Efficacy and safety of systemic chemotherapy and intra-arterial chemotherapy with/without radiotherapy for bladder preservation or as neo-adjuvant therapy in patients with muscle-invasive bladder cancer: A single-centre study of 163 patients

Introduction Patients with muscle-invasive bladder cancer (MIBC) often undergo various preoperative treatments to improve survival; however, their efficacy and safety remain unclear. Materials and methods The anti-tumour effects and adverse events were evaluated in 163 MIBC patients who received systemic chemotherapy (SC, n = 34), intra-arterial chemotherapy (IAC, n = 50), or combined IAC and radiotherapy (IAC + R, n = 79). Results Pathological complete responses were observed in 17.6%, 22.0%, and 43.0% of patients in the SC, IAC, and IAC + R groups, respectively, with respective 5-year overall survival rates of 42.0%, 46.7%, and 50.3%. Multivariate analysis showed that successful IAC + R protocol administration was a significant predictor for survival (hazard ratio = 0.16, p = 0.028). The incidence of severe adverse events was higher in the IAC + R group (36.7%) than in the SC (9.8%) and IAC groups (16.0%). Conclusions IAC + R was useful for patients with MIBC. Successful completion and optimal patient selection were important for this treatment strategy

Coronary artery dominance and the risk of adverse clinical events following percutaneous coronary intervention: insights from the prospective, randomised TWENTE trial

Aims: To investigate the prognostic value of coronary dominance for various adverse clinical events following the implantation of drug-eluting stents. Methods and results: We assessed two-year follow-up data of 1,387 patients from the randomised TWENTE trial. Based on the origin of the posterior descending coronary artery, coronary circulation was categorised into left and non-left dominance (i.e., right and balanced). Target vessel-related myocardial infarction (MI) was defined according to the updated Academic Research Consortium (ARC) definition (2x upper reference limit of creatine kinase [CK], confirmed by CK-MB elevation), and periprocedural MI (PMI) as MI ≤48 hours following PCI. One hundred and thirty-six patients (9.8%) had left and 1,251 (90.2%) non-left dominance. Target lesions were more frequently located in dominant arteries (p<0.005). Left dominance was associated with more severe calcifications (p=0.006) and more bifurcation lesions (p=0.031). Non-left dominance tended to be less frequent in men (p=0.09). Left coronary dominance was associated with more target vessel-related MI (14 [10.3%] vs. 62 [5.0%], p=0.009). Left dominance independently predicted PMI (adjusted HR 2.19, 95% CI: 1.15-4.15, p=0.017), while no difference in other clinical endpoints was observed between dominance groups. Conclusions: In the population of the TWENTE trial, we observed a higher incidence of periprocedural myocardial infarction in patients who had left coronary dominance. - See more at: http://www.pcronline.com/eurointervention/ahead_of_print/201402-11/#sthash.p3Zkzx7X.dp

Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes

Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable disorder, but specific genetic factors underlying risk remain elusive. To assess the role of structural variation in ADHD, we identified 222 inherited copy number variations (CNVs) within 335 ADHD patients and their parents that were not detected in 2026 unrelated healthy individuals. Although no excess CNVs, either deletions or duplications, were found in the ADHD cohort relative to controls, the inherited rare CNV-associated gene set was significantly enriched for genes reported as candidates in studies of autism, schizophrenia and Tourette syndrome, including A2BP1, AUTS2, CNTNAP2 and IMMP2L. The ADHD CNV gene set was also significantly enriched for genes known to be important for psychological and neurological functions, including learning, behavior, synaptic transmission and central nervous system development. Four independent deletions were located within the protein tyrosine phosphatase gene, PTPRD, recently implicated as a candidate gene for restless legs syndrome, which frequently presents with ADHD. A deletion within the glutamate receptor gene, GRM5, was found in an affected parent and all three affected offspring whose ADHD phenotypes closely resembled those of the GRM5 null mouse. Together, these results suggest that rare inherited structural variations play an important role in ADHD development and indicate a set of putative candidate genes for further study in the etiology of ADHD

Fstl1 Antagonizes BMP Signaling and Regulates Ureter Development

Bone morphogenetic protein (BMP) signaling pathway plays important roles in urinary tract development although the detailed regulation of its activity in this process remains unclear. Here we report that follistatin-like 1 (Fstl1), encoding a secreted extracellular glycoprotein, is expressed in developing ureter and antagonizes BMP signaling activity. Mouse embryos carrying disrupted Fstl1 gene displayed prominent hydroureter arising from proximal segment and ureterovesical junction defects. These defects were associated with significant reduction in ureteric epithelial cell proliferation at E15.5 and E16.5 as well as absence of subepithelial ureteral mesenchymal cells in the urinary tract at E16.5 and E18.5. At the molecular level, increased BMP signaling was found in Fstl1 deficient ureters, indicated by elevated pSmad1/5/8 activity. In vitro study also indicated that Fstl1 can directly bind to ALK6 which is specifically expressed in ureteric epithelial cells in developing ureter. Furthermore, Sonic hedgehog (SHH) signaling, which is crucial for differentiation of ureteral subepithelial cell proliferation, was also impaired in Fstl1-/- ureter. Altogether, our data suggest that Fstl1 is essential in maintaining normal ureter development by antagonizing BMP signaling

Proteoglycan-Specific Molecular Switch for RPTPσ Clustering and Neuronal Extension

Heparan and chondroitin sulfate proteoglycans (HSPGs and CSPGs, respectively) regulate numerous cell surface signaling events, with typically opposite effects on cell function. CSPGs inhibit nerve regeneration through receptor protein tyrosine phosphatase sigma (RPTPσ). Here we report that RPTPσ acts bimodally in sensory neuron extension, mediating CSPG inhibition and HSPG growth promotion. Crystallographic analyses of a shared HSPG-CSPG binding site reveal a conformational plasticity that can accommodate diverse glycosaminoglycans with comparable affinities. Heparan sulfate and analogs induced RPTPσ ectodomain oligomerization in solution, which was inhibited by chondroitin sulfate. RPTPσ and HSPGs colocalize in puncta on sensory neurons in culture, whereas CSPGs occupy the extracellular matrix. These results lead to a model where proteoglycans can exert opposing effects on neuronal extension by competing to control the oligomerization of a common receptor

A Transposon in Comt Generates mRNA Variants and Causes Widespread Expression and Behavioral Differences among Mice

Background: Catechol-O-methyltransferase (COMT) is a key enzyme responsible for the degradation of dopamine and norepinephrine. COMT activity influences cognitive and emotional states in humans and aggression and drug responses in mice. This study identifies the key sequence variant that leads to differences in Comt mRNA and protein levels among mice, and that modulates synaptic function and pharmacological and behavioral traits. Methodology/Principal Findings: We examined Comt expression in multiple tissues in over 100 diverse strains and several genetic crosses. Differences in expression map back to Comt and are generated by a 230 nt insertion of a B2 short interspersed element (B2 SINE) in the proximal 39 UTR of Comt in C57BL/6J. This transposon introduces a premature polyadenylation signal and creates a short 39 UTR isoform. The B2 SINE is shared by a subset of strains, including C57BL/6J

Use of n-butyl cyanoacrylate in abdominal and pelvic embolotherapy: indications and techniques, complications, and their management

The purpose of this article is to describe the indications for use of n-butyl cyanoacrylate (NBCA) in abdominal and pelvic embolotherapy, appropriate techniques for NBCA embolotherapy, and NBCA-related complications and their management. NBCA embolotherapy is a feasible and effective method for treating a variety of abdominal and pelvic vascular lesions or tumors; however, the techniques suitable for each case and knowledge of NBCA-related complications are essential to achieve favorable outcomes

Fidelity Variants of RNA Dependent RNA Polymerases Uncover an Indirect, Mutagenic Activity of Amiloride Compounds

In a screen for RNA mutagen resistance, we isolated a high fidelity RNA dependent RNA polymerase (RdRp) variant of Coxsackie virus B3 (CVB3). Curiously, this variant A372V is also resistant to amiloride. We hypothesize that amiloride has a previously undescribed mutagenic activity. Indeed, amiloride compounds increase the mutation frequencies of CVB3 and poliovirus and high fidelity variants of both viruses are more resistant to this effect. We hypothesize that this mutagenic activity is mediated through alterations in intracellular ions such as Mg2+ and Mn2+, which in turn increase virus mutation frequency by affecting RdRp fidelity. Furthermore, we show that another amiloride-resistant RdRp variant, S299T, is completely resistant to this mutagenic activity and unaffected by changes in ion concentrations. We show that RdRp variants resist the mutagenic activity of amiloride via two different mechanisms: 1) increased fidelity that generates virus populations presenting lower basal mutation frequencies or 2) resisting changes in divalent cation concentrations that affect polymerase fidelity. Our results uncover a new antiviral approach based on mutagenesis

Ultrasonographic examination of rheumatoid arthritis patients who are free of physical synovitis: power Doppler subclinical synovitis is associated with bone erosion

Objective. The aim of this study was to investigate the characteristics of power Doppler (PD) subclinical synovitis in patients with RA who achieve clinical remission free from physical synovitis. Methods. Twenty-nine RA patients were consecutively enrolled. All of the patients had achieved clinical remission [simplified disease activity index (SDAI) 3.3] for at least 6 months at the musculoskeletal ultrasound (MSKUS) examination. Additionally, none of the patients exhibited tender joints at 68 sites or swollen joints at 66 sites. MSKUS of bilateral wrist and finger joints, including the first to fifth MCP joints, the first IP joint and the second to fifth PIP joints, was performed and the findings obtained by grey scale (GS) and PD were graded on a semi-quantitative scale from 0 to 3. Results. The median disease duration upon the introduction of DMARDs was 3 months and that at MSKUS examination was 21 months. The percentages of patients with PD synovitis in at least one joint were PD grade 1, 58.6%; PD grade 2, 31.0% and PD grade 3, 6.9%. The use of biological agents was low in patients with PD synovitis grade 2 (P<0.05). The presence of US bone erosion was high by patient (P<0.05) and by joint (P<0.0001) with PD synovitis as compared with those without PD synovitis. However, no correlations were found between PD synovitis measures and serum biomarkers, including angiogenesis factors. Conclusion. PD subclinical synovitis correlates with several clinical characteristics, whereas conventional serum biomarkers are not useful for indicating the presence of subclinical PD synovitis