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Abstract NADH:ubiquinone oxidoreductase (respiratory complex I) plays a major role in energy metabolism by coupling electron transfer from NADH to quinone with proton translocation across the membrane. Complex I deficiencies were found to be the most common source of human mitochondrial dysfunction that manifest in a wide variety of neurodegenerative diseases. Seven subunits of human complex I are encoded by mitochondrial DNA (mtDNA) that carry an unexpectedly large number of mutations discovered in mitochondria from patients’ tissues. However, whether or how these genetic aberrations affect complex I at a molecular level is unknown. Here, we used Escherichia coli as a model system to biochemically characterize two mutations that were found in mtDNA of patients. The V253AMT-ND5 mutation completely disturbed the assembly of complex I, while the mutation D199GMT-ND1 led to the assembly of a stable complex capable to catalyze redox-driven proton translocation. However, the latter mutation perturbs quinone reduction leading to a diminished activity. D199MT-ND1 is part of a cluster of charged amino acid residues that are suggested to be important for efficient coupling of quinone reduction and proton translocation. A mechanism considering the role of D199MT-ND1 for energy conservation in complex I is discussed.

Background: The other side of radiotherapy (RT), in addition to the cytotoxic effect, is the ability to modulate the immune system in terms of activation or suppression, also depending on the dose and fractionation delivered. This immune RT effect can be detected both locally in the irradiated tumor site and in the peripheral blood. The aim of this study was to assess the consequence of pelvic irradiation on peripheral immune cells and cytokine secretions in localized prostate cancer (PC) patients undergoing pelvic irradiation with a simultaneous moderately hypofractionated prostate/prostate bed boost by Volumetric Modulated Arc Therapy (VMAT). Furthermore, we analyzed whether there was a correlation between these peripheral immune parameters and acute and late genitourinary (GU) and gastrointestinal (GI) toxicity. Methods: Thirty-eight PC patients were treated with pelvis irradiation (dose per fraction 1.8 Gy) and simultaneous hypofractionated (median dose per fraction: 2.7 Gy) prostate/prostate bed boost. A longitudinal analysis was performed for 12 months on peripheral blood to assess changes in 9 different lymphocyte subpopulations by flow cytometry and 10 circulating cytokines by Multiplex Luminex assay and ELISA. Results: Our analysis revealed that basal IFN-γ serum values were significantly lower in the definitive (curative intent for patients with prostate) patient group respect to the post-operative one. All the lymphocyte subsets and IFN-α, IFN-β and Il-2 peripheral concentrations displayed significant variations between the different time points considered. The immune cell population that suffers the greatest RT toxicity in the blood was B lymphocyte. We found an interesting correlation between basal TGF-β1 and late GU toxicity. In particular, TGF-β1 concentrations before RT were significantly higher in patients that experienced grade 2-3 of late GU toxicity, respect to grade 0-1. Exploring possible correlations between some clinical/biological findings and radiation planning parameters, we found no statistical significance. Conclusions: Our study analyzed, in the context of hypofractionated radiotherapy in prostate cancer, different parameters of the peripheral immune system. We have highlighted longitudinally the peripheral behavior of the different lymphocyte subpopulations and of a group of 10 cytokines during the first year after RT. One of the analyzed cytokines, such as TGF-β1, has proven to be promising predictive factor of severe late GU toxicity. [ABSTRACT FROM AUTHOR]

Novel benzodiazepine (NBz) detections in Victorian coronial cases started early in 2018 and have continued to increase in number and type up to December 2022. The 11 different NBz detections included etizolam (n  = 82), flualprazolam (n  = 43), clonazolam or 8-aminoclonazolam (n  = 30), bromazolam (n  = 15), clobromazolam (n  = 13), phenazepam (n  = 13), flubromazolam (n  = 12), flubromazepam (n  = 8), desalkylflurazepam (n  = 6), diclazepam (n  = 2), and estazolam (n  = 1). The pattern of detections varied over the 5-year period, with different compounds appearing over different time frames. The most recent NBz to appear were bromazolam, clobromazolam, flubromazepam, and phenazepam, whereas etizolam had been seen regularly in case work since 2018. Of the total 133 deaths, 95 were considered drug-related deaths by forensic pathologists with at least one additional CNS depressant also present capable of contributing to death. All deaths involved other (non-benzodiazepine) CNS active drugs, although many involved multiple NBz, with five or more different benzodiazepines detected in eight cases. [ABSTRACT FROM AUTHOR]

Background/Objectives: Mental disorders in nursing students, although very common under normal circumstances, have worsened over time due to the COVID-19 pandemic. This study aimed to assess (1) what the prevalence of anxiety and depression symptoms in Italian nursing students was and (2) what factors were associated with them. Methods: In May 2023, a cross-sectional study was conducted on the bachelor's degree Nursing course in an Italian university. Levels of anxiety and stress were assessed using the Generalized Anxiety Disorder Scale (GAD-7) and the Patient Health Questionnaire (PHQ-9), respectively. In addition, socio-demographic variables and data on mental health, drug intake, and substance use were collected. Multiple binary logistic regression adjusted analyses were used to identify predictive factors. Results: A total of 148 nursing students completed the questionnaire. A total of 9.5% reported a previous diagnosis of a mental disorder, and, of these, 35.7% reported that it was diagnosed after the start of the COVID-19 pandemic. The mean GAD-7 and PHQ-9 score was 9.68 (SD = 5.2) and 8.37 (SD = 5.6), respectively. Protective factors for depressive symptoms included not having a previous diagnosis of a mental disorder (adjusted odds ratio = 0.10, 95% CI: 0.002–0.47, p < 0.001) and a perceived high (adjusted odds ratio = 0.03, 95% CI: 0.003–0.22 p < 0.001) or medium (adjusted odds ratio = 0.14, 95% CI: 0.03–0.82, p < 0.05) socioeconomic level, while the predictor of anxiety symptoms was returning home once a month for students studying away from their residence (adjusted odds ratio = 6.4, 95% CI: 1.01–40.8, p < 0.05). Conclusions: Urgent investments are needed in universities to implement mental health promotion programmes and to offer counselling services to reduce and prevent mental health problems among students. [ABSTRACT FROM AUTHOR]

Introduction: Influenza A is a virus from the Orthomixoviridae family responsible for high lethality rates and morbidity, despite clinically proven vaccination strategies and some anti-viral therapies. The eicosanoid Lipoxin A4 (LXA4) promotes the resolution of inflammation by decreasing cell recruitment and pro-inflammatory cytokines release, but also for inducing activation of apoptosis, efferocytosis, and macrophage reprogramming. Objective: Here, we evaluated whether a synthetic lipoxin mimetic, designated AT-01-KG, would improve the course of influenza A infection in a murine model. Method: Mice were infected with influenza A/H1N1 and treated with AT-01-KG (1.7 μg/kg/day, i.p.) at day 3 post-infection. Results: AT-01-KG attenuated mortality, reducing leukocyte infiltration and lung damage at day 5 and day 7 post-infection. AT-01-KG is a Formyl Peptide Receptor 2 (designated FPR2/3 in mice) agonist, and the protective responses were not observed in fpr2/3 −/− animals. In mice treated with LXA4 (50 μg/kg/day, i.p., days 3–6 post-infection), at day 7, macrophage reprogramming was observed, as seen by a decrease in classically activated macrophages and an increase in alternatively activated macrophages in the lungs. Furthermore, the number of apoptotic cells and cells undergoing efferocytosis was increased in the lavage of treated mice. Treatment also modulated the adaptive immune response, increasing the number of T helper 2 cells (Th2) and regulatory T (Tregs) cells in the lungs of the treated mice. Conclusion: Therefore, treatment with a lipoxin A4 analog was beneficial in a model of influenza A infection in mice. The drug decreased inflammation and promoted resolution and beneficial immune responses, suggesting it may be useful in patients with severe influenza. [ABSTRACT FROM AUTHOR]

Different factors influence the recovery rate and treatment outcome of children with wasting using ready-to-use therapeutic food (OTP). Hence, our study aimed to assess determinants of the recovery rate among children with severe acute malnutrition (SAM) managed in OTP. A facility-based retrospective cohort study was conducted on 561 children treated in OTP. The proportion of recovery was 77.4%. The presence of edema, provision of amoxicillin, folic acid, and weight gain in the first 3 weeks were determinants of improved recovery rate. A better recovery rate could be achieved through improving the adherence to the proper administration of routine medications. [ABSTRACT FROM AUTHOR]

A multi‐analyte liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) method is described, involving the separation of delta‐9‐tetrahydrocannabinol (delta‐9‐THC) and delta‐8‐THC in addition to other commonly encountered drugs and metabolites. Briefly, sample preparation involved an alkaline liquid–liquid extraction (methyl tert‐butyl ether) of blood (100 μl). The solvent layer was transferred, evaporated to dryness, reconstituted, and samples then separated on an Agilent Poroshell 120 EC‐C18 100 Å (50 mm × 3.0 mm, 2.7 μm) analytical column using a multi‐step gradient elution of 50 mM ammonium formate in water (pH 3.5) and 0.1% formic acid in methanol over 14 min. A SCIEX Triple Quad 6500+ system operating in scheduled multiple reaction monitoring and positive electrospray ionization was used for detection. There were no interferences, and matrix effects were generally acceptable (±20% of neat response). Linearity was achieved within the calibration range, including methylamphetamine (MA) (10–1000 ng/ml), 3,4‐methylenedioxy‐N‐methylamphetamine (MDMA) (10–1,000 ng/ml), cocaine (10–1000 ng/ml), and two THC isomers (1–100 ng/ml). Accuracies of MA, MDMA, cocaine, and two THC isomers were 3.6 to 8.9%, −1.2 to 4%, −5.3 to 5.8%, and −11 to 14%, respectively; while precision estimates of the same were 1.6 to 5.4%, 1.7 to 5.3%, 1.2 to 4.5%, and 2 to 10%, respectively. Autosampler stability and dilution integrity were within acceptable limits, and no carryover was detected at the limit of detection. This validated LC‐MS/MS method made the routine identification of both delta‐9‐THC and delta‐8‐THC in blood possible. [ABSTRACT FROM AUTHOR]

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Prostate cancer (PCa) is the third highest cause of cancer death in men. PCa is a very heterogeneous tumor form in terms of grade, phenotypes, and genetics, often accompanied by complex networks. PCa is characterized by slow growth that does not compromise the patient's quality of life, unlike more aggressive forms showing rapid growth and progression. Early diagnosis, even for the most aggressive forms, increases the possibilities of cure with less aggressive treatments and fewer side effects. However, it is important to know how to decrease the exposure to modifiable risk factors, including diet, sedentary life, smoking and alcohol, can represent an effective tool to reduce the incidence of PCa. In addition, the chronic exposure to environmental factors, most of which act as endocrine disruptors, is the focus of recent studies for their potential role in promoting the onset and progression of PCa. Although molecular therapies and clinical trials for biomarker identification have been introduced into the management of PCa, these still lag behind research performed in other solid tumors. This review provides an overview of the modifiable factors of PCa, linked to lifestyle and environmental pollutants, which together with the development of new therapeutic targets, can reduce the incidence of PCa and improve the quality of life of patients. [ABSTRACT FROM AUTHOR]