Resolvin D1 Halts Remote Neuroinflammation and Improves Functional Recovery after Focal Brain Damage Via ALX/FPR2 Receptor-Regulated MicroRNAs

Remote damage is a secondary phenomenon that usually occurs after a primary brain damage in regions that are distant, yet functionally connected, and that is critical for determining the outcomes of several CNS pathologies, including traumatic brain and spinal cord injuries. The understanding of remote damage-associated mechanisms has been mostly achieved in several models of focal brain injury such as the hemicerebellectomy (HCb) experimental paradigm, which helped to identify the involvement of many key players, such as inflammation, oxidative stress, apoptosis and autophagy. Currently, few interventions have been shown to successfully limit the progression of secondary damage events and there is still an unmet need for new therapeutic options. Given the emergence of the novel concept of resolution of inflammation, mediated by the newly identified ω3-derived specialized pro-resolving lipid mediators, such as resolvins, we reported a reduced ability of HCb-injured animals to produce resolvin D1 (RvD1) and an increased expression of its target receptor ALX/FPR2 in remote brain regions. The in vivo administration of RvD1 promoted functional recovery and neuroprotection by reducing the activation of Iba-1+ microglia and GFAP+ astrocytes as well as by impairing inflammatory-induced neuronal cell death in remote regions. These effects were counteracted by intracerebroventricular neutralization of ALX/FPR2, whose activation by RvD1 also down-regulated miR-146b and miR-219a-1-dependent inflammatory markers. In conclusion, we propose that innovative therapies based on RvD1-ALX/ FPR2 axis could be exploited to curtail remote damage and enable neuroprotective effects after acute focal brain damage

Intermittent theta-burst stimulation rescues dopamine-dependent corticostriatal synaptic plasticity and motor behavior in experimental parkinsonism. Possible role of glial activity.

Background: Recent studies support the therapeutic utility of repetitive transcranial magnetic stimulation in Parkinson's disease (PD), whose progression is correlated with loss of corticostriatal long-term potentiation and long-term depression. Glial cell activation is also a feature of PD that is gaining increasing attention in the field because astrocytes play a role in chronic neuroinflammatory responses but are also able to manage dopamine (DA) levels. Methods: Intermittent theta-burst stimulation protocol was applied to study the effect of therapeutic neuromodulation on striatal DA levels measured by means of in vivo microdialysis in 6-hydroxydopamine-hemilesioned rats. Effects on corticostriatal synaptic plasticity were studied through in vitro intracellular and whole-cell patch clamp recordings while stepping test and CatWalk were used to test motor behavior. Immunohistochemical analyses were performed to analyze morphological changes in neurons and glial cells. Results: Acute theta-burst stimulation induced an increase in striatal DA levels in hemiparkinsonian rats, 80 minutes post-treatment, correlated with full recovery of plasticity and amelioration of motor performances. With the same timing, immediate early gene activation was restricted to striatal spiny neurons. Intense astrocytic and microglial responses were also significantly reduced 80 minutes following theta-burst stimulation. Conclusion: Taken together, these results provide a first glimpse on physiological adaptations that occur in the parkinsonian striatum following intermittent theta-burst stimulation and may help to disclose the real potential of this technique in treating PD and preventing DA replacement therapy-associated disturbances

Modulation of apoptosis by caprine herpesvirus 1 infection in a neuronal cell line

Caprine herpesvirus type 1 (CpHV-1), like other members of the alpha subfamily of herpesviruses, establishes latent infections in trigeminal ganglion neurons. Our groups previously demonstrated that CpHV-1 induces apoptosis in goat peripheral blood mononuclear cells and in an epithelial bovine cell line, but the ability of CpHV-1 to induce apoptosis in neuronal cells remains unexplored. In this report, the susceptibility of Neuro 2A cells to infection by CpHV-1 was examined. Following infection of cultured cells with CpHV-1, expression of cell death genes was evaluated using real-time PCR and Western blot assays. Analysis of virus-infected cells revealed activation of caspase-8, a marker for the extrinsic pathway of apoptosis, and caspase-9, a marker for the intrinsic pathway of apoptosis at 12 and 24 h post-infection. Significant increase in the levels of cleaved caspase-3 was also observed at the acme of cytopathic effect at 24 h post-infection. In particular, at 3 and 6 h post-infection, several proapototic genes were under-expressed. At 12 h post-infection several proapototic genes such as caspases, TNF, Cd70, and Traf1 were over expressed while Bcl2a1a, Fadd, and TNF genes were underexpressed. In conclusion, the simultaneous activation of caspase-8 and caspase-9 suggests that CpHV-1 can trigger the death-receptor pathway and the mitochondrial pathway separately and in parallel. Our findings are significant because this is the first published study showing the effect of CpHV-1 infection in neuronal cells in terms of gene expression and apoptosis modulation

Prognostic Role of CSF β-amyloid 1-42/1-40 Ratio in Patients Affected by Amyotrophic Lateral Sclerosis

The involvement of β-amyloid (Aβ) in the pathogenesis of amyotrophic lateral sclerosis (ALS) has been widely discussed and its role in the disease is still a matter of debate. Aβ accumulates in the cortex and the anterior horn neurons of ALS patients and seems to affect their survival. To clarify the role of cerebrospinal fluid (CSF) Aβ 1-42 and Aβ 42/40 ratios as a potential prognostic biomarker for ALS, we performed a retrospective observational study on a cohort of ALS patients who underwent a lumbar puncture at the time of the diagnosis. CSF Aβ 1-40 and Aβ 1-42 ratios were detected by chemiluminescence immunoassay and their values were correlated with clinical features. We found a significant correlation of the Aβ 42/40 ratio with age at onset and Mini Mental State Examination (MMSE) scores. No significant correlation of Aβ 1-42 or Aβ 42/40 ratios to the rate of progression of the disease were found. Furthermore, when we stratified patients according to Aβ 1-42 concentration and the Aβ 42/40 ratio, we found that patients with a lower Aβ 42/40 ratio showed a shorter survival. Our results support the hypothesis that Aβ 1-42 could be involved in some pathogenic mechanism of ALS and we suggest the Aβ 42/40 ratio as a potential prognostic biomarker

T Cell Cancer Therapy Requires CD40-CD40L Activation of Tumor Necrosis Factor and Inducible Nitric-Oxide-Synthase-Producing Dendritic Cells

Effective cancer immunotherapy requires overcoming immunosuppressive tumor microenvironments. We\ua0found that local nitric oxide (NO) production by tumor-infiltrating myeloid cells is important for adoptively transferred CD8(+) cytotoxic T\ua0cells to destroy tumors. These myeloid cells are phenotypically similar to inducible nitric oxide synthase (NOS2)- and tumor necrosis factor (TNF)-producing dendritic cells (DC), or Tip-DCs. Depletion of immunosuppressive, colony stimulating factor 1 receptor (CSF-1R)-dependent arginase 1(+) myeloid cells enhanced NO-dependent tumor killing. Tumor elimination via NOS2 required the CD40-CD40L pathway. We also uncovered a strong correlation between survival of colorectal cancer patients and NOS2, CD40, and TNF expression in their tumors. Our results identify a network of pro-tumor factors that can be targeted to boost cancer immunotherapies

Predicting needlestick and sharps injuries in nursing students: Development of the SNNIP scale

© 2020 The Authors. Nursing Open published by John Wiley & Sons Ltd. Aim: To develop an instrument to investigate knowledge and predictive factors of needlestick and sharps injuries (NSIs) in nursing students during clinical placements. Design: Instrument development and cross-sectional study for psychometric testing. Methods: A self-administered instrument including demographic data, injury epidemiology and predictive factors of NSIs was developed between October 2018–January 2019. Content validity was assessed by a panel of experts. The instrument's factor structure and discriminant validity were explored using principal components analysis. The STROBE guidelines were followed. Results: Evidence of content validity was found (S-CVI 0.75; I-CVI 0.50–1.00). A three-factor structure was shown by exploratory factor analysis. Of the 238 participants, 39% had been injured at least once, of which 67.3% in the second year. Higher perceptions of “personal exposure” (4.06, SD 3.78) were reported by third-year students. Higher scores for “perceived benefits” of preventive behaviours (13.6, SD 1.46) were reported by second-year students

Pattern of care and effectiveness of treatment for glioblastoma patients in the real world: Results from a prospective population-based registry. Could survival differ in a high-volume center?

BACKGROUND: As yet, no population-based prospective studies have been conducted to investigate the incidence and clinical outcome of glioblastoma (GBM) or the diffusion and impact of the current standard therapeutic approach in newly diagnosed patients younger than aged 70 years. METHODS: Data on all new cases of primary brain tumors observed from January 1, 2009, to December 31, 2010, in adults residing within the Emilia-Romagna region were recorded in a prospective registry in the Project of Emilia Romagna on Neuro-Oncology (PERNO). Based on the data from this registry, a prospective evaluation was made of the treatment efficacy and outcome in GBM patients. RESULTS: Two hundred sixty-seven GBM patients (median age, 64 y; range, 29-84 y) were enrolled. The median overall survival (OS) was 10.7 months (95% CI, 9.2-12.4). The 139 patients 64aged 70 years who were given standard temozolomide treatment concomitant with and adjuvant to radiotherapy had a median OS of 16.4 months (95% CI, 14.0-18.5). With multivariate analysis, OS correlated significantly with KPS (HR = 0.458; 95% CI, 0.248-0.847; P = .0127), MGMT methylation status (HR = 0.612; 95% CI, 0.388-0.966; P = .0350), and treatment received in a high versus low-volume center (HR = 0.56; 95% CI, 0.328-0.986; P = .0446). CONCLUSIONS: The median OS following standard temozolomide treatment concurrent with and adjuvant to radiotherapy given to (72.8% of) patients aged 6470 years is consistent with findings reported from randomized phase III trials. The volume and expertise of the treatment center should be further investigated as a prognostic factor

Relationship between asymmetric nostril use and human emotional odours in cats

Abstract Cat social behaviour and cognition has received a growing interest during the last decades. Recent studies reported that cats efficiently engage in interspecific communication with humans and suggest that cats are sensitive to human emotional visual and auditory cues. To date, there is no evidence on the social and informative role of human emotional odours, which may affect human-cat communication. In this study, we presented cats with human odours collected in different emotional contexts (fear, happiness, physical stress and neutral) and evaluated the animals’ behavioural responses. We found that “fear” odours elicited higher stress levels than “physical stress” and “neutral”, suggesting that cats perceived the valence of the information conveyed by “fear” olfactory signals and regulate their behaviour accordingly. Moreover, the prevalent use of the right nostril (right hemisphere activation) with the increase of stress levels, particularly in response to “fear” odours, provides first evidence of lateralized emotional functions of olfactory pathways in cats

A Functional Analysis of the Unclassified Pro2767Ser BRCA2 Variant Reveals Its Potential Pathogenicity that Acts by Hampering DNA Binding and Homology-Mediated DNA Repair

BRCA1 and BRCA2 are the genes most frequently associated with hereditary breast and ovarian cancer (HBOC). They are crucial for the maintenance of genome stability, particularly in the homologous recombination-mediated repair pathway of DNA double-strand breaks (HR-DSBR). Widespread BRCA1/2 next-generation sequencing (NGS) screening has revealed numerous variants of uncertain significance. Assessing the clinical significance of these variants is challenging, particularly regarding the clinical management of patients. Here, we report the functional characterization of the unclassified BRCA2 c.8299C > T variant, identified in a young breast cancer patient during BRCA1/2 NGS screening. This variant causes the change of Proline 2767 to Serine in the DNA binding domain (DBD) of the BRCA2 protein, necessary for the loading of RAD51 on ssDNA during the HR-DSBR. Our in silico analysis and 3D-structure modeling predicted that the p.Pro2767Ser substitution is likely to alter the BRCA2 DBD structure and function. Therefore, to evaluate the functional impact of the p.Pro2767Ser variant, we used a minigene encoding a truncated protein that contains the BRCA2 DBD and the nearby nuclear localization sequence. We found that the ectopically expressed truncated protein carrying the normal DBD, which retains the DNA binding function and lacks the central RAD51 binding domain, interferes with endogenous wild-type BRCA2 mediator functions in the HR-DSBR. We also demonstrated that the BRCA2 Pro2767Ser DBD is unable to compete with endogenous BRCA2 DNA binding, thereby suggesting that the p.Pro2767Ser substitution in the full-length protein causes the functional loss of BRCA2. Consequently, our data suggest that the p.Pro2767Ser variant should be considered pathogenic, thus supporting a revision of the ClinVar interpretation. Moreover, our experimental strategy could be a valid method with which to preliminarily evaluate the pathogenicity of the unclassified BRCA2 germline variants in the DBD and their risk of predisposing to HBOC

I monumenti ai caduti della Grande Guerra di Gubbio (Perugia) e Lugo (Ravenna). Conoscere, comunicare, valorizzare la memoria dei luoghi

Il territorio nazionale è disseminato di monumenti ai caduti della Prima Guerra Mondiale, che incarnano sia valori antropologici e sociali sia valori storico-artistici e architettonici da riscoprire e tutelare. Il contributo, a partire dall’analisi di due casi studio esemplari, propone una metodologia integrata finalizzata alla catalogazione di questo patrimonio culturale italiano capace di integrare alle informazioni storiche i relativi modelli conoscitivi digitali (2D e 3D) e un abaco di linee guida propedeutiche agli interventi di restauro, conservazione e valorizzazione. La possibilità di mettere a punto protocolli di documentazione e catalogazione capaci di innescare processi di gestione, ricerca, diagnostica, conservazione, restauro e valorizzazione del patrimonio culturale, apre nuovi scenari in cui i modelli conoscitivi digitali diventano il supporto per la raccolta di diverse informazioni utilizzabili a livello multidisciplinare. La disponibilità dei database di integrare dati diversi, acquisiti attraverso tecniche di rilievo tradizionali e metodologie avanzate, consente di mettere a punto un sistema informativo multimediale in cui le diverse informazioni possono essere utilizzate come base per progetti di comunicazione dedicati. La metodologia proposta è applicata nello specifico ai monumenti ai caduti della Prima Guerra Mondiale, particolarmente significativi a scala nazionale in quanto espressione fisica della memoria e di grande valore storico-artistico, architettonico e sociale, ed è finalizzata alla catalogazione (e quindi alla documentazione e alla conoscenza) e alla definizione di linee guida su base tipologica propedeutiche alla conservazione, al restauro e alla valorizzazione.The Italian territory is full of Monuments to the Fallen Soldiers of the First World War, which embody both anthropological and social significances and historical-artistic and architectural values to be rediscovered and protected. The paper, starting from the analysis of two exemplary case studies, proposes an integrated methodology aimed at cataloguing this Italian cultural heritage and able to integrate historical information with digital models (2D and 3D) and a set of guidelines preliminary to restoration, conservation and enhancement. The opportunity of developing documentation and cataloguing protocols able to trigger processes of management, research, diagnostics, conservation, restoration and enhancement of cultural heritage opens up new scenarios in which digital models become the support for the collection of different information to be managed at a multidisciplinary level. The capability of databases to integrate different data, acquired through traditional survey techniques and advanced methodologies, allows the development of a multimedia information system in which different information can be used as a basis for specific communication projects. The proposed methodology is specifically applied to the Monuments to the Fallen of the First World War, particularly significant on a national scale as a physical expression of memory and of great historical-artistic, architectural and social value. The research is aimed at cataloguing (and therefore at documentation and knowledge) and to the definition of guidelines set for this specific typology of monument and preliminary to restoration, conservation and enhancement