Spontaneous self-assembly of an unsymmetric trinuclear triangular copper(II) pyrazolate complex, [Cu3(μ3-OH)(μ-pz) 3(MeCOO)2(Hpz)] (Hpz = pyrazole). Synthesis, experimental and theoretical characterization, reactivity, and catalytic activity

The almost quantitative formation of the triangular trinuclear copper derivative [Cu3(μ3-OH)(μ-pz)3(MeCOO) 2(Hpz)] (1) (Hpz = pyrazole), has been simply achieved by adding Hpz to an ethanol solution of Cu(MeCOO)2·H2O. An X-ray molecular structure determination shows that 1 is completely unsymmetric and that trinuclear units result assembled in an extended bidimensional network formed through acetate bridges and hydrogen bonds. EPR and magnetic measurements are consistent with the presence of a single unpaired electron. Theoretical density functional calculations carried out for S = 1/2 provide a thorough description of the electronic structure of 1, allowing a detailed assignment of its UV-vis absorption spectrum. Compound 1 reacts with MeONa, yielding [Cu 3(μ3-OH)(μ-pz)3(MeCOO)(MeO)(Hpz)] (2) and [Cu3(μ3-OH)(μ-pz)3(MeO) 2(Hpz)] (3) through the substitution of one and two acetate ions, respectively, with MeO- ion(sS). The spontaneous self-assembly of the triangular trinuclear Cu3 moiety seems to occur only with pyrazole as can be inferred by the results obtained in the reactions of copper(II) acetate with some substituted pyrazoles leading to the formation of mononuclear [Cu(MeCOO)2(L)2] (4-8) and dinuclear [Cu(MeCOO) 2(L)]2 (9-11) (L = substituted pyrazole) compounds. Also the presence of acetate ions seems to play a leading role in determining the formation of the trinuclear triangular arrangement, as indicated by the formation of a mononuclear derivative, [Cu(CF3COO) 2(Hpz)]2 (compound 12), in the reaction of copper(II) trifluoroacetate with pyrazole. Compounds 1-3, as well as some other mono- and dinuclear copper(II)-substituted pyrazole complexes, have been tested as catalyst precursors in cyclopropanation reaction, observing the formation of products in a syn:anti ratio opposite that normally reported

A rare case of solitary fibrous tumour of the pelvis in an 18-year-old young man: Ct and mri features with pathologic correlations

Solitary fibrous tumors (SFTs) are mesenchymal neoplasms of fibroblastic origin, even if commonly seen in the pleura, they can occur anywhere in the body. SFT presents as a slow growing, often asymptomatic mass, generally affecting middle-aged adults regardless of the sex. We report a rare case of an 18-year-old man referred to our institution to perform computed tomography (CT) and magnetic resonance imaging (MRI), to investigate a pelvic mass incidentally discovered at abdominal ultrasound examination. A well circumscribed, heterogenous and hypervascular lesion was described at imaging, with absence of calcifica-tions, hemorrhage, necrosis nor cystic degeneration. The mass removal was performed via the Da Vinci-assisted robotic surgery. Histopathological evaluation confirmed the diagnosis of SFT. CT and MRI can aid the identification of SFT, providing useful information which needs to be supported by histopathological analysis

A26-3 Tip design in a new steroid-elution pacing lead influences ventricular electrical parameter variations in DDD pacemaker implanted patients

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Fitomassa remanescente de pastagem e rendimento de grãos de milho e soja em função de formas de semeadura, tempos de diferimento e adubação da pastagem.

O uso das áreas de lavoura para cultivo de pastagens anuais de inverno, manejadas com pastejo direto de gado de corte ou de leite, pode afetar o rendimento de grãos das culturas de verão. O objetivo desse trabalho foi avaliar o efeito de formas de semeadura da pastagem anual de inverno, do tempo de retirada dos animais antes da dessecação da pastagem (tempo de diferimento) e da adubação com esterco de aves sobre a fitomassa remanescente da pastagem e rendimento de grãos de milho e de soja, durante cinco anos de experimentação. Foram estudadas duas formas de semeadura das pastagens (semeadura direta e semeadura + gradagem), quatro tempos de diferimento (sem pastejo e retirada dos animais aos 28 e 14 dias antes e no dia da dessecação), com e sem aplicação de 8 m3 ha-1 de cama de aviário. No período estudado, as formas de semeadura de pastagem anual de inverno não afetam o rendimento de grãos de milho e de soja cultivados em sucessão à pastagem. Os tratamentos com pastejo resultam em menor fitomassa remanescente da pastagem do que o sem pastejo, mas nenhum deles afeta o rendimento de grãos de milho e soja cultivados em sucessão à pastagem. Há resposta diferenciada entre os anos estudados à aplicação de esterco de aves sobre a fitomassa remanescente de pastagem e o rendimento de grãos de milho e de soja

The effects of somatostatin analogues on liver volume and quality of life in polycystic liver disease: a meta-analysis of randomized controlled trials

A clear evidence on the benefits of somatostatin analogues (SA) on liver outcome in patients affected by polycystic liver disease is still lacking. We performed a meta-analysis of RCTs and a trial sequential analysis (TSA) evaluating the effects of SA in adult patients with polycystic liver disease on change in liver volume. As secondary outcome, we evaluated the effects on quality of life as measured by SF36-questionnaire. Six RCTs were selected with an overall sample size of 332 adult patients with polycystic liver disease (mean age: 46 years). Mean liver volume at baseline was 3289 ml in SA group and 3089 ml in placebo group. Overall, unstandardized mean difference in liver volume was − 176 ml (95%CI, − 406, 54; p < 0.133). Heterogeneity was low (I2:0%, p < 0.992). However, we performed a moderator analysis and we found that a higher eGFR significantly correlates to a more pronounced effect of SA on liver volume reduction (p = 0.036). Cumulative Z-curve in TSA did not reach either significance and futility boundaries or required information size. Three RCTs have evaluated Quality of life parameters measured by SF36-QOL questionnaire for a total of 124 patients; no significant difference was found on the effect of SA on QOL parameters when compared with placebo. The present meta-analysis revealed a potential effect of SA on reduction of liver volume and quality of life parameters, but results did not reach a statistical significance. These data could be explained by the need of further studies, as demonstrated through TSA, to reach an adequate sample size to confirm the beneficial outcomes of SAs treatment

Two New Pimelic Diphenylamide HDAC Inhibitors Induce Sustained Frataxin Upregulation in Cells from Friedreich's Ataxia Patients and in a Mouse Model

BACKGROUND: Friedreich's ataxia (FRDA), the most common recessive ataxia in Caucasians, is due to severely reduced levels of frataxin, a highly conserved protein, that result from a large GAA triplet repeat expansion within the first intron of the frataxin gene (FXN). Typical marks of heterochromatin are found near the expanded GAA repeat in FRDA patient cells and mouse models. Histone deacetylase inhibitors (HDACIs) with a pimelic diphenylamide structure and HDAC3 specificity can decondense the chromatin structure at the FXN gene and restore frataxin levels in cells from FRDA patients and in a GAA repeat based FRDA mouse model, KIKI, providing an appealing approach for FRDA therapeutics. METHODOLOGY/PRINCIPAL FINDINGS: In an effort to further improve the pharmacological profile of pimelic diphenylamide HDACIs as potential therapeutics for FRDA, we synthesized additional compounds with this basic structure and screened them for HDAC3 specificity. We characterized two of these compounds, 136 and 109, in FRDA patients' peripheral blood lymphocytes and in the KIKI mouse model. We tested their ability to upregulate frataxin at a range of concentrations in order to determine a minimal effective dose. We then determined in both systems the duration of effect of these drugs on frataxin mRNA and protein, and on total and local histone acetylation. The effects of these compounds exceeded the time of direct exposure in both systems. CONCLUSIONS/SIGNIFICANCE: Our results support the pre-clinical development of a therapeutic approach based on pimelic diphenylamide HDACIs for FRDA and provide information for the design of future human trials of these drugs, suggesting an intermittent administration of the drug.Journal ArticleResearch Support, N.I.H. ExtramuralResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Spinocerebellar ataxia types 1, 2, 3, and 6: disease severity and nonataxia symptoms.

OBJECTIVE: To identify factors that determine disease severity and clinical phenotype of the most common spinocerebellar ataxias (SCAs), we studied 526 patients with SCA1, SCA2, SCA3. or SCA6. METHODS: To measure the severity of ataxia we used the Scale for the Assessment and Rating of Ataxia (SARA). In addition, nonataxia symptoms were assessed with the Inventory of Non-Ataxia Symptoms (INAS). The INAS count denotes the number of nonataxia symptoms in each patient. RESULTS: An analysis of covariance with SARA score as dependent variable and repeat lengths of the expanded and normal allele, age at onset, and disease duration as independent variables led to multivariate models that explained 60.4% of the SARA score variance in SCA1, 45.4% in SCA2, 46.8% in SCA3, and 33.7% in SCA6. In SCA1, SCA2, and SCA3, SARA was mainly determined by repeat length of the expanded allele, age at onset, and disease duration. The only factors determining the SARA score in SCA6 were age at onset and disease duration. The INAS count was 5.0 +/- 2.3 in SCA1, 4.6 +/- 2.2 in SCA2, 5.2 +/- 2.5 in SCA3, and 2.0 +/- 1.7 in SCA6. In SCA1, SCA2, and SCA3, SARA score and disease duration were the strongest predictors of the INAS count. In SCA6, only age at onset and disease duration had an effect on the INAS count. CONCLUSIONS: Our study suggests that spinocerebellar ataxia (SCA) 1, SCA2, and SCA3 share a number of common biologic properties, whereas SCA6 is distinct in that its phenotype is more determined by age than by disease-related factors

MutLα heterodimers modify the molecular phenotype of Friedreich ataxia

This article has been made available through the Brunel Open Access Publishing Fund.Background: Friedreich ataxia (FRDA), the most common autosomal recessive ataxia disorder, is caused by a dynamic GAA repeat expansion mutation within intron 1 of FXN gene, resulting in down-regulation of frataxin expression. Studies of cell and mouse models have revealed a role for the mismatch repair (MMR) MutS-heterodimer complexes and the PMS2 component of the MutLα complex in the dynamics of intergenerational and somatic GAA repeat expansions: MSH2, MSH3 and MSH6 promote GAA repeat expansions, while PMS2 inhibits GAA repeat expansions. Methodology/Principal Findings: To determine the potential role of the other component of the MutLα complex, MLH1, in GAA repeat instability in FRDA, we have analyzed intergenerational and somatic GAA repeat expansions from FXN transgenic mice that have been crossed with Mlh1 deficient mice. We find that loss of Mlh1 activity reduces both intergenerational and somatic GAA repeat expansions. However, we also find that loss of either Mlh1 or Pms2 reduces FXN transcription, suggesting different mechanisms of action for Mlh1 and Pms2 on GAA repeat expansion dynamics and regulation of FXN transcription. Conclusions/Significance: Both MutLα components, PMS2 and MLH1, have now been shown to modify the molecular phenotype of FRDA. We propose that upregulation of MLH1 or PMS2 could be potential FRDA therapeutic approaches to increase FXN transcription. © 2014 Ezzatizadeh et al.This article has been made available through the Brunel Open Access Publishing Fund

Pharmacological screening using an FXN-EGFP cellular genomic reporter assay for the therapy of Friedreich ataxia

Copyright @ 2013 Li et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Friedreich ataxia (FRDA) is an autosomal recessive disorder characterized by neurodegeneration and cardiomyopathy. The presence of a GAA trinucleotide repeat expansion in the first intron of the FXN gene results in the inhibition of gene expression and an insufficiency of the mitochondrial protein frataxin. There is a correlation between expansion length, the amount of residual frataxin and the severity of disease. As the coding sequence is unaltered, pharmacological up-regulation of FXN expression may restore frataxin to therapeutic levels. To facilitate screening of compounds that modulate FXN expression in a physiologically relevant manner, we established a cellular genomic reporter assay consisting of a stable human cell line containing an FXN-EGFP fusion construct, in which the EGFP gene is fused in-frame with the entire normal human FXN gene present on a BAC clone. The cell line was used to establish a fluorometric cellular assay for use in high throughput screening (HTS) procedures. A small chemical library containing FDA-approved compounds and natural extracts was screened and analyzed. Compound hits identified by HTS were further evaluated by flow cytometry in the cellular genomic reporter assay. The effects on FXN mRNA and frataxin protein levels were measured in lymphoblast and fibroblast cell lines derived from individuals with FRDA and in a humanized GAA repeat expansion mouse model of FRDA. Compounds that were established to increase FXN gene expression and frataxin levels included several anti-cancer agents, the iron-chelator deferiprone and the phytoalexin resveratrol.Muscular Dystrophy Association (USA), the National Health and Medical Research Council (Australia), the Friedreich’s Ataxia Research Alliance (USA), the Brockhoff Foundation (Australia), the Friedreich Ataxia Research Association (Australasia), Seek A Miracle (USA) and the Victorian Government’s Operational Infrastructure Support Program

Metabolomic Approaches for Detection and Identification of Biomarkers and Altered Pathways in Bladder Cancer

Metabolomic analysis has proven to be a useful tool in biomarker discovery and the molecular classification of cancers. In order to find new biomarkers, and to better understand its pathological behavior, bladder cancer also has been studied using a metabolomics approach. In this article, we review the literature on metabolomic studies of bladder cancer, focusing on the different available samples (urine, blood, tissue samples) used to perform the studies and their relative findings. Moreover, the multi-omic approach in bladder cancer research has found novel insights into its metabolic behavior, providing excellent start-points for new diagnostic and therapeutic strategies. Metabolomics data analysis can lead to the discovery of a “signature pathway” associated with the progression of bladder cancer; this aspect could be potentially valuable in predictions of clinical outcomes and the introduction of new treatments. However, further studies are needed to give stronger evidence and to make these tools feasible for use in clinical practice