High-dose Exposure Research Articles

Clinical assessment and patient education of chemical intolerance

Chemical intolerance (CI) is characterized by multi-system symptoms initiated by a one-time high dose or persistent low-dose exposure to environmental toxicants. Symptoms of this “medically unexplained illness” often include fatigue, headache, weakness, rash, mood changes, musculoskeletal pain, gastrointestinal, difficulties with memory, concentration, and respiratory problems. A general disease mechanism called toxicant-induced loss of tolerance (TILT) explains the initiation, symptoms, and intolerances to chemicals, foods, and medicines reported worldwide by individuals with this condition. TILT is a 2-stage disease process initiated by a major chemical exposure, or a series of low-level exposures, followed by multisystem symptoms and onset of new intolerances. Despite its prevalence of up to 20%, most primary care physicians are not aware of this disease process and thus have been unable to recognize patients with CI. This case series describes three family medicine clinic patients who had multisystem symptoms that were triggered by chemical exposures, saw multiple specialists with no improvement, who were eventually diagnosed with CI and went through a behaviorally based avoidance education program. This report describes the impact of a coordinated educational intervention for patients with CI. We offer several educational tools for health practitioners to discuss with their patients. These patient stories highlight the importance for physicians to be knowledgeable about CI in order to facilitate symptom reduction and improve the quality of life for these patients.

The aryl hydrocarbon receptor in β-cells mediates the effects of TCDD on glucose homeostasis in mice

ObjectiveChronic exposure to persistent organic pollutants (POPs) is associated with increased incidence of type 2 diabetes, hyperglycemia, and poor insulin secretion in humans. Dioxins and dioxin-like compounds are a broad class of POPs that exert cellular toxicity through activation of the aryl hydrocarbon receptor (AhR). We previously showed that a single high-dose injection of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, aka dioxin; 20 μg/kg) in vivo reduced fasted and glucose-stimulated plasma insulin levels for up to 6 weeks in male and female mice. TCDD-exposed male mice were also modestly hypoglycemic and had increased insulin sensitivity, whereas TCDD-exposed females were transiently glucose intolerant. Whether these effects are driven by AhR activation in β-cells requires investigation. MethodsWe exposed female and male β-cell specific Ahr knockout (βAhrKO) mice and littermate Ins1-Cre genotype controls (βAhrWT) to a single high dose of 20 μg/kg TCDD and tracked the mice for 6 weeks. ResultsUnder baseline conditions, deleting AhR from β-cells caused hypoglycemia in female mice, increased insulin secretion ex vivo in female mouse islets, and promoted modest weight gain in male mice. Importantly, high-dose TCDD exposure impaired glucose homeostasis and β-cell function in βAhrWT mice, but these phenotypes were largely abolished in TCDD-exposed βAhrKO mice. ConclusionOur study demonstrates that AhR signaling in β-cells is important for regulating baseline β-cell function in female mice and energy homeostasis in male mice. We also show that β-cell AhR signaling largely mediates the effects of TCDD on glucose homeostasis in both sexes, suggesting that the effects of TCDD on β-cell function and health are driving metabolic phenotypes in peripheral tissues.

Metabolomic interference induced by short-chain chlorinated paraffins in human normal hepatic cells

Short-chain chlorinated paraffins (SCCPs) are an emerging class of persistent organic pollutants (POPs) that are widely detected in environmental matrices and human samples. Because of their environmental persistence, long-range transport potential, bioaccumulation potential, and biotoxicity, SCCPs pose a significant threat to human health. In this study, metabolomics technology was applied to reveal the metabolomic interference in human normal hepatic (L02) cells after exposure to low (1 μg/L), moderate (10 μg/L), and high (100 μg/L) doses of SCCPs. Principal component analysis (PCA) and metabolic effect level index (MELI) values showed that all three SCCP doses caused notable metabolic perturbations in L02 cells. A total of 72 metabolites that were annotated by MS/MS and matched with the experimental spectra in the Human Metabolome Database (HMDB) or validated by commercially available standards were selected as differential metabolites (DMs) across all groups. The low-dose exposure group shared 33 and 36 DMs with the moderate- and high-dose exposure groups, respectively. The moderate-dose exposure group shared 46 DMs with the high-dose exposure group. In addition, 33 DMs were shared among the three exposure groups. Among the 72 DMs, 9, 9, and 45 metabolites participated in the amino acid, nucleotide, and lipid metabolism pathways, respectively. The results of pathway enrichment analysis showed that the most relevant metabolic pathways affected by SCCPs were the lipid metabolism, fatty acid β-oxidation, and nucleotide metabolism pathways, and that compared with low-dose exposure, moderate- and high-dose SCCP exposures caused more notable perturbations of these metabolic pathways in L02 cells. Exposure to SCCPs perturbed glycerophospholipid and sphingolipid metabolism. Significant alterations in the levels of phosphatidylcholines, phosphatidylethanolamines, and sphingomyelins indicated SCCP-induced biomembrane damage. SCCPs inhibited fatty acid β-oxidation by decreasing the levels of short- and medium-chain acylcarnitines in L02 cells, indicating that the energy supplied by fatty acid oxidation was reduced in these cells. Furthermore, compared with low- and moderate-dose SCCPs, high-dose SCCPs produced a significantly stronger inhibition of fatty acid β-oxidation. In addition, SCCPs perturbed nucleotide metabolism. The higher hypoxanthine levels observed in L02 cells after SCCP exposures indicate that SCCPs may induce several adverse effects, including hypoxia, reactive oxygen species production, and mutagenesis in L02 cells.

Fetal bladder rupture after high-dose maternal opioid treatment: a case report

Abstract Objectives Fetal bladder rupture is rare and mainly caused by lower urinary tract obstruction (LUTO). Our case report describes a rupture at a gestational age of 31 weeks following high-dose maternal opioid exposure during intensive care treatment. Opioids perturb the interplay of afferent and efferent signals between the bladder, urethra, and the central nervous system (CNS) which is crucial in contributing to urinary retention. They rapidly cross the human placenta, affecting also the fetus. To date, there is no clear proof of the connection between maternal opioid treatment and fetal bladder rupture, but the association seems to strengthen. Case presentation A 18-year old first Gravida at 31 weeks of gestation developed a severe sepsis with progressive hypoxic lung failure and need for intubation. During the ICU-treatment, several opioids were administered for sedation and pain relief. Four days after induction of opioid treatment the ultrasound revealed a decompressed fetal bladder, hematoma and significant ascites. Fetal bladder rupture with urinary ascites was suspected. A caesarean section was performed at 33 weeks of gestation due to massive fetal urinary ascites, fetal deterioration and imminent abdominal compartment syndrome. Adequate ventilation and circulation could only be established after percutaneous drainage of 350 mL of abdominal fluid, that was confirmed to be urine. A defect of the bladder was confirmed by ultrasound. On the fifth day of life, the bladder was closed surgically by pediatric surgery. Conclusions Growing awareness of the possible connection between maternal opioid therapy and fetal bladder rupture is necessary to plan follow-up ultrasound examinations to assess the fetal situation.

Pharmacokinetic Variability of Oral Cannabidiol and Its Major Metabolites after Short-Term High-Dose Exposure in Healthy Subjects

Introduction: Cannabidiol (CBD) is a widely utilized nonpsychoactive cannabinoid available as a prescriptive drug treatment and over-the-counter supplement. In humans, CBD is metabolized and forms the major active metabolite 7-hydroxy-cannabidiol (7-OH-CBD), which is further metabolized to 7-carboxy-cannabidiol (7-COOH-CBD). In the current study, plasma concentrations of CBD, 7-OH-CBD, and 7-COOH-CBD were measured, and the potential influences of sex, race, and body mass index (BMI) on the pharmacokinetic variability were assessed. Methods: Blood samples from a previously conducted CBD drug interaction study in healthy volunteers (n = 12) were utilized. The subjects received orally administered CBD (Epiodiolex®), 750 mg twice daily for 3 days and a single dose on the 4th day. Nine plasma samples were collected, and plasma concentrations of CBD, 7-OH-CBD, and 7-COOH-CBD were analyzed by LC-MS/MS. Peak plasma concentration (Cmax), time to Cmax (Tmax), area under the curve (AUC), and metabolite‐to‐parent drug exposure ratios (MPR) were calculated. Statistical analysis was performed to determine the correlations of Cmax, AUC, and MPR of CBD, 7-OH-CBD, and 7-COOH-CBD in different sex, race, BMI, and body weight. Results: For CBD, the mean Cmax was 389.17 ± 153.23 ng/mL, and the mean AUC was 1,542.19 ± 488.04 ng/mL*h. For 7-OH-CBD, the mean Cmax was 81.35 ± 36.64 ng/mL, the mean AUC was 364.70 ± 105.59 ng/mL*h, and the mean MPR was 0.25 ± 0.07. For 7-COOH-CBD, the mean Cmax was 1,717.33 ± 769.22 ng/mL, the mean AUC was 9,888.42 ± 3,961.47 ng/mL*h, and the mean MPR was 7.11 ± 3.48. For 7-COOH-CBD, a 2.25-fold higher Cmax was observed in female subjects (p = 0.0155) and a 1.97-fold higher AUC for female subjects (p = 0.0285) with the normalization of body weight. A significant linearity (p = 0.0135) of 7-OH-CBD AUC with body weight in females was observed. No significant differences were identified in Cmax, AUC, and PMR with race and BMI. Conclusion: Observed differences in sex were in agreement with previously reported findings. A larger population pharmacokinetics study is warranted to validate the observed higher Cmax and AUC in females and significant linearity with body weight in females from the current study.

Comparison of Three Antagonists of Hedgehog Pathway to Promote Skeletal Muscle Regeneration after High Dose Irradiation.

The current geopolitical context has brought the radiological nuclear risk to the forefront of concerns. High-dose localized radiation exposure leads to the development of a musculocutaneous radiation syndrome affecting the skin and subcutaneous muscles. Despite the implementation of a gold standard treatment based on an invasive surgical procedure coupled with autologous cell therapy, a muscular defect frequently persists. Targeting the modulation of the Hedgehog (Hh) signaling pathway appears to be a promising therapeutic approach. Activation of this pathway enhances cell survival and promotes proliferation after irradiation, while inhibition by Cyclopamine facilitates differentiation. In this study, we compared the effects of three antagonists of Hh, Cyclopamine (CA), Vismodegib (VDG) and Sonidegib (SDG) on differentiation. A stable cell line of murine myoblasts, C2C12, was exposed to X-ray radiation (5 Gy) and treated with CA, VDG or SDG. Analysis of proliferation, survival (apoptosis), morphology, myogenesis genes expression and proteins production were performed. According to the results, VDG does not have a significant impact on C2C12 cells. SDG increases the expression/production of differentiation markers to a similar extent as CA, while morphologically, SDG proves to be more effective than CA. To conclude, SDG can be used in the same way as CA but already has a marketing authorization with an indication against basal cell cancers, facilitating their use invivo. This proof of concept demonstrates that SDG represents a promising alternative to CA to promotes differentiation of murine myoblasts. Future studies on isolated and cultured satellite cells and invivo will test this proof of concept.

Effects of polystyrene nanoplastics (PSNPs) on the physiology of Allium sativum L.: Photosynthetic pigments, antioxidant enzymes, phytohormones, and nutritional quality

Nanoplastics (NPs) arouse increasing attention recently. Many studies have shown possible negative effects on plants exposed to NPs, but more data are needed on various species of plants to elucidate the potential phytotoxicity mechanisms of NPs. In this work, a pot experiment was conducted to analyze toxicity induced by polystyrene nanoplastics (PSNPs; particle size, 75.10 nm) at diverse doses (0.05, 0.1, 0.25, 0.5, 1.0 mg/g dry soil weight) to seedlings of garlic (Allium sativum L.). The photosynthetic pigments, antioxidant enzyme activities, common phytohormones and styrene contents, and nutritional quality of leaves of A. sativum seedlings were determined. Results showed that the toxic effects of PSNPs on plants at 42 days after exposure were stronger than those at 28 days. Chlorophyll a, chlorophyll b, as well as carotenoids levels within A. sativum leaves treated with PSNPs for 42 days decreased, with the highest decreasing rates of 40.22%, 41.29%, and 27.38%, respectively. The malondialdehyde (MDA) level within A. sativum leaves was noticeably up-regulated at 0.5 and 1.0 mg/g of PSNPs. Furthermore, the guaiacol peroxidase (POD) and catalase (CAT) activities and the abscisic acid (ABA) contents increased significantly with increasing the concentrations of PSNPs. After exposure for 42 days, allicin, soluble sugar and soluble protein levels decreased with increasing the concentration of PSNPs. The highest styrene content in leaves of A. sativum was obtained for the treatment group of the 0.5 mg/g PSNPs, showing an increase of 23.73% relative to control. Collectively, PSNPs were translocated into the leaves of A. sativum from roots, significantly affected the photosynthetic pigments contents, and significantly induced oxidative stress in A. sativum. Furthermore, high doses of PSNPs exposure impaired the A. sativum’s nutritive quality. These research results can provide basic data for accurately evaluating the ecological toxicity of NPs on crops.

CXCL10 upregulation in radiation-exposed human peripheral blood mononuclear cells as a candidate biomarker for rapid triage after radiation exposure

Purpose In case of a nuclear accident, individuals with high-dose radiation exposure (>1–2 Gy) should be rapidly identified. While ferredoxin reductase (FDXR) was recently suggested as a radiation-responsive gene, the use of a single gene biomarker limits radiation dose assessment. To overcome this limitation, we sought to identify reliable radiation-responsive gene biomarkers. Materials and methods Peripheral blood mononuclear cells (PBMCs) were isolated from mice after total body irradiation, and gene expression was analyzed using a microarray approach to identify radiation-responsive genes. Results In light of the essential role of the immune response following radiation exposure, we selected several immune-related candidate genes upregulated by radiation exposure in both mouse and human PBMCs. In particular, the expression of ACOD1 and CXCL10 increased in a radiation dose-dependent manner, while remaining unchanged following lipopolysaccharide (LPS) stimulation in human PBMCs. The expression of both genes was further evaluated in the blood of cancer patients before and after radiotherapy. CXCL10 expression exhibited a distinct increase after radiotherapy and was positively correlated with FDXR expression. Conclusions CXCL10 expression in irradiated PBMCs represents a potential biomarker for radiation exposure.

Acute Large Dose Irradiation Sensitizes Surviving Cells to Subsequent Irradiation; Implications for Stereotactic Body Radiation Therapy.

To determine if the radiation sensitivity of cells that survive acute high-dose radiation exposure used in stereotactic body radiation therapy (SBRT), differs from the sensitivity of non-irradiated cells and cells that survive multiple 2 Gy doses of radiation. Isogenic rodent and two human tumor cell lines were exposed to 14 × 2 Gy of radiation, or a single acute dose of 12 Gy. The most resistant cell line was also exposed to an acute dose of 15 Gy. One week after 12 Gy, and 4 days after 14 × 2 Gy, surviving cells were exposed to 0-8 Gy in 2 Gy doses and cell survival was assessed by colony formation. In addition, the colony forming efficiency of 12 Gy survivors was evaluated for 1 month postirradiation. For cells exposed to 15 Gy, the response of surviving cells to 6 Gy was determined for up to 35 days postirradiation and compared to the 6 Gy surviving fraction of control cells. The radiation sensitivity of cells that survived 12 Gy exposure, and cells that survived 14 fractions of 2 Gy irradiation did not differ from the response of unirradiated control cells. However, the growth rate and colony forming efficiency of 12 Gy survivors was transiently reduced for greater than 2 weeks postirradiation. In contrast to the unchanged sensitivity of 12 Gy surviving cells at day 7 postirradiation, 15 Gy survivors exhibited enhanced sensitivity to radiation for up to 21 days postirradiation and suggests a biological basis for SBRT.

Toxicity of ZnFe-SO4 layered double hydroxide in Tetradesmus obliquus and evaluation of some physiological responses of the microalgae for stress management

Layered double hydroxides (LDHs), regarding their physical and structural properties, have different and wide applications industry and their increasing use may raise ecological and human health concerns. However, the potential toxicity mechanisms of LDHs in different organisms are still unclear. In the present work, after synthesizing of ZnFe-SO4 LDH and studying of its characterization by XRD, FT-IR, SEM, EDX-mapping, TEM and Raman, its toxicity in Tetradesmus obliquus was evaluated. According to experimental results, the growth of the algae and content of photosynthetic pigments were significantly decreased after treatment with 100 mg/L of ZnFe-SO4 LDH. The high dose exposure to the LDH also inhibited the activity of SOD and POD enzymes, possibly due to the LDH- catalyzed reactive oxygen species production. In addition, lipid peroxidation and the content of phenolic compounds, as no-enzymatic antioxidants were increased by enhancement of the LDH concentration. The rise of phenol, flavonoids and MDA contents could be regarded as some manifestations and responses to the toxic effects of the contaminant in the algae cells. The results provided a better understanding of the undesirable effects and toxicity of LDHs in aquatic organisms.

Effect of carvedilol versus placebo on cardiac function in anthracycline-exposed survivors of childhood cancer (PREVENT-HF): a randomised, controlled, phase 2b trial

Carvedilol improves cardiac function in patients with heart failure but remains untested as cardioprotective therapy in long-term childhood cancer survivors (ie, those who have completed treatment for childhood cancer and are in remission) at risk for heart failure due to high-dose anthracycline exposure. We aimed to evaluate the activity and safety of low-dose carvedilol for heart failure risk reduction in childhood cancer survivors at highest risk for heart failure. PREVENT-HF was a randomised, double-blind, phase 2b trial done at 30 hospitals in the USA and Canada. Patients were eligible if they had any cancer diagnosis that resulted in at least 250 mg/m2 cumulative exposure to anthracycline by age 21 years; completed their cancer treatment at least 2 years previously; an ejection fraction of at least 50% or fractional shortening of at least 25%, or both; and bodyweight of at least 40 kg. Patients were randomly assigned (1:1) with automated computer-generated permuted block randomisation (block size of 4), stratified by age at diagnosis, time since diagnosis, and history of chest-directed radiotherapy, to carvedilol (up-titrated from 3·125 g per day to 12·5 mg per day) or placebo orally for 2 years. Participants, staff, and investigators were masked to study group allocation. The primary endpoint was to establish the effect of carvedilol on standardised left ventricular wall thickness-dimension ratio Z score (LVWT/Dz). Treatment effects were analysed with a linear mixed-effects model for normally distributed data with a linear time effect and testing the significance of treatment*time interaction in the modified intention-to-treat (mITT) cohort (ie, all randomly assigned participants who had a baseline and at least one subsequent echocardiogram measurement). Safety was assessed in the ITT population (ie, all randomly assigned participants). This trial was registered with ClinicalTrials.gov, NCT027175073, and enrolment and follow-up are complete. Between July 3, 2012, and June 22, 2020, 196 participants were enrolled, of whom 182 (93%) were eligible and randomly assigned to either carvedilol (n=89) or placebo (n=93; ITT population). Median age was 24·7 years (IQR 19·6-36·6), 91 (50%) participants were female, 91 (50%) were male, and 119 (65%) were non-Hispanic White. As of data cutoff (June 10, 2022), median follow-up was 725 days (IQR 378-730). 151 (n=75 in the carvedilol group and n=76 in the placebo group) of 182 participants were included in the mITT population, among whom LVWT/Dz was similar between the two groups (-0·14 [95% CI -0·43 to 0·16] in the carvedilol group vs -0·45 [-0·77 to -0·13] in the placebo group; difference 0·31 [95% CI -0·10 to 0·73]; p=0·14). Two (2%) of 89 patients in the carvedilol group two adverse events of grade 2 or higher (n=1 shortness of breath and n=1 arthralgia) and none in the placebo group. There were no adverse events of grade 3 or higher and no deaths. Low-dose carvedilol appears to be safe in long-term childhood cancer survivors at risk for heart failure, but did not result in significant improvement of LVWT/Dz compared with placebo. These results do not support the use of carvedilol for secondary heart failure prevention in anthracycline-exposed childhood cancer survivors. National Cancer Institute, Leukemia & Lymphoma Society, St Baldrick's Foundation, Altschul Foundation, Rally Foundation, American Lebanese Syrian Associated Charities.

Phenotypic and transcriptional changes in lens epithelial cells following acute and fractionated ionizing radiation exposure

Purpose Exposure to ionizing radiation is one of the known risk factors for the development of lens opacities. It is believed that radiation interactions with lens epithelial cells (LEC) are the underlying cause of cataract development, however, the exact mechanisms have yet to be identified. The aim of this study was to investigate how different radiation dose and fractionation impact normal LEC function. Materials and methods A human derived LEC cell line (HLE-B3) was exposed to a single acute x-ray dose (0.25 Gy) and 6 fractionated doses (total dose of 0.05, 0.1, 0.25, 0.5, 1, and 2 Gy divided over 5 equal fractions). LEC were examined for proliferation using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and migration using a Boyden chamber assay at various time points (0.25, 0.5, 1, 2, 4, 7, 9, 11, and 14 d) post-irradiation. Transcriptomic analysis through RNA sequencing was also performed to identify differentially expressed genes and regulatory networks in cells following 4 different acute exposures and 1 fractionated exposure. Results Exposure to an acute dose of 0.25 Gy significantly increased proliferation and migration rates, peaking at 7 d post irradiation (20% and 240% greater than controls, respectively), before returning to baseline levels by day 14. Fractionated exposures had minimal effects up to a dose of 0.5 Gy, but significantly reduced proliferation and migration after 1 and 2 Gy by up to 50%. The largest transcriptional response occurred 12 h after an acute 0.25 Gy dose, with 362 genes up-regulated and 288 genes down-regulated. A unique panel of differentially expressed genes was observed between moderate versus high dose exposures, suggesting a dose-dependent transcriptional response in LEC that is more pronounced at lower doses. Gene ontology and upstream regulator analysis identified multiple biological processes and molecular functions implicated in the radiation response, in particular differentiation, motility, receptor/ligand binding, cell signaling and epithelial-mesenchymal cell transition. Conclusions Overall, this research provides novel insights into the dose and fractionation effects on functional changes and transcriptional regulatory networks in LEC, furthering our understanding of the mechanisms behind radiation induced cataracts.

The impact of chronic Trimethylamine N-oxide administration on liver oxidative stress, inflammation, and fibrosis

TMAO, a gut microbiota derived byproduct, has been associated with various cardiometabolic diseases by promoting oxidative stress and inflammation. The liver is the main organ for TMAO production and chronic exposure to high doses of TMAO could alter its function. In this study, we evaluated the effect of chronic exposure of high TMAO doses on liver oxidative stress, inflammation, and fibrosis.TMAO was administered daily via gastric gavage to laboratory rats for 3 months. Blood was drawn for the quantification of TMAO, and liver tissues were harvested for the assessment of oxidative stress (MDA, GSH, GSSG, GPx, CAT, and 8-oxo-dG) and inflammation by quantification of IL-1α, TNF-α, IL-10, TGF-β, NOS and COX-2 expression. The evaluation of fibrosis was made by Western blot analysis of α-SMA and Collagen-3 protein expression. Histological investigation and immunohistochemical staining of iNOS were performed in order to assess the liver damage. After 3 months of TMAO exposure, TMAO serum levels enhanced in parallel with increases in MDA and GSSG levels in liver tissue and lower values of GSH and GSH/GSSG ratio as well as a decrease in GPx and CAT activities. Inflammation was also highlighted, with enhanced iNOS, COX-2, and IL-10 expression, without structural changes and without induction of liver fibrosis.

Genetic and prognostic analysis of blastoid and pleomorphic mantle cell lymphoma: a multicenter analysis in China.

Blastoid or pleomorphic mantle cell lymphoma (B/P-MCL) is characterized by high invasiveness and unfavorable outcomes, which is still a challenge for treating MCL. This retrospective study was performed to comprehensively analyze the clinical, genomic characteristics and treatment options of patients with B/PMCL from multicenter in China. Data were obtained from 693 patients with B/PMCL from three centers in China between April 1999 and December 2019. Seventy-four patients with BMCL (n = 43) or PMCL (n = 31) were included in the analysis. The median age of the cohort was 60.0years with a male-to-female ratio of 2.89:1. The 3-year progression-free survival (PFS) and overall survival (OS) rates were 44.1% and 46.0%, respectively. Mutations of TP53, ATM, NOTCH1, NOTCH2, NSD2, SMARCA4, CREBBP, KMT2D, FAT1, and TRAF2 genes were the most common genetic changes in B/P-MCL. Progression of disease within 12months (POD12) could independently predict the poor prognosis of patients with blastoid and pleomorphic variants. Patients with POD12 carried a distinct mutation profile (TP53, SMARCA4, NSD2, NOTCH2, KMT2D, PTPRD, CREBBP, and CDKN2A mutations) compared to patients with non-POD12. First-line high-dose cytosine arabinoside exposure obtained survival benefits in these populations, and BTKi combination therapy as the front-line treatment had somewhat improvement in survival with no significant difference in the statistic. In conclusion, B/P-MCL had inferior outcomes and a distinct genomic profile. Patients with POD12 displayed a distinct mutation profile and a poor prognosis. New therapeutic drugs and clinical trials for B/P-MCL need to be further explored.

Comparative study between radiation exposure in common urological procedures

BackgroundFluoroscopy has become essential to urological surgery since advancement of endourology. Fluoroscopy use has increased, placing urologists as well as staff members at risk for occupational radiation exposure and related dangers. This study compared radiation exposure for staff personnel in percutaneous nephrolithotomy (PCNL), ureteroscopy (URS) and extracorporeal shock wave lithotripsy (ESWL). Then, study determined the maximum number of PCNL, URS and ESWL cases that staff members can handle safely each year.ResultsRadiation exposure in PCNL group was higher than URS and ESWL especially for surgeon. Dose of radiation exposure in ESWL for surgeon, assistant and nurse was 2.4 microsievert (μSv), 0.9 μSv and 0.8 μSv, respectively. Dose of radiation exposure in URS for surgeon, assistant and nurse was 18.5 μSv, 14.3 μSv and 13.1 μSv, respectively. Dose of radiation exposure in PCNL for surgeon, assistant and nurse was 73 μSv, 51.3 μSv and 47.6 μSv, respectively.ConclusionIncreased stone size and increased fluoroscopy time were associated with high radiation exposure. PCNL procedure was 8.8 times more likely to exhibit high-dose exposure than other procedures. Urologists can perform: 274 PCNL case, 1081 URS case and 8333 ESWL case per year within safe radiation exposure limits advised by International Commission on Radiation Protection (ICRP).

Long-term health complications of chemical weapon exposure: a study on Halabja chemical attack survivors (Iraqi Kurds)

Objective In 1988, the Iraqi government used a range of chemical weapons (CWs) against the Iraqi Kurds of Halabja. Here, we aim to investigate the long-term health consequences in exposed survivors as they are not sufficiently studied. Materials and methods This was a retrospective study conducted from November 2019 to May 2020 assessing the health status of all exposed Halabja chemical attack survivors compared to non-exposed people from the same area. Results and discussion Two hundred thirty survivors and 240 non-exposed participants were enrolled in this study, with control participants matched to age, gender, and occupation. Among the survivors, females were more prevalent. The respiratory system was the most common single exposure route (83, 36.1%), with 138 (60%) of the survivors being exposed by multiple routes. The vast majority (88.7%) of survivors had activities of daily living (ADL) impairment. There was female predominance in mild and moderate cases, with more males in severe cases (p < 0.01). Respiratory and cardiac diseases were significantly more common in the survivors compared to the controls (p < 0.001). Survivors with multiple CW exposure routes had significantly higher rates of ADL impairment (p < 0.001) and cardiac disease, respiratory diseases, and miscarriage (p < 0.01), than those with a single exposure route. Conclusion In this study comparing CW survivors with a local control population, a single, high-dose exposure to CWs was associated with significant increases in chronic respiratory and cardiac conditions, in addition to high rates of ADL impairment. Similar studies are needed in other, more recent CW survivor cohorts.

The Role of Oleuropein, Derived from Olives, in Human Skin Fibroblast Cells: Investigating the Underlying Molecular Mechanisms of Cytotoxicity and Antioxidant and Anti‐Inflammatory Activities

Oleuropein is the main compound in olives, producing a relatively bitter taste for unprocessed and raw olives. It has been dramatically applied in herbal and traditional medicine and contains several biological functions, anti‐inflammatory effects, antimicrobial characteristics, and anticancer and antioxidant activities. The present study dealt with the cytotoxic effect, reactive oxygen species (ROS) suppressor, and wound‐healing activity of oleuropein on normal skin cells. Oleuropein’s cytotoxic and apoptotic effects were evaluated using MTT, flow cytometry, and DAPI staining. Moreover, oleuropein’s possible free radical scavenging properties were studied through several methods, including the 2, 2‐diphenyl‐1‐picrylhydrazyl (DPPH) and ABTS tests. The scratch assay was performed for wound‐healing features, and qRT‐PCR evaluated the expression of apoptosis‐associated genes. Oleuropein was found to have a cytotoxic effect on skin cells at higher exposure doses. Apoptosis was induced in the flow cytometry histogram of the cells treated with oleuropein. The results also revealed the strong anti‐inflammation and antioxidant effect of oleuropein. They suggested that more studies are necessary to assess the possible pharmacological use of oleuropein to prevent or decrease skin‐related diseases.

Effects of multiple anesthetic exposures on rhesus macaque brain development: a longitudinal structural MRI analysis.

Concerns about the potential neurotoxic effects of anesthetics on developing brain exist. When making clinical decisions, the timing and dosage of anesthetic exposure are critical factors to consider due to their associated risks. In our study, we investigated the impact of repeated anesthetic exposures on the brain development trajectory of a cohort of rhesus monkeys (n = 26) over their first 2yr of life, utilizing longitudinal magnetic resonance imaging data. We hypothesized that early or high-dose anesthesia exposure could negatively influence structural brain development. By employing the generalized additive mixed model, we traced the longitudinal trajectories of brain volume, cortical thickness, and white matter integrity. The interaction analysis revealed that age and cumulative anesthetic dose were variably linked to white matter integrity but not to morphometric measures. Early high-dose exposure was associated with increased mean, axial, and radial diffusivities across all white matter regions, compared to late-low-dose exposure. Our findings indicate that early or high-dose anesthesia exposure during infancy disrupts structural brain development in rhesus monkeys. Consequently, the timing of elective surgeries and procedures that require anesthesia for children and pregnant women should be strategically planned to account for the cumulative dose of volatile anesthetics, aiming to minimize the potential risks to brain development.

Dual-vat photopolymerization 3D printing of vitrimers

Herein, the processing of multi-material vitrimers with heterogenous properties along their x-,y- and z-axis is demonstrated using dual-vat digital light processing (DLP) 3D printing. The printer is based on a conventional vat exchange set-up containing two vats and a cleaning station, which are positioned on a linearly moving platform, and are exchanged automatically during the layer-by-layer build-up of the object. Two thiol-acrylate resins are selected bearing ample -OH and ester moieties, which undergo thermo-activated transesterification in the presence of an organic phosphate as catalyst. Based on the functionality of the acrylate monomers, printing of multi-material structures with flexible (σ = 1.1 MPa, ε = 14.0%) and rigid (σ = 33.3 MPa, ε = 4.4%) domains is feasible. A good interlayer adhesion between the soft and hard domains is evidenced by uniaxial tensile tests, whilst optical microscopy is used to study the interface. Dynamic mechanical analysis further shows that the stiffness of the photopolymers varies over several orders of magnitude (E’23 °C = 209 kPa - 507 MPa). Jacobs working curves of the two different resins reveal comparable printing parameters at higher exposure doses, which do not only facilitate the printing of multiple materials between individual layers (z-heterogeneity) but also within the same layer (x,y-heterogeneity). This is confirmed by the printing of a multi-material gripper as “proof of concept” demonstrator, which contains soft inner teeth and a stiff outer core. Gripping and releasing of objects is shown by exploiting the glass transition-based shape memory properties of the stiff domains. Moreover, due to the dynamic nature of the covalent bonds, damages inserted into the gripper are intrinsically repairable due to a thermo-activated macroscopic reflow. Shape memory experiments further confirmed that the multi-material gripper fully regains its function after the thermal mending process. Thus, the results clearly show that objects with a high degree of functionality can be realized by combining multi-material 3D printing with the chemistry of vitrimers. This is of particular interest for future soft robotic applications and for mimicking biological composite structures.

Mechanistic insights into aniline-induced liver injury: Role of the mmu_circ_26984/Myh9/NLRP3 axis and modulation by N-acetylcysteine

Aniline is a widely used chemical. Chronic or high-dose exposure to aniline can lead to hepatocellular damage. Although the hepatic pathogenicity of aniline has been established in previous studies, studies involving pathogenic genes during aniline-induced liver injury are limited. Our study first discovered and identified the role and mechanism underlying a new circRNA mmu_circ_26984 in aniline-induced chemical liver injury. Further, we discuss the protective effect of N-acetylcysteine (NAC) in this pathway. After constructing in vitro and in vivo models of aniline treatment, we screened the circRNA with significant differences in expression in AML12 cells from control and aniline-treated groups by circRNA microarray analysis. Next, using RNA pulldown, liquid chromatography-mass spectrometry (LC-MS), and RNA immunoprecipitation, we analyzed the relationship between mmu_circ_26984 and myosin heavy chain 9 (Myh9). Subsequently, we determined the specific mechanism of action of mmu_circ_26984 and Myh9 in aniline-induced liver injury and the protective effect of NAC against aniline-induced liver injury process using Cell Counting Kit-8, Western blot, RNA extraction, a reverse transcription quantitative polymerase chain reaction (RT-qPCR), fluorescence in situ hybridization, immunohistochemistry, and immunofluorescence. The expression of mmu_circ_26984 was significantly increased in liver tissues and AML12 cells of aniline-treated mice compared with the control group. This high expression of mmu_circ_26984 increased the expression of injury-related inflammatory factors, such as NLRP3, Caspase-1, IL-18, and IL-1β in vivo and ex vivo, which exacerbated the level of liver injury. The interaction of mmu_circ_26984 with Myh9 also affected the course of liver injury. Mmu_circ_26984 overexpression and reduced treatment affected the levels of Myh9 expression in AML12 cells, as well as downstream inflammatory factors associated with injury, such as NLRP3. In addition, NAC reduced the process of liver injury mediated by the mmu_circ_26984/Myh9/NLRP3 axis. In conclusion, mmu_circ_26984 is a potential molecular marker and therapeutic target in the process of aniline-induced liver injury that can mediate aniline-exposure-induced liver injury via modulation of the mmu_circ_26984/Myh9/NLRP3 axis, and NAC can effectively attenuate the effect of this liver injury.