114 research outputs found

    AUTOPHAGY OF METALLOTHIONEINS PREVENTS TNF-INDUCED OXIDATIVE STRESS AND TOXICITY IN HEPATOMA CELLS

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    Lysosomal membrane permeabilization (LMP) induced by oxidative stress has recently emerged as a prominent mechanism behind TNF cytotoxicity. This pathway relies on diffusion of hydrogen peroxide into lysosomes containing redox-active iron, accumulated by breakdown of iron-containing proteins and subcellular organelles. Upon oxidative lysosomal damage, LMP allows relocation to the cytoplasm of low mass iron and acidic hydrolases that contribute to DNA and mitochondrial damage, resulting in death by apoptosis or necrosis. Here we investigate the role of lysosomes and free iron in death of HTC cells, a rat hepatoma line, exposed to TNF following metallothionein (MT) upregulation. Iron-binding MT does not normally occur in HTC cells in significant amounts. Intracellular iron chelation attenuates TNF and cycloheximide (CHX)-induced LMP and cell death, demonstrating the critical role of this transition metal in mediating cytokine lethality. MT upregulation, combined with starvation-activated MT autophagy almost completely suppresses TNF and CHX toxicity, while impairment of both autophagy and MT upregulation by silencing of Atg7, and Mt1a and/or Mt2a, respectively, abrogates protection. Interestingly, MT upregulation by itself has little effect, while stimulated autophagy alone depresses cytokine toxicity to some degree. These results provide evidence that intralysosomal iron-catalyzed redox reactions play a key role in TNF and CHX-induced LMP and toxicity. The finding that chelation of intralysosomal iron achieved by autophagic delivery of MT, and to some degree probably of other iron-binding proteins as well, into the lysosomal compartment is highly protective provides a putative mechanism to explain autophagy-related suppression of death by TNF and CHX

    Procjena kritińćnih tońćaka lezija papaka u mlijeńćnih krava: preliminarno istraŇĺivanje novog sustava bodovanja

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    Lameness is a serious animal welfare and production issue in the modern dairy herds. The development of a scoring system that is able to categorize the farm on the basis of its hazard risk level may help clinicians and farmers to identify potential issues and to reduce costs caused by lameness. The aim of this study was to develop an easy and fast score for evaluation of the structural and managerial factors potentially involved in the pathogenesis of foot lesions, and categorization of dairy farms. A total of six free-stall dairy farms were evaluated during a 3 month-period. The score developed in this study was composed of evaluation of the housing system, flooring, the farm design, the use of footbaths, the frequency of hoof trimming, and the continuing education of the employers. For each parameter, a score of 0 to 2 was assigned where the score 0 meant the least appropriate condition, the score 2 represented the best. The Farm Score showed a significant correlation with foot lesion prevalence (P = 0.0011, R2 0.94) and with the theoretical assessment of additional cost per animal (P = 0.001, R2 0.95). The significant correlation between the Farm Score, the foot lesion prevalence and the theoretical assessment of additional costs per animal may underline the potential usefulness of the score designed in this study. The Farm Score may be considered as a cheap and fast way to evaluate the hazard risk level for claw health on a dairy farm.U mlijeńćnim je stadima hromost danas vaŇĺno pitanje dobrobiti i proizvodnje Ňĺivotinja. Razvoj sustava bodovanja za kategorizaciju farmi na temelju razine rizika od hromosti moŇĺe pomońái klinińćarima, odnosno stońćarima, pri utvrńĎivanju potencijalnih problema i smanjenju troŇ°kova uzrokovanih tom boleŇ°ńáu. Cilj ovog istraŇĺivanja bio je razviti jednostavan i brz sustav za procjenu strukturnih i upravljańćkih ńćimbenika u proizvodnji koji bi mogli biti ukljuńćeni u patogenezu lezija papaka i posluŇĺiti za kategorizaciju mlijeńćnih farmi. Tijekom tri mjeseca istraŇĺivano je ukupno Ň°est mlijeńćnih farmi sa slobodnim nańćinom drŇĺanja. Sustav bodovanja farmi uspostavljen u ovom istraŇĺivanju ukljuńćivao je nastambe za Ňĺivotinje, podove, organizaciju farme, upotrebu kupki za papke, uńćestalost obrade papaka i kontinuiranom edukaciju zaposlenika. Svakom je pokazatelju dodijeljen bod od 0 do 2, pri ńćemu 0 oznańćuje najmanje prikladno stanje, a 2 najbolje stanje. Sustav bodovanja na farmi pokazao je znakovit odnos sa prevalencijom lezija papaka (P = 0,0011, R2 0,94) kao i sa teoretskom procjenom dodatnih troŇ°kova po Ňĺivotinji (P = 0,001, R2 0,95). Navedeno naglaŇ°ava potencijalnu korist sustava bodovanja uspostavljenog u ovom istraŇĺivanju kao jeftinog i brzog nańćina procjene razine rizika za zdravlje papaka na mlijeńćnim farmama

    First report of the presence of Necrodes littoralis (L.) (Coleoptera: Silphidae) on a human corpse in Italy

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    The colonization of a human body by Necrodes littoralis (L.) (Coleoptera: Silphidae) is reported for the first time in Italy. This species is both necrophagous and predator of necrophagous fauna. The body colonized by the coleopteran was found indoors, in an advanced decomposition stage, in a suburban area of Cosenza (Calabria, Southern Italy) in November. Insects (adults, puparia and larvae) were collected on and around the body. Puparia and larvae were raised in the laboratory until the adult stage for morphological identification, which was carried out through taxonomical keys. Besides N. littoralis, also the presence of Calliphora vicina Robineau-Desvoidy, Chrysomya albiceps (Wiedemann) (Diptera: Calliphoridae), Hydrotaea dentipes (Fabricius) (Diptera: Muscidae), and Creophilus maxillosus (L.) (Coleoptera: Staphylinidae) was detected. Necrodes littoralis is a species of forensic interest because it may colonize human and vertebrate corpses and has been reported elsewhere in Europe

    Sex differences in brain homotopic co-activations: a meta-analytic study

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    An element of great interest in functional connectivity is ‚Äėhomotopic connectivity‚Äô (HC), namely the connectivity between two mirrored areas of the two hemispheres, mainly mediated by the fibers of the corpus callosum. Despite a long tradition of studying sexual dimorphism in the human brain, to our knowledge only one study has addressed the influence of sex on HC. We investigated the issue of homotopic co-activations in women and men using a coordinate-based meta-analytic method and data from the BrainMap database. A first unexpected observation was that the database was affected by a sex bias: women-only groups are investigated less often than men-only ones, and they are more often studied in certain domains such as emotion compared to men, and less in cognition. Implementing a series of sampling procedures to equalize the size and proportion of the datasets, our results indicated that females exhibit stronger interhemispheric co-activation than males, suggesting that the female brain is less lateralized and more integrated than that of males. In addition, males appear to show less intense but more extensive co-activation than females. Some local differences also appeared. In particular, it appears that primary motor and perceptual areas are more co-activated in males, in contrast to the opposite trend in the rest of the brain. This argues for a multidimensional view of sex brain differences and suggests that the issue should be approached with more complex models than previously thought. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00429-022-02572-0

    Exploratory study on the associations between lifetime post-traumatic stress spectrum, sleep, and circadian rhythm parameters in patients with bipolar disorder

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    : The present study aimed at exploring whether lifetime post-traumatic stress spectrum symptoms are associated with chronotype in patients with bipolar disorder (BD). Moreover, we explored whether the chronotype can moderate the potential associations between lifetime post-traumatic stress spectrum symptoms and rest-activity circadian and sleep-related parameters. A total of 74 BD patients were administered the Trauma and Loss Spectrum Self-Report (TALS-SR) lifetime version for lifetime post-traumatic stress spectrum symptoms, the Pittsburgh Sleep Quality Index (PSQI) for self-reported sleep quality, and the Reduced Morningness-Eveningness Questionnaire (rMEQ) to discriminate evening chronotypes (ETs), neither chronotype (NT), and morning chronotype (MT). Actigraphic monitoring was used to objectively evaluate sleep and circadian parameters. Patients classified as ET reported significantly higher scores in the re-experiencing domain, as well as poorer sleep quality, lower sleep efficiency, increased wake after sleep onset, and delayed mid-sleep point compared with both NT and MT (p-value ‚ȧ 0.05). Moreover, ET presented significantly higher scores in the TALS-SR maladaptive coping domain than NT and lower relative amplitude than MT (p-value ‚ȧ 0.05). Moreover, higher TALS-SR total symptomatic domains scores were significantly correlated with poor self-reported sleep quality. Regression analyses showed that the PSQI score maintained the association with the TALS total symptomatic domains scores after adjusting for potentially confounding factors (age and sex) and that no interaction effect was observed between the chronotype and the PSQI. Conclusions: This exploratory study suggests that patients with BD classified as ET showed significantly higher lifetime post-traumatic stress spectrum symptoms and more disrupted sleep and circadian rhythmicity with respect to other chronotypes. Moreover, poorer self-reported sleep quality was significantly associated with lifetime post-traumatic stress spectrum symptoms. Further studies are required to confirm our results and to evaluate whether targeting sleep disturbances and eveningness can mitigate post-traumatic stress symptoms in BD

    The correlation between play behavior, serum cortisol and neutrophil-to-lymphocyte ratio in welfare assessment of dairy calves within the first month of life

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    Welfare assessment of dairy calves is commonly conducted through the observation of their behavior and the analysis of physiological parameters. Despite the large number of studies on this topic, there is a lack of research on the possible correlation between the physiological parameters and behavior at basal level in dairy calves. For this reason, the present study aimed to investigate the possible correlations between serum cortisol, neutrophil-to-lymphocyte ratio (N/L) and locomotor play behavior in 21 Friesian dairy calves within their first month of life. Every week, an arena test after blood collection was performed. A significant positive correlation between serum cortisol levels and N/L (rrm = 0.381; 95% CI = 0.083, 0.617; p = 0.012) and a negative correlation between time spent running and N/L (rrm = ‚ąí0.351; 95% CI = ‚ąí0.575, ‚ąí0.077; p = 0.012) were found. On the contrary, no significant correlation between time spent running and cortisol levels was detected. Cortisol levels and N/L were higher in the newborn and had a constant decrease until reaching a stable value after the 24th day of life. These findings suggest a better predictivity of N/L, compared to serum cortisol, on locomotor play behavior

    Functional Characterization of p.(Arg160Gln) PCSK9 Variant Accidentally Found in a Hypercholesterolemic Subject

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    Familial hypercholesterolaemia (FH) is an autosomal dominant dyslipidaemia, characterised by elevated LDL cholesterol (LDL-C) levels in the blood. Three main genes are involved in FH diagnosis: LDL receptor (LDLr), Apolipoprotein B (APOB) and Protein convertase subtilisin/kexin type 9 (PCSK9) with genetic mutations that led to reduced plasma LDL-C clearance. To date, several PCSK9 gain-of-function (GOF) variants causing FH have been described based on their increased ability to degrade LDLr. On the other hand, mutations that reduce the activity of PCSK9 on LDLr degradation have been described as loss-of-function (LOF) variants. It is therefore important to functionally characterise PCSK9 variants in order to support the genetic diagnosis of FH. The aim of this work is to functionally characterise the p.(Arg160Gln) PCSK9 variant found in a subject suspected to have FH. Different techniques have been combined to determine efficiency of the autocatalytic cleavage, protein expression, effect of the variant on LDLr activity and affinity of the PCSK9 variant for the LDLr. Expression and processing of the p.(Arg160Gln) variant had a result similar to that of WT PCSK9. The effect of p.(Arg160Gln) PCSK9 on LDLr activity is lower than WT PCSK9, with higher values of LDL internalisation (13%) and p.(Arg160Gln) PCSK9 affinity for the LDLr is lower than WT, EC50 8.6 ¬Ī 0.8 and 25.9 ¬Ī 0.7, respectively. The p.(Arg160Gln) PCSK9 variant is a LOF PCSK9 whose loss of activity is caused by a displacement of the PCSK9 P‚Äô helix, which reduces the stability of the LDLr-PCSK9 complex.This research was funded by Grupos Consolidados Gobierno Vasco 2021, grant number IT1720-22. A.L.-S. was supported by a grant PIF (2019‚Äď2020), Gobierno Vasco and partially supported by Fundaci√≥n Biof√≠sica Bizkaia. S.J-B. was supported by a Margarita Salas Grant 2022 from the University of the Basque Country

    Presence and correlates of autistic traits among patients with social anxiety disorder

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    IntroductionDue to their similar behavioral presentation, it can sometimes be challenging to distinguish between a social anxiety disorder (SAD) and the social avoidance that is frequently described in autism spectrum disorder (ASD). Moreover, a growing body of evidences is reporting that a significant proportion of subjects with ASD also meet the requirements for SAD and, vice versa, subjects with SAD tend to exhibit a higher prevalence of autistic traits.AimIn this framework, the current study aims to evaluate prevalence and correlates of autistic traits in a sample of adult subjects diagnosed with SAD and healthy controls (HC), also evaluating which autism spectrum dimensions may statistically predict higher SAD symptoms.Methods56 subjects with a clinical diagnosis of SAD and 56 gender and age matched HC were recruited from the Psychiatric Clinic of the University of Pisa. Subjects were assessed with the SCID-5, the Social Anxiety Spectrum ‚Äď Short Version (SHY- SV) and the Adult Autism Subthreshold Spectrum (AdAS Spectrum).ResultsSAD group scored significantly higher in all AdAS Spectrum and SHY-SV domains and total score compared to the HC group with no significant gender difference. SHY-SV total and domain scores, were strongly and positively and strongly correlated with all AdAS Spectrum domains and total score. AdAS Spectrum total score and Childhood/Adolescence, Non-Verbal Communication, Empathy and Restricted interests and Rumination domain scores score were significant predictors of higher SHY-SV score.ConclusionOur results confirm the link between SAD and autistic traits also in adult population, describing not only high levels of autistic traits in SAD adults, but also significant correlations between many core features of the two disorders and a predictive role of autistic traits on higher SAD symptoms

    Validation of the short version of the obsessive compulsive spectrum questionnaire

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    AimIn the recent years, a rising amount of research has stressed the importance of a dimensional perspective on mental disorders. In particular, the conceptualization of an obsessive‚Äďcompulsive spectrum appears to be in line with the very first descriptions of Obsessive‚ÄďCompulsive Disorder and has been partially acknowledged by the inclusion of the ‚ÄúOCD-spectrum related syndromes and disorders‚ÄĚ section in the DSM-5. The goal of the current study is to ascertain the psychometric characteristics of the Obsessive‚ÄďCompulsive Spectrum‚ÄďShort Version (OBS-SV), a novel questionnaire designed to measure the complete range of obsessive‚Äďcompulsive symptoms, from severe full blown to subthreshold ones.MethodsForty three subjects with a clinical diagnosis of OCD according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5); 42 subjects with a clinical diagnosis of social anxiety disorder (SAD), and 60 individuals without current or lifetime mental disorders (HC) were recruited from the Psychiatric Clinic of the University of Pisa. Subjects were assessed with the SCID-5, the Yale Brown Obsessive Compulsive Scale (Y-BOCS) and the OBS-SV.ResultsOBS-SV showed strong test‚Äďretest reliability for both the total and the domains scores, as well as a high level of internal consistency. The Pearson‚Äôs coefficients for the OBS-SV domain scores ranged from 0.771 to 0.943, and they were positively and strongly linked with one another (p‚ÄČ<‚ÄČ0.001). The OBS-SV total score had a strong correlation with each of the OBS-SV domain scores. All correlation coefficients between OBS-SV and additional measures of OCS were observed to be strong, significant and positive. Both OBS-SV domain and overall score differences between diagnostic groups were found to be statistically significant. From HCs, to the SAD, up to the OC group, which had the highest values, the OBS-SV total score grew dramatically and progressively.ConclusionThe OBS-SV demonstrated significant convergent validity with other dimensional OCD measures, excellent internal consistency, and test‚Äďretest reliability. Across the three diagnostic categories, the questionnaire functioned differently, with a rising score gradient from healthy controls through SAD patients to OCD subjects

    MRI versus mammography plus ultrasound in women at intermediate breast cancer risk: study design and protocol of the MRIB multicenter, randomized, controlled trial

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    In women at high/intermediate lifetime risk of breast cancer (BC-LTR), contrast-enhanced magnetic resonance imaging (MRI) added to mammography ¬Ī ultrasound (MX ¬Ī US) increases sensitivity but decreases specificity. Screening with MRI alone is an alternative and potentially more cost-effective strategy. Here, we describe the study protocol and the characteristics of enrolled patients for MRIB feasibility, multicenter, randomized, controlled trial, which aims to compare MRI alone versus MX+US in women at intermediate breast cancer risk (aged 40-59, with a 15-30% BC-LTR and/or extremely dense breasts). Two screening rounds per woman were planned in ten centers experienced in MRI screening, the primary endpoint being the rate of cancers detected in the 2 arms after 5 years of follow-up. From July 2013 to November 2015, 1254 women (mean age 47 years) were enrolled: 624 were assigned to MX+US and 630 to MRI. Most of them were aged below 50 (72%) and premenopausal (45%), and 52% used oral contraceptives. Among postmenopausal women, 15% had used hormone replacement therapy. Breast and/or ovarian cancer in mothers and/or sisters were reported by 37% of enrolled women, 79% had extremely dense breasts, and 41% had a 15-30% BC-LTR. The distribution of the major determinants of breast cancer risk profiles (breast density and family history of breast and ovarian cancer) of enrolled women varied across centers
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