Essential role of diastolic oscillatory potentials in adrenergic control of guinea pig sino-atrial node discharge

Background: The diastolic oscillatory after-potential Vos and pre-potential ThVos play an essential role in the pacemaker mechanism of sino-atrial node (SAN). The aim of this study was to investigate whether these oscillatory potentials are also involved in adrenergic control of SAN discharge. Methods: Vos and ThVos were visualized by superfusing guinea pig SAN in high [K+]o. The actions of adrenergic agonists on oscillatory potentials were studied by means of a microelectrode technique. Statistical significance was determined by means of Student's paired t-test. Results: In non-spontaneous SAN, norepinephrine (NE) decreased the resting potential into a voltage range ("oscillatory zone") where increasingly larger ThVos appeared and initiated spontaneous discharge. In slowly discharging SAN, NE gradually increased the rate by increasing the amplitude and slope of earlier-occurring ThVos and of Vos until these oscillations fused with initial diastolic depolarization (DD1). In the presence of NE, sudden fast rhythms were initiated by large Vos that entered a more negative oscillatory zone and initiated a large ThVos. Recovery from NE exposure involved the converse changes. The β-adrenergic agonist isoproterenol had similar actions. Increasing calcium load by decreasing high [K+]o, by fast drive or by recovery in Tyrode solution led to growth of Vos and ThVos which abruptly fused when a fast sudden rhythm was induced. Low [Ca2+]o antagonized the adrenergic actions. Cesium (a blocker of If) induced spontaneous discharge in quiescent SAN through ThVos. In spontaneous SAN, Cs+increased Vos and ThVos, thereby increasing the rate. Cs+ did not hinder the positive chronotropic action of NE. Barium increased the rate, as Cs+ did. Conclusion: Adrenergic agonists: (i) initiate SAN discharge by decreasing the resting potential and inducing ThVos; (ii) gradually accelerate SAN rate by predominantly increasing size and slope of earlier and more negative ThVos; (iii) can induce sudden fast rhythms through the abrupt fusion of large Vos with large ThVos; (iv) increase Vos and ThVosby increasing cellular calcium; and (v) do not modify the oscillatory potentials by means of the hyperpolarization-activated current If. The results provide evidence for novel mechanisms by which the SAN dominant pacemaker activity is initiated and enhanced by adrenergic agonists

Cytochrome P450 2E1 variable number tandem repeat polymorphisms and health risks: A genotype-phenotype study in cancers associated with drinking and/or smoking

Cytochrome P450 2E1 (CYP2E1) is one of the main enzymes involved in the oxidation of ethanol and in the transformation of a number of potentially dangerous compounds. It has various polymorphic sites, one of which is a variable number tandem repeat (VNTR) polymorphism previously described in the 5'-flanking region. The aim of this study was to investigate the genotype-phenotype association between CYP2E1 VNTR polymorphisms and risky health habits in healthy subjects and to analyze the associations between these polymorphisms with drinking- and/or smoking-related cancers. We analyzed 166 healthy subjects by genotyping for the CYP2E1 VNTR polymorphism associated with drinking and/or smoking habits by the more sensitive restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) method, using the NlaIV restriction enzyme. Sixty cases of pancreatic adenocarcinoma (PA) and 66 with hepatocellular carcinoma (HCC), were also genotyped. Statistical analysis was carried out to investigate the genotype-phenotype associations and to compare certain genotypes and cancer. We found 7 genotypes both in the healthy subjects and patients. The A1/A1 genotype was observed to be mainly associated with non-drinkers and -smokers (87.5 and 75.0%, respectively); moreover it was never found in the PA or HCC patients. Conversely, a weak association between A2/A3 with smokers (45.8%) and A4/A4 with drinkers (53.9%) was detected. In addition, the A4/A4 genotype was found to be significantly associated to PA [odds ratio (OR)=3.25; 95% confidence interval (CI) 1.21-7.50]. Our data demonstrate that certain CYP2E1 VNTR genotypes are associated with drinking and/or smoking habits; consequently, they may contribute either to the decreased or increased risk of developing drinking- and/or smoking-related cancers. In particular, we hypothesize that the A1/A1 VNTR genotype may have a protective role against drinking- and/or smoking-related cancers, and that A4/A4 may be a high-risk genotype during the early stages of cancer

Dual Contrastive Loss and Attention for GANs

Generative Adversarial Networks (GANs) produce impressive results on unconditional image generation when powered with large-scale image datasets. Yet generated images are still easy to spot especially on datasets with high variance (e.g. bedroom, church). In this paper, we propose various improvements to further push the boundaries in image generation. Specifically, we propose a novel dual contrastive loss and show that, with this loss, discriminator learns more generalized and distinguishable representations to incentivize generation. In addition, we revisit attention and extensively experiment with different attention blocks in the generator. We find attention to be still an important module for successful image generation even though it was not used in the recent state-of-the-art models. Lastly, we study different attention architectures in the discriminator, and propose a reference attention mechanism. By combining the strengths of these remedies, we improve the compelling state-of-the-art Fr\'{e}chet Inception Distance (FID) by at least 17.5% on several benchmark datasets. We obtain even more significant improvements on compositional synthetic scenes (up to 47.5% in FID)

ALLELIC VARIANTS OF CYP2E1 GENE IN HEPATOCARCINOMA PATIENTS AND IN HEPATIC TUMOR CELL LINES

Background and Aims: Hepatic enzyme CYP2E1 is involved in the metabolism of a number of exogenous and endogenous substances (i.e. ethanol, drugs and chemical carcinogens). Being polymorphic, CYP2E1 gene can give different xeno-metabolic capabilities in a population and it is well known that inadequate or no enzymatic deactivation of xenobiotics could induce an increased susceptibility to disease and cancer. In particular, one of the 5 -flanking region polymorphisms, able to differentiate CYP2E1 gene transcriptional activity, is caused by the appearance/disappearance of RsaI and PstI restriction sites, which generates two different alleles, namely *C1(Rsa+/Pst−) and *C2(Rsa−/Pst+) respectively, reported to be in complete linkage disequilibrium. Methods: To confirm the existence of a correlation between some particular CYP2E1 genotypes/haplotypes and hepatocarcinoma, we determined CYP2E1 PstI/RsaI genotypes/haplotypes by RFLP-PCR in a cohort of central western Sicily hepatocarcinoma patients and in a population of healthy students from the same geographic area. Results: In hepatocarcinoma patients, modal genotype association was Rsa++/Pst−−, corresponding to CYP2E1 *C1/*C1 haplotype, whereas the Rsa+−/Pst−+ association, equivalent to CYP2E1 *C1/*C2 haplotype, resulted to have the lowest frequency both in patients and in controls. Moreover, both in patients and in controls, noncanonical genotype associations were frequent and arose from a no-linkage disequilibrium between the two polymorphic sites. Other authors reported this finding as a rare occurrence. Thus, from analysis of only one restriction site, Rsa++ genotype was approximately 1.5-fold more frequent in patients than in controls, and the non-canonical Rsa+− genotype was found relatively frequent in patients. Moreover, HuH7 and HA22T transformed hepatocarcinoma cell lines also showed the Rsa+− genotype. Conclusions: These results suggest that the presence in CYP2E1 genotype of at least one allele with an Rsa I restriction site is correlated with hepatocarcinoma. As this site is known a consensus sequence for some specific CYP gene transcription factors, like HNF-1, it may be supposed that a single nucleotide polymorphism can alter the possibility of HNF-1 to bind CYP2E1 promoter. This could determine a marked change in the transcriptional activity of the gene, incompetence in xenobiotic metabolism or in toxic substance deactivation and an increased susceptibility to neoplastic diseases, such as hepatocarcinoma

Quality assessment of medical record as a tool for clinical risk management: a three year experience of a teaching hospital Policlinico Umberto I, Rome

Introduction: The medical record was defined by the Italian Ministry of Health in 1992 as "the information tool designed to record all relevant demographic and clinical information on a patient during a single hospitalization episode". Retrospective analysis of medical records is a tool for selecting direct and indirect indicators of critical issues (organizational, management and technical). The project’s aim being the promotion of an evaluation and self-evaluation process of medical records as a Clinical Risk Management tool to improve the quality of care within hospitals. Methods: The Authors have retrospectively analysed, using a validated grid, 1,184 medical records of patients admitted to the Teaching Hospital “Umberto I” in Rome during a three-year period (2013-2015). Statistical analysis was performed using SPSS for Windows © 19:00. All duly filled out criteria (92) were examined. “Strengths” and "Weaknesses" were identified through data analysis and Best and Bad Practice were identified based on established criteria. Conclusion: The data analysis showed marked improvements (statistically significant) in the quality of evaluated clinical documentation and indirectly upon behaviour. However, when examining some sub-criteria, critical issues emerge; these could be subject to future further corrective action

Fine-needle aspiration accuracy in the diagnosis of primary epithelioid angiosarcoma of the adrenal gland: a case report and review of the literature

Primary epithelioid angiosarcoma of the adrenal gland is extremely rare. Only 37 cases have been reported in the scientific literature.Here we describe the case of a 55-year-old woman affected by metastatic angiosarcoma in the right adrenal gland, who died few days after the histological diagnosis made by fine-needle aspiration (FNA). This is the second case of primary epithelioid angiosarcoma diagnosed by FNA among scientific articles published in English in PubMed. Microscopically, the tumor showed a predominant epithelioid differentiation, thus making the diagnostic process more difficult than usual. Immunohistochemical examination revealed positive reactivity for cytokeratin, CD31, and CD34. The literature shows that epithelioid adrenal angiosarcoma has poor clinical outcome, especially when metastatic at presentation

The Role of Carbon Dioxide Laser Therapy in Penile Kaposi’s Sarcoma: A Case Series of Three HIV-Negative HHV-8-Positive Patients

Kaposi’s sarcoma (KS) is a rare tumor of vascular origin. It is quite common in HIV patients. It is rarely located on the glans penis, especially in HIV-negative patients (just some tens in the literature). Owing to the rarity of the disease, both the real impact on survival and the most suitable therapy are not known. However, in this 3-patient case series, carbon dioxide laser therapy was effective both for local control and survival. In fact, two late relapses but no disease-related death were recorded. Probably, KS in HIV-negative patients is a slowly progressive disease, not so aggressive as in HIV-positive patients. Laser therapy is easy, fast, and cheap, and may treat the disease radically. If these data are confirmed by further studies, in the foreseeable future, laser therapy may become the gold standard for treating HIV-negative patients affected by penile KS

Mythical numbers and the proceeds of organised crime: estimating mafia proceeds in Italy

Organised crime is a field vulnerable to mythical numbers, i.e. exaggerated estimates lacking empirical support, but acquiring acceptance through repetition. The figures on mafia proceeds in Italy are a striking example of this problem. This study proposes an estimation of mafia proceeds in Italy from nine criminal activities (sexual exploitation of women, illicit firearms trafficking, drug trafficking, counterfeiting, the illicit cigarette trade, illicit gambling, illicit waste disposal, loan sharking, and extortion racketeering) by region and type of mafia (Cosa Nostra, Camorra,\u2018Ndrangheta, Apulian mafias, and other mafias). The results estimate yearly mafia proceeds at approximately \u20ac10.7 bn (0.7% of the Italian GDP), discussing the impact on the regional and national economies and the differences among the types of mafias as to their geographical sources of revenue

The Role of Attitudes Toward Medication and Treatment Adherence in the Clinical Response to LAIs: Findings From the STAR Network Depot Study

Background: Long-acting injectable (LAI) antipsychotics are efficacious in managing psychotic symptoms in people affected by severe mental disorders, such as schizophrenia and bipolar disorder. The present study aimed to investigate whether attitude toward treatment and treatment adherence represent predictors of symptoms changes over time. Methods: The STAR Network \u201cDepot Study\u201d was a naturalistic, multicenter, observational, prospective study that enrolled people initiating a LAI without restrictions on diagnosis, clinical severity or setting. Participants from 32 Italian centers were assessed at three time points: baseline, 6-month, and 12-month follow-up. Psychopathological symptoms, attitude toward medication and treatment adherence were measured using the Brief Psychiatric Rating Scale (BPRS), the Drug Attitude Inventory (DAI-10) and the Kemp's 7-point scale, respectively. Linear mixed-effects models were used to evaluate whether attitude toward medication and treatment adherence independently predicted symptoms changes over time. Analyses were conducted on the overall sample and then stratified according to the baseline severity (BPRS < 41 or BPRS 65 41). Results: We included 461 participants of which 276 were males. The majority of participants had received a primary diagnosis of a schizophrenia spectrum disorder (71.80%) and initiated a treatment with a second-generation LAI (69.63%). BPRS, DAI-10, and Kemp's scale scores improved over time. Six linear regressions\u2014conducted considering the outcome and predictors at baseline, 6-month, and 12-month follow-up independently\u2014showed that both DAI-10 and Kemp's scale negatively associated with BPRS scores at the three considered time points. Linear mixed-effects models conducted on the overall sample did not show any significant association between attitude toward medication or treatment adherence and changes in psychiatric symptoms over time. However, after stratification according to baseline severity, we found that both DAI-10 and Kemp's scale negatively predicted changes in BPRS scores at 12-month follow-up regardless of baseline severity. The association at 6-month follow-up was confirmed only in the group with moderate or severe symptoms at baseline. Conclusion: Our findings corroborate the importance of improving the quality of relationship between clinicians and patients. Shared decision making and thorough discussions about benefits and side effects may improve the outcome in patients with severe mental disorders

Clinical features and outcomes of elderly hospitalised patients with chronic obstructive pulmonary disease, heart failure or both

Background and objective: Chronic obstructive pulmonary disease (COPD) and heart failure (HF) mutually increase the risk of being present in the same patient, especially if older. Whether or not this coexistence may be associated with a worse prognosis is debated. Therefore, employing data derived from the REPOSI register, we evaluated the clinical features and outcomes in a population of elderly patients admitted to internal medicine wards and having COPD, HF or COPD + HF. Methods: We measured socio-demographic and anthropometric characteristics, severity and prevalence of comorbidities, clinical and laboratory features during hospitalization, mood disorders, functional independence, drug prescriptions and discharge destination. The primary study outcome was the risk of death. Results: We considered 2,343 elderly hospitalized patients (median age 81 years), of whom 1,154 (49%) had COPD, 813 (35%) HF, and 376 (16%) COPD + HF. Patients with COPD + HF had different characteristics than those with COPD or HF, such as a higher prevalence of previous hospitalizations, comorbidities (especially chronic kidney disease), higher respiratory rate at admission and number of prescribed drugs. Patients with COPD + HF (hazard ratio HR 1.74, 95% confidence intervals CI 1.16-2.61) and patients with dementia (HR 1.75, 95% CI 1.06-2.90) had a higher risk of death at one year. The Kaplan-Meier curves showed a higher mortality risk in the group of patients with COPD + HF for all causes (p = 0.010), respiratory causes (p = 0.006), cardiovascular causes (p = 0.046) and respiratory plus cardiovascular causes (p = 0.009). Conclusion: In this real-life cohort of hospitalized elderly patients, the coexistence of COPD and HF significantly worsened prognosis at one year. This finding may help to better define the care needs of this population