Drug-induced liver injury (DILI) has become a leading cause of severe liver disease in Western countries and therefore poses a major clinical and regulatory challenge. Whereas previously ...drug-specific pathways leading to initial injury of liver cells were the main focus of mechanistic research and classifications, current concepts see these as initial upstream events and appreciate that subsequent common downstream pathways and their attenuation by drugs and other environmental and genetic factors also have a profound impact on the risk of an individual patient to develop overt liver disease. This review summarizes current mechanistic concepts of DILI in a 3-step model that limits its principle mechanisms to three main ways of initial injury, i.e. direct cell stress, direct mitochondrial impairment, and specific immune reactions. Subsequently, initial injury initiates further downstream events, i.e. direct and death receptor-mediated pathways leading to mitochondrial permeability transition, which then results in apoptotic or necrotic cell death. For all mechanisms, mitochondria play a central role in events leading to apoptotic vs. necrotic cell death. New treatment targets consequently focus on interference with downstream pathways that mediate injury and therefore determine the ultimate outcome of DILI. Genome wide and targeted pharmacogenetic as well as metabonomic approaches are now used in order to reach the key goals of a better understanding of mechanisms in hepatotoxicity, and to develop new strategies for its prediction and treatment. However, the complexity of interactions between genetic and environmental risk factors is considerable, and DILI therefore currently remains unpredictable for most hepatotoxins.
Montreal cognitive assessment (MoCA) is a test providing a brief screening for people with cognitive impairment due to aging or neurodegenerative syndromes. In Italy, as in the rest of the world, ...several validation studies of MoCA have been carried out. This study compared, for the first time in Italy, a sample of people with probable Alzheimer’s Disease (AD) with healthy counterparts. The study also compared two community-dwelling groups of aged participants with and without probable cognitive impairment, as discriminated by two cut-off points of adjusted MMSE score. All the comparisons were carried out according to ROC statistics. Optimal cutoff for a diagnosis of probable AD was a MoCA score ≤14. Optimal cutoff for the discrimination of probable cognitive impairment was a MoCA score ≤17 (associated to MMSE cutoff of 23.8). Results confirm the substantial discrepancy in cut-off points existing between Italian and other international validation studies, showing that Italian performance on MoCA seems to be globally lower than that in other Countries. Characteristics of population might explain these results.
Abstract
The current pandemic has exerted an unprecedented psychological impact on the world population, and its effects on mental health are a growing concern. The present study aims to evaluate ...psychological well-being (PWB) during the COVID-19 crisis in university workers with one or more diseases likely to increase the risk of severe outcomes in the event of SARS-CoV-2 infection, defined as susceptible. 210 susceptible employees of an Italian University (aged 25–71 years) were recruited during the COVID-19 second wave (October–December 2020). A group comprising 90 healthy university employees (aged 26–69 years) was also recruited. The self-report Psychological General Well Being Index (PGWBI) was used to assess global PWB and the influence on six sub-domains: anxiety, depressed mood, positive well-being, self-control, general health, and vitality. We applied non-linear dimension-reduction techniques and regression methods to 45 variables in order to assess the main demographic, occupational, and general-health-related factors predicting PWB during the COVID-19 crisis. PGWBI score was higher in susceptible than in healthy workers, both as total score (mean 77.8 vs 71.3) and across almost all subscales. Age and jobs involving high social interaction before the pandemic were inversely associated with the PWB total score, general health, and self-control subscores. The current data suggest no decline in PWB during the second wave of COVID-19 health emergency in susceptible individuals of working age. Critically, higher risk for mental-health issues appears to be inversely related to age, particularly among individuals deprived of their previous level of social interaction at work.
Abstract
The gastrointestinal tract is a natural reservoir of microbiota. The gut is germ-free at birth, but rapidly becomes host to various bacteria establishing a progressively mutual relationship. ...The composition of gut microbiota is individual-specific and depends on the genotype of the host and environmental factors. Novel techniques have been used to characterize gastrointestinal microbiota, including genomic approaches. The bacterial profile shows that dominant and minor phyla are present in the gastrointestinal tract. From the proximal to the distal segments of the gut the bacterial density gradually increases, reaching an estimated 1011 to 1012 bacteria per gram of colonic content. Dynamic interactions between gut and microbiota play a physiological role in metabolic, protective and structural functions, while dysbiosis contributes to several diseases. Microbiota appear to play a role in IBS, where qualitative and quantitative changes of bacteriaoccur in IBS subtypes. Initial therapeutic approaches in IBS have focused on microbiota. The relationship between perturbations of the microbiota, mucosal inflammation and IBS remains to be further investigated.
Introduction: Health promotion is the highest level of human sensitivity directed to break down differences and produce equal opportunities for unselected people to enjoy the best health care ...potential. This study aimed to evaluate the quality of the assistance provided to immigrants by Italian general practitioners (GPs), the level of satisfaction declared by migrants, and the perception of GPs about the needs of migrants.
Methods: A survey was conducted. Both immigrant patients (regular and illegal) and some Italian GPs filled a questionnaire. Ten GPs were selected among those available to perform the study by a convenience sampling method; the immigrants were consecutively included among those attending the medical offices.
Results: Over 90% (n = 66) of immigrants declared to be fully satisfied with the overall assistance provided with easy access to care. GPs declared no problems in assisting even illegal immigrants and suggested the accurate evaluation of patients’ needs to provide successful care.
Conclusions: These findings indicate the importance of promoting health and education as provided by Italian GPs. The satisfaction declared by the interviewed immigrants is mainly attributable to the model of assistance provided in Apulia, which includes interventions for any health problem.
Drug-induced liver injury is a significant and still unresolved clinical problem. Limitations to knowledge about the mechanisms of toxicity render incomplete the detection of hepatotoxic potential ...during preclinical development. Several xenobiotics are lipophilic substances and their transformation into hydrophilic compounds by the cytochrome P-450 system results in production of toxic metabolites. Aging, preexisting liver disease, enzyme induction or inhibition, genetic variances, local 02 supply and, above all, the intrinsic molecular properties of the drug may affect this process. Necrotic death follows antioxidant consumption and oxidation of intracellular proteins, which determine increased permeability of mitochondrial membranes, loss of potential, decreased ATP synthesis, inhibition of Ca^2＋-dependent ATPase, reduced capability to sequester Ca^2＋ within mitochondria, and membrane bleb formation. Conversely, activation of nucleases and energetic participation of mitochondria are the main intracellular mechanisms that lead to apoptosis. Non-parenchymal hepatic cells are inducers of hepatocellular injury and targets for damage. Activation of the immune system promotes idiosyncratic reactions that result in hepatic necrosis or cholestasis, in which different HLA genotypes might play a major role. This review focuses on current knowledge of the mechanisms of drug-induced liver injury and recent advances on newly discovered mechanisms of liver damage. Future perspectives including new frontiers for research are discussed.
AIM: To investigate in vitro the therapeutic effect and mechanisms of silybin in a cellular model of hepatic steatosis.METHODS: Rat hepatoma Fa O cells were loaded with lipids by exposure to 0.75 ...mmol/L oleate/palmitate for 3 h to mimic liver steatosis. Then, the steatotic cells were incubated for 24 h with different concentrations(25 to 100 μmol/L) of silybin as phytosome complex with vitamin E. The effects of silybin on lipid accumulation and metabolism, and on indices of oxidative stress were evaluated by absorption and fluorescence microscopy, quantitative real-time PCR, Western blot, spectrophotometric and fluorimetric assays.RESULTS: Lipid-loading resulted in intracellular triglyceride(TG) accumulation inside lipid droplets, whose number and size increased. TG accumulation was mediated by increased levels of peroxisome proliferator-activated receptors(PPARs) and sterol regulatory element-binding protein-1c(SREBP-1c). The lipid imbalance was associated with higher production of reactive oxygen species(ROS) resulting in increased lipid peroxidation, stimulation of catalase activity and activation of nuclear factor kappa-B(NF-κB). Incubation of steatotic cells with silybin 50 μmol/L significantly reduced TG accumulation likely by promoting lipid catabolism and by inhibiting lipogenic pathways, as suggested by the changes in carnitine palmitoyltransferase 1(CPT-1), PPAR and SREBP-1c levels. The reduction in fat accumulation exerted by silybin in the steatotic cells was associated with the improvement of the oxidative imbalance caused by lipid excess as demonstrated by the reduction in ROS content, lipid peroxidation, catalase activity and NF-κB activation.CONCLUSION: We demonstrated the direct antisteatotic and anti-oxidant effects of silybin in steatotic cells, thus elucidating at a cellular level the encouraging results demonstrated in clinical and animal studies.
Primary biliary cirrhosis is a multifactor autoimmune disease characterized by hepatic and systemic manifestations,with immune system dysregulation and abnormalities in the hepatic metabolism of bile ...salts,lipids,and nutrients,as well as destruction of membrane lipids and mitochondrial dysfunction.Both oxidative and nitrosative stress are associated with ongoing manifestations of the disease.In particular,abnormalities in nitric oxide metabolism and thiol oxidation already occur at early stages,thus leading to the hypothesis that these biochemical events play a pathogenic role in primary biliary cirrhosis.Moreover,the association of these metabolic abnormalities with the progression of the disease may indicate some biochemical parameters as early diagnostic markers of disease evolution,and may open up the potential for pharmacological intervention to inhibit intra-and extra-cellular stress events for resuming hepatocellular functions.The following paragraphs summarize the current knowledge by outlining molecular mechanisms of the disease related to these stress events.
Literature on driving research suggests a relationship between cognition and driving performance in older and younger drivers. There is little research on adults and driving, despite them being the ...largest age cohort behind the wheel. Among the cognitive domains, visuospatial abilities are expected to be highly predictive of driving skills and driving fitness. The relationship between specific spatial mental transformation skills (i.e., object and self-based ones) and driving performance has not yet been examined. The present study aimed to investigate the relationship between overall cognitive functioning, self and object-based spatial mental transformation skills, and driving performance in a sample of younger and older adult drivers. Participants were comprised of one hundred younger and 83 older adult Italian drivers. Participants completed a computerized driving test assessing traffic stress resilience, visual and motor reaction time, and the ability to obtain an overview of the traffic scenario (DT, vRT, mRT, and ATAV respectively in the Shufried®-Vienna Test System-DRIVESC). The Mental Rotation Test (MRT) and the Object Perspective Taking Test (OPT) were administered in order to assess object-based and self-based spatial mental transformation skills. The Montreal Cognitive Assessment Test (MoCA) was administered control for global cognitive functioning. The effects of education and gender were also controlled in the analysis. The results of the present study suggested that: (1) The effect of age, favoring younger participants, was found in DT, vRT, mRT, and ATAVT tests. (2) The effect of global cognitive functioning was found in DT and ATAV tests. (3) The effect of the spatial mental transformation tests was found in DT, vRT (MRT only), and ATAVT (OPT only) tests. Taken together, these results suggest the specific contribution of spatial mental transformation skills in the execution of complex behaviors connected to the fitness to drive. Prospectively, the results of the present study relating spatial mental transformation skills and driving processes may be a valuable source of knowledge for researchers dealing with the relationship between cognitive resources and navigation aids.
The aims of the present study were to identify empirically supported psychosocial intervention programs for young people with conduct problems and to evaluate the underpinnings, techniques and ...outcomes of these treatments. We analyzed reviews and meta-analyses published between 1982 and 2016 concerning psychosocial intervention programs for children aged 3 to 12 years with conduct problems. Parent training should be considered the first-line approach to dealing with young children, whereas cognitive behavioral approaches have a greater effect on older youths. Family interventions have shown greater efficacy in older youths, whereas multi-component and multimodal treatment approaches have yielded moderate effects in both childhood and adolescence. Some limitations were found, especially regarding the evaluation of effects. To date, no single program has emerged as the best. However, it emerges that the choice of intervention should be age-specific and should take into account developmental differences in cognitive, behavioral, affective and communicative abilities.
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