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International audience; AimsDilated cardiomyopathy (DCM) is a complex disease where genetics interplay with extrinsic factors. This study aims to compare the phenotype, management, and outcome of familial DCM (FDCM) and non‐familial (sporadic) DCM (SDCM) across Europe.Methods and resultsPatients with DCM that were enrolled in the prospective ESC EORP Cardiomyopathy & Myocarditis Registry were included. Baseline characteristics, genetic testing, genetic yield, and outcome were analysed comparing FDCM and SDCM; 1260 adult patients were studied (238 FDCM, 707 SDCM, and 315 not disclosed). Patients with FDCM were younger (P < 0.01), had less severe disease phenotype at presentation (P < 0.02), more favourable baseline cardiovascular risk profiles (P ≤ 0.007), and less medication use (P ≤ 0.042). Outcome at 1 year was similar and predicted by NYHA class (HR 0.45; 95% CI [0.25–0.81]) and LVEF per % decrease (HR 1.05; 95% CI [1.02–1.08]. Throughout Europe, patients with FDCM received more genetic testing (47% vs. 8%, P < 0.01) and had higher genetic yield (55% vs. 22%, P < 0.01).ConclusionsWe observed that FDCM and SDCM have significant differences at baseline but similar short‐term prognosis. Whether modification of associated cardiovascular risk factors provide opportunities for treatment remains to be investigated. Our results also show a prevalent role of genetics in FDCM and a non‐marginal yield in SDCM although genetic testing is largely neglected in SDCM. Limited genetic testing and heterogeneity in panels provides a scaffold for improvement of guideline adherence.

Background The p.E318K variant of the Melanocyte Inducing Transcription Factor (MITF) has been implicated in genetic predisposition to melanoma as an intermediate penetrance allele. However, the impact of this variant on clinico-phenotypic, as well as on dermoscopic patterns features of affected patients is not entirely defined. The purpose of our study was to assess the association between the p.E318K germline variant and clinic-phenotypical features of MITF+ compared to non-carriers (MITF−), including dermoscopic findings of melanomas and dysplastic nevi. Methods we retrospectively analyzed a consecutive series of 1386 patients recruited between 2000 and 2017 who underwent genetic testing for CDKN2A, CDK4, MC1R and MITF germline variants in our laboratory for diagnostic/research purposes. The patients were probands of melanoma-prone families and apparently sporadic single or multiple primary melanoma patients. For all, we collected clinical, pathological information and dermoscopic images of the histopathologically diagnosed melanomas and dysplastic nevi, when available. Results After excluding patients positive for CDKN2A/CDK4 pathogenic variants and those affected by non-cutaneous melanomas, our study cohort comprised 984 cutaneous melanoma patients, 22 MITF+ and 962 MITF−. MITF+ were more likely to develop dysplastic nevi and multiple primary melanomas. Nodular melanoma was more common in MITF+ patients (32% compared to 19% in MITF−). MITF+ patients showed more frequently dysplastic nevi and melanomas with uncommon dermoscopic patterns (unspecific), as opposed to MITF− patients, whose most prevalent pattern was the multicomponent. Conclusions MITF+ patients tend to develop melanomas and dysplastic nevi with histopathological features, frequency and dermoscopic patterns often different from those prevalent in MITF− patients. Our results emphasize the importance of melanoma prevention programs for MITF+ patients, including dermatologic surveillance with digital follow-up.

The mechanism for hypercoagulability in malignancy is not entirely understood. Although several studies report contrasting finding about the link between elevated plasma levels of the lipoprotein(a) [Lp(a)] and the possible recurrence of venous thromboembolism, we perform a study to evaluate the impact of the Lp(a) in the development of portal vein thromboembolism (PVT) in patients with HCC. We compared 44 PVT patients with 50 healthy subjects and 50 HCC patients. The comparison between PVT patients and HCC showed in the former the mean value of serum lipoprotein levels was higher than 37.3 mg/dl (p = 0.000). The comparison between PVT versus healthy controls showed that in the former, mean value of serum lipoprotein levels was higher than 75 mg/dl (p = 0.000). The predictive value test of serum lipoprotein(a) on PVT was 0.72 and on HCC was 0.83. The odds ratio of lipoprotein(a) was 9.21 on PVT and 6.33 on HCC. Patients with PVT and HCC showed a statistical significant serum lipoprotein(a) level higher than the subjects with HCC and no PVT or the healthy subject. So we assume a role of lipoprotein(a) as predictor of venous thromboembolism in neoplastic patients.

Background and aims: Epidemiological studies conducted in European countries demonstrated that the adoption of a Mediterranean diet protect against clustered risk factors but those evaluating such benefits specifically in southern Italy are scarce. Thus, the aim of this study was to assess the association between the adherence to the Mediterranean diet and cardiovascular risk factors obesity, diabetes, and hypertension. Methods and results: A cross-sectional population-based survey including 3090 subjects was conducted in Sicily, southern Italy. Food intake was evaluated through a validated food frequency questionnaire and adherence to the dietary pattern was assessed using the MedDietScore. Linear and logistic regression models were performed to estimate odds ratios (ORs) and respective confidence intervals (CIs). After adjusting for confounding factors such as age and gender, participants in the highest tertile of the MedDietScore were less likely to be obese (OR 0.35, 95% CI: 0.24e0.51), hypertensive (OR 0.73, 95% CI: 0.55e0.97), and diabetic (OR 0.43, 95% CI: 0.24 e0.77). Linear inverse relation between the MedDietScore and BMI (r2 Z 0.34, P < 0.001), waist circumference (r2 Z 0.17, P < 0.001), and waist-to-hip ratio (r2 Z 0.06, P < 0.001) was found. Conclusion: Despite the prevalence rates of nutrition-related diseases are high in Sicily, greater adherence to the Mediterranean dietary pattern is still associated with a better health status.

At the end of 2006, a pharmacovigilance program on natalizumab was settled by the Italian Pharmaceutical Agency, and on January 2007, multiple sclerosis patients poorly responding to the immunomodulating therapies or with an aggressive clinical form of disease from onset initiated to be registered and to receive the medication. On February 2010, almost 3,000 cases have been treated with natalizumab. The drop-out rate is 10%. Almost 800 cases received cycles of natalizumab for more than 18 months. One case of PML was reported and other adverse events are similar to those described in phase III studies. The majority of cases remained stable, while in 25% of cases, an improvement of disability was documented.

Background: Isolated left ventricular non-compaction is the result of incomplete myocardial morphogenesis, leading to persistence of the embryonic myocardium. The condition is recognized by an excessively prominent trabecular meshwork and deep intertrabecular recesses of the left ventricle. Whether these intertrabecular recesses are a favorable substrate for ventricular arrhythmias is unclear. Some reports have found that the fatal ventricular arrhythmias may occur in approximately half of the patients. In this report we investigated about this association. Methods and Results: In total we evaluated a continuous series of 238 patients affected by non-compaction. Periodic Holter monitoring was performed every 6 months for 4 years. Only 11 patients had documented ventricular tachycardia, which was sustained in two cases and non-sustained in nine. In no cases we observed ventricular fibrillation. Conclusions: Non-compaction alone does not seem to be a risk factor for malignant ventricular arrhythmias.

Aims: Children presenting with hypertrophic cardiomyopathy (HCM) in infancy are reported to have a poor prognosis, but this heterogeneous group has not been systematically characterized. This study aimed to describe the aetiology, phenotype, and outcomes of infantile HCM in a well-characterized multicentre European cohort. Methods and results: Of 301 children diagnosed with infantile HCM between 1987 and 2019 presenting to 17 European centres [male n=187 (62.1%)], underlying aetiology was non-syndromic (n=138, 45.6%), RASopathy (n=101, 33.6%), or inborn error of metabolism (IEM) (n=49, 16.3%). The most common reasons for presentation were symptoms (n=77, 29.3%), which were more prevalent in those with syndromic disease (n=62, 61.4%, P&nbsp

Emotional dysregulation (ED) is currently the most frequently used term to describe children with an impaired regulation of emotional states. Recent research studies speculate whether ED may be a neurodevelopmental disorder itself, a shared risk factor, or a common key feature of several psychiatric disorders, including, among others, attention deficit hyperactivity disorder (ADHD), and bipolar spectrum disorders (BSD). The association between ADHD and ED is one of the main reasons of misconceptions in the definition of boundaries between ADHD and BSD, leading to the frequent misdiagnosis of ADHD as BSD. Since ED is a multidimensional concept, a novel instrument—the Reactivity, Intensity, Polarity and Stability (RIPoSt) scale—was recently developed to assess the different dimensions of ED, which could help in detecting specific ED profiles in clinical youths. Our study included 154 patients, aged 13.8 ± 2.3 years, diagnosed with either ADHD, BSD, or comorbid condition, and a school-based sample of 40 healthy control (HC) adolescents, aged 12.5 ± 1.2 years. The RIPoSt scale and the Child Behavior Checklist were administered to both groups. Our results indicate that affective instability and negative emotionality subscales, as well as negative emotional dysregulation, are higher in BSD, both pure and comorbid with ADHD, while emotional impulsivity is higher in the comorbid condition and similar in the ADHD and BSD alone group; all clinical groups scored higher than HC. Conversely, positive emotionality is similar among clinical groups and within them and HC. Our findings also support the validity of the RIPoSt questionnaire, since the instrument proved to have good-to-excellent internal consistency, and strongly significant positive correlations were found with the CBCL-Dysregulation Profile, which is a commonly used, indirect measure of ED. Hence, the five subscales of the RIPoSt can be reliably used as an effective tool to study the emotional dysregulation in different clinical conditions, to help disentangle the complex relationship between ADHD and juvenile BSD and to provide clinicians with crucial evidence for better diagnostic characterization and therapeutic indications.

To investigate the neuroprotective effect of brimonidine after retinal ischemia damage on mouse eye. Glaucoma is an optic neuropathy characterized by retinal ganglion cells (RGCs) death, irreversible peripheral and central visual field loss, and high intraocular pressure. Ischemia reperfusion (I/R) injury model was used in C57BL/6J mice to mimic conditions of glaucomatous neurodegeneration. Mouse eyes were treated topically with brimonidine and pattern electroretinogram were used to assess the retinal ganglion cells (RGCs) function. A wide range of inflammatory markers, as well as anti-inflammatory and neurotrophic molecules, were investigated to figure out the potential protective effects of brimonidine in mouse retina. In particular, brain-derived neurotrophic factor (BDNF), IL-6, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its death receptor DR-5, TNF-α, GFAP, Iba-1, NOS, IL-1β and IL-10 were assessed in mouse retina that underwent to I/R insult with or without brimonidine treatment. Brimonidine provided remarkable RGCs protection in our paradigm. PERG amplitude values were significantly (p < 0.05) higher in brimonidine-treated eyes in comparison to I/R retinas. Retinal BDNF mRNA levels in the I/R group dropped significantly (p < 0.05) compared to the control group (normal mice); brimonidine treatment counteracted the downregulation of retinal BDNF mRNA in I/R eyes. Retinal inflammatory markers increased significantly (p < 0.05) in the I/R group and brimonidine treatment was able to revert that. The anti-inflammatory IL-10 decreased significantly (p < 0.05) after retinal I/R insult and increased significantly (p < 0.05) in the group treated with brimonidine. In conclusion, brimonidine was effective in preventing loss of function of RGCs and in regulating inflammatory biomarkers elicited by retinal I/R injury.

Glaucoma is a heterogeneous group of chronic neurodegenerative disorders characterized by a relatively selective, progressive damage to the retinal ganglion cells (RGCs) and their axons, which leads to axon loss and visual field alterations. To date, many studies have shown the role of various elements, mainly metals, in maintaining the balance of prooxidative and antioxidative processes, regulation of fluid and ion flow through cell membranes of the ocular tissues. Based on the earlier and current research results, their relationship with the development and progression of glaucoma seems obvious and is increasingly appreciated. In this review, we aimed to summarize the current evidence on the role of trace elements in the pathogenesis and prevention of glaucomatous diseases. Special attention is also paid to the genetic background associated with glaucoma-related abnormalities of physiological processes that regulate or involve the ions of elements considered as trace elements necessary for the functioning of the cells.

In this study we analyzed the expression of circulating miRNAs, in the serum of diabetic retinopathy (DR) patients. Five miRNAs (hsa-miR-195-5p, hsa-miR-20a-5p, hsa-miR-20b-5p, hsa-miR-27b-3p and hsa-miR-451a) were validated as biomarkers for stratification of DR stages, from the early non-proliferative (NPDR) to the late proliferative (PDR) phase. Furthermore, circulating levels of these miRNAs correlated with retinal hyper-reflective spots (HRS), assessed by optical coherence tomography (OCT). The number of HRS increased with worsening of DR stages. On the contrary, no significant vascular density differences between NPDR and PDR patients were detected by angio-OCT (OCTA). A post-hoc bioinformatics analysis associated these five miRNAs to target genes belonging to the “Tumor Necrosis Factor alfa signaling” pathway, and several molecules were predicted to modify miRNAs expression. In conclusion, correlation between specific circulating miRNAs and intraretinal hyper-reflective spots was demonstrated, confirming that these miRNAs were validated as prognostic biomarkers, and also as potential pharmacological targets, warranting further clinical evaluation to explore novel therapeutics for diabetic retinopathy.

Transforming growth factor &beta, 1 (TGF&beta, 1) is a proinflammatory cytokine that has been implicated in the pathogenesis of diabetic retinopathy (DR), particularly in the late phase of disease. The aim of the present study was to validate serum TGF&beta, 1 as a diagnostic and prognostic biomarker of DR stages. Thirty-eight subjects were enrolled and, after diagnosis and evaluation of inclusion and exclusion criteria, were assigned to six groups: (1) healthy age-matched control, (2) diabetic without DR, (3) non-proliferative diabetic retinopathy (NPDR) na&iuml, ve to treatment, (4) NPDR treated with intravitreal (IVT) aflibercept, (5) proliferative diabetic retinopathy (PDR) na&iuml, ve to treatment and (6) PDR treated with IVT aflibercept. Serum levels of vascular endothelial growth factor A (VEGF-A), placental growth factor (PlGF) and TGF&beta, 1 were measured by means of enzyme-linked immunosorbent assay (ELISA). Foveal macular thickness (FMT) in enrolled subjects was evaluated by means of structural-optical coherence tomography (S-OCT). VEGF-A serum levels decreased in NPDR and PDR patients treated with aflibercept, compared to na&iuml, ve DR patients. PlGF serum levels were modulated only in aflibercept-treated NPDR patients. Particularly, TGF&beta, 1 serum levels were predictive of disease progression from NPDR to PDR. A Multivariate ANOVA analysis (M-ANOVA) was also carried out to assess the effects of fixed factors on glycated hemoglobin (HbA1c) levels, TGF&beta, 1, and diabetes duration. In conclusion, our data have strengthened the hypothesis that TGF&beta, 1 would be a biomarker and pharmacological target of diabetic retinopathy.

An outbreak of Severe Acute Respiratory Syndrome Coronavirus 2 started in China's Hubei province at the end of 2019 has rapidly become a pandemic. In Italy, a great number of patients was managed in primary care setting and the role of general practitioners and physicians working in the first-aid emergency medical service has become of utmost importance to coordinate the network between the territory and hospitals during the pandemic. Aim of this manuscript is to provide a guidance model for the management of suspected, probable, or confirmed cases of SARS-CoV-2 infection in the primary care setting, from diagnosis to treatment, applying also the recommendations of the Italian Society of General Medicine. Moreover, this multidisciplinary contribution would analyze and synthetize the preventive measures to limit the spread of SARS-CoV-2 infection in the general population as well as the perspective for vaccines.

The impact of the COVID-19 pandemic has been dramatic worldwide, with China, Italy, and now US at its epicenter. Researchers and clinicians are studying and testing different approaches in the attempt to prevent the infection and minimize its severity. Major efforts are focused on optimizing mechanical ventilation, antiviral, and supportive treatment; however, the role of heparin and low molecular weight (LMW) heparin in this setting has been largely overlooked. This review summarizes the available evidence about the role of heparan sulfate as a key entry mechanism for SARS-CoV-2; the efficacy of heparin and LMW heparin in counteracting its entry into the cell, the recent experimental findings obtained in in vitro studies using the LMW heparin enoxaparin Inhixa®, the role of heparin and LMW heparin in modulating the cytokine storm, and the evidence for the use of LMW heparin in the prevention and treatment of the thromboembolic complications of COVID-19. The available evidence suggests that LMW heparin appears as a promising tool in the treatment of COVID-19. Whether its systematic use is associated with a reduction in complications and ultimately mortality of these patients is being tested in several studies starting worldwide.

Background RASopathies are a set of relatively common autosomal dominant clinically and genetically heterogeneous disorders. Cardiac outcomes in terms of mortality and morbidity for common heart defects (such as pulmonary valve stenosis and hypertrophic cardiomyopathy) have been reported. Nevertheless, also Atypical Cardiac Defects (ACDs) are described. The aim of the present study was to report both prevalence and cardiac outcome of ACDs in patients with RASopathies. Methods A retrospective, multicentric observational study (CArdiac Rasopathy NETwork-CARNET study) was carried out. Clinical, surgical, and genetic data of the patients who were followed until December 2019 were collected. Results Forty-five patients out of 440 followed in CARNET centers had ACDs. Noonan Syndrome (NS), NS Multiple Lentigines (NSML) and CardioFacioCutaneous Syndrome (CFCS) were present in 36, 5 and 4 patients, respectively. Median age at last follow-up was 20.1 years (range 6.9-47 years). Different ACDs were reported, including mitral and aortic valve dysfunction, ascending and descending aortic arch anomalies, coronary arteries dilation, enlargement of left atrial appendage and isolated pulmonary branches diseases. Five patients (11%) underwent cardiac surgery and one of them underwent a second intervention for mitral valve replacement and severe pericardial effusion. No patients died in our cohort until December 2019. Conclusions Patients with RASopathies present a distinct CHD spectrum. Present data suggest that also ACDs must be carefully investigated for their possible impact on the clinical outcome. A careful longitudinal follow up until the individuals reach an adult age is recommended.

Background: Insight into type 5 long QT syndrome (LQT5) has been limited to case reports and small family series. Improved understanding of the clinical phenotype and genetic features associated with rare KCNE1 variants implicated in LQT5 was sought through an international multicenter collaboration. Methods: Patients with either presumed autosomal dominant LQT5 (N = 229) or the recessive Type 2 Jervell and Lange-Nielsen syndrome (N = 19) were enrolled from 22 genetic arrhythmia clinics and 4 registries from 9 countries. KCNE1 variants were evaluated for ECG penetrance (defined as QTc >460 ms on presenting ECG) and genotype-phenotype segregation. Multivariable Cox regression was used to compare the associations between clinical and genetic variables with a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, and sudden cardiac death. Results: A total of 32 distinct KCNE1 rare variants were identified in 89 probands and 140 genotype positive family members with presumed LQT5 and an additional 19 Type 2 Jervell and Lange-Nielsen syndrome patients. Among presumed LQT5 patients, the mean QTc on presenting ECG was significantly longer in probands (476.9±38.6 ms) compared with genotype positive family members (441.8±30.9 ms, P P =0.001). Event incidence did not differ significantly for Type 2 Jervell and Lange-Nielsen syndrome patients relative to the overall heterozygous cohort (10.5% [2/19]; HR 1.7 [95% CI, 0.3–10.8], P =0.590). The cumulative prevalence of the 32 KCNE1 variants in the Genome Aggregation Database, which is a human database of exome and genome sequencing data from now over 140 000 individuals, was 238-fold greater than the anticipated prevalence of all LQT5 combined (0.238% vs 0.001%). Conclusions: The present study suggests that putative/confirmed loss-of-function KCNE1 variants predispose to QT prolongation, however, the low ECG penetrance observed suggests they do not manifest clinically in the majority of individuals, aligning with the mild phenotype observed for Type 2 Jervell and Lange-Nielsen syndrome patients.

Herpes zoster (HZ) is typically characterized by pain involving the area of vesicular eruption. Several patients, however, complain of unilateral radicular pain without rash (zoster sine herpete [ZSH]). To evaluate whether the severity and duration of pain and the use of analgesics are greater in ZSH patients than in typical HZ with rash, 16 consecutive patients with acute unilateral pain, without vesicular eruption (ZSH), were compared with 16 controls suffering from typical HZ eruption. Only patients with laboratory evidence of varicella-zoster virus (VZV) reactivation were selected. Serum samples were obtained from all patients at their initial visit and 1 and 2 months later. Monthly, the administered therapies and the average pain score (visual analog scale [VAS] score) were recorded. VZV DNA persisted statistically higher in ZSH sera than HZ sera 1 month after onset (P = 0.0007). ZSH patients averaged greater pain than HZ patients, scoring VAS 76.88 and 66.88 ( P = 0.0012), respectively. ZSH patients used significantly more opioid therapy than HZ patients ( P = 0.0449; OR, 9.00). This is the first study comparing pain in ZSH and HZ patients: greater severity and duration of pain and more opioid use was detected in patients with ZSH.

Background Typically, hand-foot-and-mouth disease (HFMD) is a mild childhood illness associated with coxsackievirus (CV)-A16, CV-A6, enterovirus (EV)-A71. Objectives To identify the viral agents associated with severe cases of atypical HFMD in Italy. Study design Epidemiologically unrelated cases of severe atypical HFMD admitted to the Emergency Room (ER) of IRCCS San Martino IST (Genoa, Italy) in 2014–2016 were investigated. Serologic screening for viral positivity was performed against exanthem-inducing agents. Ten cases with serology indicative of recent EV infection were selected. Molecular assays were used to detect viral genomes in blood [EVs, Parvovirus B19 (PVB19), herpesviruses (CMV; EBV, HHV-6, -7, -8)]. Results CV-A6 was detected in 10 cases of severe atypical HFMD. Two cases were also infected with PVB19. Herpesviruses were not detected. Phylogenetic analysis mapped the CV-A6 strains into a single cluster related to two recent isolates from a German and an Asian child. Fever, systemic symptoms, severe vasculitis-like rash, and enanthem were predominant at presentation. Spontaneous recovery occurred in 1–3 weeks. Conclusions CV-A6 is emerging as a frequent cause of severe atypical HFMD in Italian adults. This viral agent is disseminating worldwide. Dermatologists must identify the manifold alterations caused by EVs and understand the diagnostic power of current virology methods.

© 2019 Elsevier Ltd The dopamine D 3 receptor (D 3 R), in the nucleus accumbens (NAc), plays an important role in alcohol reward mechanisms. The major neuronal type within the NAc is the GABAergic medium spiny neuron (MSN), whose activity is regulated by dopaminergic inputs. We previously reported that genetic deletion or pharmacological blockade of D 3 R increases GABA A α6 subunit in the ventral striatum. Here we tested the hypothesis that D 3 R-dependent changes in GABA A α6 subunit in the NAc affect voluntary alcohol intake, by influencing the inhibitory transmission of MSNs. We performed in vivo and ex vivo experiments in D 3 R knockout (D 3 R −/− ) mice and wild type littermates (D 3 R +/+ ). Ro 15-4513, a high affinity α6-GABA A ligand was used to study α6 activity. At baseline, NAc α6 expression was negligible in D 3 R +/+ , whereas it was robust in D 3 R −/− ; other relevant GABA A subunits were not changed. In situ hybridization and qPCR confirmed α6 subunit mRNA expression especially in the NAc. In the drinking-in-the-dark paradigm, systemic administration of Ro 15-4513 inhibited alcohol intake in D 3 R +/+ , but increased it in D 3 R −/− ; this was confirmed by intra-NAc administration of Ro 15-4513 and furosemide, a selective α6-GABA A antagonist. Whole-cell patch-clamp showed peak amplitudes of miniature inhibitory postsynaptic currents in NAc medium spiny neurons higher in D 3 R −/− compared to D 3 R +/+ ; Ro 15-4513 reduced the peak amplitude in the NAc of D 3 R −/− , but not in D 3 R +/+ . We conclude that D 3 R-dependent enhanced expression of α6 GABA A subunit inhibits voluntary alcohol intake by increasing GABA inhibition in the NAc.

Aim: To evaluate the gene expression changes that occur soon after the active infection of two susceptible cell types with human herpesvirus 8 (HHV-8). Materials & methods: The expression profile of 282 human genes involved in the inflammatory process was investigated in HHV-8 A1 or C3 subtype-infected and mock-infected human epithelial cells and lymphoid cells. Results: The HHV-8-induced transcriptional profiles in the epithelial and lymphoid cells were very different. A robust increase in the expression was found in genes belonging to different categories, especially the categories of inflammation response and signal transduction. Conclusion: These results indicate that during early infection, HHV-8 induces a variety of cell type-specific processes, thus providing infection signatures useful as potential targets for therapeutic intervention.

Nanostructured lipid carriers (NLCs) loaded with palmitoylethanolamide (PEA) were formulated with the aim to enhance ocular bioavailability of PEA, particularly to the back of the eye. Technological characterization (e.g., size, charge) of NLC loaded with PEA formulation (PEA-NLC) was performed, and NLC morphology was characterized by electron microscopy. Ocular pharmacokinetic study, after topical administration of the formulation, was carried out in rabbit eye. Ultra-high performance liquid chromatography tandem mass spectrometry analysis was carried out to detect PEA levels in ocular tissues. Finally, the ocular tolerability of PEA-NLC formulation was assessed in rabbit eye. The novel formulation significantly increased PEA levels in ocular tissues compared to PEA suspension. Vitreous and retinal levels of PEA were significantly higher in the group treated with PEA-NLC formulation versus PEA suspension (PEA-NLC C-max 5919 +/- 541 pmol/g and 315 +/- 70 pmol/g in vitreous and retina, respectively). The PEA-NLC formulation was characterized by high stability and robust ocular bioavailability. Therefore, this innovative formulation may be useful in clinical practice to manage retinal diseases.

Aims The Cardiomyopathy Registry of the EURObservational Research Programme is a prospective, observational, and multinational registry of consecutive patients with four cardiomyopathy subtypes: hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), and restrictive cardiomyopathy (RCM). We report the baseline characteristics and management of adults enrolled in the registry. ................................................................................................................................................................................................... Methods and results A total of 3208 patients were enrolled by 69 centres in 18 countries [HCM (n = 1739); DCM (n = 1260); ARVC (n = 143); and RCM (n = 66)]. Differences between cardiomyopathy subtypes (P < 0.001) were observed for age at diagnosis, history of familial disease, history of sustained ventricular arrhythmia, use of magnetic resonance imaging or genetic testing, and implantation of defibrillators. When compared with probands, relatives had a lower age at diagnosis (P < 0.001), but a similar rate of symptoms and defibrillators. When compared with the Long-Term phase, patients of the Pilot phase (enrolled in more expert centres) had a more frequent rate of familial disease (P < 0.001), were more frequently diagnosed with a rare underlying disease (P < 0.001), and more frequently implanted with a defibrillator (P = 0.023). Comparing four geographical areas, patients from Southern Europe had a familial disease more frequently (P < 0.001), were more frequently diagnosed in the context of a family screening (P < 0.001), and more frequently diagnosed with a rare underlying disease (P < 0.001). ................................................................................................................................................................................................... Conclusion By providing contemporary observational data on characteristics and management of patients with cardiomyopathies, the registry provides a platform for the evaluation of guideline implementation. Potential gaps with existing recommendations are discussed as well as some suggestions for improvement of health care provision in Europe.

Background Oral and oropharyngeal squamous cell carcinomas (OSCC and OPSCC) represent the majority of head and neck squamous cell carcinomas (HNSCC). Human papillomavirus (HPV) is an important etiologic factor together with Epstein-Barr virus (EBV). Little is known on the prevalence of major herpesviruses [EBV, cytomegalovirus (CMV) and HHV-6, − 7 and − 8] in HNSCCs. Methods Fifty-one formalin-fixed paraffin-embedded (FFPE) tissue samples taken at surgery (40 oropharyngeal, 11 oral) were analyzed for 40 HPV genotypes (20 high-risk types), EBV, CMV, HHV-6, − 7 and − 8 by quantitative PCR. Expression of the HPV-induced p16INK4A protein was also investigated by immunohistochemistry (IHC). Results In SCC, the prevalence of EBV was significantly higher compared to that of HPV (EBV 51% vs. HPV 19.5%; P = 0.005). HPV infection was found in 25% of OPSCC and in none of the OSCC; conversely, higher prevalence of EBV was found in OSCC (72.7%). HPV and EBV co-infection was detected only in 4 (10%) OPSCC. CMV was detected in only two cases, whereas HHV-6, − 7 and − 8 resulted negative. The prevalence of HPV but no EBV was associated with the non-keratinizing SCC type (NKSCC) compared to the keratinizing SCC type (KSCC)(HPV-DNA P

Major depressive disorder is one of the most prevalent and life-threatening forms of mental illnesses and a major cause of morbidity worldwide. Currently available antidepressants are effective for most patients, although around 30% are considered treatment resistant (TRD), a condition that is associated with a significant impairment of cognitive function and poor quality of life. In this respect, the identification of the molecular mechanisms contributing to TRD represents an essential step for the design of novel and more efficacious drugs able to modify the clinical course of this disorder and increase remission rates in clinical practice. New insights into the neurobiology of TRD have shed light on the role of a number of different mechanisms, including the glutamatergic system, immune/inflammatory systems, neurotrophin function, and epigenetics. Advances in drug discovery processes in TRD have also influenced the classification of antidepressant drugs and novel classifications are available, such as the neuroscience-based nomenclature that can incorporate such advances in drug development for TRD. This review aims to provide an up-to-date description of key mechanisms in TRD and describe current therapeutic strategies for TRD before examining novel approaches that may ultimately address important neurobiological mechanisms not targeted by currently available antidepressants. All in all, we suggest that drug targeting different neurobiological systems should be able to restore normal function but must also promote resilience to reduce the long-term vulnerability to recurrent depressive episodes.

Pityriasis rosea (PR) is a common, self-limiting exanthematous disease associated with a systemic reactivation of human herpesvirus 6 (HHV-6) and/or HHV-7. It usually occurs in the second or third decade of life whereas it is uncommon in patients younger than 10 years. We studied the clinical features and virological parameters of 31 children with PR, comparing them with those in adults. Our findings indicate that PR presents different characteristics between children and adults, mainly consisting of time lapse between herald patch and generalized eruption, duration of the exanthem, oropharyngeal involvement and persistence of HHV-6 and HHV-7 plasma viremia. Overall, these results suggest that, following HHV-6 and/or HHV-7 systemic active infection, the pathogenetic mechanisms involved in PR may at least partly be different in children and adults.

Background Pityriasis rosea (PR) is an exanthematous disease associated with the endogenous systemic reactivation of human herpesvirus-6 (HHV-6) and human herpesvirus-7 (HHV-7). Oropharyngeal lesions may be associated with the exanthema, but anecdotal evidence suggests that few dermatologists are aware of their occurrence. Objective Classifying oropharyngeal lesions in PR, establishing their prevalence, and assessing their possible association with different PR forms. Methods The records of all PR cases diagnosed in the Dermatology Clinic of Genoa University between 2003 and 2016 were retrospectively reviewed to examine sex and age of the patients, PR type, presence of enanthema, systemic symptoms, specific anti–HHV-6 and or HHV-7 serology, and HHV-6 and/or HHV-7 DNA loads. Results The oropharyngeal mucosa was carefully examined in 527 patients with PR. Painless oropharyngeal lesions were observed in 149 patients with PR (28%) and classified as erythematomacular, macular and papular, erythematovesicular, and petechial lesions. The petechial and macular and papular patterns were those most frequently observed. There was no statistically significant difference in the levels of HHV-6 and HHV-7 viremia in the plasma of patients with enanthema and those without. Limitations Because this was a retrospective study, biopsies on mucosal lesions were not performed. Conclusion Our findings showed that enanthemas are frequently associated with forms of PR different from the classic form.

An exanthem is a skin rash that may be associated with mucous membrane eruption, fever or other symptoms. It may develop as manifestation of an infectious disease or as adverse reaction to drugs. Beside the ‘classical exanthems’ commonly occurring in childhood, other exanthems, defined as ‘atypical’ for the different morphology and causal agents, may occur. Among the atypical exanthems with infectious etiology, viral, bacterial, parasitic and helminth infections are implicated. We describe herein etiology and epidemiology of the atypical exanthems caused by infectious agents. In case of exanthem, to make a correct etiological diagnosis is crucial for both the patient and community concerning issues such as time off school, immunizations and risk in pregnancy and immunocompromised individuals.

Granuloma annulare (GA) is a chronic, benign, and usually self-limiting cutaneous inflammatory disease, typically characterized by small, localized, skin-coloured papules that are usually asymptomatic or mildly pruriginous. Its aetiopathogenesis is still unknown and treatments are rarely effective. Generally, 50-70% of localized GA cases are self-limiting and show spontaneous resolution after 1-2 years, whereas disseminated GA is less likely to disappear without treatment. Treatment of generalized GA is usually based on single case reports, and only a few studies involving large case series have been published. We present the case of a patient affected by generalized GA, which resolved after colchicine treatment used for concomitant crowned dens syndrome due to calcium pyrophosphate deposition disease (CPPD). Colchicine may have worked by a direct action on GA or, alternatively, by controlling CPPD, as a possible trigger. As the low-dosage colchicine treatment was well tolerated by our patient, this could be easily used in the management of GA. However, further studies are needed to confirm the action of colchicine on GA.

The objective of this study was to evaluate the efficacy of an enhanced treatment regimen for syphilis with the addition of doxycycline and ceftriaxone to the conventional benzathine penicillin G (BPG) treatment. Sixty-nine syphilis patients were recruited and were randomly assigned to two groups: group 1 (38 patients) received standard therapy and group 2 (31 patients) received the enhanced therapy. All patients were followed-up for at least 12 months. Patients underwent physical examination and serology every 6 months as well as echocardiography and neurological examination every year. A three- to four-fold decline in the initial Venereal Disease Research Laboratory (VDRL) titre within 6 months after therapy was considered as serological cure. At 12 months, 68% of patients in group 1 and 100% in group 2 were serologically cured (P = 0.002). During follow-up, no patients in group 2 experienced complications related to syphilis. In contrast, one patient in group 1 developed neurosyphilis. In conclusion, the enhanced treatment is more effective than standard treatment and results in a higher and faster cure rate. Moreover, it provides treponemicidal antibiotic levels in the cerebrospinal fluid, thereby preventing possible late complications.

We report the first case of drug rash with eosinophilia and systemic symptoms (DRESS) following strontium ranelate (SR) treatment associated with systemic human HHV-7 reactivation. DRESS syndrome is a severe adverse drug-induced reaction presenting as a diffuse maculopapular skin rash with fever, hematological abnormalities (leukocytosis, eosinophilia, and/or atypical lymphocytosis), and multiorgan involvement. In our patient, diagnosis of DRESS was confirmed by the presence of six of the seven diagnostic criteria established in 2006 by the Japanese Research Committee on Severe Cutaneous Adverse Drug Reaction: maculopapular skin rash developing at least 3 weeks after starting therapy with a limited number of drugs, prolonged clinical symptoms after discontinuation of the causative drug, lymphadenopathy, fever, leukocyte abnormalities, and liver abnormalities. The diagnostic criteria of human herpesvirus (HHV)-6 reactivation have not been fulfilled in our patient, but a HHV-7 active infection was demonstrated by the presence of HHV-7 DNA and IgM in the patient's serum. In fact, in some DRESS instances, reactivation of HHVs other than HHV-6 may be detected, including HHV-7, Epstein-Barr virus (EBV), and cytomegalovirus (CMV). Our case underlines that not only HHV-6 but also HHV-7 systemic reactivation may be associated with a more severe and even fatal course of this syndrome.

Pityriasis rosea (PR) is an acute, self-limiting exanthematous disease associated with the endogenous systemic reactivation of human herpesvirus (HHV)-6 and/or HHV-7. The disease typically begins with a single, erythematous plaque followed by a secondary eruption with lesions on the cleavage lines of the trunk (configuration of a ‘Christmas tree'). The duration may vary from 2 weeks to a few months. Besides the typical presentation of PR, atypical forms have been described. The previous classifications of PR are mainly based on its atypical morphological features rather than on the pathogenetic mechanisms that underlie the different presentations of the disease. Notably, most of the morphologically atypical forms follow a course amenable to the classic form. The classification that we propose, taking into account the pathogenesis, clinical features, and course of the disease, is easy and intuitive and may be helpful in identifying the atypical forms of PR in order to avoid misdiagnosis and establish the best treatment options. Finally, this classification provides indications for managing potentially harmful forms of PR (such as PR in pregnancy) and PR-like eruptions.

Letter to the EditorA Case of Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) In-duced by Telaprevir Associated with HHV-6 Active InfectionFrancesco Broccolo, Giulia Ciccarese, Antonino Picciotto, Francesco DragoPII: S0168-8278(14)00668-0DOI: http://dx.doi.org/10.1016/j.jhep.2014.09.014Reference: JHEPAT 5348To appear in

The aim of this study was to evaluate whether corneal reparative activity of hyaluronan is a concentration-dependent phenomenon. Corneal blocks from rabbit eyes were cultured for 20 hours with hyaluronan in different concentrations and molecular weight ranges. In another experiment, the corneal epithelium was denuded and hyaluronan was administered as eye drops. Distances of epithelial migration increased over exposed stroma proportionally to concentration, when hyaluronan was added with a molecular weight of 800-1,400 kD. Maximum effect was observed with 0.2% hyaluronan concentration. No difference was seen when corneal blocks were cultured with hyaluronan 0.2% in different molecular weight ranges (800-1,400, 1,400-2,000, and 2,000-2,600 kD). When hyaluronan (molecular weight, 800-1,400 kD) eye drops were administered after corneal epithelial denudation in rabbits, it was found to have faster wound reparation. This effect was concentration-dependent. The 2 highest concentrations (0.2% and 0.4%) were not different for the time needed to complete wound healing. In conclusion, hyaluronan-induced stimulation of corneal wound healing fulfills standards for being considered as a pharmacological effect.

Pityriasis rosea (PR) is an acute, self-limiting exanthematous disease, associated with the reactivation of the human herpesvirus 6 (HHV-6) and/or human herpesvirus 7 (HHV-7) that usually lasts 6-8 weeks. We studied, from a clinical and virological point of view, 12 patients in whom the features of PR lasted longer than 12 weeks, defining this form of the disease as persistent PR (PPR). As in typical PR, in most of the PPR patients the disease begins with a herald patch, but compared to typical PR, systemic symptoms and oral lesions are more common. Moreover, in PPR we found a persistent reactivation of HHV-6 and/or HHV-7 with higher viral loads than in typical PR, accounting for the unusual persistence of the illness, the more frequent and severer systemic symptoms and the oral lesions. In conclusion, we describe an unusual persistent form of PR, whose prevalence has probably been underestimated so far and which should be added to the other variants of PR.

Stress and glucocorticoids alter glutamatergic transmission, and the outcome of stress may range from plasticity enhancing effects to noxious, maladaptive changes. We have previously demonstrated that acute stress rapidly increases glutamate release in prefrontal and frontal cortex via glucocorticoid receptor and accumulation of presynaptic SNARE complex. Here we compared the ex vivo effects of acute stress on glutamate release with those of in vitro application of corticosterone, to analyze whether acute effect of stress on glutamatergic transmission is mediated by local synaptic action of corticosterone. We found that acute stress increases both the readily releasable pool (RRP) of vesicles and depolarization-evoked glutamate release, while application in vitro of corticosterone rapidly increases the RRP, an effect dependent on synaptic receptors for the hormone, but does not induce glutamate release for up to 20 min. These findings indicate that corticosterone mediates the enhancement of glutamate release induced by acute stress, and the rapid non-genomic action of the hormone is necessary but not sufficient for this effect.Molecular Psychiatry advance online publication, 18 February 2014; doi:10.1038/mp.2014.5.

Acute stress rapidly increases the readily releasable pool of glutamate vesicles in prefrontal and frontal cortex through non-genomic action of corticosterone

The endogenous reactivation of HHV-6/7 may result in Pityriasis rosea (PR). The blood viral load distinguishes between latent and clinically manifest disease. We compared HHV-7/6 DNA load in saliva and blood samples of PR patients and controls. Salivary PCR assay is inadequate to detect and follow-up HHV-7 reactivation in PR. Only the plasma viral DNA load remains the direct marker of the viral replication.

Background: Populations living in the area of the Mediterranean Sea suffered by decreased incidence of cancer compared with those living in the regions of northern Europe and US countries, attributed to healthier dietary habits. Nowadays, we are assisting to a moving away from the traditional Mediterranean dietary pattern, but whether this changing is influencing risk of cancers is still unclear. The aim of the study was to review recent evidence on potential relationship between the adherence to the Mediterranean diet and cancer. Discussion: The most recent pooled analyses of epidemiological studies supported strongly the hypothesis that the Mediterranean diet may play a role in preventing several types of cancers, especially those of digestive tract, whereas contrasting results were reported for hormone-dependent cancers. Specific aspects of the Mediterranean diet such as high fruit and vegetables and low red processed meat intake may explain such protective effects. Moreover, evidence regarding olive oil and whole grains increase the beneficial effects of such dietary pattern against cancer. Conclusions: Literature evidence actually demonstrates that the increased adherence to the Mediterranean dietary pattern is beneficial to health across populations and may translate a protective effect with certain cancers.

In recent years, there has been increasing public interest in plant antioxidants, thanks to the potential anticarcinogenic and cardioprotective actions mediated by their biochemical properties. The red (or blood) orange (Citrus sinensis(L.) Osbeck) is a pigmented sweet orange variety typical of eastern Sicily (southern Italy), California, and Spain. In this paper, we discuss the main health-related properties of the red orange that include anticancer, anti-inflammatory, and cardiovascular protection activities. Moreover, the effects on health of its main constituents (namely, flavonoids, carotenoids, ascorbic acid, hydroxycinnamic acids, and anthocyanins) are described. The red orange juice demonstrates an important antioxidant activity by modulating many antioxidant enzyme systems that efficiently counteract the oxidative damage which may play an important role in the etiology of numerous diseases, such as atherosclerosis, diabetes, and cancer. The beneficial effects of this fruit may be mediated by the synergic effects of its compounds. Thus, the supply of natural antioxidant compounds through a balanced diet rich in red oranges might provide protection against oxidative damage under differing conditions and could be more effective than, the supplementation of an individual antioxidant.

Background Although atypical exanthems pose a severe diagnostic challenge, they have not been studied widely. Objective To identify the clinical features, laboratory parameters and other characteristics that help establish the etiology of atypical exanthems. Methods We collected the following information from 260 consecutive patients with atypical exanthems, including 108 children and 152 adults: demographic data, exanthem and enanthem morphology, clinical symptoms, month of outbreak and total duration. Throat, rectal, and vesicle swabs as well as urine and skin samples were examined for bacterial and viral signs. Serologic studies were performed for the most common infectious agents. Results Seven morphological patterns were identified: macular erythema, papular erythema, macular-papular erythema, erythematovesicular, macular-papular erythema with petechiae, erythema with pustules, and urticarial. Ninety-four cases were due to viruses, 38 to bacteria, 65 to drugs, 3 to parasites, and one to viruses-plus-drugs. Nineteen of the 25 cases with a petechial pattern had an infectious etiology (12 viral and 7 bacterial) and only 4 were iatrogenic. Sixty-one of 69 patients with enanthems were infectious (57 viral and 4 bacterial), 6 were iatrogenic, and 2 remained undiagnosed. The petechial pattern was infectious in 80% of cases (14 viral and 2 bacterial). Four cases were iatrogenic. During the spring and summer, 60% of exanthems were infectious and 21% were iatrogenic. Picornavirus infections exhibited summer prevalence (57%), peaking in July. Limitations There were a variable number of patients with each of the morphological patterns. Conclusions Morphological patterns, seasonal occurrence, and enanthem are key for etiological diagnosis of atypical exanthems.

Pityriasis rosea is an acute exanthem with many clinical and epidemiologic features of an infectious disease. To date, human herpesvirus (HHV)-6 and HHV-7 appear to be the most indicted culprits, and the evidence in favor of this hypothesis and the controversial results produced elsewhere are discussed. The complex pathophysiology of HHV-6 and HHV-7 infection, their diffusion in the population at large, the difficulties of understanding whether the infection is still latent or is clinically manifest, and well as whether pityriasis rosea depends on a reinfection or on a viral reactivation, all make the issue extremely difficult to study and understand.

Aim: Developments within nanomedicine have revealed a great potential for drug delivery to the brain. In this study nanoparticulate systems as drug carriers for riluzole, with sufficiently high loading capacity and small particle size, were prepared to a reach therapeutic drug level in the brain. Materials & method: Solid lipid nanoparticles containing riluzole have great potential as drug-delivery systems for amyotrophic lateral sclerosis and were produced by using the warm oil-in-water microemulsion technique. The resulting systems obtained were approximately 88 nm in size and negatively charged. Drug-release profiles demonstrated that a drug release was dependent on medium pH. Biodistribution of riluzole blended into solid lipid nanoparticles was carried out after administration to rats and the results were compared with those obtained by riluzole aqueous dispersion administration. Rats were sacrificed at time intervals of 8, 16 and 30 h, and the riluzole concentration in the blood and organs such as the brain, liver, spleen, heart and kidney was determined. Results: It was demonstrated that these solid lipid nanoparticles were able to successfully carry riluzole into the CNS. Moreover, a low drug biodistribution in organs such as the liver, spleen, heart, kidneys and lung was found when riluzole was administered as drug-loaded solid lipid nanoparticles. Conclusion: Riluzole-loaded solid lipid nanoparticles showed colloidal size and high drug loading, a greater efficacy than free riluzole in rats, a higher capability to carry the drug into the brain and a lower indiscriminate biodistribution.