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Objectives: Intrathecal baclofen (ITB) pumps are an effective treatment for spasticity; however infection rates have been reported in 3-26% of patients in the literature. The multidisciplinary ITB service has been established at The National Hospital for Neurology and Neurosurgery, UCLH, Queen Square, London for over 20 years. Our study was designed to clarify the rate of infection in our ITB patient cohort and secondly, to formulate and implement best practice guidelines and to determine prospectively, whether they effectively reduced infection rates., Methods: Clinical record review of all patients receiving ITB pre-intervention; January 2013-May 2015, and following practice changes; June 2016-June 2018., Results: Four of 118 patients receiving ITB during the first time period (3.4%, annual incidence rate of infection 1.4%) developed an ITB-related infection (three following ITB pump replacement surgery, one after initial implant). Infections were associated with 4.2% of ITB-related surgical procedures. Three of four pumps required explantation. Following change in practice (pre-operative chlorhexidine skin wash and intraoperative vancomycin wash of the fibrous pocket of the replacement site), only one of 160 ITB patients developed infection (pump not explanted) in the second time period (0.6%, annual incidence rate 0.3%). The infection rate related to ITB surgical procedures was 1.1%. In cases of ITB pump replacement, the infection rate was reduced to 3.3% from 17.6%., Conclusions: This study suggests that a straightforward change in clinical practice may lower infection rates in patients undergoing ITB therapy., (© 2019 International Neuromodulation Society.)

Background: Pulmonary hypertension (PH) is a well-known independent risk factor for mortality and morbidity after cardiac surgery. However, no weight is given to PH in the current guidelines for the management of patients with aortic stenosis (AS) undergoing aortic valve replacement (AVR). The aim of our study was to evaluate the impact of preoperative PH on early and five-year survival in patients with severe AS undergoing isolated AVR., Methods: From January 2005 to July 2010, 422 consecutive patients with severe AS underwent isolated AVR. According to systolic pulmonary artery pressure (sPAP), PH was classified as none (sPAPS<35 mmHg, N=224), mild-moderate (35≤sPAP<50 mmHg, N=159) and severe (sPAP≥50 mmHg, N=39)., Results: Overall in-hospital mortality was 2.8%. Unadjusted mortality was 0.9%, 3.8% and 10.2% for patients with normal, mild-moderate and severe PH (p=0.003). In multivariable analysis, severe PH (OR 4.1, 95 CI 1.1-15.3, p=0.04) and New York Heart Association class III-IV (OR 14.9, 95% CI 1.8-117.8, p=0.01) were independent risk factors of in-hospital mortality. Multivariable predictors of five-year survival were extracardiac arteriopathy (HR 2.8, 95%CI 1.6-4.9, p<0.0001), severe PH (HR 2.4, 95%CI 1.2-4.6 p=0.01), NHYA III-IV class (HR 2.3, 95% CI 1.3-4, p=0.003), preoperative serum creatinine (HR 2.2, 95%CI, 1.6-3.1,p<0.0001) and age (HR 1.08, 95%CI 1.03-1.13, p=0.01). Five-year survival was 86%±3% with normal sPAP, 81%±4% with mild-moderate PH and 63±10% with severe PH (p<0.001)., Conclusions: In patients undergoing isolated AVR with severe AS, severe PH is an independent predictor of in-hospital mortality and five-year survival., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Schistosoma mansoni and Plasmodium falciparum are pathogen parasites that spend part of their lives in the blood stream of the human host and are therefore heavily exposed to fluxes of toxic reactive oxygen species (ROS). SmTGR, an essential enzyme of the S. mansoni ROS detoxification machinery, is known to be inhibited by Auranofin although the inhibition mechanism has not been completely clarified. Auranofin also kills P. falciparum, even if its molecular targets are unknown. Here, we used computational and docking techniques to investigate the molecular mechanism of interaction between SmTGR and Auranofin. Furthermore, we took advantage of the homology relationship and of docking studies to assess if PfTR, the SmTGR malaria parasite homologue, can be a putative target for Auranofin. Our findings support a recently hypothesized molecular mechanism of inhibition for SmTGR and suggest that PfTR is indeed a possible and attractive drug target in P. falciparum., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Aroyl-pyrrolyl-hydroxy-amides (APHAs) are a class of synthetic HDAC inhibitors described by us since 2001. Through structure-based drug design, two isomers of the APHA lead compound 1, the 3-(2-benzoyl-1-methyl-1H-pyrrol-4-yl)-N-hydroxy-2-propenamide 2 and the 3-(2-benzoyl-1-methyl-1H-pyrrol-5-yl)-N-hydroxy-2-propenamide 3 (iso-APHAs) were designed, synthesized and tested in murine leukemia cells as antiproliferative and cytodifferentiating agents. To improve their HDAC activity and selectivity, chemical modifications at the benzoyl moieties were investigated and evaluated using three maize histone deacetylases: HD2, HD1-B (class I human HDAC homologue), and HD1-A (class II human HDAC homologue). Docking experiments on HD1-A and HD1-B homology models revealed that the different compounds selectivity profiles could be addressed to different binding modes as observed for the reference compound SAHA. Smaller hydrophobic cap groups improved class II HDAC selectivity through the interaction with HD1-A Asn89-Ser90-Ile91, while bulkier aromatic substituents increased class I HDAC selectivity. Taking into account the whole enzyme data and the functional test results, the described iso-APHAs showed a behaviour of class I/IIb HDACi, with 4b and 4i preferentially inhibiting class IIb and class I HDACs, respectively. When tested in the human leukaemia U937 cell line, 4i showed altered cell cycle (S phase arrest), joined to high (51%) apoptosis induction and significant (21%) differentiation activity.