Development of a Practical Synthesis of the Fragment of OPC-167832.

A concise and practical synthesis has been developed to provide the 8-fluoro-5-hydroxy-3,4-diydrocarbostyril () fragment of OPC-167832 in 41% yield and in >99% purity over four steps from 3-amino-4-fluorophenol. The key feature of this process is the development of a telescoped one-pot synthesis of the quinolone via a chemoselective amidation/acid-induced cyclization that allows for simple product isolation without the need for column chromatography.

A preliminary study of bilateral color mapping of pig bladder vasculature demonstrates potential for acute hemi-ischemic events.

Background: Chronic ischemia is a known risk factor for the development of lower urinary tract symptoms (LUTS) and bladder hypocontractility. Less is known, however, about the impact of acute ischemia. Classic teaching suggests that collateral circulation is robust in the bladder and, therefore, loss of a single source of blood flow should have no deleterious effect.

Phases of decompensation during acute ischemia demonstrated in an porcine bladder model.

Background: The aim of this project was to develop an ex-vivo porcine bladder model to test the effects of increasing durations of acute ischemia on detrusor function.

Methods: Porcine bladders were perfused through bilateral vesical arteries at physiologic flow (4 mL/min) and filled through a urethral catheter. Intravesical pressures were continuously recorded using standard urodynamics equipment.

Artifacts and abnormal findings may limit the use of asymptomatic volunteers as controls for studies of multichannel urodynamics.

Background: Multichannel urodynamics is the gold standard for the evaluation of lower urinary tract symptoms (LUTS). When performing studies to validate new adjuncts to urodynamic testing with control patients undergoing urodynamic investigation, there is difficulty in the interpretation of urodynamic results in the asymptomatic patient due to artifacts and the invasive nature of the procedure. The purpose of this investigation was to examine urodynamics in asymptomatic volunteers in order to better understand the role of control participants in urodynamic research studies.

Automated quantification of low amplitude rhythmic contractions (LARC) during real-world urodynamics identifies a potential detrusor overactivity subgroup.

Objectives: Detrusor overactivity (DO) is characterized by non-voiding detrusor smooth muscle contractions during the bladder filling phase and often contributes to overactive bladder. In some patients DO is observed as isolated or sporadic contractions, while in others DO is manifested as low amplitude rhythmic contractions (LARC). The aim of this study was to develop an objective method to quantify LARC frequencies and amplitudes in urodynamic studies (UDS) and identify a subgroup DO of patients with LARC.

NEW CONCEPTS IN BLADDER SENSATION AND URINARY URGENCY.

Purpose Of Review: The purpose of this review is to summarize the current state of knowledge regarding the evaluation and measurement of urinary urgency and bladder sensation.

Recent Findings: New technologies have been developed to improve our diagnostic capabilities in urinary urgency and bladder sensation. Recent developments include MRI-based neuroimaging and novel tablet-based sensation meters that can be used during urodynamics as well as during oral hydration.

Quantification of bladder wall biomechanics during urodynamics: A methodologic investigation using ultrasound.

Overactive bladder is often characterized by biomechanical changes in the bladder wall, but there is no established method to measure these changes in vivo. The goal of this study was to develop a novel method to determine detrusor wall biomechanical parameters during urodynamics through the incorporation of transabdominal ultrasound imaging. Individuals with overactive bladder (OAB) underwent ultrasound imaging during filling.

Conditioning neoadjuvant therapies for improved immunotherapy of cancer.

Recent advances in the treatment of melanoma and non-small cell lung cancer (NSCLC) by combining conventional therapies with anti-PD1/PD-L1 immunotherapies, have renewed interests in immunotherapy of cancer. The emerging concept of conventional cancer therapies combined with immunotherapy differs from the classical concept in that it is not simply taking advantage of their additive anti-tumor effects, but it is to use certain therapeutic regimens to condition the tumor microenvironment for optimal response to immunotherapy. To this end, low dose immunogenic chemotherapies, epigenetic modulators and inhibitors of cell cycle progression are potential candidates for rendering tumors highly responsive to immunotherapy.

Simulated space radiation sensitizes bone but not muscle to the catabolic effects of mechanical unloading.

Deep space travel exposes astronauts to extended periods of space radiation and mechanical unloading, both of which may induce significant muscle and bone loss. Astronauts are exposed to space radiation from solar particle events (SPE) and background radiation referred to as galactic cosmic radiation (GCR). To explore interactions between skeletal muscle and bone under these conditions, we hypothesized that decreased mechanical load, as in the microgravity of space, would lead to increased susceptibility to space radiation-induced bone and muscle loss.

Low amplitude rhythmic contraction frequency in human detrusor strips correlates with phasic intravesical pressure waves.

Purpose: Low amplitude rhythmic contractions (LARC) occur in detrusor smooth muscle and may play a role in storage disorders such as overactive bladder and detrusor overactivity. The purpose of this study was to determine whether LARC frequencies identified in vitro from strips of human urinary bladder tissue correlate with in vivo LARC frequencies, visualized as phasic intravesical pressure (p ) waves during urodynamics (UD).

Methods: After IRB approval, fresh strips of human urinary bladder were obtained from patients.

Non-invasive characterization of real-time bladder sensation using accelerated hydration and a novel sensation meter: An initial experience.

Aims: The purpose of this investigation was to develop a non-invasive, objective, and unprompted method to characterize real-time bladder sensation.

Methods: Volunteers with and without overactive bladder (OAB) were prospectively enrolled in a preliminary accelerated hydration study. Participants drank 2L Gatorade-G2® and recorded real-time sensation (0-100% scale) and standardized verbal sensory thresholds using a novel, touch-screen "sensation meter.

A pilot study to measure dynamic elasticity of the bladder during urodynamics.

Aims: Previous studies using isolated strips of human detrusor muscle identified adjustable preload tension, a novel mechanism that acutely regulates detrusor wall tension. The purpose of this investigation was to develop a method to identify a correlate measure of adjustable preload tension during urodynamics.

Methods: Patients reporting urgency most or all of the time based on ICIq-OAB survey scores were prospectively enrolled in an extended repeat fill-and-empty urodynamics study designed to identify a correlate of adjustable preload tension which we now call "dynamic elasticity.

Dynamical System Modeling to Simulate Donor T Cell Response to Whole Exome Sequencing-Derived Recipient Peptides Demonstrates Different Alloreactivity Potential in HLA-Matched and -Mismatched Donor-Recipient Pairs.

Immune reconstitution kinetics and subsequent clinical outcomes in HLA-matched recipients of allogeneic stem cell transplantation (SCT) are variable and difficult to predict. Considering SCT as a dynamical system may allow sequence differences across the exomes of the transplant donors and recipients to be used to simulate an alloreactive T cell response, which may allow better clinical outcome prediction. To accomplish this, whole exome sequencing was performed on 34 HLA-matched SCT donor-recipient pairs (DRPs) and the nucleotide sequence differences translated to peptides.

Dendrimer-enabled transformation of Anaplasma phagocytophilum.

Anaplasma phagocytophilum is an obligate intracellular bacterium that causes the emerging infection, granulocytic anaplasmosis. While electroporation can transform A. phagocytophilum isolated from host cells, no method has been developed to transform it while growing inside the ApV (A.

Acute length adaptation and adjustable preload in the human detrusor.

Aims: The biomechanical properties of length adaptation and adjustable preload have been previously identified in detrusor smooth muscle in animal models. This in vitro study aims to show that human detrusor smooth muscle exhibits length adaptation and adjustable preload tension which could play an important role in both overactive bladder and detrusor underactivity.

Methods: In order to demonstrate length adaptation, human detrusor smooth muscle strips are stretched and contracted beyond an optimum length and then contracted three times at the previous optimum length to determine if maximum active tension could be re-established.

Simulating lesions in multi-layer, multi-columnar model of neocortex.

The paper presents results of modeling global and focal loss of layers in a multi-columnar model of neocortex. Specifically, the spread of activity across columns in conditions of inhibitory blockade is compared. With very low inhibition activity spreads through all layers, however, deep layers are critical for spread of activity when inhibition is only moderately blocked.

Biological Restraint on the Izhikevich Neuron Model Essential for Seizure Modeling.

We propose a simple modification of the Izhikevich neuron model to restrict firing rates of neurons. We demonstrate how this modification affects overall network activity using a simple artificial network. Such restraint on the Izhikevich neuron model would be especially important in larger scale simulations or when frequency dependent short-term plasticity is one of the network components.

Uniquely shaped cardiovascular stents enhance the pressure generation of intravascular blood pumps.

Objective: Advances in the geometric design of blood-contacting components are critically important as the use of minimally invasive, intravascular blood pumps becomes more pervasive in the treatment of adult and pediatric patients with congestive heart failure. The present study reports on the evaluation of uniquely shaped filaments and diffuser blades in the development of a protective stent for an intravascular cavopulmonary assist device for patients with a single ventricle.

Methods: We performed numeric modeling, hydraulic testing of 11 stents with an axial flow blood pump, and blood bag experiments (n = 6) of the top-performing stent geometries to measure the levels of hemolysis.