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Understanding changes of right ventricular (RV) geometry and function in repaired Tetralogy of Fallot (rToF) patients can improve decision-making for pulmonary valve replacement. Therefore, we aimed to assess the magnitude and clinical correlations of RV changes in rToF patients.Clinical and MRI data of rToF patients who underwent repeated cardiac magnetic resonance imaging (MRI) at two centers between December 2003 and September 2020 were analyzed together with anatomical factors, including RV outflow tract obstruction, pulmonary artery branch stenosis, and tricuspid regurgitation. Adverse cardiac events and/or NYHA class worsening were documented and correlated with MRI changes. QRS length was reported at each MRI.Two-hundred-and-nineteen rToF patients (53% males, aged 20.2 ± 10.1 years) were enrolled. An increase of ventricular dimensions, except LVEDVi, and worsening of right and left ejection fractions were found over an average period of 5 years of follow-up. These changes were statistically significant but within 10% of the initial value. No significant changes were reported on a year-to-year basis, except in a small group of patients (6%) in whom no predictive factors were identified. Despite similar RV dimensions at the first examination, younger patients had a higher RV ejection fraction and a different annual rate of change of ventricular dimensions compared to older ones. Patients with arrhythmias (20%) were more frequently older and had larger RV dimensions but showed no significant correlations with MRI changes/years. Changes in RV dimensions and function occur rarely and very slowly in rToF patients. A small percentage of patients experience a significant worsening in a short time interval without any recognized risk factors. Arrhythmias appear to occur in a small percentage of cases in the late 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.

© 2015 IBRO. Dopamine D3 receptors (D3Rs) are implicated in several aspects of cognition, but their role in aversive conditioning has only been marginally uncovered. Investigations have reported that blockade of D3Rs enhances the acquisition of fear memories, a phenomenon tightly linked to the neuropeptide pituitary adenylate cyclase-activating peptide (PACAP). However, the impact of D3R ablation on the PACAPergic system in regions critical for the formation of new memories remains unexplored. To address this issue, levels of PACAP and its receptors were compared in the hippocampus and cerebral cortex (CX) of mice devoid of functional D3Rs (D3R-/-) and wild-types (WTs) using a series of comparative immunohistochemical and biochemical analyses. Morphometric and stereological data revealed increased hippocampal area and volume in D3R-/- mice, and augmented neuronal density in CA1 and CA2/3 subfields. PACAP levels were increased in the hippocampus of D3R-/- mice. Expression of PACAP receptors was also heightened in mutant mice. In the CX, PACAP immunoreactivity (IR), was restricted to cortical layer V in WTs, but was distributed throughout layers IV-VI in D3R-/- mice, along with increased mRNAs, protein concentration and staining scores. Consistently, PAC1, VPAC1 and VPAC2 IRs were variably redistributed in CX, with a general upregulation in cortical layers II-IV in knockout animals. Our interpretation of these findings is that disturbed dopamine neurotransmission due to genetic D3R blockade may enhance the PACAP/PAC1-VPAC axis, a key endogenous system for the processing of fear memories. This could explain, at least in part, the facilitated acquisition and consolidation of aversive memories in D3R-/- mice.

Automatic management of atrial stimulation by verification of atrial threshold (ACM) has recently been made feasible. We investigated circadian atrial threshold variability over the long term and the predictors of successful automatic atrial threshold measurement, in order to provide practical clues for programming ACM features, in such a way as to achieve daily threshold verification and99% effective atrial stimulation.Six daily attempts to measure atrial threshold were programmed in patients receiving an EnPulse pacemaker (Medtronic Inc., Minneapolis, MN, USA). Atrioventricular (AV) conduction was maximized by programming Search AV+ (SAV+) to a resting Paced AV delay = 400 ms in the first month, and 600 ms thereafter.Seventy-six patients had a median follow-up of 12 months. Median ACM success was 77%. Concordance between automatically and manually measured thresholds was observed during the entire follow-up (Rho = 0.82, P0.001). Daily variability in atrial threshold was0.5 V in94% of measurements in the first trimester after implantation, and0.5 V in99% of measurements thereafter, as well as any time after pacemaker replacement. Atrial threshold was measured on 86% of days: the predictors of ACM failure were AV block (AVB), high%Atrial pacing, and atrial fibrillation. Programming SAV+ to achieve 600 ms resting Paced AV decreased%Vpacing in patients with normal AV conduction and first-degree AVB, improving the ability to detect atrial threshold.The reliability of ACM is high over a long follow-up. On the basis of atrial threshold variability, a practical approach to ACM programming should be two daily atrial threshold measurements in patients with normal AV conduction and%Apor = 40%, or with normal sinus activity and AVB, whereas 3-4 measurements should be recommended in patients with first-degree AVB and%Ap40% or with recurrent atrial fibrillation and AVB. The lowest adapted stimulation output should achieve at least threshold +1 V in the first trimester after implantation, then threshold +0.5 V thereafter, in order to achieve99.5% effective atrial stimulation.

Passive avoidance (PA) conditioning is a fear motivated task able to initiate a cascade of altered gene expression within the hippocampus, a structure critical to learning and memory. We have previously shown that neurofibromin (NF1) and amyloid precursor protein (APP), two genes implicated in cognitive function, are differentially expressed in brain of dopamine D 3 receptor knock-out mice (D3R-/-), suggesting that the receptor might have a role in their trascriptional regulation. Here in this study, we hypothesized that during acquisition of PA conditioning the expression of NF1 and APP genes could be influenced by D3Rs. To address this issue, we analyzed the expression of NF1 and APP in the hippocampus of both wild-type (WT) and D3R-/- mice subjected to the single trial step-through PA paradigm. Our finding demonstrated that (1) D 3R-/- mice exhibit increased cognitive performance as compared to WT mice in the step-through PA trial; (2) acquisition of PA increased D3R and NF1, but not APP expression in WT mice hippocampus; (3) PA-driven NF1 induction in WT was abrogated in D3R-/- mice and finally that (4) the heightened basal APP expression observed in naive D3R-/- mice was totally reversed by acquisition of PA. In conclusion, the present finding show for the first time that both D 3R and NF1 genes are upregulated following PA conditioning and suggest that hippocampal D3Rs might be relevant to NF1 transcriptional regulation in the hippocampus. © 2012 Springer Science+Business Media New York.

The effects of the arginine salt of pyroglutamic acid (2-oxo-pyrrolidone carboxylic acid, PCA) on learning and memory capacities of old rats were studied in a subchronic treatment schedule (i.p. injection of 0.1 and 1 g/kg/day for 15 days). The acquisition and extinction of active avoidance behaviour were studied in a pole-jumping test situation. The retention of passive avoidance response was examined in a step-through passive avoidance task. PCA facilitated the rate of acquisition of pole-jumping response, and inhibited the extinction of the response. The dose of 1 g/kg was more potent than 0.1 g/kg in this respect. Also in the passive avoidance task, the treatment with PCA was followed by an improvement of avoidance retention. These results indicate that PCA is a behaviourally active compound in that it improves learning and memory capacities in old rat.

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

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.

Summary A complex array of inhibitory interneurons tightly controls hippocampal activity, but how such diversity specifically affects memory processes is not well understood. We find that a small subclass of type 1 cannabinoid receptor (CB1R)-expressing hippocampal interneurons determines episodic-like memory consolidation by linking dopamine D1 receptor (D1R) signaling to GABAergic transmission. Mice lacking CB1Rs in D1-positive cells (D1-CB1-KO) display impairment in long-term, but not short-term, novel object recognition memory (NOR). Re-expression of CB1Rs in hippocampal D1R-positive cells rescues this NOR deficit. Learning induces an enhancement of in vivo hippocampal long-term potentiation (LTP), which is absent in mutant mice. CB1R-mediated NOR and the associated LTP facilitation involve local control of GABAergic inhibition in a D1-dependent manner. This study reveals that hippocampal CB1R-/D1R-expressing interneurons control NOR memory, identifying a mechanism linking the diversity of hippocampal interneurons to specific behavioral outcomes., Graphical Abstract, Highlights • CB1Rs are present in hippocampal D1R-positive interneurons • CB1R/D1R-positive interneurons control the late phase of recognition memory • CB1R/D1R-positive interneurons control learning-induced facilitation of LTP, Oliveira da Cruz et al. show that a specific subpopulation of hippocampal CB1 and D1 receptor-positive neurons controls late consolidation of recognition memory and associated synaptic plasticity by moderating local inhibitory GABAergic activity in the hippocampus.

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.

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.

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.

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.

Introduction. Pityriasis rosea (PR) is an exanthematous disease related to human herpesvirus- (HHV-) 6/7 reactivation. The network of mediators involved in recruiting the infiltrating inflammatory cells has never been studied.Object. To investigate the levels of serum cytokines, growth factors, and chemokines in PR and healthy controls in order to elucidate the PR pathogenesis.Materials and Methods. Interleukin- (IL-) 1, IL-6, IL-17, interferon- (IFN-)γ, tumor necrosis factor- (TNF-)α, vascular endothelial growth factor (VEGF), granulocyte colony stimulating factor (G-CSF), and chemokines, CXCL8 (IL-8) and CXCL10 (IP-10), were measured simultaneously by a multiplex assay in early acute PR patients’ sera and healthy controls. Subsequently, sera from PR patients were analysed at 3 different times (0, 15, and 30 days).Results and discussion. Serum levels of IL-17, IFN-γ, VEGF, and IP-10 resulted to be upregulated in PR patients compared to controls. IL-17 has a key role in host defense against pathogens stimulating the release of proinflammatory cytokines/chemokines. IFN-γhas a direct antiviral activity promoting NK cells and virus specific T cells cytotoxicity. VEGF stimulates vasculogenesis and angiogenesis. IP-10 can induce chemotaxis, apoptosis, cell growth, and angiogenesis.Conclusions. Our findings suggest that these inflammatory mediators may modulate PR pathogenesis in synergistic manner.

Parvovirus B19 (B19V) infection may differently manifest in various age groups. Erythema infectiosum ('fifth disease') is the most common B19V manifestations in children. Arthralgias and arthritis, with or without rash, are common manifestations of B19V infection in adults. Pruritus is usually present in adults and children. However, other cutaneous manifestations and atypical exanthems have been occasionally reported during B19V infection. To investigate the putative role of B19V infection in atypical exanthems, a total of 390 consecutive patients with atypical exanthems were analysed for B19V infection by determining B19V IgG and IgM antibodies titres in acute and convalescent phase as well as B19V DNA detection in serum by polymerase chain reaction (PCR). Atypical exanthems resulted related to B19V infection in 6 of the 120 pediatric (5%) and 14 of the 270 adult patients (5.2%). In conclusion this study reveals that atypical exanthems related to B19V infection are possible both in children and in adults, with a similar prevalence.

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.

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.

Viral infections have been associated with autoimmune connective tissue diseases. To evaluate whether active infection by Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpesvirus (HHV)-6, -7, -8, as well as parvovirus B19 (B19V) occur in patients with autoimmune connective tissue diseases, viral DNA loads were assessed in paired samples of serum and peripheral blood mononuclear cells (PBMCs) of 115 patients affected by different disorders, including systemic sclerosis, systemic, and discoid lupus erythematosus, rheumatoid arthritis, and dermatomyositis. Two additional groups, patients affected by inflammatory diseases (n=51) and healthy subjects (n=58) were studied as controls. The titers of anti-HHV-6 and anti-EBV antibodies were also evaluated. Cell-free HHV-6 serum viremia was detected in a significantly higher proportion of connective tissue diseases patients compared to controls (P

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.

Background: Little is known about the involvement of human herpesviruses 6 and 7 (HHV-6 and HHV-7) in autoimmune connective tissue diseases (ACTD). Objective: To determine the prevalence of active infection with HHV-6 and HHV-7 in patients with ACTD. Study design: The presence and quantity of HHV-6 DNA was determined by quantitative real-time PCR in a cross-sectional study of serum, peripheral blood mononuclear cells, and tissues obtained from 58 ACTD patients and 38 healthy subjects (HS). Specific anti-HHV-6 antibody titer was also measured. Results: HHV-6 serum viremia occurred in a significantly higher proportion of ACTD patients compared to HS [26/58 (44.8%) vs. 1/38 (2.6%), p = 0.001] with the highest reactivation frequency [7/10 (70%)] observed in patients with scleroderma. Moreover, HHV-6 in serum was associated with ACTD activity (22/38 vs. 4/20, p < 0.05). Higher titers of HHV-6 antibodies were found in ACTD patients than in HS, although HHV-6 seroprevalence among patients with ACTD and HS was similar. HHV-7 viremia was not detected in any patients or HS controls. Conclusion: The frequent reactivation of HHV-6 in scleroderma and other ACTD, especially when active, suggests that HHV-6 may play a role in the pathogenesis of these diseases. © 2009 Elsevier B.V. All rights reserved

Pityriasis rosea is an acute, self-healing exanthem characterized by oval erythematous-squamous lesions of the trunk and limbs, that usually spares face, scalp, palms, and soles. Constitutional symptoms, which have the character of true prodromes; clinical features, which resemble those of the known exanthems; and many epidemiologic data all suggest an infectious origin. A host of infectious agents have been incriminated, but, recently, human herpesvirus 6 and 7 have been extensively studied. The goal of this review is to outline the epidemiologic, clinical, histologic, and ultrastructural features of pityriasis rosea, but mainly to stress its possible human herpesvirus nature. In addition, clues have been added to help the reader to go through the complex subtleties of the virologic investigation. © 2008 American Academy of Dermatology, Inc.

BACKGROUND: Noncompaction of left ventricular myocardium is a rare congenital cardiomyopathy resulting from an incomplete myocardial morphogenesis that leads to the persistence of the embryonic myocardium. This condition is characterized by a thin compacted epicardial and an extremely thickened endocardial layer with prominent trabeculations and deep intertrabecular recesses. It is not clear, in noncompaction of myocardium, whether intertrabecular recesses could be responsible for thrombi formation and thromboembolic complications. METHODS: The prevalence of stroke and echocardiographic finding of thrombus was evaluated in a continuous series of 229 patients (men and women) affected by noncompaction of the left ventricular myocardium, who were included in the SIEC registry. We excluded patients affected by atrial fibrillation. RESULTS: The mean age of the patients was 49.5 years. Fifty percent of the patients were affected by a ventricular systolic dysfunction. The mean period of follow-up was 7.3 years. Only four patients had a history of ischemic stroke. A large thrombus into the left ventricular chamber was observed in a 1-year-old child affected by Behcet's disease (high risk of thrombi formation). CONCLUSION: Noncompaction of the left ventricular myocardium, by itself, does not seem to be a risk factor for stroke or embolic results, so there is no indication for oral anticoagulant therapy. © 2008 Italian Federation of Cardiology.

Background: Isolated left ventricular noncompaction is the result of incomplete myocardial morphogenesis, leading to persistence of the embryonic myocardium. The condition is recognised by an excessively prominent trabecular meshwork and deep intertrabecular recesses of the left ventricle. Whether these intertrabecular recesses are a favorable substrate for supraventricular arrhythmias is unclear, even if the incidence of chronic heart failure seems to be high. Results: We evaluated a continuous series of 238 patients affected by noncompaction. In 4 cases the patients reported palpitations and in 4 an episode of syncope. Periodic holter monitoring was performed every 6 months for 4 years. Only 9 patients had documented atrial fibrillation. In no cases we observed supraventricular tachycardia. Conclusions: Noncompaction alone does not seem to be a risk factor for supraventricular arrhythmias. © 2007 Elsevier Ireland Ltd. All rights reserved.

Background A routine sports evaluation identified constant alternation between a junctional and idioventricular rhythm in a 9-year-old child. During exercise testing, electrography demonstrated that the child was in junctional rhythm without any apparent P waves, and had a reduced increase in heart rate. Endocardial atrial pacing captured the atrium and demonstrated that atrioventricular conduction was normal, but the recovery time of the ectopic rhythm was very long. Three-dimensional electrophysiological mapping revealed 1:1 retrograde homogeneous conduction through the right atrium. Investigations Electrocardiography, Holter monitoring, echocardiography, exercise stress testing, atrial pacing, three-dimensional electroanatomical mapping of the right atrium and genetic testing. Diagnosis Sinus node dysfunction. Management Pacemaker implantation was postponed until a later stage in the patient's development.

It is known that alpha-melanocyte stimulating hormone (alpha-MSH) may exert anti-inflammatory effects and facilitate reparative processes in different tissues. The effective message sequence of alpha-MSH resides in the COOH-terminal tripeptide alpha-MSH(11-13). This study was undertaken to investigate the effects of topical administration of the COOH-terminal tripeptide sequence of alpha-MSH (alpha-MSH(11-13), KPV) on corneal epithelial wound healing in rabbits and the possible role of nitric oxide (NO) in these effects. The whole corneal epithelium was denuded in both eyes by mechanical abrasion. The area of the corneal epithelial defect was stained with fluorescein, photographed, and then measured before the treatment and every 12 h by a computerized software. The mean epithelial wound area and the mean percent of epithelial defect remaining at each follow-up control were compared between experimental groups. Rabbits were topically treated with KPV 1, 5 or 10 mg/ml (30 microl), two drops four times in a day, for 4 days, starting immediately after corneal abrasion, while control animals received topical phosphate-buffered saline as vehicle. In order to study the role of NO in corneal repair processes, the NO donor, sodium nitroprusside (SP, 10 mg/ml, 30 microl) was administered in both eyes, two drops four times in a day, for 4 days. The effects of KPV or SP were challenged by pre-treatment with the nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME, 10 mg/ml, 30 microl) 30 min prior to KPV or SP instillation. The mean percent epithelial defect remaining each time was significantly smaller in animals treated with KPV or SP in comparison to controls. Sixty hours later, eight out of eight (100%) corneas treated with KPV or SP were completely re-epithelized (P

Objectives The aim of our study was to evaluate arterial embolism (AE) occurrence rates and predictors in patients suffering from bradycardia and wearing a pacemaker with antitachycardia pacing therapies. Background Atrial fibrillation (AF) is associated with a high incidence of AE. Methods A total of 725 patients (360 men, age 71 ± 11 years) were implanted with a DDDRP pacemaker (Medtronic AT500, Medtronic Inc., Minneapolis, Minnesota). At baseline 225 (31.0%) patients received antiplatelet therapy and 264 (36.4%) patients received anticoagulation agents. Results Over a median 22-month follow-up (25th to 75th interquartile range 16 to 30 months), AE occurred in 14 (1.9%) patients: 7 patients suffered a nonfatal ischemic stroke (0.6% per year), 4 patients had transient ischemic attack (0.34% per year), and 3 patients had embolic complications. Among baseline patients’ characteristics, multivariate logistic analysis showed that embolic events are independently associated to ischemic heart disease (7.0 odds ratio [OR], 95% confidence interval [CI] 2.3 to 21.3, p = 0.001), prior embolic event (7.3 OR, 95% CI 1.2 to 43.9, p = 0.029), diabetes (5.0 OR, 95% CI 1.2 to 15.7, p = 0.032), and hypertension (4.1 OR, 95% CI 1.1 to 15.6, p = 0.036). The risk of embolism, adjusted for known risk factors, was 3.1 times increased (95% CI 1.1 to 10.5, p = 0.044) in patients with device-detected atrial fibrillation episodes longer than one day during follow-up. Conclusions In a cohort of patients with bradycardia and AF, arterial embolism was common in patients with ischemic cardiopathy, hypertension, diabetes mellitus, and in patients with known stroke risk factors. Atrial fibrillation occurrences longer than one day were independently associated with embolic events.

Background. Blastomycosis-like pyoderma is a disorder of uncertain etiology that has been described in association with a variety of underlying conditions, including inflammatory and neoplastic pathologic conditions and in association with a primary immunodeficiency state. The response to therapy, antibiotics in particular, is said to be variable or poor. Methods. We examined two patients with blastomycosis-like pyoderma in whom no underlying pathologic or immunologic abnormalities were found. We treated them with antibiotics according to bacterial resistance tests. In the second case topical disodium chromoglycate was added. Results. Treatment cleared or markedly improved the lesions. Conclusions. Antibiotic treatment guided by susceptibility tests is recommended. The addition of topical disodium chromoglycate may be useful.

Background: Antibodies to stratified epithelia characterize chronic ulcerative stomatitis, an entity that very closely resembles erosive lichen planus both clinically and histologically. These antibodies are directed against a 70-kd antigen. Objective: Our aim was to verify whether antibodies to stratified epithelia are present in patients with common lichen planus. Patients and methods: One hundred thirty-eight patients with various forms of lichen planus were studied. Indirect immunofluorescence was performed on both monkey esophagus and HEp2-2000 cells. Immunoblotting was done with cultured keratinocytes used as the source antigen. Results: Nineteen patients had antibodies to stratified epithelia (in 9 directed against an antigen of 70 kd). Forty-eight patients had circulating antibodies detected by indirect immunofluorescence on both monkey esophagus and HEp2-2000 cells (in 7 directed against an antigen of 70 kd). Indirect immunofluorescence was positive only on HEp2-2000 cells in 21 patients. Indirect immunofluorescence was negative in 50 patients on both HEp2-2000 cells and monkey esophagus. None of the last 71 patients had antibodies directed to an antigen of 70 kd. Limitations: This is a serological study; results from direct immunofluorescence studies would be interesting. Conclusion: Antibodies to stratified epithelia directed to an antigen of 70 kd are not exclusive to chronic ulcerative stomatitis, but are also present in some patients with lichen planus. © 2007 American Academy of Dermatology, Inc.