Serum Osteoprotegerin Levels and the Vascular Reactivity Index in Patients with Hypertension.

: Osteoprotegerin (OPG), a soluble glycoprotein found in serum, has been associated with both the presence and severity of atherosclerosis. OPG is regarded as the mediator in the process of vascular endothelial dysfunction. Impaired endothelial function has an intimate link with hypertension (HTN) and is associated with significant morbidity and mortality.

Cyanotriazoles are selective topoisomerase II poisons that rapidly cure trypanosome infections.

Millions who live in Latin America and sub-Saharan Africa are at risk of trypanosomatid infections, which cause Chagas disease and human African trypanosomiasis (HAT). Improved HAT treatments are available, but Chagas disease therapies rely on two nitroheterocycles, which suffer from lengthy drug regimens and safety concerns that cause frequent treatment discontinuation. We performed phenotypic screening against trypanosomes and identified a class of cyanotriazoles (CTs) with potent trypanocidal activity both in vitro and in mouse models of Chagas disease and HAT.

Discovery of Novel Quinoline-Based Proteasome Inhibitors for Human African Trypanosomiasis (HAT).

Human African Trypanosomiasis (HAT) is a vector-borne disease caused by kinetoplastid parasites of the genus. The disease proceeds in two stages, with a hemolymphatic blood stage and a meningo-encephalic brain stage. In the latter stage, the parasite causes irreversible damage to the brain leading to sleep cycle disruption and is fatal if untreated.

Discovery and Preclinical Pharmacology of INE963, a Potent and Fast-Acting Blood-Stage Antimalarial with a High Barrier to Resistance and Potential for Single-Dose Cures in Uncomplicated Malaria.

A series of 5-aryl-2-amino-midazohiaiazole (ITD) derivatives were identified by a phenotype-based high-throughput screening using a blood stage () growth inhibition assay. A lead optimization program focused on improving antiplasmodium potency, selectivity against human kinases, and absorption, distribution, metabolism, excretion, and toxicity properties and extended pharmacological profiles culminated in the identification of (), which demonstrates potent cellular activity against 3D7 (EC = 0.006 μM) and achieves "artemisinin-like" kill kinetics with a parasite clearance time of <24 h.

NITD-688, a pan-serotype inhibitor of the dengue virus NS4B protein, shows favorable pharmacokinetics and efficacy in preclinical animal models.

Dengue virus (DENV) is a mosquito-borne flavivirus that poses a threat to public health, yet no antiviral drug is available. We performed a high-throughput phenotypic screen using the Novartis compound library and identified candidate chemical inhibitors of DENV. This chemical series was optimized to improve properties such as anti-DENV potency and solubility.

A Cyclic Phosphoramidate Prodrug of 2'-Deoxy-2'-Fluoro-2'--Methylguanosine for the Treatment of Dengue Virus Infection.

Monophosphate prodrug analogs of 2'-deoxy-2'-fluoro-2'--methylguanosine have been reported as potent inhibitors of hepatitis C virus (HCV) RNA-dependent RNA polymerase. These prodrugs also display potent anti-dengue virus activities in cellular assays although their prodrug moieties were designed to produce high levels of triphosphate in the liver. Since peripheral blood mononuclear cells (PBMCs) are among the major targets of dengue virus, different prodrug moieties were designed to effectively deliver 2'-deoxy-2'-fluoro-2'--methylguanosine monophosphate prodrugs and their corresponding triphosphates into PBMCs after oral administration.

Discovery and Characterization of Clinical Candidate LXE408 as a Kinetoplastid-Selective Proteasome Inhibitor for the Treatment of Leishmaniases.

Visceral leishmaniasis is responsible for up to 30,000 deaths every year. Current treatments have shortcomings that include toxicity and variable efficacy across endemic regions. Previously, we reported the discovery of GNF6702, a selective inhibitor of the kinetoplastid proteasome, which cleared parasites in murine models of leishmaniasis, Chagas disease, and human African trypanosomiasis.

Structure-activity relationship of uridine-based nucleoside phosphoramidate prodrugs for inhibition of dengue virus RNA-dependent RNA polymerase.

To identify a potent and selective nucleoside inhibitor of dengue virus RNA-dependent RNA polymerase, a series of 2'- and/or 4'-ribose sugar modified uridine nucleoside phosphoramidate prodrugs and their corresponding triphosphates were synthesized and evaluated. Replacement of 2'-OH with 2'-F led to be a poor substrate for both dengue virus and human mitochondrial RNA polymerases. Instead of 2'-fluorination, the introduction of fluorine at the ribose 4'-position was found not to affect the inhibition of the dengue virus polymerase with a reduction in uptake by mitochondrial RNA polymerase.

Everyday memory problems in alcohol abuse and dependence: Frequency, patterns and patient-proxy agreement.

Using self-report to assess everyday memory in alcoholics presents challenges given the presence of both memory and metamemory deficits. Accordingly, evaluation of the reliability and validity of proxy ratings as well as the frequency of these memory lapses are of clinical importance. In the present study, 180 patient-proxy dyads completed the Prospective and Retrospective Memory Questionnaire (PRMQ).

A Deterrence Approach to Regulate Nurses' Compliance with Electronic Medical Records Privacy Policy.

Hospitals have become increasingly aware that electronic medical records (EMR) may bring about tangible/intangible benefits to managing institutions, including reduced medical errors, improved quality-of-care, curtailed costs, and allowed access to patient information by healthcare professionals regardless of limitations. However, increased dependence on EMR has led to a corresponding increase in the influence of EMR breaches. Such incursions, which have been significantly facilitated by the introduction of mobile devices for accessing EMR, may induce tangible/intangible damage to both hospitals and concerned individuals.

In vitro antiviral activity of adenosine analog NITD008 against tick-borne flaviviruses.

There are currently no antiviral therapies available for the tick-borne flaviviruses associated with hemorrhagic fevers: Kyasanur Forest disease virus (KFDV), both classical and the Alkhurma hemorrhagic fever virus (AHFV) subtype, and Omsk hemorrhagic fever virus (OHFV). In this brief study, we describe the in vitro antiviral activity of adenosine analog NITD008 against KFDV, AHFV, OHFV, as well as Tick-borne Encephalitis virus (TBEV). Alongside the well-established activity of NITD008 against mosquito-borne flaviviruses, our results have demonstrated the feasibility of identifying nucleoside analog inhibitors that have pan-flavivirus activity.

The search for nucleoside/nucleotide analog inhibitors of dengue virus.

Nucleoside analogs represent the largest class of antiviral agents and have been actively pursued for potential therapy of dengue virus (DENV) infection. Early success in the treatment of human immunodeficiency virus (HIV) infection and the recent approval of sofosbuvir for chronic hepatitis C have provided proof of concept for this class of compounds in clinics. Here we review (i) nucleoside analogs with known anti-DENV activity; (ii) challenges of the nucleoside antiviral approach for dengue; and (iii) potential strategies to overcome these challenges.

Synergistic suppression of dengue virus replication using a combination of nucleoside analogs and nucleoside synthesis inhibitors.

Dengue virus (DENV) is the most prevalent mosquito-borne viral pathogen in humans. Currently, there is no clinically approved vaccine or antiviral for DENV. Combination therapy is a common practice in antiviral treatment and a potential approach to search for new treatments for infectious pathogens.

A novel chitosan-γPGA polyelectrolyte complex hydrogel promotes early new bone formation in the alveolar socket following tooth extraction.

A novel chitosan-γPGA polyelectrolyte complex hydrogel (C-PGA) has been developed and proven to be an effective dressing for wound healing. The purpose of this study was to evaluate if C-PGA could promote new bone formation in the alveolar socket following tooth extraction. An animal model was proposed using radiography and histomorphology simultaneously to analyze the symmetrical sections of Wistar rats.

Activation of peripheral blood mononuclear cells by dengue virus infection depotentiates balapiravir.

In a recent clinical trial, balapiravir, a prodrug of a cytidine analog (R1479), failed to achieve efficacy (reducing viremia after treatment) in dengue patients, although the plasma trough concentration of R1479 remained above the 50% effective concentration (EC(50)). Here, we report experimental evidence to explain the discrepancy between the in vitro and in vivo results and its implication for drug development. R1479 lost its potency by 125-fold when balapiravir was used to treat primary human peripheral blood mononuclear cells (PBMCs; one of the major cells targeted for viral replication) that were preinfected with dengue virus.

Development of a FACS-based assay for evaluating antiviral potency of compound in dengue infected peripheral blood mononuclear cells.

Dengue fever is the most important arthropod-transmitted viral disease affecting humans. It is a blood-borne disease characterized by persistent fever and joint pain. In the blood, primary peripheral blood mononuclear cells (PBMCs), in particular monocytes, are the main target of the dengue virus (DENV).

Ten years of dengue drug discovery: progress and prospects.

To combat neglected diseases, the Novartis Institute of Tropical Diseases (NITD) was founded in 2002 through private-public funding from Novartis and the Singapore Economic Development Board. One of NITD's missions is to develop antivirals for dengue virus (DENV), the most prevalent mosquito-borne viral pathogen. Neither vaccine nor antiviral is currently available for DENV.

Effect of the precrack preparation with an ultrasonic instrument on the ceramic bracket removal.

Background/purpose: In terms of fracture mechanics, a precrack preparation may facilitate the propagation of a break through the expected fracture plane during the bracket debonding process. The purpose of this study was to evaluate the effect of an ultrasonic precrack preparation on the debonding force and failure modes of ceramic bracket removal.

Methods: Eighty extracted premolars were assigned to four groups: Inspire, precrack Inspire, Clarity, and precrack Clarity groups, with each group containing 20 teeth.

Application and development of ultrasonics in dentistry.

Since the 1950s, dentistry's ultrasonic instruments have developed rapidly. Because of better visualization, operative convenience, and precise cutting ability, ultrasonic instruments are widely and efficiently applied in the dental field. This article describes the development and improvement of ultrasonic instruments in several dental fields.

A novel decision-tree method for structured continuous-label classification.

Structured continuous-label classification is a variety of classification in which the label is continuous in the data, but the goal is to classify data into classes that are a set of predefined ranges and can be organized in a hierarchy. In the hierarchy, the ranges at the lower levels are more specific and inherently more difficult to predict, whereas the ranges at the upper levels are less specific and inherently easier to predict. Therefore, both prediction specificity and prediction accuracy must be considered when building a decision tree (DT) from this kind of data.

Conformational flexibility of the Dengue virus RNA-dependent RNA polymerase revealed by a complex with an inhibitor.

We report a highly reproducible method to crystallize the RNA-dependent RNA polymerase (RdRp) domain of dengue virus serotype 3 (DENV-3), allowing structure refinement to a 1.79-Å resolution and revealing amino acids not seen previously. We also present a DENV-3 polymerase/inhibitor cocrystal structure at a 2.

Synthesis and antiviral activity of 4,6-disubstituted pyrimido[4,5-b]indole ribonucleosides.

A series of new pyrimido[4,5-b]indole ribonucleosides bearing phenyl or hetaryl group at position 4 has been prepared by selective Pd-catalyzed cross-coupling reactions of the corresponding protected 4,6-dichloropyrimido[4,5-b]indole ribonucleoside with (het)arylboronic acids or stannanes followed by deprotection. Further cross-couplings under harsher conditions and employing X-Phos ligand proceeded at the position 6 leading to 4,6-disubstituted pyrimido[4,5-b]indole ribonucleosides. Some of these compounds displayed antiviral activity against Dengue virus.

High-accuracy thickness measurement of a transparent plate with the heterodyne central fringe identification technique.

In a modified Twyman-Green interferometer, the optical path variation is measured with the heterodyne central fringe identification technique, as the light beam is focused by a displaced microscopic objective on the front/rear surface of the test transparent plate. The optical path length variation is then measured similarly after the test plate is removed. The geometrical thickness of the test plate can be calculated under the consideration of dispersion effect.