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Introduction The assessment of the risk of virus transmission through papers, such as postcards, is important. However, the stability of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza A virus (IAV) on different types of papers is currently unknown. Investigation of the survival time of these viruses on different types of papers will provide insights into their risk of long-distance transport by postal items. Methods We evaluated the stability of SARS-CoV-2 and IAV, mixed with a culture medium, on the surface of postcards with various coatings, including plain paper (PP), inkjet paper (IP), and inkjet photo paper (IPP). The surface structure of each paper was microscopically assessed. Results The surface structures of PP, IP, and IPP varied greatly depending on the presence or absence, and type, of coat layer, regardless of the base material. IP and IPP surfaces were less conducive to virus survival than PP surfaces, because of the difference in surface shapes. The survival times of SARS-CoV-2 on each paper were approximately 59.8 (PP), 6.5 (IP), and 9.8 h (IPP), and significantly longer than those of IAV (10.3, 1.8, and 3.3 h, respectively). Conclusions The risk of SARS-CoV-2 transmission via paper, such as postcards, is significantly higher than that of IAV transmission. While PP, IP, and IPP have the same base material, their surface structures differ, which affects viral stability. The IP and IPP surfaces are less suitable for virus survival. This study provides novel insights into the risks of viral transmission via paper.

SummaryBackgroundPsychotic experiences predict adverse health outcomes, particularly if they are persistent. However, it is unclear what distinguishes persistent from transient psychotic experiences.AimsIn a large population-based cohort, we aimed to (a) describe the course of hallucinatory experiences from childhood to adolescence, (b) compare characteristics of youth with persistent and remittent hallucinatory experiences, and (c) examine prediction models for persistence.MethodYouth were assessed longitudinally for hallucinatory experiences at mean ages of 10 and 14 years (n = 3473). Multi-informant-rated mental health problems, stressful life events, self-esteem, non-verbal IQ and parental psychopathology were examined in relation to absent, persistent, remittent and incident hallucinatory experiences. We evaluated two prediction models for persistence with logistic regression and assessed discrimination using the area under the curve (AUC).ResultsThe persistence rate of hallucinatory experiences was 20.5%. Adolescents with persistent hallucinatory experiences had higher baseline levels of hallucinatory experiences, emotional and behavioural problems, as well as lower self-esteem and non-verbal IQ scores than youth with remittent hallucinatory experiences. Although the prediction model for persistence versus absence of hallucinatory experiences demonstrated excellent discriminatory power (AUC-corrected = 0.80), the prediction model for persistence versus remittance demonstrated poor accuracy (AUC-corrected = 0.61).ConclusionsThis study provides support for the dynamic expression of childhood hallucinatory experiences and suggests increased neurodevelopmental vulnerability in youth with persistent hallucinatory experiences. Despite the inclusion of a wide array of psychosocial parameters, a prediction model discriminated poorly between youth with persistent versus remittent hallucinatory experiences, confirming that persistent hallucinatory experiences are a complex multifactorial trait.

Xylitol has reported to decrease gingival inflammation and nasopharyngeal pneumonia, which indicated that xylitol may have potential application in respiratory diseases. Although some studies have reported the inhalation toxicity of xylitol, however, the longest period tested was only for 14 days. The inhalation toxicity of xylitol is insufficient. This work investigated the potential subacute toxicity of xylitol according to the OECD TG 412. Rats were randomly divided into a control group and different dosage groups (2 g/m3, 3 g/m3, 5 g/m3), and exposed for 6 hours/day, 5 days/week for 28 days. At the end of the exposure or recovery period, clinical signs, mortality, body weight, food consumption, hematology, blood biochemistry, gross pathology, organ weight, and histopathology were examined. Compared with the control group, rats of both sexes in the exposure groups exhibited no significant changes in body weight, organ mass, and food uptake. After the xylitol exposure, aspartate aminotransferase activity in the xylitol group (3 g/m3) was significantly higher than that in the control group, while other blood indicators and pathological changes of liver and the analysis of the recovery group showed no changes, suggesting that xylitol exerted no observable toxic effect on the liver. Finally, other observations including the histopathology of target organs and hematology also showed no alterations. These results indicated that xylitol had no significant inhalation toxicity at doses up to 5 g/m3. These subacute inhalation toxicity results of xylitol showed that its no-observed-adverse-effect concentration (NOAEC) in rats was determined to 5 g/m3.

Tramadol (TR) is a centrally acting analgesic drug that is used to relieve pain. The therapeutic (0.1–0.8 mg/l), toxic (1–2 mg/l) and lethal (>2 mg/l) ranges were reported for TR. The present study was designed to evaluate which doses of TR can induce liver mitochondrial toxicity. Mitochondria were isolated from the five rats’ liver and were incubated with therapeutic to lethal concentrations (1.7–600 μM) of TR. Biomarkers of oxidative stress including: reactive oxygen species (ROS), lipid peroxidation (LPO), protein carbonyl content, glutathione (GSH) content, mitochondrial function, mitochondrial membrane potential (MMP) and mitochondrial swelling were assessed. Our results showed that ROS and LPO at 100 μM and protein carbonylation at 600 μM concentrations of TR were significantly increased. GSH was decreased specifically at 600 μM concentration. Mitochondrial function, MMP and mitochondrial swelling decreased in isolated rat liver mitochondria after exposure to 100 and 300 μM, respectively. This study suggested that TR at therapeutic and toxic levels by single exposure could not induce mitochondrial toxicity. But, in lethal concentration (≥100 μM), TR induced oxidative damage and mitochondria dysfunction. This study suggested that ROS overproduction by increasing of TR concentration induced mitochondrial dysfunction and caused mitochondrial damage via Complex II and membrane permeability transition pores disorders, MMP collapse and mitochondria swelling.

Aβ42 is one of the most extensively studied blood and Cerebrospinal fluid (CSF) biomarkers for the diagnosis of symptomatic and prodromal Alzheimer’s disease (AD). Because of the heterogeneity and transient nature of Aβ42 oligomers (Aβ42Os), the development of technologies for dynamically detecting changes in the blood or CSF levels of Aβ42 monomers (Aβ42Ms) and Aβ42Os is essential for the accurate diagnosis of AD. The currently commonly used Aβ42 ELISA test kits usually mis-detected the elevated Aβ42Os, leading to incomplete analysis and underestimation of soluble Aβ42, resulting in a comprised performance in AD diagnosis. Herein, we developed a dual-target lateral flow immunoassay (dLFI) using anti-Aβ42 monoclonal antibodies 1F12 and 2C6 for the rapid and point-of-care detection of Aβ42Ms and Aβ42Os in blood samples within 30 min for AD diagnosis. By naked eye observation, the visual detection limit of Aβ42Ms or/and Aβ42Os in dLFI was 154 pg/mL. The test results for dLFI were similar to those observed in the enzyme-linked immunosorbent assay (ELISA). Therefore, this paper-based dLFI provides a practical and rapid method for the on-site detection of two biomarkers in blood or CSF samples without the need for additional expertise or equipment. Graphical Abstract

BackgroundPsychosis is associated with many forms of adversity, deprivation and living in urban areas.AimsTo investigate whether psychosis is part of a syndemic of multiple adversities.MethodDrawing on UK Biobank (UKBB) data (Project ID: 57601), we sought to understand mechanisms by which childhood, recent/contemporary and place-based adversities might cluster and interact to be implicated in pathways by which psychoses evolve. We investigated the associations between adversities, potential mediating inflammatory markers and ICD-10 diagnoses (F20–F31) of psychotic disorders. We fitted logistic regression models initially including all relevant candidate variables and used backwards deletion to retain theoretically plausible and statistically significant (P < 0.05) associations with psychotic disorders. The candidate variables were entered in a partial least squares structural equation model (PLS-SEM) to test for syndemic interactions between risk factors. We tested whether the findings were sensitive to demographics, gender and ethnicity.ResultsWe fitted a PLS-SEM including psychosis as a syndemic outcome, and identified three latent constructs: lifetime adversity, current adversity and biomarkers. Factor loadings were above 0.30, and all structural paths were significant (P < 0.05). There were moderate associations between lifetime adversity and current adversity (standardised coefficient s.c. = 0.178) and between current adversity and biomarkers (s.c. = 0.227). All three latent constructs showed small but significant associations with psychosis (s.c. < 0.04). Lifetime adversity and current adversity were more strongly associated among ethnic minorities (combined) than White British people.ConclusionsOur findings stress the importance of interactions between childhood and contemporary adversities in preventive and therapeutic interventions for psychotic disorders, especially among ethnic minorities.

The authors would like to thank Luneau Technology Portugal for lending the Visionix VX120., Purpose: To study the effect of near-vision reading task on optical quality of the eye when performed on a computer monitor and on printed paper, and to identify which of the two results in greater changes. Methods: Two groups of subjects performed a 30-min reading task in two different conditions: on a computer monitor and on printed paper. Ocular, corneal, and internal wavefront aberrations (Zernike coefficients up to 6th order), root-mean-square of low- and high-order aberrations, spherical equivalent, vectoral components of ocular astigmatism ( J45 and J0), and the compensation factor between internal and corneal aberrations were measured before and after the tasks. Their changes were analyzed in each group and between groups. Results: Statistically significant changes in wavefront aberrations and in root mean square of low- and high-order aberrations were observed in both groups which was significantly greater when the task was performed on printed paper. Partial loss of compensation mechanism and variation in spherical equivalent in a negative direction occurred after both reading tasks; however, it was statistically significant only with printed paper reading task. The vectoral components of ocular astigmatism did not show statistically significant changes in either groups. Conclusion: Near-vision reading tasks can change the optical quality of the eye, especially when the task is performed on printed paper., This work was supported by the Portuguese Foundation for Science and Technology (FCT) in the framework of the Strategic Funding UID/FIS/04650/2019 and by the project PTDC/FIS-OTI/ 31486/2017.

Urinary tract infections (UTIs) make up a significant proportion of the global burden of disease in vulnerable groups and tend to substantially impair the quality of life of those affected, making timely detection of UTIs a priority for public health. However, economic and societal barriers drastically reduce accessibility of traditional lab-based testing methods for critical patient groups in low-resource areas, negatively affecting their overall healthcare outcomes. As a result, cellulose-based materials such as paper and thread have garnered significant interest among researchers as substrates for so-called frugal analytical devices which leverage the material’s portability and adaptability for facile and reproducible diagnoses of UTIs. Although the field may be only in its infancy, strategies aimed at commercial penetration can appreciably increase access to more healthcare options for at-risk people. In this review, we catalogue recent advances in devices that use cellulose-based materials as the primary housing or medium for UTI detection and chart out trends in the field. We also explore different modalities employed for detection, with particular emphasis on their ability to be ported onto discreet casings such as sanitary products. Graphical abstract

Two novel methods of measuring the dimensions of oral lesions are described, which would be of help in deciding relative efficacies of different therapeutic agents when used in clinical trials after larger studies quantitatively assessed for inter/intraobserver variability.

Cancer is one of the leading causes of death in the world. It is very important to find drugs with high efficiency, low toxicity, and low side effects for the treatment of cancer. Flavonoids and their derivatives with broad biological functions have been recognized as anti-tumor chemicals. 8-Formylophiopogonanone B (8-FOB), a naturally existed homoisoflavonoids with rarely known biological functions, needs pharmacological evaluation. In order to explore the possible anti-tumor action of 8-FOB, we used six types of tumor cells to evaluate in vitro effects of this agent on cell viability and tested the effects on clone formation ability, scratching wound-healing, and apoptosis. In an attempt to elucidate the mechanism of pharmacological action, we examined 8-FOB-induced intracellular oxidative stress and -disrupted mitochondrial function. Results suggested that 8-FOB could suppress tumor cell viability, inhibit cell migration and invasion, induce apoptosis, and elicit intracellular ROS production. Among these six types of tumor cells, the nasopharyngeal carcinoma CNE-1 cells were the most sensitive cancer cells to 8-FOB treatment. Intracellular ROS production played a pivotal role in the anti-tumor action of 8-FOB. Our present study is the first to document that 8-FOB has anti-tumor activity in vitro and increases intracellular ROS production, which might be responsible for its anti-tumor action. The anti-tumor pharmacological effect of 8-FOB is worthy of further investigation.

In the present study, and for the waste valorization, Moringa oleifera seeds-removed ripened pods (SRRP) were used for papersheet production and for the extraction of bioactive compounds. Fibers were characterized by SEM–EDX patterns, while the phytoconstituents in ethanol extract was analyzed by HPLC. The inhibition percentage of fungal mycelial growth (IFMG) of the treated Melia azedarach wood with M. oleifera SRRP extract at the concentrations of 10,000, 20,000, and 30,000 µg/mL against the growth of Rhizoctonia solani and Fusarium culmorum was calculated and compared with fluconazole (25 µg). The produced papersheet was treated with the ethanol extract (4000, 2000, and 1000 µg/mL) and assayed for its antibacterial activity against Agrobacterium tumefaciens, Erwinia amylovora, and Pectobacterium atrosepticum by measuring the inhibition zones and minimum inhibitory concentrations (MICs). According to chemical analysis of M. oleifera SRRP, benzene:alcohol extractives, holocellulose, lignin, and ash contents were 7.56, 64.94, 25.66 and 1.53%, respectively, while for the produced unbleached pulp, the screen pulp yield and the Kappa number were 39% and 25, respectively. The produced papersheet showed tensile index, tear index, burst index, and double fold number values of 58.8 N m/g, 3.38 mN m2/g, 3.86 kPa m2/g, and 10.66, respectively. SEM examination showed that the average fiber diameter was 16.39 µm, and the mass average of for elemental composition of C and O by EDX were, 44.21%, and 55.79%, respectively. The main phytoconstituents in the extract (mg/100 g extract) by HPLC were vanillic acid (5053.49), benzoic acid (262.98), naringenin (133.02), chlorogenic acid (66.16), and myricetin (56.27). After 14 days of incubation, M. oleifera SRRP extract-wood treated showed good IFMG against R. solani (36.88%) and F. culmorum (51.66%) compared to fluconazole, where it observed 42.96% and 53.70%, respectively. Moderate to significant antibacterial activity was found, where the minimum inhibitory concentration (MIC) values were 500, 650, and 250 µg/mL against the growth of A. tumefaciens, E. amylovora, and P. atrosepticum respectively, which were lower than the positive control used (Tobramycin 10 µg/disc). In conclusion, M. oleifera SRRP showed promising properties as a raw material for pulp and paper production as well as for the extraction of bioactive compounds.

N, N-Dimethylformamide (DMF) can cause liver damage in occupationally exposed workers, but the molecular mechanism of DMF-induced liver damage has not been fully elucidated. Researches have proved that lncRNA plays a major function in chemical-induced liver toxicity and can be used as a biomarker and therapeutic target for liver injury. In order to verify that lncRNA also participates in DMF-induced liver damage, we treated HL-7702 cells with 75 or 150 mM DMF, and obtained lncRNA expression profiles through high-throughput sequencing. Among the differentially expressed lncRNAs, lncRNA SNHG12 was proved to be significantly downregulated in DMF-treated HL-7702 cells and participate in DMF-mediated apoptosis, even under long-term low-dose DMF exposure (5–10 mM, 8 weeks). In addition, according to bioinformatics analysis, miR-218-5p is expected to be a potential target of SNHG12, which was verified by the dual luciferase reporter assay in HEK293FT cells. MiR-218-5p mimic can induce apoptosis in HL-7702 cells. Among the predicted targets of miR-218-5p, protein kinase C epsilon (PRKCE) was reported to be involved in apoptosis, and was indeed downregulated by miR-218-5p mimic in our study. Further experiments showed that changes of the expression of SNHG12 can affect the expression of PRKCE. In the epidemiological study of occupational population, we also found that SNHG12 was downregulated in the serum exosomes of workers exposed to DMF. These results indicated that SNHG12 can mediate DMF-induced apoptosis of HL-7702 cells through miR-218-5p/PRKCE pathway.

This study investigated the hemato- and genotoxic effects of formaldehyde (FA) and the possible mitigating role of hesperidin (HP) and N-acetylcysteine (NAC), each alone and in combination. Sixty-four adult male albino rats were divided into eight equal groups; the study was conducted for 8 weeks; Group I (negative control: received no medication), Group II (positive control: received distilled water), Group III (received HP 50 mg/kg/day), Group IV (received NAC 50 mg/kg/day), Group V (received FA 10 mg/kg/day), Group VI (FA + HP), Group VII (FA + NAC), and Group VIII (FA + HP + NAC). Groups VI, VII, VIII received the same previously mentioned doses and for the same duration. All treatments were given by intraperitoneal administration. At the end of the study, complete blood count, oxidative stress, histopathological changes, immunohistochemical staining of inducible nitric oxide synthase, and proliferating cell nuclear antigen and genotoxicity by comet assay in the bone marrow of treated rats were assessed. FA administration caused significant hematotoxicity represented by elevated white blood cell numbers and serum malondialdehyde levels and reduced red blood cell numbers, platelets, and serum superoxide dismutase values. Histologically, it induced an increase in fat cell numbers in bone marrow tissue with a widening of marrow spaces and decreased cellularity of hematopoietic cells, megakaryocytes, and granulocytes. FA exposure significantly decreased immunoreactivity for proliferating cell nuclear antigen, whereas the immunoreactivity for inducible nitric oxide synthase was increased. Genotoxicity, as measured by comet assay, revealed a significant increase in comet% and tail length in FA-treated group when compared with other groups. The cotreatment with HP and NAC revealed their ability to protect against hematological changes, oxidative damage, histopathological, and immunohistochemical changes, and genotoxicity induced by FA.

Objectives: Survey studies are a commonly used method for data collection in surgical education research. Nevertheless, studies investigating survey design and response rates in surgical education research are lacking. The aim of this study was to gain an insight into survey response rates among surgical residents and medical students, and provide an initial reporting guideline for future survey studies in this field. Design: PubMed (MEDLINE) was systematically searched for survey studies in surgical education from January 2007 until February 2020, according to the PRISMA statements checklist. Study selection was conducted by 2 authors, independently. Surveys directed at surgical residents and/or medical students were included if data on response rates was available. Studies reporting solely from nonsurgical fields of medicine, paramedicine, or nursing were excluded. Subgroup analyses were performed, comparing response rates for varying modes of survey, per country, and for the 10 journals with the most identified surveys. Results: From the 5,693 records screened for a larger surgical survey database, a total of 312 surveys were included; 173 studies focused on surgical residents and 139 on medical students. The mean (SD) response rate was 55.7% (24.7%) for surgical residents and 69.0% (20.8%) for medical students. The number of published surveys increased yearly, mostly driven by an increase in surgical resident surveys. Although most surveys were Web-based (n = 166, 53.2%), this survey mode resulted in the lowest response rates (mean 52.6%). The highest response rates, with a mean of 79.8% (13.1%), were seen in in-person surveys (n = 89, 28.5%). Wide variations in response rates were seen between different countries and journals. Conclusions: Web-based surveys are gaining popularity for medical research in general and for surgical education specifically; however, this mode results in lower response rates than those of in-person surveys. The response rate of in-person surveys is especially high when focusing on medical students. To improve reporting of survey studies, we present the first step towards a reporting guideline.

The Golden trumpet Handroanthus chrysotrichus is a tree that presents beneficial health properties against various diseases. Thus, this study aims to verify the toxicity of H. chrysotrichus bark extract, observing the effects of exposure to this extract in mice. For this, mice were separated in groups: saline (sterile solution .9%); H. chrysotrichus crude extract (HCCE) 10; HCCE 50, and HCCE 100 mg. kg−1 (p.o.). We analyzed HCCE effects on acute (single exposure) and subchronic protocol (14 days exposure). After both exposures, acute, and subchronic, we collected samples from blood, brain, liver, and kidney tissues for biochemical evaluation. In addition, after subchronic exposure, we performed behavioral tests. Acute exposure caused an increase of lipid peroxidation in liver tissue. Moreover, we observed a significant carbonyl increase in liver and brain tissues from HCCE 50 mg. kg−1. Kidneys presented carbonyl increase in mice treated with the highest concentration. Besides, creatinine increased in the group of the acute exposure at HCCE 100 mg. kg−1. Total leukocyte count decreased in all concentrations tested. Sub-chronic exposure at HCCE 100 mg. kg−1 caused a decrease in the number of crossing and an increase in its self-grooming frequency in the open field test. In this exposure, the brain and liver had a significant increase in carbonyl levels in all concentrations. We concluded that H. chrysotrichus cause behavioral and biochemical alterations in mice. HCCE primary targets seem to be the liver, kidneys, and white cells.

Thalidomide causes teratogenic effects in several animal species and in humans. Accordingly, the World Health Organization banned thalidomide when mothers who took thalidomide during pregnancy delivered abnormal fetuses. After four decades, thalidomide underwent drug “re-purposing” since its antiangiogenic and immunomodulatory effects were therapeutic for multiple myeloma. There are no reports of thalidomide’s effects on prokaryotes, but it showed teratogenic effects in Arabidopsis thaliana, an ancestor of the plant kingdom. This proof of concept study clearly shows that thalidomide caused a significant and reproducible decrease in germination rate, nitric oxide (NO) production, and chlorophyll content of fennel plantlets. Thalidomide also induced the formation of abnormal fennel plantlets with stunting, wrinkling, and curling of fennel shoots and leaves. Notably, quantitative analysis showed that thalidomide caused a 50% increase in the formation of abnormal fennel plantlets and that these negative effects of thalidomide showed a 2.50- to 4-fold decrease when fennel seeds were co-incubated with an NO donor (Spermine NoNoate) or a stable cGMP analog 8-bromo Guanosine 3′,5′-cyclic monophosphate (8-Bromo-cGMP). This study is important because it confirms that thalidomide’s negative effects on fennel seed germination and growth are mediated by attenuation of NO and disruption of NO signaling. This reproducible model of thalidomide-induced, NO-dependent damage in a plant system can be used to further investigate the molecular mechanisms of thalidomide action in plants. Importantly, this study establishes a link between the evolution of development of higher plants and mammals.

Colchicine poisoning is complicated and has a high mortality rate. The aim of this study was to identify the pathogenic characteristics of colchicine poisoning cases and to propose a comprehensive treatment procedure. A total of 43 patients were divided into survival (n = 32) and death groups (n = 11) according to prognosis. The clinical data (basic information, clinical manifestations, laboratory tests, examination results, therapeutic schedule, response evaluation, and prognosis) were analyzed, and the comprehensive treatment was proposed. The ingestion doses were ≤0.5, 0.5–0.8, and ≥0.8 mg/kg, and the survival rates were 100, 83.33, and 28.60%. The causes of death were cardiovascular and bone marrow hematopoietic failures. We found that the order of organ damage was digestive tract, coagulation, muscle, heart, hematopoietic, lung, liver, and kidney, while the recovery order was digestive tract, coagulation, heart, hematopoietic, lung, muscle, kidney, and liver. Different doses of recombinant human granulocyte colony-stimulating factor and recombinant human thrombopoietin can shorten the severity and duration of neutropenia and thrombocytopenia. Plasma exchange combined with continuous veno-venous hemodialysis filtration treatment can increase survival time. The prognosis is positively correlated with the dose. Early removal of toxicants from the digestive tract and blood is essential. It is vital to give comprehensive treatment of multiple organ injuries， include the use of recombinant human granulocyte colony-stimulating factor, recombinant human thrombopoietin, plasma exchange, and continuous veno-venous hemodialysis filtration.

Malaria and leishmaniasis are the public health problems in southern Iran. The main activity of vector control is indoor residual spraying using pyrethroids, using different insecticides as larviciding and impregnated bednets. The aim of study was to evaluate the biological assays of bendiocarb wettable powder (WP) at different surfaces of wall. The residual effect of bendiocarb WP80 at 400 milligram/meter square (mg/m2) was evaluated on various local surfaces of rooms such as mud and plaster as well as thatch roofs and wooden. World Health Organization standard cones using contact bioassays were carried out using laboratory reared sugar-fed, 48–72 h old females of Anopheles stephensi. Contact bioassays were carried out on sprayed surfaces for 150 days. Contact bioassay on surfaces treated with bendiocarb WP80 at different surfaces was estimated about 2 months. Fumigant tests of bendiocarb WP80 at 400 mg/m2 revealed 50–93.83% mortality with 1 month persistency. The results showed that carbamate insecticide could be used as rotation with pyrethroids for malaria vector control. Monitoring and evaluation of environmental toxicology of pesticides is important for decision making for choosing appropriate pesticides for disease vector control.

Hypoxia is a nonphysiological oxygen tension which is common in most malignant tumors. Hypoxia stimulates complicated cell signaling networks in cancer cells, e.g., the HIF, PI3K, MAPK, and NFκB pathways. Then, cells release a number of cytokines such as VEGFA to promote the growth of peripheral blood vessels and lead to metastasis. In the current work, understanding of the internal hypoxic environment in solid tumor tissue was attempted by developing a folding paper system. A paper-based solid tumor was constructed by folding a filter paper cultured with cancer cells. The cellular response in each layer could be analyzed by disassembling the folded paper after the culture course. The result showed that an internal hypoxic environment was successfully reproduced in the paper-based solid tumor. The cells in the inner layer expressed high levels of HIF1-α and VEGFA. Hence, proliferation and migration of endothelial cells were shown to be induced by the cells located in the internal hypoxic environment. Moreover, the paper-based solid tumor was transplanted into nude mice for the study of hypoxic response and angiogenesis. The crosstalk between internal and external parts of solid tumor tissue could be analyzed by sectioning each layer of the paper-based solid tumor. This approach provides a favorable analytical method for the discovery of the interaction between cancer cells, hypoxia, and peripheral angiogenesis.

Homocysteine (Hcy) is an excitatory amino acid that contains thiol group and derives from the methionine metabolism. It increases vulnerability of the neuronal cells to excitotoxic and oxidative damage. This study aimed to investigate the hyperhomocysteinemia (hHcy) effects on rat cerebellum and the possible protective role of quercetin administration in Hcy-treated rats, using behavioral and biochemical analyzes. To this end, the adult male rats were divided randomly into the control group that received vehicle, Hcy group received Hcy (400 μg/kg), Hcy + Que group received Hcy + quercetin (50 mg/kg), quercetin group received quercetin for 14 days. On Day 14 after the final treatment, lipid peroxidation level, the superoxide dismutase (SOD), and glutathione peroxidase (GPx) activities were evaluated in the cerebellum. After completion of treatment, the rat’s performance on rotarod and locomotor activity was evaluated. The results showed that Hcy treatment elicited cerebellar lipid peroxidation, impaired locomotor activity and increased latency to fall on the rotarod. Quercetin failed to attenuate significantly motoric impairment, increased significantly the cerebellar lipid peroxidation and GPx activity in the Hcy + Que group. Our results suggest that Hcy induced cerebellar toxicity and quercetin had no significant protective effects against Hcy toxicity in the cerebellum of adult rats.

Diabetic nephropathy (DN) is becoming a worldwide public health problem and its pathophysiological mechanism is not well understood. Emerging evidences indicated that cadmium (Cd), an industrial material but also an environmental toxin, may be involved in the development and progression of diabetes and diabetes-related kidney disease. However, the underlying mechanism is still unclear. Herein, a DN animal model was constructed by exposing to Cd, the metabolomic profiling of DN mice were obtained by using ultra performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS), pattern recognition and pathway analysis were performed to screen potential biomarker. Moreover, western blotting was employed to verify the possible mechanism involved in the occurrence of Cd-induced DN. A total of 66 metabolites in serum have been screened out and identified as biomarkers, including free fatty acids, phospholipids, sphingomyelins, glycerides, and others. Significant differences were demonstrated between the metabolic profiles, including decreased levels of phospholipid and increased content of triglyceride, diacylglycerols, ceramide, lysophosphatidylcholine in Cd-induced DN mice compared with control. Protein expression level of p38 MAPK and Wnt/β-catenin were significantly increased. UPLC-Q-TOF/MS-based serum metabolomics coupled with pattern recognition methods and pathway analysis provide a powerful approach to identify potential biomarkers and is a new strategy to predict the underlying mechanism of disease caused by environmental toxicant.

Infections caused by resistant microorganisms are a complex global public health challenge, and the way to combat the increase of resistance is the development of more modern and faster techniques for resistance detection. This study aimed to evaluate the transport of inactivated bacteria impregnated in a filter paper disk to detect carbapenem resistance genes by multiplex real-time PCR (qPCR) using high-resolution melting (HRM). A total of 88 isolates of 10 different species of Enterobacterales harboring well-characterized carbapenem resistance genes were evaluated. A full 10-µL loop of fresh growth of bacteria were impregnated in a filter paper disk, which was left at room temperature for 2 days in order to simulate the time spent in transportation. Bacterial inactivation was performed with 70% ethanol at 15 min. Afterwards, the DNA was extracted from the paper disks for further analysis by qPCR HRM. The time of 15 min in 70% ethanol was enough to inactivate all the isolates tested. It was possible to correctly identify the presence of the carbapenem resistance gene by HRM qPCR in 87 isolates (98.87%) that were transported in the filter paper disks. Our results indicated that it is possible to use filter paper to transport inactivated bacteria and to identify carbapenem resistance genes by qPCR HRM. This alternative tends to facilitate the access to this technology by many laboratories which do not have the qPCR equipment.

BackgroundRecovery in schizophrenia is a complex process, involving clinical, societal and personal recovery. Until now, studies analysed these domains separately, without examining their mutual relations and changes over time.AimsThis study aimed to examine different states of recovery and transition rates between states.MethodThe Pharmacotherapy Monitoring and Outcome Survey (2006–2017) yearly assesses patients with schizophrenia in the Northern Netherlands. Data from 2327 patients with one up to 11 yearly measurements on clinical, societal and personal recovery were jointly analysed with a mixture latent Markov model (MLMM).ResultsThe selected MLMM had four states that differed in degree and pattern of recovery outcomes. Patients in state 1 were least recovered on any domain (16% of measurements), and partly recovered in states 2 (25%; featured by negative symptoms) and 3 (21%; featured by positive symptoms). Patients in state 4 (38%) were most recovered, except for work, study and housekeeping. At the subsequent measurement, the probability of remaining in the same state was 77–89%, transitioning to a better state was 4–12% and transitioning to a worse state was 4–6%; no transitions occurred between states 1 and 4. Female gender, shorter illness duration and less schizophrenia were more prevalent in better states.ConclusionsQuite a high recovery rate was present among a substantial part of the measurements (38%, state 4), with a high probability (89%) of remaining in this state. Transition rates in the other states might increase to a more favourable state by focusing on adequate treatment of negative and positive symptoms and societal problems.

We analyze the stability of a unique coexistence equilibrium point of a system of ordinary differential equations (ODE system) modelling the dynamics of a metapopulation, more specifically, a set of local populations inhabiting discrete habitat patches that are connected to one another through dispersal or migration. We assume that the inter-patch migrations are detailed balanced and that the patches are identical with intra-patch dynamics governed by a mean-field ODE system with a coexistence equilibrium. By making use of an appropriate Lyapunov function coupled with LaSalle’s invariance principle, we are able to show that the coexistence equilibrium point within each patch is locally asymptotically stable if the inter-patch dispersal network is heterogeneous, whereas it is neutrally stable in the case of a homogeneous network. These results provide a mathematical proof confirming the existing numerical simulations and broaden the range of networks for which they are valid.

Objective This study was designed to investigate the effects of liquefied petroleum gas (LPG) on hematotoxic, cardiotoxic, and hepatotoxic indices and the modifying influence of selected polyphenols. Methods Adult male Wistar rats were exposed to1000 ppm LPG for 10 min at 12-h interval for 30 days with or without cotreatment with 50 mg/kg rutin, quercetin, tannic acid, or gallic acid followed by hematological, biochemical, and histopathological evaluations in animal tissues. Results Exposure to LPG induced hematotoxicity, cardiotoxicity, and hepatotoxicity. This is reflected in alterations to levels or activities of blood parameters (hemoglobin, packed cell volume, red blood cells, mean corpuscular volume, mean corpuscular hemoglobin, and platelets), enzymatic and nonenzymatic oxidative stress markers, nitrite, lactate dehydrogenase, creatine kinase-MB, transaminases, γ-glutamyl transpeptidase, bilirubin, and plasma albumin. LPG exposure also caused dyslipidemia and histoarchitectural changes. Treatment with the selected polyphenols effectively attenuated LPG-induced toxicity in rat tissues. Conclusion The results indicate that continuous exposure to LPG could lead to blood-, heart-, and liver-related diseases and dietary polyphenols could provide benefits in diseases associated with LPG inhalation toxicity.

Cypermethrin, one kind of pyrethroid pesticides, has been shown to act as endocrine-disrupting chemicals (EDCs). The purpose of this study was to explore the roles of Sertoli cell apoptosis through mitochondrial pathway associated with calcium (Ca2+) in cypermethrin-induced male reproductive toxicology. The mouse Sertoli cells TM4 were cultured with 0 μM, 10 μM, 20 μM, 40 μM and 80 μM of cypermethrin. We used flow cytometry, Fluo-4 AM, western blot and JC-1 Assay Kit to examine apoptosis, intracellular Ca2+, expressions of mitochondrial apoptotic pathway-related proteins and mitochondrial membrane potential. We found cypermethrin increased apoptosis rate of TM4 cells significantly and with a significant increase in intracellular Ca2+ concentration. Cypermethrin significantly decreased the protein expressions of cytosolic B-cell lymphoma-2 (Bcl-2) and mitochondrial cytochrome c (Cyt-c). The protein expressions of cytosolic Bcl-2-associated x (Bax), Cyt-c, cleaved caspase-3, calmodulin (CaM), Ca2+/CaM-dependent protein kinases II (CaMKII) and phosphorylated CaMKII were increased significantly in cypermethrin-exposed TM4 cells. Cypermethrin decreased mitochondrial membrane potential significantly. Then, Bcl-2 family and Ca2+/CaM/CaMKII pathway participate in cypermethrin-induced homeostasis. Ca2+ overload activates mitochondrial pathway by increasing permeability of mitochondrial membrane and decreasing mitochondrial membrane potential. We suggest cypermethrin induces Sertoli cell apoptosis involving mitochondrial pathway associated with Ca2+ regulated by Bcl-2 family and Ca2+/CaM/CaMKII pathway. The study provides a new insight into mechanisms involved in cypermethrin-induced male reproductive toxicology.

BackgroundClozapine is associated with increased risk of myocarditis. However, many common side-effects of clozapine overlap with the clinical manifestations of myocarditis. As a result, there is uncertainty about which signs, symptoms and investigations are important in distinguishing myocarditis from benign adverse effects of clozapine. Clarity on this issue is important, since missing a diagnosis of myocarditis or discontinuing clozapine unnecessarily may both have devastating consequences.AimsTo examine the clinical characteristics of clozapine-induced myocarditis and to identify which signs and symptoms distinguish true myocarditis from other clozapine adverse effects.MethodA retrospective analysis of the record database for 247 621 patients was performed. A natural language processing algorithm identified the instances of patients in which myocarditis was suspected. The anonymised case notes for the patients of each suspected instance were then manually examined, and those whose instances were ambiguous were referred for an independent assessment by up to three cardiologists. Patients with suspected instances were classified as having confirmed myocarditis, myocarditis ruled out or undetermined.ResultsOf 254 instances in 228 patients with suspected myocarditis, 11.4% (n = 29 instances) were confirmed as probable myocarditis. Troponin and C-reactive protein (CRP) had excellent diagnostic value (area under the curve 0.975 and 0.896, respectively), whereas tachycardia was of little diagnostic value. All confirmed instances occurred within 42 days of clozapine initiation.ConclusionsSuspicion of myocarditis can lead to unnecessary discontinuation of clozapine. The ‘critical period’ for myocarditis emergence is the first 6 weeks, and clinical signs including tachycardia are of low specificity. Elevated CRP and troponin are the best markers for the need for further evaluation.

The aim of this study is to implement lifetime attributable risk (LAR) predictions for radiation induced cancers for Swedish cohorts of patients of various age and sex, undergoing diagnostic investigations by nuclear medicine methods. Methods: Calculations are performed on Swedish groups of patients with Paget's disease and with bone metastases from prostatic cancer and diagnosed with bone scintigraphy with an administration of 500 MBq 99mTc-phosphonate. Results: The inclusion of patient survival rates into the calculations lowers the induced radiation cancer risk, as it takes into account that cohorts of patients have shorter predicted survival times than the general population. Conclusion: LAR estimations could be valuable for referring physicians, nuclear medicine physicians, nurses, medical physicists, radiologists, and oncologists and as well as ethical committees for risk estimates for specific subgroups of patients. Caution is however advised with respect to application of LAR predictions to individuals (because of individual sensitivities, circumstances, etc.).

Objective The aim of the study was to evaluate the ionizing radiation exposure in patients with Coronavirus disease 2019 (COVID-19). Materials and Methods This was a retrospective study in which all patients presented with suggestive symptoms of COVID-19 were included. The study was carried out in a university-affiliated private hospital in Istanbul, Turkey. Biological radiation dose exposure (cumulative effective dose: CED) was evaluated in millisievert (mSv) units. Results A total of 1410 patients were included in the study. Of all study subjects, 804 patients (57%) underwent only one chest computed tomography (CT) procedure. Six hundred and six patients (43%) had two or more chest CT procedures. Median CED was 6.02 (min–max:1.67–16.27) mSv. The number of patients who were exposed to ≤ 5 mSv were 149 (24.6%), whereas 457 patients (75.4%) were exposed to >5 mSv. Conclusion The radiation exposure in COVID-19 patients seems unjustifiably high. Awareness should be increased as to the proper use of chest CT in COVID-19 as per to the society recommendations.

Mono-2-ethyhexyl phthalate (MEHP), an environmental xenoestrogen, is widely used in the production of polyvinyl chloride materials and can be easily accumulated in human body. MBP is the active monoester metabolite of di butyl phthalate that is widely used as plasticizer in many products such as plastic toys, food packaging, personal care products, as well as an additive in lubricants, eliminating foams, and lotions. The presented in-vitro cytotoxicity study focused on time-dependent and combinatory exposure scenarios. We chose these phthalates because they are posed a considerable interest because of their contribution to insulin resistance, type-2 diabetes and obesity. All experiments performed in INS-1 pancreatic beta cells show moderate cytotoxicity with a time-dependent increase in effectiveness. INS-1 cells were treated with 0.001, 0.01, 0.1, 1, or 10-μM MEHP and MBP for 24, 48, and 72 h. Our results showed that cell viability was decreased and total oxidant levels were increased. Also, mRNA expression levels with asscociated beta cells were measured and for MBP dose groups, all mRNA expression levels were decreased. In conclusion, these findings suggest that, MEHP and MBP are have a negative and distruptor role on pancreatic beta cells and it will be linked with insulin resistance and type 2 diabetes.

The titanium dioxide nanoparticles (NPs) have been applied to biomedical, pharmaceutical, and food additive fields. However, the effect on health and the environment are conflicting; thus, it has been reviewing several times. In this context, establishing standard robust protocols for detecting cytotoxicity and genotoxicity of nanomaterials became essential for nanotechnology development. The cell type and the intrinsic characteristics of titanium dioxide NPs can influence nanotoxicity. In this work, the cyto- and genotoxicity effects of standard reference material titanium dioxide NPs in primary bovine fibroblasts and immortalized Chinese hamster ovary epithelial (CHO) cells were determined and compared for the first time. Titanium dioxide NPs exposure revealed no cytotoxicity for primary bovine fibroblasts, while only higher concentrations tested (10 μg/ml) induce genotoxic effects in this cell model. In contrast, the lower concentrations of the titanium dioxide NPs cause the cyto- and genotoxic effects in CHO cells. Therefore, our finding indicates that the CHO line was more sensitive toward the effects of titanium dioxide NPs than the primary bovine fibroblast, which should be valuable for their environmental risk assessment.

Nickel oxide nanoparticles (Nano NiO) evoke hepatotoxicity, while whether it affects the hepatic metabolism remains unclear. The aim of this study was to explore the differential metabolites and their metabolic pathways in rat serum and to further verify the potential mechanism of bile acids’ (BAs) metabolism dysregulation after Nano NiO exposure. Sixteen male Wistar rats were intratracheally instilled with Nano NiO (0.24 mg/kg body weight) twice a week for 9 weeks. Liquid chromatography/mass spectrometry was applied to filter the differentially expressed metabolites in rat serum. Western blot was employed to detect the protein contents. Twenty-one differential metabolites that associated with BAs, lipid and phospholipid metabolism pathways were identified in rat serum after Nano NiO exposure. Decreased cholic acid and deoxycholic acid implied that the BAs metabolism was disturbed. The nickel content increased in liver after Nano NiO exposure. The protein expression of cholesterol 7α-hydroxylase (CYP7A1) was down-regulated, and the bile salt export pump was up-regulated after Nano NiO administration in rat liver. Moreover, dehydroepiandrosterone sulphotransferase (SULT2A1) and cytochrome P450 (CYP) 3A4 were elevated in the exposure group. In conclusion, Nano NiO might trigger the disturbances of BAs, lipid and phospholipid metabolism pathways in rats. The diminished serum BAs induced by Nano NiO might be related to the down-regulation of synthetase and to the overexpression of transmembrane protein and detoxification enzymes in BAs metabolism.

Imidazolidinyl urea (IU) is used as an antimicrobial preservative in cosmetic and pharmaceutical products. IU induces allergic contact dermatitis, however, the mechanism has not yet been elucidated. Mas-related G protein-coupled receptor-X2 (MRGPRX2) triggers drug-induced pseudo-allergic reactions. The aims of this study were to determine whether IU activated mast cells through MRGPRX2 to further trigger contact dermatitis. Wild-type (WT) and KitW-sh/HNihrJaeBsmJNju (MUT) mice were treated with IU to observe its effects on local inflammation and mast cells degranulation in vivo. Laboratory of allergic disease 2 cells were used to detect calcium mobilization and release of inflammatory mediators in vitro. WT mice showed a severe local inflammatory response and contact dermatitis, whereas only slight inflammatory infiltration was observed in MUT mice. Thus, MRGPRX2 mediated the IU-induced activation of mast cells. However, histamine, a typical allergen, was not involved in this process. Tryptase expressed by mast cells was the major non-histaminergic inflammatory mediator of contact dermatitis. IU induced anaphylactic reaction via MRGPRX2 and further triggering non-histaminergic contact dermatitis, which explained why antihistamines are clinically ineffective against some chronic dermatitis.

IntroductionSparse data and conflicting evidence exist on the prevalence and prognosis of organophosphate (OP)-related cardiac toxicity. We aimed to characterize the cardiac abnormalities of OP after an acute cholinergic crisis in adults without previous cardiovascular conditions.Patients and MethodsWe did a prospective observational study in a tertiary-care hospital of north India (Postgraduate Institute of Medical Education and Research, Chandigarh) in 74 patients aged ≥ 13 years admitted with acute OP poisoning after self-ingestion. A systemic evaluation, including clinical characteristics, electrocardiography, and echocardiography, was performed to estimate the prevalence and prognosis of cardiac injury. A rate-corrected QT interval was calculated using Bazett’s method, and >440 milliseconds was used to define prolongation.ResultsChlorpyrifos was the most commonly ingested OP (n = 29). The patients had a similar occurrence of hypotension (n = 10) and hypertension (n = 9) at admission, and electrocardiography demonstrated sinus tachycardia in 38 (51.3%) and sinus bradycardia in one case. During the hospital stay, 3 out of 74 patients had a prolonged rate-corrected QT interval (457, 468, and 461 milliseconds), and one patient developed supraventricular tachycardia. Eight (10.8%) patients developed the intermediate syndrome, and six (8.1%) died. None of the hemodynamic or electrocardiographic abnormalities was associated with in-hospital mortality or intermediate syndrome development on univariant analysis. Baseline echocardiography at hospital discharge was performed in 27 patients (admitted during 2018) and normal in all except mild tricuspid regurgitation in one. At a 6-month follow-up, 23 cases were available for cardiovascular screening (including echocardiography) and had a normal evaluation.ConclusionCardiac toxicity is uncommon after acute OP self-ingestion and lacks prognostic significance.

This study aims to investigate the effects of melamine exposure from the weaning period (21st postnatal days in rats) on liver tissue. Female Wistar albino rats (n = 18) were divided into three groups. About 0.1-ml saline was applied to the control group by gavage for 21 days from the postnatal 21st day. The second group was taken 50-mg/kg melamine (in 0.1-ml saline) and the third group was taken 75-mg/kg melamine (in 0.1-ml saline) p.o. On the postnatal 45th day, all rats were sacrificed under anesthesia. Then, liver tissues were cut into three parts and two of them placed in neutral formalin for histopathological and flow cytometric analysis, and one of them placed in 2.5% glutaraldehyde. Histopathological analysis was performed with hematoxylin & eosin, Masson trichrome, periodic acid Schiff stained sections, and also with transmission electron microscopy. Apoptosis (Annexin V positivity) was analyzed by flow cytometry. According to histopathological analysis, hepatocyte damage, sinusoidal dilatation, and inflammatory cell infiltration significantly increased in both melamine groups compared with the control group. Apoptosis significantly increased in the 50 and 75-mg melamine groups compared with the control group. In the results of transmission electron microscopy analysis, there was abnormal chromatin distribution in the hepatocyte nuclei, loss in the cristae of the mitochondria, and organelle loss in large areas in the cytoplasm in both melamine exposure groups. As result, melamine exposure from the weaning period causes liver damage with increasing doses.

Parkinson’s disease (PD) is a common neurodegenerative disorder of the central nervous system. However, the pathogenetic mechanisms of PD are far from understood. The aim of this study was to determine the protective effect of baicalin in a Caenorhabditis elegans model of PD. C. elegans worms were stimulated for 24 h with 6-hydroxydopamine (6-OHDA, 50 mM) and treated with or without baicalin (1, 10, or 100 μM). At all tested concentrations, baicalin improved the reversal and omega turn behavioral phenotypes, as well as the survival, of 6-OHDA-stimulated worms. It also inhibited 6-OHDA-induced oxidative stress by decreasing malondialdehyde levels, increasing superoxide dismutase, glutathione reductase, catalase, and glutathione levels and up-regulating mRNA expression of the antioxidant-related genes sod-1, sod-2, sod-3, daf-2, and daf-16. Additionally, it significantly decreased the expression of the apoptosis-related gene ced-3 and increased that of the anti-apoptosis-related gene ced-9. The expression levels of cleaved caspase-3 and B-cell lymphoma 2 in 6-OHDA-treated worms were reversed by baicalin. Apoptosis was suppressed by 6-OHDA in loss-of-function strains via the p38 mitogen-activated protein kinase (MAPK) signaling pathway. Furthermore, the apoptotic effects of 6-OHDA were blocked in sek-1 and pmk-1 mutants. Finally, the mRNA expression of sek-1 and pmk-1 and the protein expression of p38 MAPK and stress-activated protein kinase/extracellular signal-regulated kinase 1 were up-regulated by 6-OHDA and reversed by baicalin. Baicalin may protect against 6-OHDA injury by inhibiting apoptosis and decreasing oxidative stress through the p38 MAPK signaling pathway.