so it has a great potential to be used as a tanning agent. Specifically, this study has been able to determine that, of the polyphenols present in WOP, 39.6% correspond to tannins that are capable of tanning the skin. Additionally, it contains 14.3% non-tannins, that is, molecules that by themselves do not have the capacity to tan the leather but promote the tanning mechanism and improve the properties of the tanned leather.
The phenotype of renal involvement in anti-neutrophil cytoplasmic antibodies (ANCA) vasculitis has a major influence on survival, and histological subgrouping of diagnostic renal biopsies has been ...proposed to aid in the prediction of renal outcome. We aimed to validate this histological subgrouping and to investigate the additional value of ANCA serotype in the prediction of renal outcome.
Data were retrospectively collected from the time of diagnosis by systematic review of medical records from 136 patients with renal biopsies recruited to cohorts from the UK and Spain, over 15 years. The end point, renal survival, was the composite of end-stage renal disease (ESRD) or death from any cause. The occurrence of ESRD, Stage 4 Kidney Disease Outcomes Quality Initiative-Chronic Kidney Disease, was assessed separately, in order to establish a severity index risk of chronic kidney disease.
Renal survival at 5 years was 96% in the focal, 86% in the crescentic, 81% in the mixed and 61% in the sclerotic subgroups (P = 0.03). Myeloperoxidase (MPO)-ANCA was associated with more severe disease when compared with PR3-ANCA, as demonstrated by a lower frequency of focal and higher frequency of sclerotic subgroups, by more advanced interstitial fibrotic change and by lower glomerular filtration rate at diagnosis and worse renal function at 1 and 2 years.
We have confirmed the predictive value for renal survival of the ANCA vasculitis histology classification in a multi-centre study. We found a worse renal outcome in patients with tubulointerstitial fibrosis and atrophy. MPO-ANCA positive patients had a worse renal prognosis due to more severe glomerular injury. These results contribute to patient stratification in renal vasculitis for therapeutic, epidemiological and basic research.
Marine fish are threatened by anthropogenic chemical discharges. However, knowledge on adverse effects on deep-sea fish or their detoxification capabilities is limited. Herein, we compared the basal ...activities of selected hepatic detoxification enzymes in several species (Solea solea, Dicentrarchus labrax, Trachyrhynchus scabrus, Mora moro, Cataetix laticeps and Alepocehalus rostratus) collected from the coast, middle and lower slopes of the Blanes Canyon region (Catalan continental margin, NW Mediterranean Sea). The xenobiotic-detoxifying enzymes analysed were the phase-I carboxylesterases (CbEs), and the phase-II conjugation activities uridine diphosphate glucuronyltransferase (UDPGT) and glutathione S-transferase (GST). Moreover, some antioxidant enzyme activities, i.e., catalase (CAT), glutathione peroxidase (GPX) and glutathione reductase (GR), were also included in this comparative study. Because CbE activity is represented by multiple isoforms, the substrates α-naphthyl acetate (αNA) and ρ-nitrophenyl acetate (ρNPA) were used in the enzyme assays, and in vitro inhibition kinetics with dichlorvos were performed to compare interspecific CbE sensitivity.
Activity of xenobiotic detoxification enzymes varied among the species, following a trend with habitat depth and body size. Thus, UDPGT and some antioxidant enzyme activities decreased in fish inhabiting lower slopes of deep-sea, whereas UDPGT and αNA-CbE activities were negatively related to fish size. A trend between CbE activities and the IC50 values for dichlorvos suggested S. solea and M. moro as potentially more sensitive to anticholinesterasic pesticides, and T. scabrus as the most resistant one. A principal component analysis considering all enzyme activities clearly identified the species but this grouping was not related to habitat depth or phylogeny. Although these results can be taken as baseline levels of the main xenobiotic detoxification enzymes in Mediterranean fish, further research is needed to evaluate their response to environmental contaminant exposure.
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•There was a negative trend between CbE activities and IC50 values for dichlorvos.•UDPGT and some antioxidant defences decreased with habitat depth.•CbE activities in deep-sea fish are mostly microsomal.•Factor analysis of the hepatic biomarkers defined species differences.•T. scabrus seemed to be the species better equipped for xenobiotic detoxification.
Spinal muscular atrophy is a rare, autosomal recessive, neuromuscular disease caused by biallelic loss of the survival motor neuron 1 (SMN1) gene, resulting in motor neuron dysfunction. In this ...STR1VE-EU study, we aimed to evaluate the safety and efficacy of onasemnogene abeparvovec gene replacement therapy in infants with spinal muscular atrophy type 1, using broader eligibility criteria than those used in STR1VE-US.
STR1VE-EU was a multicentre, single-arm, single-dose, open-label phase 3 trial done at nine sites (hospitals and universities) in Italy (n=4), the UK (n=2), Belgium (n=2), and France (n=1). We enrolled patients younger than 6 months (180 days) with spinal muscular atrophy type 1 and the common biallelic pathogenic SMN1 exon 7–8 deletion or point mutations, and one or two copies of SMN2. Patients received a one-time intravenous infusion of onasemnogene abeparvovec (1·1 × 1014 vector genomes vg/kg). The outpatient follow-up consisted of assessments once per week starting at day 7 post-infusion for 4 weeks and then once per month until the end of the study (at age 18 months or early termination). The primary outcome was independent sitting for at least 10 s, as defined by the WHO Multicentre Growth Reference Study, at any visit up to the 18 months of age study visit, measured in the intention-to-treat population. Efficacy was compared with the Pediatric Neuromuscular Clinical Research (PNCR) natural history cohort. This trial is registered with ClinicalTrials.gov, NCT03461289 (completed).
From Aug 16, 2018, to Sept 11, 2020, 41 patients with spinal muscular atrophy were assessed for eligibility. The median age at onasemnogene abeparvovec dosing was 4·1 months (IQR 3·0–5·2). 32 (97%) of 33 patients completed the study and were included in the ITT population (one patient was excluded despite completing the study because of dosing at 181 days). 14 (44%, 97·5% CI 26–100) of 32 patients achieved the primary endpoint of functional independent sitting for at least 10 s at any visit up to the 18 months of age study visit (vs 0 of 23 untreated patients in the PNCR cohort; p<0·0001). 31 (97%, 95% CI 91–100) of 32 patients in the ITT population survived free from permanent ventilatory support at 14 months compared with six (26%, 8–44) of 23 patients in the PNCR natural history cohort (p<0·0001). 32 (97%) of 33 patients had at least one adverse event and six (18%) had adverse events that were considered serious and related to onasemnogene abeparvovec. The most common adverse events were pyrexia (22 67% of 33), upper respiratory infection (11 33%), and increased alanine aminotransferase (nine 27%). One death, unrelated to the study drug, occurred from hypoxic-ischaemic brain damage because of a respiratory tract infection during the study.
STR1VE-EU showed efficacy of onasemnogene abeparvovec in infants with symptomatic spinal muscular atrophy type 1. No new safety signals were identified, but further studies are needed to show long-term safety. The benefit–risk profile of onasemnogene abeparvovec seems favourable for this patient population, including those with severe disease at baseline.
Novartis Gene Therapies.
Sea turtles are frequently proposed as indicator species for assessing ocean health. To faciliate the use of these species as bioindicators requires the development of tools for rapidly and ...effectively assessing individual health. Here, we collected 104 blood samples from 69 loggerhead sea turtles, Caretta caretta, undergoing rehabilitation to determine the connection between health status, the activity of B-esterases, and other biochemical parameters. To determine the optimal assay protocol for B-esterases, we measured the activity and kinetics of cholinesterases-(ChEs) and carboxylesterases (CEs) using 3 and 5 commercial substrates, respectively, at different assay conditions. IC50 values for the activity of B-esterases were calculated within a concentration range for model pesticide inhibitors. Turtles’ health status was determined via routine veterinary procedures. During rehabilitation (which was associated with improving health status), we observed a decrease in the activity of most enzymes (especially in acetylcholinesterase) alongside an increase in CE when using p-nitrophenyl acetate as a substrate. As such, it is possible that the activity rates of plasmatic B-esterases could serve as an indicator of health status. There is also high potential that B-esterases could be specifically sensitive to marine pollutants although to further validate this would require future studies to specifically correlate B-esterarse activities to pollutant concentrations in blood or excreta.
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•Loggerhead turtles undergoing rehabilitation exhibited a decrease in plasmatic AChE activity.•Increases in pNPA-CE activity in loggerhead turtles may be linked to immune-system modulation.•Higher hydrolysis rates on plasmatic B-esterase measurements in marine turtles were seen at pH = 8.•Gas embolism significantly affected αNB-CE measurements in marine turtles.
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