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Background: Progressive supranuclear palsy (PSP) patients can show ventricular enlargement mimicking normal pressure hydrocephalus (NPH). The aim of this study was to distinguish PSP patients with marked ventricular dilatation (PSP-vd) from those with normal ventricular system and to evaluate the coexistence of NPH in PSP-vd patients. Methods: One hundred three probable PSP patients, 18 definite NPH patients, and 41 control subjects were enrolled in the study. Evans index (EI) > 0.32 associated with callosal angle (CA) < 100° was used to identify PSP-vd patients. Automated ventricular volumetry (AVV) and Magnetic Resonance Hydrocephalic Index (MRHI) were performed on T1-weighted MR images to evaluate the presence of NPH in PSP-vd patients. Results: Twelve (11.6%) out of 103 PSP patients had both abnormal EI and CA values (PSP-vd). In two of these 12 patients, AVV and MRHI values suggested PSP + NPH. In the remaining 10 PSP-vd patients, AVV and MRHI values were higher than PSP patients with normal ventricular system and controls, but lower than PSP + NPH and NPH patients, suggesting a non-hydrocephalic ventricular enlargement. Discussion: Our study provides evidence that the combination of EI and CA biomarkers allowed to identify PSP patients with marked ventricular dilatation mimicking NPH. Only a few of these patients had PSP + NPH. Recognition of these PSP patients with enlarged ventricles can positively impact the care of this disease, helping clinicians to identify patients with PSP + NPH who could benefit from shunt procedure and avoid surgery in those with enlarged ventricles without NPH.

Background: The R2 component of blink reflex recovery cycle (R2BRrc) is a simple neurophysiological tool to detect the brainstem hyperexcitability commonly occurring in several neurological diseases such as Parkinson's disease and atypical parkinsonisms. In our study, we investigated for the first time the usefulness of R2BRrc to assess brainstem excitability in patients with idiopathic Normal Pressure Hydrocephalus (iNPH) in comparison with healthy subjects. Methods: Eighteen iNPH patients and 25 age-matched control subjects were enrolled. R2BRrc was bilaterally evaluated at interstimulus intervals (ISIs) of 100, 150, 200, 300, 400, 500 and 750 ms in all participants. We investigated the diagnostic performance of R2BRrc in differentiating iNPH patients from control subjects using ROC analysis. Midbrain area and Magnetic Resonance Hydrocephalic Index (MRHI), an MRI biomarker for the diagnosis of iNPH, were measured on T1-weighted MR images, and correlations between R2BRrc values and MRI measurements were investigated. Results: Fourteen (78%) of 18 iNPH patients showed an enhanced R2BRrc at ISIs 100-150-200 ms, while no control subjects had abnormal R2BRrc. The mean amplitude of bilateral R2BRrc at the shortest ISIs (100-150-200 ms) showed high accuracy in differentiating iNPH patients from controls (AUC = 0.89). R2BRrc values significantly correlated with midbrain area and MRHI values. Conclusions: This study represents the first evidence of brainstem hyperexcitability in iNPH patients. Given its low cost and wide availability, R2BRrc could be a useful tool for selecting elderly subjects with mild gait and urinary dysfunction who should undergo an extensive diagnostic workup for the diagnosis of NPH.

A clinically actionable understanding of multiple sclerosis (MS) etiology goes through GWAS interpretation, prompting research on new gene regulatory models. Our previous investigations suggested heterogeneity in etiology components and stochasticity in the interaction between genetic and non-genetic factors. To find a unifying model for this evidence, we focused on the recently mapped transient transcriptome (TT), that is mostly coded by intergenic and intronic regions, with half-life of minutes. Through a colocalization analysis, here we demonstrate that genomic regions coding for the TT are significantly enriched for MS-associated GWAS variants and DNA binding sites for molecular transducers mediating putative, non-genetic, determinants of MS (vitamin D deficiency, Epstein Barr virus latent infection, B cell dysfunction), indicating TT-coding regions as MS etiopathogenetic hotspots. Future research comparing cell-specific transient and stable transcriptomes may clarify the interplay between genetic variability and non-genetic factors causing MS. To this purpose, our colocalization analysis provides a freely available data resource at www.mscoloc.com.

BackgroundNeuroanatomical abnormalities in first-episode psychosis (FEP) tend to be subtle and widespread. The vast majority of previous studies have used small samples, and therefore may have been underpowered. In addition, most studies have examined participants at a single research site, and therefore the results may be specific to the local sample investigated. Consequently, the findings reported in the existing literature are highly heterogeneous. This study aimed to overcome these issues by testing for neuroanatomical abnormalities in individuals with FEP that are expressed consistently across several independent samples.MethodsStructural Magnetic Resonance Imaging data were acquired from a total of 572 FEP and 502 age and gender comparable healthy controls at five sites. Voxel-based morphometry was used to investigate differences in grey matter volume (GMV) between the two groups. Statistical inferences were made at p < 0.05 after family-wise error correction for multiple comparisons.ResultsFEP showed a widespread pattern of decreased GMV in fronto-temporal, insular and occipital regions bilaterally; these decreases were not dependent on anti-psychotic medication. The region with the most pronounced decrease – gyrus rectus – was negatively correlated with the severity of positive and negative symptoms.ConclusionsThis study identified a consistent pattern of fronto-temporal, insular and occipital abnormalities in five independent FEP samples; furthermore, the extent of these alterations is dependent on the severity of symptoms and duration of illness. This provides evidence for reliable neuroanatomical alternations in FEP, expressed above and beyond site-related differences in anti-psychotic medication, scanning parameters and recruitment criteria.

Equine penile squamous cell carcinoma (epSCC) is the most frequent tumor of the external male genitalia, representing 67.5% of equine genital cancers. epSCC is associated with papilloma virus (PV) infection and has been recently proposed as a model for human PV-induced squamous cell carcinomas. It has already been suggested that epSCC might undergo epithelial-to-mesenchymal transition (EMT). This work aims to investigate in detail this process and the possible role of PV oncoproteins in epSCC. For this purpose, 18 penile SCCs were retrospectively selected and tested for both EcPV2 presence and oncoproteins (EcPV2 E6 and EcPV2 E7) expression. Moreover, immunohistochemical EMT characterization was carried out by analyzing the main epithelial markers (E-cadherin, β-catenin, and pan-cytokeratin AE3/AE1), the main mesenchymal markers (N-cadherin and vimentin), and the main EMT-related transcription factors (TWIST-1, ZEB-1). PCR analysis was positive for EcPV2 in 16 out of 18 samples. EMT was investigated in epSCC positive for EcPV2. The immunohistochemistry results suggested the presence of EMT processes in the neoplastic cells at the tumor invasive front. Moreover, the significant upregulation of RANKL, together with BCATN1, LEF1, and FOSL1 genes, might suggest a canonical Wnt pathway activation, similarly to what is reported in human penile squamous cell carcinomas

Despite promising immunotherapy strategies in human melanoma, there are few studies on the immune environment of canine melanocytic tumors. In humans, the activation of immunosuppressive cell subpopulations, such as regulatory T cells (Tregs) that express forkhead box protein P3 (FoxP3), the engagement of immunosuppressive surface receptors like cytotoxic T lymphocyte antigen (CTLA-4), and the secretion of molecules inhibiting lymphocyte activation, such as indoleamine-pyrrole 2,3-dioxygenase (IDO), are recognized as immunoescape mechanisms that allow tumor growth and progression. The aim of our study was to investigate the expression of these immunosuppression markers in canine melanocytic tumors and to postulate their possible role in melanoma biology and progression. Fifty-five formalin-fixed, paraffin-embedded canine melanocytic tumors (25 oral melanomas; 20 cutaneous melanomas; 10 cutaneous melanocytomas) were selected to investigate the expression of FoxP3, CTLA-4, and IDO by immunohistochemistry and RT-qPCR (real-time quantitative polymerase chain reaction). All of the tested markers showed high gene and protein expression in oral melanomas and were differently expressed in cutaneous melanomas when compared to their benign counterpart. IDO expression was associated with an increased hazard of death both in univariable and multivariable analyses ( P < .05). FoxP3 protein expression >6.9 cells/HPF (high-power field) was an independent predictor of death ( P < .05). CTLA-4 gene and protein expressions were associated with a worse prognosis, but only in the univariable analysis ( P < .05). FoxP3, CTLA-4, and IDO likely play a role in canine melanoma immunoescape. Their expression, if supported by future studies, could represent a prognostic tool in canine melanoma and pave the way to future immunotherapeutic approaches in dogs.

E-cadherin, a glycoprotein involved in cell-cell adhesion, has a pivotal role in epithelial-mesenchymal transition, a process through which neoplastic epithelial cells develop an invasive phenotype. In human cutaneous melanomas, decreased E-cadherin expression is associated with shorter survival and increased Breslow thickness, whereas in the dog its role is poorly understood. Tumor thickness and modified Clark level were recently proposed as useful features to assess canine melanocytic tumors, but no studies investigated their association with E-cadherin expression. We performed immunohistochemistry on 77 formalin-fixed, paraffin-embedded primary canine melanocytic tumors. A 3-tier and a 2-tier classification system for assessing E-cadherin expression were tested, with the latter being more informative for the assessment of canine melanocytic tumors. E-cadherin expression was lower in cutaneous melanomas than melanocytomas, as well as in amelanotic tumors compared to pigmented tumors. In amelanotic melanomas, absent E-cadherin expression was associated with an unfavorable outcome, suggesting a potential use of this marker in defining the prognosis of amelanotic melanomas. E-cadherin expression was lower in tumors with greater tumor thickness and modified Clark level ≥IV, suggesting its possible utility in identifying the most invasive tumors. The expression of E-cadherin in oral melanomas was heterogeneous, but was associated with pigmentation and clinical outcome; thus, E-cadherin evaluation could be advantageous to detect the most aggressive neoplasms. However, cutaneous melanomas without E-cadherin expression frequently had a favorable clinical outcome. Hence, its importance as prognostic factor should be carefully considered depending on the tumor origin.

PSYSCAN Consortium., In the last 2 decades, several neuroimaging studies investigated brain abnormalities associated with the early stages of psychosis in the hope that these could aid the prediction of onset and clinical outcome. Despite advancements in the field, neuroimaging has yet to deliver. This is in part explained by the use of univariate analytical techniques, small samples and lack of statistical power, lack of external validation of potential biomarkers, and lack of integration of nonimaging measures (eg, genetic, clinical, cognitive data). PSYSCAN is an international, longitudinal, multicenter study on the early stages of psychosis which uses machine learning techniques to analyze imaging, clinical, cognitive, and biological data with the aim of facilitating the prediction of psychosis onset and outcome. In this article, we provide an overview of the PSYSCAN protocol and we discuss benefits and methodological challenges of large multicenter studies that employ neuroimaging measures., The PSYSCAN Project is supported by grant agreement no. 603196 under the European Union’s Seventh Framework Programme.

L'articolo presenta "Le Linee guida per la valutazione di aziende sequestrate e confiscate" alla criminalità organizzata, evidenziando alcuni criteri per guidare la scelta del metodo di valutazione appropriato e suggerendo l'inclusione di una prospettiva di stakeholder negli studi di valutazione aziendale. The article presents "The Guidelines for the business valuation of seized and confiscated firms” from the organized crime, by pointing out some criteria to guide the selection of the appropriate valuation method and suggesting the inclusion of a stakeholder perspective in the business valuation studies.

Canine testicular tumors account for about 90 % of tumors affecting the male genitalia. Seminomas (SEM), Sertoli cell tumors (SCT), and interstitial cell tumors (ICT) are the most common histological diagnoses, but their incidence shows high variability among studies. Our aim is to report the results on the analysis of testicular tumors recorded by the population-based Umbria Canine Cancer Registry (CCR) for a 5-year time period and to assess the value of tumor major diameter, measured during trimming, in discriminating neoplastic from non-neoplastic lesions. The study was conducted on 388 testicular tumors (on 1969 total male tumors) diagnosed in 355 dogs from 2014 to 2018. The median incidence was 35 cases/100,000 dogs, with a proportion equal to 19,7 % of all tumors. The incidence on neutered male dogs was 352/100,000. Most tumors were ICTs (50 %), with fewer SEMs and SCTs (29 % and 17 %, respectively). Only 3 % of tumors were mixed germ cell-sex cord-stromal tumors (MGC-SCST). Ten percent of cases had multiple tumors in the same testicle, with SEM-ICT being prevalent (69.2 %). Tumors in cryptorchid testes were 5.9 % of the total, mostly SCT (60.9 %). Mean age at diagnosis was 10.7 ± 2.7, with similar values for different tumor types. Significant incidence ratios (IRR) were found in Golden retriever (IRR 7.18, CI95 % 4.72-10.92) and in English cocker spaniel (IRR 2.30, CI95 % 1.28-4.13) when compared with mixed breed dogs. A value of 0.3 cm (major diameter) of lesions at the moment of trimming was helpful in discriminating a final tumor histological diagnosis from a non-tumor lesion. Since the number of tumors included in this evaluation was limited, further studies to confirm the diagnostic value of this measure are recommended. Our results provided information on the incidence of canine testicular tumors in Umbria region that can be compared with future results and incidence from other geographical areas if provided with reliable data on the total population, can offer solid information on the incidence and proportion of different tumor types in specific territories, contributing also to the supervision of its inhabitants' health. Moreover, pathological data such as the major diameter of tumors can be obtained and contribute to diagnostic routine and standardization.

Le linee guida mirano ad analizzare le specificità delle aziende sequestrate e confiscate ai fini del processo di stima del valore di tali delicate realtà aziendali, esaltando in particolare come l’applicazione del metodo valutativo costituisca solo una fase del più ampio processo di stima, che deve necessariamente considerare elementi qualitativi, ma anche quantitativi di difficile ponderazione.

Background: Severe coronavirus disease 2019 (COVID-19) is associated with multiple comorbidities and is characterized by an auto-aggressive inflammatory state leading to massive collateral damage. To identify preventive and therapeutic strategies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it is important to ascertain the molecular interactions between virus and host, and how they translate into disease pathophysiology. Methods: We matched virus-human protein interactions of human coronaviruses and other respiratory viruses with lists of genes associated with autoimmune diseases and comorbidities associated to worse COVID-19 course. We then selected the genes included in the statistically significant intersection between SARS-CoV-2 network and disease associated gene sets, identifying a meta-interactome. We analyzed the meta-interactome genes expression in samples derived from lungs of infected humans, and their regulation by IFN-β. Finally, we performed a drug repurposing screening to target the network’s most critical nodes. Results: We found a significant enrichment of SARS-CoV-2 interactors in immunological pathways and a strong association with autoimmunity and three prognostically relevant conditions (type 2 diabetes, coronary artery diseases, asthma), that present more independent physiopathological subnetworks. We observed a reduced expression of meta-interactome genes in human lungs after SARS-CoV-2 infection, and a regulatory potential of type I interferons. We also underscored multiple repurposable drugs to tailor the therapeutic strategies. Conclusions: Our data underscored a plausible genetic background that may contribute to the distinct observed pathophysiologies of severe COVID-19. Also, these results may help identify the most promising therapeutic targets and treatments for this condition.

In horses, penile squamous cell carcinomas (epSCCs) are among the most common cutaneous neoplastic lesions. These tumors usually arise in benign lesions such as viral plaques and papillomas frequently induced by Equus caballus papillomavirus type 2 (EcPV2) infection. In the last decade, the introduction of immune checkpoint inhibitors (ICI) for the treatment of human cancers has demonstrated promising results. Among the most commonly targeted pathways, there is PD-1/PD-L1 and CTLA-4. The aim of this study is to investigate the expression of the PD-1/PD-L1 pathway and CTLA-4 in the tumor microenvironment of epSCCs to assess the feasibility of an immunotherapeutic approach. Twenty equine epithelial tumors were retrospectively selected and submitted to RT-qPCR for PD-1 and PD-L1 genes. After testing antibodies cross-reactivity by western blotting, immunohistochemistry for PD-L1 and CTLA-4 was performed. Results from RT-qPCR demonstrated that 3/20 cases expressed the PD-L1 gene, whereas the PD-1 gene was not detected. Immunohistochemical positivity for PD-L1 was found only in one case. CTLA-4-positive cells were observe in all cases but were few (Mdn = 4.8, IQR = 2.3–7.1 cells/HPF). In this study group, PD-1/PD-L1 and CTLA-4 do not appear to be highly expressed and therefore the use of ICI in epSCCs may not have promising rates of response.

Progressive supranuclear palsy (PSP) patients can show ventricular enlargement mimicking normal pressure hydrocephalus (NPH). The aim of this study was to distinguish PSP patients with marked ventricular dilatation (PSP-vd) from those with normal ventricular system and to evaluate the coexistence of NPH in PSP-vd patients.One hundred three probable PSP patients, 18 definite NPH patients, and 41 control subjects were enrolled in the study. Evans index (EI) 0.32 associated with callosal angle (CA) 100° was used to identify PSP-vd patients. Automated ventricular volumetry (AVV) and Magnetic Resonance Hydrocephalic Index (MRHI) were performed on T1-weighted MR images to evaluate the presence of NPH in PSP-vd patients.Twelve (11.6%) out of 103 PSP patients had both abnormal EI and CA values (PSP-vd). In two of these 12 patients, AVV and MRHI values suggested PSP + NPH. In the remaining 10 PSP-vd patients, AVV and MRHI values were higher than PSP patients with normal ventricular system and controls, but lower than PSP + NPH and NPH patients, suggesting a non-hydrocephalic ventricular enlargement.Our study provides evidence that the combination of EI and CA biomarkers allowed to identify PSP patients with marked ventricular dilatation mimicking NPH. Only a few of these patients had PSP + NPH. Recognition of these PSP patients with enlarged ventricles can positively impact the care of this disease, helping clinicians to identify patients with PSP + NPH who could benefit from shunt procedure and avoid surgery in those with enlarged ventricles without NPH.

SUMMARYWe exploited genetic information to assess non-genetic influences in autoimmunity. We isolated gene modules whose products physically interact with environmental exposures related to autoimmunity, and analyzed their nominal statistical evidence of association with autoimmune and non-autoimmune diseases in genome-wide association studies (GWAS) data. Epstein Barr virus (EBV) and other Herpesviruses interactomes emerged as specifically associated with multiple sclerosis (MS), possibly under common regulatory mechanisms. Analyses of MS blood and brain transcriptomes, cytofluorimetric studies of endogenous EBV-infected lymphoblastoid lines, and lesion immunohistochemistry, confirmed a dysregulation of MS-associated EBV interactors, suggesting their contribution to CD40 signaling alterations in MS. These interactors resulted enriched in modules from inherited axonopathies-causing genes, supporting a link between EBV and neurodegeneration in MS, in accord with the observed transcriptomic dysregulations in MS brains. They were also enriched with top-ranked pharmaceutical targets prioritized on a genetic basis. This study delineates a disease-specific influence of herpesviruses on MS biology.