Early and late results of surgery for Wolff-Parkinson-White syndrome

Surgical treatment for accessory atrioventricular connections was performed in 60 patients with Wolff-Parkinson-White syndrome between 1981 and 1986. The initial procedure successfully divided 69 of 73 pathways identified preoperatively, including 39 of 40 left free wall pathways, 23 of 24 posteroseptal pathways, six of seven right free wall pathways, and one of two anteroseptal pathways. Three additional pathways were identified for the first time during follow-up. The primary procedure was successful in curing 53 (88%) of the 60 patients and in dividing 69 (91%) of the total of 76 pathways. Subsequent procedures increased the overall clinical cure rate to 97%. The surgery was performed with low morbidity and no perioperative or late mortality. Patients were followed-up for a mean of 6.4 years (range four to nine years). No patient showed clinical or electrocardiographic evidence of recurrence of a pathway which had been divided surgically. We conclude that regardless of pathway site, surgical treatment carries a low risk and has a high probability of avoiding lifelong antiarrhythmic therapy.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75341/1/j.1445-5994.1991.tb04698.x.pd

DRAM-3 modulates autophagy and promotes cell survival in the absence of glucose

Macroautophagy is a membrane-trafficking process that delivers cytoplasmic constituents to lysosomes for degradation. The process operates under basal conditions as a mechanism to turnover damaged or misfolded proteins and organelles. As a result, it has a major role in preserving cellular integrity and viability. In addition to this basal function, macroautophagy can also be modulated in response to various forms of cellular stress, and the rate and cargoes of macroautophagy can be tailored to facilitate appropriate cellular responses in particular situations. The macroautophagy machinery is regulated by a group of evolutionarily conserved autophagy-related (ATG) proteins and by several other autophagy regulators, which either have tissue-restricted expression or operate in specific contexts. We report here the characterization of a novel autophagy regulator that we have termed DRAM-3 due to its significant homology to damage-regulated autophagy modulator (DRAM-1). DRAM-3 is expressed in a broad spectrum of normal tissues and tumor cells, but different from DRAM-1, DRAM-3 is not induced by p53 or DNA-damaging agents. Immunofluorescence studies revealed that DRAM-3 localizes to lysosomes/autolysosomes, endosomes and the plasma membrane, but not the endoplasmic reticulum, phagophores, autophagosomes or Golgi, indicating significant overlap with DRAM-1 localization and with organelles associated with macroautophagy. In this regard, we further proceed to show that DRAM-3 expression causes accumulation of autophagosomes under basal conditions and enhances autophagic flux. Reciprocally, CRISPR/Cas9-mediated disruption of DRAM-3 impairs autophagic flux confirming that DRAM-3 is a modulator of macroautophagy. As macroautophagy can be cytoprotective under starvation conditions, we also tested whether DRAM-3 could promote survival on nutrient deprivation. This revealed that DRAM-3 can repress cell death and promote long-term clonogenic survival of cells grown in the absence of glucose. Interestingly, however, this effect is macroautophagy-independent. In summary, these findings constitute the primary characterization of DRAM-3 as a modulator of both macroautophagy and cell survival under starvation conditions

Removal of ecotoxicity of 17α-ethinylestradiol using TAML/peroxide water treatment

17α -ethinylestradiol (EE2), a synthetic oestrogen in oral contraceptives, is one of many pharmaceuticals found in inland waterways worldwide as a result of human consumption and excretion into wastewater treatment systems. At low parts per trillion (ppt), EE2 induces feminisation of male fish, diminishing reproductive success and causing fish population collapse. Intended water quality standards for EE2 set a much needed global precedent. Ozone and activated carbon provide effective wastewater treatments, but their energy intensities and capital/operating costs are formidable barriers to adoption. Here we describe the technical and environmental performance of a fast- developing contender for mitigation of EE2 contamination of wastewater based upon smallmolecule, full-functional peroxidase enzyme replicas called “TAML activators”. From neutral to basic pH, TAML activators with H2O2 efficiently degrade EE2 in pure lab water, municipal effluents and EE2-spiked synthetic urine. TAML/H2O2 treatment curtails estrogenicity in vitro and substantially diminishes fish feminization in vivo. Our results provide a starting point for a future process in which tens of thousands of tonnes of wastewater could be treated per kilogram of catalyst. We suggest TAML/H2O2 is a worthy candidate for exploration as an environmentally compatible, versatile, method for removing EE2 and other pharmaceuticals from municipal wastewaters.Heinz Endowments, the Swiss National Science Foundation, the Steinbrenner Institute for a Steinbrenner Doctoral Fellowship. NMR instrumentation at CMU was partially supported by NSF (CHE-0130903 and CHE-1039870)

Multiple Scale Reorganization of Electrostatic Complexes of PolyStyrene Sulfonate and Lysozyme

We report on a SANS investigation into the potential for these structural reorganization of complexes composed of lysozyme and small PSS chains of opposite charge if the physicochemical conditions of the solutions are changed after their formation. Mixtures of solutions of lysozyme and PSS with high matter content and with an introduced charge ratio [-]/[+]intro close to the electrostatic stoichiometry, lead to suspensions that are macroscopically stable. They are composed at local scale of dense globular primary complexes of radius ~ 100 {\AA}; at a higher scale they are organized fractally with a dimension 2.1. We first show that the dilution of the solution of complexes, all other physicochemical parameters remaining constant, induces a macroscopic destabilization of the solutions but does not modify the structure of the complexes at submicronic scales. This suggests that the colloidal stability of the complexes can be explained by the interlocking of the fractal aggregates in a network at high concentration: dilution does not break the local aggregate structure but it does destroy the network. We show, secondly, that the addition of salt does not change the almost frozen inner structure of the cores of the primary complexes, although it does encourage growth of the complexes; these coalesce into larger complexes as salt has partially screened the electrostatic repulsions between two primary complexes. These larger primary complexes remain aggregated with a fractal dimension of 2.1. Thirdly, we show that the addition of PSS chains up to [-]/[+]intro ~ 20, after the formation of the primary complex with a [-]/[+]intro close to 1, only slightly changes the inner structure of the primary complexes. Moreover, in contrast to the synthesis achieved in the one-step mixing procedure where the proteins are unfolded for a range of [-]/[+]intro, the native conformation of the proteins is preserved inside the frozen core

Fate and effects of silver nanoparticles at the aquatic-terrestrial interface: A floodplain mesocosm experiment

The production volume of engineered inorganic nanoparticles (EINP) successively increased over the last years. Once released into the natural environment, these particles may change their size and surface properties in interaction with other substances. This is expected to control their mobility and their impact on biochemical processes. However, the underlying processes are not fully understood yet. Transformation processes and long-term fate of citrate-coated silver nanoparticles (Ag NP) were investigated in an innovative floodplain mesocosm, which was run with river Rhine water and natural soil from an adjacent floodplain for 33 weeks. Flooding events were simulated every three weeks. The Ag NP with a concentration of 5 mg L-1 were continuously introduced into the water for three weeks followed by a three-week period without spiking. Every third week the ecotoxicological impact of Ag NP was determined by means of Gammarus mortality and feeding assays. At the end of the experiment, the total Ag concentrations were measured in profiles of the floodplain soil and the sediment as well as in algae that developed in the mesocosm. The total Ag concentration in the aquatic phase in the main zone as well as in the floodplain fluctuated according to the periodic Ag NP pulse. Further, significant amounts of Ag accumulated in algae (up to 4.7 mg g-1) and exposed leaves (up to 170 μg g-1). However, for the applied experimental conditions we did neither observed mortality nor sublethal effects on Gammarus feeding activity. More than 40 % of the Ag remained in the sediment of the main zone and 7 % were transported during flooding into the floodplain soil. Furthermore, 0.5 % of the Ag was still in the water phase. Most of the particles were immobilized in the top layer of the sediments and soil. Only very little transport in deeper soil layers was observed in the soil columns and sediment. Accumulation in algae, sediment, and soil is alarming for long-term environmental impact assessments and the long lifetime in the aqueous phase suggests long-range transport of Ag NP in rivers

Targeting quiescent leukemic stem cells using second generation autophagy inhibitors

In chronic myeloid leukemia (CML), tyrosine kinase inhibitor (TKI) treatment induces autophagy that promotes survival and TKI-resistance in leukemic stem cells (LSCs). In clinical studies hydroxychloroquine (HCQ), the only clinically approved autophagy inhibitor, does not consistently inhibit autophagy in cancer patients, so more potent autophagy inhibitors are needed. We generated a murine model of CML in which autophagic flux can be measured in bone marrow-located LSCs. In parallel, we use cell division tracing, phenotyping of primary CML cells, and a robust xenotransplantation model of human CML, to investigate the effect of Lys05, a highly potent lysosomotropic agent, and PIK-III, a selective inhibitor of VPS34, on the survival and function of LSCs. We demonstrate that long-term haematopoietic stem cells (LT-HSCs: Lin−Sca-1+c-kit+CD48−CD150+) isolated from leukemic mice have higher basal autophagy levels compared with non-leukemic LT-HSCs and more mature leukemic cells. Additionally, we present that while HCQ is ineffective, Lys05-mediated autophagy inhibition reduces LSCs quiescence and drives myeloid cell expansion. Furthermore, Lys05 and PIK-III reduced the number of primary CML LSCs and target xenografted LSCs when used in combination with TKI treatment, providing a strong rationale for clinical use of second generation autophagy inhibitors as a novel treatment for CML patients with LSC persistence

Physical conditioning and mental stress reduction - a randomised trial in patients undergoing cardiac surgery

<p>Abstract</p> <p>Background</p> <p>Preoperative anxiety and physical unfitness have been shown to have adverse effects on recovery from cardiac surgery. This study involving cardiac surgery patients was primarily aimed at assessing the feasibility of delivering physical conditioning and stress reduction programs within the public hospital setting. Secondary aims were to evaluate the effect of these programs on quality of life (QOL), rates of postoperative atrial fibrillation (AF) and length of stay (LOS) in hospital.</p> <p>Methods</p> <p>Elective patients scheduled for coronary artery bypass graft and/or valve surgery at a public hospital in Melbourne, Australia were enrolled. Patients were randomized to receive either holistic therapy (HT) or usual care (UC). HT consisted of a series of light physical exercise sessions together with a mental stress reduction program administered in an outpatient setting for the first two weeks after placement on the waiting list for surgery. A self-administered SF-36 questionnaire was used to measure QOL and hospital records to collect data on LOS and rate of postoperative AF.</p> <p>Results</p> <p>The study population comprised 117 patients of whom 60 received HT and 57 received UC. Both programs were able to be delivered within the hospital setting but ongoing therapy beyond the two week duration of the program was not carried out due to long waiting periods and insufficient resources. HT, as delivered in this study, compared to UC did not result in significant changes in QOL, LOS or AF incidence.</p> <p>Conclusions</p> <p>Preoperative holistic therapy can be delivered in the hospital setting, although two weeks is insufficient to provide benefits beyond usual care on QOL, LOS or postoperative AF. Further research is now required to determine whether a similar program of longer duration, or targeted to high risk patients can provide measurable benefits.</p> <p>Trial registration</p> <p>This trial was conducted as part of a larger study and according to the principles contained in the CONSORT statement 2001.</p

Hemodynamic Effects of Fenofibrate and Coenzyme Q10 in Type 2 Diabetic Subjects With Left Ventricular Diastolic Dysfunction

OBJECTIVE—To investigate the effects of fenofibrate and coenzyme Q10 (CoQ) on diastolic function, ambulatory blood pressure (ABP), and heart rate (HR) in type 2 diabetic subjects with left ventricular diastolic dysfunction (LVDD)