Nanopartículas de dióxido de titânio promovem efeitos histopatológicos e genotóxicos em Danio rerio após exposição aguda e crônica

Titanium dioxide nanoparticles (TiO2-NPs) are among the most used nanomaterials worldwide, but studies evaluating its genotoxicity and histopathological effects are scarce, dealing with short exposure times and low concentrations for human use. The aim was to evaluate TiO2-NPs genotoxicity and histological alterations in the intestine and liver of zebrafish after exposure to human consumption compatible concentrations. Fishes were acutely (96 hours) and chronically (30 days) exposed to 5.0, 20 and 40 mg L-1 of TiO2-NPs and later euthanized for organ and blood analysis through histological procedures and the micronucleus test, respectively. An increase in the thickness of intestinal villi was observed after acute and chronic exposure in the higher concentrations. The liver showed an increase in vacuolated hepatocytes after both exposures, besides an increase in hepatocytes with peripheral nucleus. Genotoxicity was only observed after chronic exposure, demonstrated by the increase in micronucleus and cell buddings. These findings indicate that TiO2-NPs cause histopathological damage even in acute exposures, as the intestine serves as a barrier for NPs and the liver is an organ that accumulates Ti. Genotoxicity was possibly mediated by reactive oxygen species through chronic inflammation, leading to tissue damage and carcinogenesis in longer exposures that represents human exposure time.Nanopartículas de dióxido de titânio (Nano-TiO2) estão entre os nanomateriais mais usados em todo o mundo, mas os estudos avaliando sua genotoxicidade e efeitos histopatológicos são escassos, tratando-se de curtos tempos de exposição e baixas concentrações para uso humano. O objetivo foi avaliar a genotoxicidade de Nano-TiO2 e as alterações histológicas no intestino e no fígado de peixes-zebra após exposição a concentrações compatíveis com o consumo humano. Os peixes foram expostos agudamente (96 horas) e cronicamente (30 dias) a 5, 20 e 40 mg L-1 de Nano-TiO2 e posteriormente eutanasiados para análise de órgãos e sangue por meio de procedimentos histológicos e teste de micronúcleo, respectivamente. Um aumento na espessura das vilosidades intestinais foi observado após exposição aguda e crônica nas concentrações mais altas. O fígado apresentou aumento de hepatócitos vacuolizados após ambas as exposições, além de aumento de hepatócitos com núcleo periférico. A genotoxicidade só foi observada após exposição crônica, demonstrada pelo aumento de micronúcleos e brotamentos celulares. Esses achados indicam que as Nano-TiO2 causam danos histopatológicos mesmo em exposições agudas, pois o intestino serve como uma barreira para as NPs e o fígado é um órgão que acumula Ti. A genotoxicidade foi possivelmente mediada por espécies reativas de oxigênio por meio de inflamação crônica, levando a danos nos tecidos e carcinogênese em exposições mais longas que representam o tempo de exposição humana

Cytotoxicity evaluation of haloperidol, clozapine and a new molecule with antipsychotic potential, PT-31, in NIH-3T3 cells

Schizophrenia is an illness that affects 26 million people worldwide. However, conventional antipsychotics present side effects and toxicity, highlighting the need for new antipsychotics. We aimed to evaluate the cytotoxicity of haloperidol (HAL), clozapine (CLO), and a new molecule with antipsychotic potential, PT-31, in NIH-3T3 cells. The neutral red uptake assay and the MTT assay were performed to evaluate cell viability and mitochondrial activity, morphological changes were assessed, and intracellular reactive oxygen species (ROS) detection was performed. HAL and CLO (0.1 μM) showed a decrease in cell viability in the neutral red uptake assay and in the MTT assay. In addition, cell detachment, content decrease, rounding and cell death were also observed at 0.1 μM for both antipsychotics. An increase in ROS was observed for HAL (0.001, 0.01 and 1 μM) and CLO (0.01 and 1 μM). PT-31 did not alter cell viability in any of the assays, although it increased ROS at 0.01 and 1 μM. HAL and CLO present cytotoxicity at 0.1 μM, possibly through apoptosis and necrosis. In contrast, PT-31 does not present cytotoxicity to NIH-3T3 cells. Further studies must be performed for a better understanding of these mechanisms and the potential risk of conventional antipsychotics

Cytotoxicity evaluation of haloperidol, clozapine and a new molecule with antipsychotic potential, PT-31, in NIH-3T3 cells

Abstract Schizophrenia is an illness that affects 26 million people worldwide. However, conventional antipsychotics present side effects and toxicity, highlighting the need for new antipsychotics. We aimed to evaluate the cytotoxicity of haloperidol (HAL), clozapine (CLO), and a new molecule with antipsychotic potential, PT-31, in NIH-3T3 cells. The neutral red uptake assay and the MTT assay were performed to evaluate cell viability and mitochondrial activity, morphological changes were assessed, and intracellular reactive oxygen species (ROS) detection was performed. HAL and CLO (0.1 μM) showed a decrease in cell viability in the neutral red uptake assay and in the MTT assay. In addition, cell detachment, content decrease, rounding and cell death were also observed at 0.1 μM for both antipsychotics. An increase in ROS was observed for HAL (0.001, 0.01 and 1 μM) and CLO (0.01 and 1 μM). PT-31 did not alter cell viability in any of the assays, although it increased ROS at 0.01 and 1 μM. HAL and CLO present cytotoxicity at 0.1 μM, possibly through apoptosis and necrosis. In contrast, PT-31 does not present cytotoxicity to NIH-3T3 cells. Further studies must be performed for a better understanding of these mechanisms and the potential risk of conventional antipsychotics

Evaluation of a quality improvement intervention to reduce anastomotic leak following right colectomy (EAGLE): pragmatic, batched stepped-wedge, cluster-randomized trial in 64 countries

Background Anastomotic leak affects 8 per cent of patients after right colectomy with a 10-fold increased risk of postoperative death. The EAGLE study aimed to develop and test whether an international, standardized quality improvement intervention could reduce anastomotic leaks. Methods The internationally intended protocol, iteratively co-developed by a multistage Delphi process, comprised an online educational module introducing risk stratification, an intraoperative checklist, and harmonized surgical techniques. Clusters (hospital teams) were randomized to one of three arms with varied sequences of intervention/data collection by a derived stepped-wedge batch design (at least 18 hospital teams per batch). Patients were blinded to the study allocation. Low- and middle-income country enrolment was encouraged. The primary outcome (assessed by intention to treat) was anastomotic leak rate, and subgroup analyses by module completion (at least 80 per cent of surgeons, high engagement; less than 50 per cent, low engagement) were preplanned. Results A total 355 hospital teams registered, with 332 from 64 countries (39.2 per cent low and middle income) included in the final analysis. The online modules were completed by half of the surgeons (2143 of 4411). The primary analysis included 3039 of the 3268 patients recruited (206 patients had no anastomosis and 23 were lost to follow-up), with anastomotic leaks arising before and after the intervention in 10.1 and 9.6 per cent respectively (adjusted OR 0.87, 95 per cent c.i. 0.59 to 1.30; P = 0.498). The proportion of surgeons completing the educational modules was an influence: the leak rate decreased from 12.2 per cent (61 of 500) before intervention to 5.1 per cent (24 of 473) after intervention in high-engagement centres (adjusted OR 0.36, 0.20 to 0.64; P < 0.001), but this was not observed in low-engagement hospitals (8.3 per cent (59 of 714) and 13.8 per cent (61 of 443) respectively; adjusted OR 2.09, 1.31 to 3.31). Conclusion Completion of globally available digital training by engaged teams can alter anastomotic leak rates. Registration number: NCT04270721 (http://www.clinicaltrials.gov)