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In the field of cardiovascular diseases, elevated levels of serum uric acid (UA) reflect a marked activation of the xanthine oxidase pathway with increase in free radicals production; it is often associated with an inflammatory state, oxygen consumption and endothelial dysfunction. All these associations have been also confirmed in heart failure (HF) but the pathophysiological role of UA in this setting is not well understood. The aim of this study was to evaluate the prognostic role of UA in outpatients enrolled in the Italian Registry of Congestive Heart Failure (IN-CHF).All patients met the European Society of Cardiology (ESC) criteria for diagnosis of HF. We considered patients with complete clinical data and UA level available at the baseline and at 1-year follow-up. The study population was composed of 877 patients aged 63 ± 12 years. One-year mortality was 10.8% and dead patients had a higher level of UA than survivors (7.1 mg dl⁻¹ vs 6.6 mg dl⁻¹, p0.0207). In multivariable full model of analysis, UA did not result in an independent predictor of death in overall population, but only in patients with low body mass index (BMI) (≤22 kg m⁻²) (hazard ratio (HR): 2.38, 95% confidence interval (CI) 1.36-4.18). In this subgroup, a statistically significant gradual relationship between UA and survival was detected starting from values higher than 8 mg dl⁻¹.Elevated level of UA is not an independent predictor of mortality in chronic HF, but it markedly worsens outcome if associated with low level of BMI. This association is likely an indicator of chronic inflammatory and catabolic state.

Aims. The European Federation of Psychiatric Trainees (EFPT), founded in London in 1992, is an independent international federation of psychiatric trainees' national associations. The EFPT is engaged in several actions in order to pursue its general aims to promote high standards of quality of psychiatric training and promote the collaboration and networking between European psychiatric trainees. Methods. Member associations constitute the general assembly that meets annually during the European Forum of Psychiatric Trainees. During the Forum, working groups are created and the activities for the next year are planned. Results. Regular activities of the EFPT include the production of statements expressing the standpoint of trainees on educational issues, the conduction of research projects, the creation of new national trainees' associations, the facilitation of networking among European psychiatric trainees and the organization an annual meeting (EFPT Forum). The last EFPT Forum has been organized in Sorrento (Italy) on May 2012. Psychiatric trainees from 37 European countries have registered to this event. Discussion. EFPT activities constitute a opportunity for psychiatric trainees to directly participate in the improvement of their psychiatric training and to establish a network with European colleagues that will contribute to their professonal development.

This study sought to prospectively assess which factors were related to short-term worsening heart failure (HF) leading to or not to hospital admission, in long-term outpatients followed by cardiologists. The subsequent decision-making process was also analyzed. The study population consisted of 2,701 outpatients enrolled in the registry of the Italian Network on Congestive Heart Failure (IN-CHF) and followed by 133 cardiology centers (19% of all existing Italian cardiology centers). Clinical and follow-up data were collected by local trained clinicians; 215 patients (8%) had short-term decompensation (on average 2 months after the index outpatient visit). Multivariate analysis showed that previous hospitalization, long duration of symptoms, ischemic etiology, atrial fibrillation, higher functional class (New York Heart Association classification III to IV), higher heart rate, and low systolic blood pressure were independently associated with HF destabilization. Poor compliance (21%) and infection (12%) were the most frequent precipitating factors, but a precipitating factor was not identified in 40% of the patients. Poor compliance was more common in women, but no other clinical characteristics emerged as being related with a specific precipitating factor. Fifty-seven percent of the patients with a short-term recurrence of worsening HF required hospital admission; infusion treatment with inotropes and/or vasodilators was necessary in 19% of them. Long-term therapy was changed in 48% of the patients. Thus, in ambulatory HF patients, short-term worsening HF can be predicted according to the clinical characteristics on an outpatient basis. Nearly 1/3 of precipitating factors can be prevented. Patient education and avoidance of inappropriate treatment may reduce the number of relapses.

Objectives: The role of atrial fibrillation (AF) in older patients with heart failure (HF) is controversial because many variables seem to influence their outcome. We investigated the predictivity of AF in 3 age groups of outpatients with HF. Methods: We analyzed 8,178 outpatients enrolled in the Italian Network on Congestive Heart Failure Registry with HF diagnosed according to the European Society of Cardiology criteria. A trained cardiologist established the diagnosis of AF and HF at the entry visit at each center. We stratified the population into 3 age groups, as follows: group A, ≤65 years; group B, 66–75 years, and group C, >75 years. Results: Group A was composed of 4,261 patients, 683 with AF (16.0%); in group B there were 2,651 patients, 638 with AF (24.1%), and group C was composed of 1,266 patients, 412 with AF (32.5%). The 1-year mortality rate was higher in AF patients in all groups. In a multivariate model, AF remained an independent risk factor for death in groups A and B, but not in group C [group A: hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.10–1.81; group B: HR 1.29, 95% CI 1.00–1.67; group C: HR 1.05, 95% CI 0.78–1.43]. Conclusion: The prevalence of AF increased with age and was associated with a higher mortality rate. However, AF independently predicted all-cause mortality only in patients aged ≤75 years.

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Item does not contain fulltext Susanne Piras Latrines, antieke toiletten, modern onderzoek Meppel:Edu'Actief ,1994 90-5117-175-7

The generation of food waste at both the supplier and the consumer levels stems from a complex set of interacting behaviours. Computational and mathematical models provide various methods to simulate, diagnose and predict different aspects within the complex system of food waste generation and prevention. This chapter outlines four different modelling approaches that have been used previously to investigate food waste: discrete event simulation, which has been used to examine how the shelf life of milk and many actions taken around shopping and use of milk within a household influence food waste; machine learning and Bayesian networks, which have been used to provide insight into the determinants of household food waste; agent-based modelling, which has been used to provide insight into how innovation can reduce retail food waste; and mass balance estimation, which has been used to model and estimate food waste from data related to human metabolism and calories consumed.

Purpose: A recurrent 17 bp duplication (c.657ins17bp) of a segment of the paired-like homeodomain transcription factor 3 (PITX3) gene on human chromosome 10 has been reported in seven families with autosomal dominant posterior polar cataracts with or without anterior segment mesenchymal dysgenesis (ASMD). ASMD can include Peters anomaly with corneal clouding, iridolenticular corneal adhesions, displaced Schwalbe’s line, and cataract as described previously in a large Australian family. This study reports the examination of PITX3 in this Australian family.Methods: Clinical examinations of the proband and her relatives were performed as part of routine follow up. A polymerase chain reaction (PCR) based test for the duplication in PITX3 was developed, and DNA from 21 members of the proband’s family was tested.Results: All clinically affected members of the family had the same 17 bp duplication of PITX3. There was no difference in the size of the duplication between the severely affected individuals and the more mildly affected individuals. Prenatal diagnosis was performed for two offspring of one affected person. In the first pregnancy, the fetus was shown to carry the duplication while in the second pregnancy, the fetus was shown to be homozygous for the normal allele.Conclusions: The results show that in some individuals within one family, duplication of this segment of PITX3 can result in severe symptoms leading to functional blindness while in other individuals in the same family or in other families, the same duplication leads to treatable cataract with minimal visual impairment.

During a screening for compounds that could act against Mycobacterium tuberculosis, a series of new cellular antiproliferative agents was identified. The most cytotoxic molecules were evaluated against a panel of human cell lines derived from hematological and solid human tumors. In particular, (E)-2-(1H-benzo[d] [1,2,3]triazol-1-yl)-3-(4-methoxyphenyl)acrylonitrile (1) was found to be of a potency comparable to etoposide and greater than 6-mercaptopurine in all cell lines tested. Accordingly, a synthesis of a new series of (E)-2-(5,6-dichloro-1H-benzo[d] [1,2,3]triazol-1-yl)-3-(4-R-phenyl)acrylonitriles was conducted in order to extend the studies of structure-activity relationship (SAR) for this class of molecules. With the aim to evaluate if 3-aryl-2-[1H-benzotriazol-1-yl]acrylonitriles were able to act like tubulin binding agents, the effects on cell cycle distribution of the most active compounds (1, 2a, 3 and 4) were analyzed in K562 cells. A detailed molecular modeling study of the putative binding mode of this series of compounds on tubulin is also reported.

Loss-of-function mutations in the gene encoding for the protein progranulin (PGRN), GRN, are one of the major genetic abnormalities involved in frontotemporal lobar degeneration. However, genetic variations, mainly missense, in GRN have also been linked to other neurodegenerative diseases. We found 12 different pathogenic/likely pathogenic variants in 21 patients identified in a cohort of Italian patients affected by various neurodegenerative disorders. We detected the p.Thr272SerfsTer10 as the most frequent, followed by the c.1179+3A>G variant. We characterized the clinical phenotype of 12 patients from 3 pedigrees carrying the c.1179+3A>G variant, demonstrated the pathogenicity of this mutation, and detected other rarer variants causing haploinsufficiency (p.Met1?, c.709-2A>T, p.Gly79AspfsTer39). Finally, by applying bioinformatics, neuropathological, and biochemical studies, we characterized 6 missense/synonymous variants (p.Asp94His, p.Gly117Asp, p.Ala266Pro, p.Val279Val, p.Arg298His, p.Ala505Gly), including 4 previously unreported. The designation of variants is crucial for genetic counseling and the enrollment of patients in clinical studies.

Heme oxygenase 1 (HO-1) up-regulation drives cell adaptation to different stressors. Previous works from our lab have shown that HO-1 plays a crucial role in neuroblastoma cells (NB) response to oxidative stress (OS), but also demonstrated that sensitivity to OS increases after retinoic acid-induced NB-differentiation. In this study, we evaluated the involvement of the molecular mechanisms of HO-1 induction in NB cell response to OS, analyzing its main activator Nrf2 and its main repressor Bach1. We showed that retinoic acid-differentiated NB cells are more susceptible to OS as they reduce the ability to up-regulate HO-1. We demonstrated that Bach1 displacement from HO-1 promoter in undifferentiated cells enables the binding of Nrf2, while in differentiated cells, Bach1 displacement was impaired preventing Nrf2 binding and HO-1 induction. Furthermore, we considered the role played by miRNA494, which could be involved in Bach1 post-transcriptional regulation. Preliminary data showed that miRNA494 is down-regulated in differentiated cells and that its inhibition in undifferentiated cells increases sensitivity to OS. In conclusion, this study highlights the role of Bach1 in the regulation of HO-1 in NB cell response to OS.

In this work, we present and discuss a comprehensive set of both newly and previously synthesized compounds belonging to 5 distinct molecular classes of linear aromatic N-polycyclic systems that efficiently inhibits bovine viral diarrhea virus (BVDV) infection. A coupled in silico/in vitro investigation was employed to formulate a molecular rationale explaining the notable affinity of all molecules to BVDV RNA dependent RNA polymerase (RdRp) NS5B. We initially developed a three-dimensional common-feature pharmacophore model according to which two hydrogen bond acceptors and one hydrophobic aromatic feature are shared by all molecular series in binding the viral polymerase. The pharmacophoric information was used to retrieve a putative binding site on the surface of the BVDV RdRp and to guide compound docking within the protein binding site. The affinity of all compounds towards the enzyme was scored via molecular dynamics-based simulations, showing high correlation with in vitro EC50 data. The determination of the interaction spectra of the protein residues involved in inhibitor binding highlighted amino acids R295 and Y674 as the two fundamental H-bond donors, while two hydrophobic cavities HC1 (residues A221, I261, I287, and Y289) and HC2 (residues V216, Y303, V306, K307, P408, and A412) fulfill the third pharmacophoric requirement. Three RdRp (K263, R295 and Y674) residues critical for drug binding were selected and mutagenized, both in silico and in vitro, into alanine, and the affinity of a set of selected compounds towards the mutant RdRp isoforms was determined accordingly. The agreement between predicted and experimental data confirmed the proposed common molecular rationale shared by molecules characterized by different chemical scaffolds in binding to the BVDV RdRp, ultimately yielding compound 6b (EC50 = 0.3 μM; IC50 = 0.48 μM) as a new, potent inhibitor of this Pestivirus.

In this preliminary study we report the antiviral screening of triazolo[4,5-g]quinoline derivatives (compounds 1–6). 4,9-Dihydrotriazolo[4,5-g]quinoline-1-oxide (1) stood out as a new, small molecule endowed with a selective, promising activity in cell-based assays against HIV-1wt and clinically relevant NNRTI resistant mutants. In order to identify the molecular target, compound 1 was assayed in enzyme assay against the HIV-1wt RT. The molecular modeling strategy adopted yielded a rationale, in terms of molecular interactions and free energy of binding, for the possible reasons of the activity of this compound against NNRTI-resistant HIV-1 mutants with the RT isoforms K103N and Y181C.