Optimization of TopoIV Potency, ADMET Properties, and hERG Inhibition of 5-Amino-1,3-dioxane-Linked Novel Bacterial Topoisomerase Inhibitors: Identification of a Lead with Efficacy against MRSA.

Novel bacterial topoisomerase inhibitors (NBTIs) are among the most promising new antibiotics in preclinical/clinical development. We previously reported dioxane-linked NBTIs with potent antistaphylococcal activity and reduced hERG inhibition, a key safety liability. Herein, polarity-focused optimization enabled the delineation of clear structure-property relationships for both microsomal metabolic stability and hERG inhibition, resulting in the identification of lead compound .

Fatigue failure and success rate of lithium disilicate table-tops as a function of cement thickness.

Purpose Under thin, partial coverage restoration the proper cement thickness to be clinically employed still remains an issue. The aim of this study was to determine the failure and success rates of simplified lithium disilicate occlusal veneers as a function of cement thickness. The null hypothesis was that cement thickness has no effect on the fatigue resistance.

Formulation, Stability, Pharmacokinetic, and Modeling Studies for Tests of Synergistic Combinations of Orally Available Approved Drugs against Ebola Virus In Vivo.

Outbreaks of Ebola ebolavirus (EBOV) have been associated with high morbidity and mortality. Milestones have been reached recently in the management of EBOV disease (EVD) with licensure of an EBOV vaccine and two monoclonal antibody therapies. However, neither vaccines nor therapies are available for other disease-causing filoviruses.

Assessment of impression material accuracy in complete-arch restorations on four implants.

Statement Of Problem: New polyvinyl siloxane (PVS) materials with enhanced properties have been developed to improve and facilitate implant impression techniques. However, studies on their accuracy are lacking.

Purpose: The purpose of this in vitro study was to determine the accuracy and precision of implant impressions made with some recently introduced materials on a simulated patient requiring an all-on-4 implant-supported prosthesis.

Novel bacterial topoisomerase inhibitors derived from isomannide.

A series of Novel Bacterial Topoisomerase Inhibitors (NBTIs) employing a linker derived from isomannide were synthesized and evaluated. Reduced hERG inhibition was observed compared to structure-matched analogues with different linkers, and compound 6 showed minimal proarrhythmic potential using an in vitro panel of cardiac ion channels. Compound 6 also displayed excellent activity against fluoroquinolone-resistant MRSA (MIC = 2 μg/mL) and other Gram-positive pathogens.

A systematic strategy for estimating hERG block potency and its implications in a new cardiac safety paradigm.

Introduction: hERG block potency is widely used to calculate a drug's safety margin against its torsadogenic potential. Previous studies are confounded by use of different patch clamp electrophysiology protocols and a lack of statistical quantification of experimental variability. Since the new cardiac safety paradigm being discussed by the International Council for Harmonisation promotes a tighter integration of nonclinical and clinical data for torsadogenic risk assessment, a more systematic approach to estimate the hERG block potency and safety margin is needed.

An impedance-based approach using human iPSC-derived cardiomyocytes significantly improves in vitro prediction of in vivo cardiotox liabilities.

Current in vitro approaches to cardiac safety testing typically focus on mechanistic ion channel testing to predict in vivo proarrhythmic potential. Outside of the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative, structural and functional cardiotoxicity related to chronic dosing effects are of great concern as these effects can impact compound attrition. Development and implementation of an in vitro cardiotoxicity screening platform that effectively identifies these liabilities early in the discovery process should reduce costly attrition and decrease preclinical development time.

Zirconia-composite bonding after plasma of argon treatment.

Purpose: To compare the shear bond strength (SBS) values of resin cement to zirconia treated with a new activating method.

Materials And Methods: Forty-five zirconia specimens were divided into three groups: no treatment (group 1), plasma of argon cleaning for 375 seconds (group 2), and plasma of argon cleaning for 750 seconds (group 3). Composite cylinders were bonded with a self-adhesive cement.

A prospective study of risk factors for neurological complications in childhood bacterial meningitis.

Objective: To prospectively analyze the prognostic factors for neurological complications of childhood bacterial meningitis.

Methods: This prospective study enrolled 77 children from 1 month until 16 years of age, treated for bacterial meningitis during the period of January 1, 2009 through December 31, 2010. 16 relevant predictors were chosen to analyze their association with the incidence of neurological complications.

Early neurologic complications and long-term sequelae of childhood bacterial meningitis in a limited-resource country (Kosovo).

Purpose: Since neurologic complications of childhood bacterial meningitis are encountered frequently despite antibiotic treatments, the purpose of this study was to analyze early neurologic complications and long-term sequelae of bacterial meningitis in children in a limited-resource country (Kosovo)

Methods: This study uses a retrospective chart review of children treated for bacterial meningitis in two study periods: 277 treated during years 1997-2002 and 77 children treated during years 2009-2010.

Results: Of the 277 vs 77 children treated for bacterial meningitis, 60 (22%) vs 33 (43%) patients developed early neurologic complications, while there were 15 (5.4%) vs 2 (2.

Novel potent human ether-a-go-go-related gene (hERG) potassium channel enhancers and their in vitro antiarrhythmic activity.

A variety of drugs has been reported to cause acquired long QT syndrome through inhibition of the IKr channel. Screening compounds in early discovery and development stages against their ability to inhibit IKr or the hERG channel has therefore become an indispensable procedure in the pharmaceutical industry. In contrast to numerous hERG channel blockers discovered during screening, only (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)-3-oxo-propyl]-1-[3-(2,3,5-trifluoro-phenyl)-prop-2-ynyl]-piperidine-3-carboxylic acid (RPR260243) has been reported so far to enhance the hERG current.

Gender, social support, and posttraumatic stress in postwar Kosovo.

The effects of social support and traumatic experiences on mental health in conflict situations may be different by gender. The Kosovo Emergency Department Study was conducted in July and August 2001 to assess mental health 2 years after the end of the war in Kosovo. Of 306 emergency department patients (87.

Mental health status among ethnic Albanians seeking medical care in an emergency department two years after the war in Kosovo: a pilot project.

Study Objective: The long-term psychological effects of war are under appreciated in clinical settings. Describing the postwar psychosocial burden on medical care can help direct public health interventions. We performed an emergency department (ED)-based assessment of the mental health status of ethnic Albanian patients 2 years after the North Atlantic Treaty Organization-led bombing of Serbia and Kosovo in 1999.

Post-war Kosovo: Part 3. Development and rehabilitation of emergency services.

The recent crisis in Kosovo led to nearly complete destruction of a healthcare system serving the needs of approximately 2 million people. Even prior to the crisis, the pre-existing healthcare system had inadequate provisions for the delivery of Emergency Medical Services. More than 440 diverse governmental and non-governmental organizations (NGOs) arrived to assist (and often compete) in the rehabilitation of Kosovo's healthcare needs.

Blockade of human cardiac potassium channel human ether-a-go-go-related gene (HERG) by macrolide antibiotics.

Several macrolides have been reported to cause QT prolongation and ventricular arrhythmias such as torsades de pointes. To clarify the underlying ionic mechanisms, we examined the effects of six macrolides on the human ether-a-go-go-related gene (HERG)-encoded potassium current stably expressed in human embryonic kidney-293 cells. All six drugs showed a concentration-dependent inhibition of the current with the following IC(50) values: clarithromycin, 32.

Temperature profile for glacial ice at the South Pole: implications for life in a nearby subglacial lake.

Airborne radar has detected approximately 100 lakes under the Antarctic ice cap, the largest of which is Lake Vostok. International planning is underway to search in Lake Vostok for microbial life that may have evolved in isolation from surface life for millions of years. It is thought, however, that the lakes may be hydraulically interconnected.

Myocardial contrast echocardiography can be used to assess the microvascular response to vascular endothelial growth factor-121.

Background: Therapeutic angiogenesis is a new approach to treating ischemic heart disease, and the optimal method for assessing its efficacy is unclear. We used myocardial contrast echocardiography (MCE) to evaluate the therapeutic response to the angiogenic agent, vascular endothelial growth factor-121 (VEGF121).

Methods And Results: After placement of an ameroid constrictor (day 0) around the left anterior descending artery (LAD), dogs were given intracoronary VEGF121 protein (108 microg, n=6) or placebo (n=6) on days 7 and 21, and subcutaneous VEGF121 (1 mg) or placebo on days 8 to 20 and 22 to 27.

Observation of high-energy neutrinos using Cerenkov detectors embedded deep in Antarctic ice.

Neutrinos are elementary particles that carry no electric charge and have little mass. As they interact only weakly with other particles, they can penetrate enormous amounts of matter, and therefore have the potential to directly convey astrophysical information from the edge of the Universe and from deep inside the most cataclysmic high-energy regions. The neutrino's great penetrating power, however, also makes this particle difficult to detect.

Stent-based gene therapy.

Delivery of gene therapy to inhibit intimal hyperplasia has been proposed to prevent postangioplasty restenosis. We sought to apply gene therapy by using a stent-based technique. There are several hurdles that must be overcome before gene-stent therapy can be applied successfully in clinical trials.

Regulation of immunomodulatory functions by granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor in vivo.

The present study was designed to investigate in vivo immunomodulatory properties of hematopoietic growth factors. The influence on the activation of cytokine synthesis and on the expression of surface antigens associated with cellular activation of G-CSF or GM-CSF was investigated in cancer patients receiving these factors. One single dose of growth factor was administered to patients with bladder cancer (G-CSF group) or small cell lung cancer (GM-CSF group) before chemotherapy.

Long-term safety of treatment with recombinant human granulocyte colony-stimulating factor (r-metHuG-CSF) in patients with severe congenital neutropenias.

Congenital neutropenias include a heterogenous group of diseases characterized by a decrease in circulating neutrophils. In phase I/II/III studies in patients with severe congenital and cyclic neutropenia, treatment with recombinant human granulocyte colony-stimulating factor (r-metHuG-CSF) resulted in a rise in the absolute neutrophil counts (ANC) and a reduction in infections. We report the effects of long-term safety of subcutaneous r-metHuG-CSF administration in 54 patients (congenital n = 44.

[Long-term treatment with recombinant human granulocyte colony stimulating factor in patients with severe congenital neutropenia].

Severe congenital neutropenia is a disorder of myelopoiesis characterized by severe neutropenia secondary to either a maturational arrest of myelopoiesis at the level of promyelocytes (Kostmann-Syndrome; SCN) or regular cyclic fluctuations in the number of blood neutrophils with a median ANC below 500/microliter (cyclic neutropenia). We have treated 32 patients with SCN and 4 patients with cyclic neutropenia. Thirty of 32 patients with SCN and all 4 patients with SCN responded to r-met HuG-CSF treatment with an increase of the median ANC to above 1000/microliter.

Sulfate and nitrate concentrations from a South greenland ice core.

An ice core in south Greenland covering the period 1869 to 1984 was analyzed for oxygen isotopes and chloride, nitrate, and sulfate concentrations. The data show that the "excess" (nonsea-salt) sulfate concentration has tripled since approximately 1900 to 1910 and the nitrate concentration has doubled since approximately 1955. The increases may be attributable to the deposition of these chemical specis from air masses carrying North American and Eurasian anthropogenic emissions.

A 1500-year record of tropical precipitation in ice cores from the quelccaya ice cap, peru.

Two ice cores, covering 1500 years of climatic information, from the summit (5670 meters) of the tropical Quelccaya ice cap, in the Andes of southern Peru, provide information on general environmental conditions including droughts, volcanic activity, moisture sources, temperature, and glacier net balance. The net balance record reconstructed from these cores reflects major precipitation trends for the southern Andes of Peru. These records indicate extended dry periods between 1720 and 1860, 1250 and 1310, and 570 and 610; wet conditions prevailed between 1500 and 1720.