A Comparison of Imaging Outcomes From 2 Weightbearing CT Modalities.

Background: The use of weightbearing images to diagnose foot and ankle injuries continues to offer hope for improved insight into pathologies, but weightbearing CT imaging has been limited by availability. The ability to apply force to the lower limb in a horizontal bore CT system may offer an adaptation to currently available imaging systems that provides access to weightbearing images without the acquisition of additional expensive imaging space or equipment.

Methods: In order to determine whether a horizontal CT system could produce the same results as a standing CT, 3 images of one foot from 10 subjects was obtained and standard measures were calculated.

Caffeine is negatively associated with depression in patients aged 20 and older.

Introduction: Previous studies have observed the association between caffeine intake and depression, but few have considered the potential threshold effect of this issue. Therefore, the study aimed to examine the association between caffeine consumption and depression in patients aged 20 years or older using curve fitting analysis.

Methods: The population was 3,263 patients from the 2017 to 2018 National Health and Nutrition Examination Survey (NHANES) with reliable answers to questions of caffeine intake and depression.

Association between snoring and insulin levels in the US population: a cross-sectional study.

Purpose: Snoring may cause a number of problems such as tiredness, obesity, and even severe diseases, but the correlation between snoring and insulin secretion, which has important clinical significance, has rarely been studied. The objective of this study was to evaluate the correlation between snoring frequency and insulin secretion and discuss the potential mechanisms, thereby estimating the health condition of β-cells of individuals who snore.

Methods: The analyses used data from National Health and Nutrition Examination Survey (NHANES) from 2015 to 2018.

The Rotator Cable Does Not Stress Shield the Crescent Area During Shoulder Abduction.

Background: It is accepted by the orthopaedic community that the rotator cable (RCa) acts as a suspension bridge that stress shields the crescent area (CA). The goal of this study was to determine if the RCa does stress shield the CA during shoulder abduction.

Methods: The principal strain magnitude and direction in the RCa and CA and shoulder abduction force were measured in 20 cadaveric specimens.

Humeral offset as a predictor of outcomes after reverse shoulder arthroplasty.

Introduction: The Grammont-style reverse shoulder arthroplasty (RSA) relies on medialization and distalization of the shoulder center of rotation. Lateralized designs have recently gained popularity. The amount of lateralization, however, remains a controversial topic.

Discovery and Characterization of Potent Dual P-Glycoprotein and CYP3A4 Inhibitors: Design, Synthesis, Cryo-EM Analysis, and Biological Evaluations.

Targeted concurrent inhibition of intestinal drug efflux transporter P-glycoprotein (P-gp) and drug metabolizing enzyme cytochrome P450 3A4 (CYP3A4) is a promising approach to improve oral bioavailability of their common substrates such as docetaxel, while avoiding side effects arising from their pan inhibitions. Herein, we report the discovery and characterization of potent small molecule inhibitors of P-gp and CYP3A4 with encequidar (minimally absorbed P-gp inhibitor) as a starting point for optimization. To aid in the design of these dual inhibitors, we solved the high-resolution cryo-EM structure of encequidar bound to human P-gp.

Locating the rotator cable during subacromial arthroscopy: bursal- and articular-sided anatomy.

Background: The rotator cable (RCa) is an important articular-sided structure of the cuff capsular complex that helps prevent suture pull out during rotator cuff repairs (RCRs) and plays a role in force transmission. Yet, the RCa cannot be located during bursal-sided RCRs. The purpose of this study is to develop a method to locate the RCa in the subacromial space and compare its bursal- and articular-sided dimensions.

Discovery of Encequidar, First-in-Class Intestine Specific P-glycoprotein Inhibitor.

Many chemotherapeutics, such as paclitaxel, are administered intravenously as they suffer from poor oral bioavailability, partly because of efflux mechanism of P-glycoprotein in the intestinal epithelium. To date, no drug has been approved by the U.S.

Partial Distal Biceps Avulsion Results in a Significant Loss of Supination Force.

Background: Partial avulsions of the short and/or long head of the distal biceps tendon cause pain and loss of strength. The goal of the present study was to quantify the loss of supination and flexion strength following a series of surgical releases designed to simulate partial and complete short and long head traumatic avulsions.

Methods: Mechanical testing was performed to measure supination moment arms and flexion force efficiency on 18 adult fresh-frozen specimens in pronation, neutral, and supination.

HM30181A, a potent P-glycoprotein inhibitor, potentiates the absorption and antitumor efficacy of paclitaxel in an orthotopic brain tumor model.

Objective: Delivery of chemotherapeutic drugs to the brain has remained a major obstacle in the treatment of glioma, owing to the presence of the blood-brain barrier and the activity of P-gp, which pumps its substrate back into the systemic circulation. The aim of the present study was to develop an intravenous formulation of HM30181A (HM) to inhibit P-gp in the brain to effectively deliver paclitaxel (PTX) for the treatment of malignant glioma.

Methods: Two formulations of solubilized HM were designed on the basis of different solid dispersion strategies: i) spray-drying [polyvinlypyrrolidone (PVP)-HM] and ii) solvent evaporation [HP-β-cyclodextrin (cyclodextrin)-HM].

Purification and Regulation of Pyruvate Kinase from the Foot Muscle of the Anoxia and Freeze Tolerant Marine Snail, Littorina littorea.

The intertidal marine snail, Littorina littorea, has evolved to survive bouts of anoxia and extracellular freezing brought about by changing tides and subsequent exposure to harsh environmental conditions. Survival in these anoxic conditions depends on the animals entering a state of metabolic rate depression in order to maintain an appropriate energy production-consumption balance during periods of limited oxygen availability. This study investigated the kinetic, physical, and regulatory properties of pyruvate kinase (PK), which catalyzes the final reaction of aerobic glycolysis, from foot muscle of L.

Characterizing the regulation of pyruvate kinase in response to hibernation in ground squirrel liver (Urocitellus richardsonii).

The Richardson's ground squirrel (Urocitellus richardsonii) undergoes numerous changes to its core physiological and metabolic processes over the months it spends hibernating during the winter. Winter torpor is characterized by an overall reduction in metabolic rate, a lowering of core body temperature, and a switch to preferential consumption of lipids instead of carbohydrates. The alterations in central metabolic pathways are often accomplished by the regulation of key enzymes within the glycolytic pathway.

The effect of tendon rotation on distal biceps repair.

Background: The distal biceps tendon externally rotates from proximal to distal before inserting onto the radius. Our hypothesis is that an externally rotated (anatomic) repair would re-create native supination moment arm and flexion force, whereas an internally rotated (nonanatomic) repair would result in reduced force transmission.

Methods: The mechanical tests performed in this study measured isometric moment arms and elbow flexion force using a validated elbow simulator as previously published.

Glucose-6-phosphate dehydrogenase is posttranslationally regulated in the larvae of the freeze-tolerant gall fly, Eurosta solidaginis, in response to freezing.

The freeze-tolerant larvae of the goldenrod gall fly (Eurosta solidaginis) undergo substantial alterations to their molecular physiology during the winter including the production of elevated quantities of glycerol and sorbitol, which function as cryoprotectants to survive whole body freezing. Production of these cryoprotectants depends on cytosolic pools of nicotinamide adenine dinucleotide phosphate H (NADPH), a major source being the pentose phosphate pathway (PPP). Glucose-6-phosphate dehydrogenase (G6PDH) mediates the rate-limiting and committed step of the PPP and therefore its molecular properties were explored in larvae sampled from control versus frozen states.

Clinical and functional impairment after nonoperative treatment of distal biceps ruptures.

Background: Clinical and functional impairment after nonoperative treatment of distal biceps ruptures is not well understood. The goal of this study was to measure patients' perceived disability, kinematic adjustment, and forearm supination power after nonoperative treatment of distal biceps ruptures.

Methods: Fourteen individuals after nonoperative treatment of distal biceps ruptures were matched to a control group of 18 uninjured volunteers.

KX2-361: a novel orally bioavailable small molecule dual Src/tubulin inhibitor that provides long term survival in a murine model of glioblastoma.

Purpose: A major challenge to developing new therapies for patients with malignant brain tumors is that relatively few small molecule anticancer drugs penetrate the blood-brain barrier (BBB) well enough to provide therapeutically effective concentrations in brain tissue before drug exposure in non-CNS tissues results in unacceptable toxicity.

Methods: KX2-361, a member of a novel family of compounds with Src-kinase and tubulin polymerization inhibitory activity, demonstrates good oral bioavailability and readily crosses the BBB in mice. The objective of this study was to investigate the activity of KX2-361 against human and murine glioma cells and assess its therapeutic effect in a syngeneic orthotopic model of glioblastoma.

Discovery of Novel Dual Mechanism of Action Src Signaling and Tubulin Polymerization Inhibitors (KX2-391 and KX2-361).

The discovery of potent, peptide site directed, tyrosine kinase inhibitors has remained an elusive goal. Herein we describe the discovery of two such clinical candidates that inhibit the tyrosine kinase Src. Compound 1 is a phase 3 clinical trial candidate that is likely to provide a first in class topical treatment for actinic keratosis (AK) with good efficacy and dramatically less toxicity compared to existing standard therapy.

Regulation of pyruvate kinase in skeletal muscle of the freeze tolerant wood frog, Rana sylvatica.

The wood frog (Rana sylvatica) can survive the winter in a frozen state, in which the frog's tissues are also exposed to dehydration, ischemia, and anoxia. Critical to wood frog survival under these conditions is a global metabolic rate depression, the accumulation of glucose as a cryoprotectant, and a reliance on anaerobic glycolysis for energy production. Pyruvate kinase (PK) catalyzes the final reaction of aerobic glycolysis, generating pyruvate and ATP from phosphoenolpyruvate (PEP) and ADP.

The development of benzimidazoles as selective rho kinase inhibitors.

Rho Kinase (ROCK) is a serine/threonine kinase whose inhibition could prove beneficial in numerous therapeutic areas. We have developed a promising class of ATP-competitive inhibitors based upon a benzimidazole scaffold, which show excellent potency toward ROCK (IC(50)<10nM). This report details the optimization of selectivity for ROCK over other related kinases such as Protein kinase A (PKA).

Non-additivity of functional group contributions in protein-ligand binding: a comprehensive study by crystallography and isothermal titration calorimetry.

Additivity of functional group contributions to protein-ligand binding is a very popular concept in medicinal chemistry as the basis of rational design and optimized lead structures. Most of the currently applied scoring functions for docking build on such additivity models. Even though the limitation of this concept is well known, case studies examining in detail why additivity fails at the molecular level are still very scarce.

Enhancement of hydrophobic interactions and hydrogen bond strength by cooperativity: synthesis, modeling, and molecular dynamics simulations of a congeneric series of thrombin inhibitors.

Accurately predicting the binding affinity of ligands to their receptors by computational methods is one of the major challenges in structure-based drug design. One of the potentially significant errors in these predictions is the common assumption that the ligand binding affinity contributions of noncovalent interactions are additive. Herein we present data obtained from two separate series of thrombin inhibitors containing hydrophobic side chains of increasing size that bind in the S3 pocket and with, or without, an adjacent amine that engages in a hydrogen bond with Gly 216.

Think twice: understanding the high potency of bis(phenyl)methane inhibitors of thrombin.

Successful design of potent and selective protein inhibitors, in terms of structure-based drug design, strongly relies on the correct understanding of the molecular features determining the ligand binding to the target protein. We present a case study of serine protease inhibitors with a bis(phenyl)methane moiety binding into the S3 pocket. These inhibitors bind with remarkable potency to the active site of thrombin, the blood coagulation factor IIa.