Managing children's forearm fractures in the emergency department.

Forearm fractures are the most common fractures among children and young people aged up to 19 years and these patients frequently present to the emergency department (ED). Many of these fractures can be treated in the ED without the need for inpatient admission. This article examines the assessment, diagnosis and management of forearm fractures.

Eating pathology and psychological outcomes in young adults in self-regulation interventions using daily self-weighing.

Objective: Self-regulation interventions encouraging daily weighing prevent weight gain in young adults; however, concerns have been raised that such interventions may have undesirable effects on eating pathology, depression, and health-related quality of life (HRQL). The present study examined whether self-regulation interventions and self-weighing frequency were associated with these indices in normal weight individuals and those with overweight or obesity.

Methods: Young adults ( = 599), 18-35 years with a body mass index (BMI) 21.

Mild Illness during Outbreak of Shiga Toxin-Producing Escherichia coli O157 Infections Associated with Agricultural Show, Australia.

During a large outbreak of Shiga toxin-producing Escherichia coli illness associated with an agricultural show in Australia, we used whole-genome sequencing to detect an IS1203v insertion in the Shiga toxin 2c subunit A gene of Shiga toxin-producing E. coli. Our study showed that clinical illness was mild, and hemolytic uremic syndrome was not detected.

Novel Series of Potent Glucokinase Activators Leading to the Discovery of AM-2394.

Glucokinase (GK) catalyzes the phosphorylation of glucose to glucose-6-phosphate. We present the structure-activity relationships leading to the discovery of AM-2394, a structurally distinct GKA. AM-2394 activates GK with an EC50 of 60 nM, increases the affinity of GK for glucose by approximately 10-fold, exhibits moderate clearance and good oral bioavailability in multiple animal models, and lowers glucose excursion following an oral glucose tolerance test in an ob/ob mouse model of diabetes.

5-Alkyl-2-urea-Substituted Pyridines: Identification of Efficacious Glucokinase Activators with Improved Properties.

Two 1-(4-aryl-5-alkyl-pyridin-2-yl)-3-methylurea glucokinase activators were identified with robust in vivo efficacy. These two compounds possessed higher solubilities than the previously identified triaryl compounds (i.e.

A pilot randomized controlled trial testing the effects of a routine-based intervention on outcomes in a behavioural weight loss programme.

Background: Structured routines aimed at eating and sleep have been successfully employed in weight loss interventions for children. Although such routines are discussed in lifestyle modification programmes for adults, they are not a primary focus.

Purpose: The purpose of this study is to determine if establishing healthy eating and sleep routines may improve outcomes in a behavioural weight loss (BWL) intervention.

C5-Alkyl-2-methylurea-Substituted Pyridines as a New Class of Glucokinase Activators.

Glucokinase (GK) activators represent a class of type 2 diabetes therapeutics actively pursued due to the central role that GK plays in regulating glucose homeostasis. Herein we report a novel C5-alkyl-2-methylurea-substituted pyridine series of GK activators derived from our previously reported thiazolylamino pyridine series. Our efforts in optimizing potency, enzyme kinetic properties, and metabolic stability led to the identification of compound 26 (AM-9514).

Failure to replicate depletion of self-control.

The limited resource or strength model of self-control posits that the use of self-regulatory resources leads to depletion and poorer performance on subsequent self-control tasks. We conducted four studies (two with community samples, two with young adult samples) utilizing a frequently used depletion procedure (crossing out letters protocol) and the two most frequently used dependent measures of self-control (handgrip perseverance and modified Stroop). In each study, participants completed a baseline self-control measure, a depletion or control task (randomized), and then the same measure of self-control a second time.

Structure-assisted discovery of the first non-retinoid ligands for Retinol-Binding Protein 4.

Retinol-Binding Protein 4 (RBP4) is a plasma protein that transports retinol (vitamin A) from the liver to peripheral tissues. This Letter highlights our efforts in discovering the first, to our knowledge, non-retinoid small molecules that bind to RBP4 at the retinol site and reduce serum RBP4 levels in mice, by disrupting the interaction between RBP4 and transthyretin (TTR), a plasma protein that binds RBP4 and protects it from renal excretion. Potent compounds were discovered and optimized quickly from high-throughput screen (HTS) hits utilizing a structure-based approach.

Characterization of a novel glucokinase activator in rat and mouse models.

Glucokinase (GK) is a hexokinase isozyme that catalyzes the phosphorylation of glucose to glucose-6-phosphate. Glucokinase activators are being investigated as potential diabetes therapies because of their effects on hepatic glucose output and/or insulin secretion. Here, we have examined the efficacy and mechanisms of action of a novel glucokinase activator, GKA23.

Discovery and optimization of 5-(2-((1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)oxy)pyridin-4-yl)-1,2,4-oxadiazoles as novel gpr119 agonists.

We describe the discovery and optimization of 5-(2-((1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)oxy)pyridin-4-yl)-1,2,4-oxadiazoles as novel agonists of GPR119. Previously described aniline 2 had suboptimal efficacy in signaling assays using cynomolgus monkey (cyno) GPR119 making evaluation of the target in preclinical models difficult. Replacement of the aniline ring with a tetrahydroquinoline ring constrained the rotation of the aniline C-N bond and gave compounds with increased efficacy on human and cyno receptors.

Discovery and optimization of N-(3-(1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yloxy)phenyl)benzenesulfonamides as novel GPR119 agonists.

The discovery and optimization of novel N-(3-(1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yloxy)phenyl)benzenesulfonamide GPR119 agonists is described. Modification of the pyridylphthalimide motif of the molecule with R(1)=-Me and R(2)=-(i)Pr substituents, incorporated with a 6-fluoro substitution on the central phenyl ring offered a potent and metabolically stable tool compound 22.

Discovery and optimization of arylsulfonyl 3-(pyridin-2-yloxy)anilines as novel GPR119 agonists.

We describe the discovery of a series of arylsulfonyl 3-(pyridin-2-yloxy)anilines as GPR119 agonists derived from compound 1. Replacement of the three methyl groups in 1 with metabolically stable moieties led to the identification of compound 34, a potent and efficacious GPR119 agonist with improved pharmacokinetic (PK) properties.

Discovery and optimization of a series of liver X receptor antagonists.

The present report describes our efforts to convert an existing LXR agonist into an LXR antagonist using a structure-based approach. A series of benzenesulfonamides was synthesized based on structural modification of a known LXR agonist and was determined to be potent dual liver X receptor (LXR α/β) ligands. Herein we report the identification of compound 54 as the first reported LXR antagonist that is suitable for pharmacological in vivo evaluation in rodents.

Fracture of a ceramic component in total hip replacement.

Fracture of a ceramic component in total hip replacement is a rare but potentially catastrophic complication. The incidence is likely to increase as the use of ceramics becomes more widespread. We describe such a case, which illustrates how inadequate initial management will lead to further morbidity and require additional surgery.

Discovery of a new binding mode for a series of liver X receptor agonists.

Structural modification of a series of dual LXRα/β agonists led to the identification of a new class of LXRβ partial agonists. An X-ray co-crystal structure shows that a representative member of this series, pyrrole 5, binds to LXRβ with a reversed orientation compared to 1.

Developing strategies to enhance health services research capacity in a predominantly rural Canadian health authority.

Context: This article outlines the planning, implementation and preliminary evaluation of a research capacity building (RCB) initiative within a predominantly rural Canadian health authority, Interior Health (IH), including initiative characteristics and key activities designed to initiate and enhance health services research capacity within the organization. Interior Health is one of 5 geographic health authorities in British Columbia. Over half of the population IH serves is considered to be rural/remote (approximately 3 people/km2), contributing to difficulties in sharing research information (ie geographical distance to meet in-person and a diverse set of needs and/or priority topics that warrant research support).

Discovery and optimization of a novel Neuromedin B receptor antagonist.

The discovery and parallel synthesis of potent, small molecule antagonists of Neuromedin B receptor based on the ary-hexahydro-dibenzodiazepin-1-one core is described.

Identification of a PPARdelta agonist with partial agonistic activity on PPARgamma.

The discovery and optimization of a series of potent PPARdelta full agonists with partial agonistic activity against PPARgamma is described.

Identification and characterization of a non-retinoid ligand for retinol-binding protein 4 which lowers serum retinol-binding protein 4 levels in vivo.

Retinol-binding protein 4 (RBP4) transports retinol from the liver to extrahepatic tissues, and RBP4 lowering is reported to improve insulin sensitivity in mice. We have identified A1120, a high affinity (K(i) = 8.3 nm) non-retinoid ligand for RBP4, which disrupts the interaction between RBP4 and its binding partner transthyretin.

Application of an allosteric model to describe the interactions among retinol binding protein 4, transthyretin, and small molecule retinol binding protein 4 ligands.

Retinol binding protein 4 (RBP4) is a serum protein that serves as the major transport protein for retinol (vitamin A). Recent reports suggest that elevated levels of RBP4 are associated with insulin resistance and that insulin sensitivity may be improved by reducing serum RBP4 levels. This can be accomplished by administration of small molecules, such as fenretinide, that compete with retinol for binding to RBP4 and disrupt the protein-protein interaction between RBP4 and transthyretin (TTR), another serum protein that protects RBP4 from renal clearance.

Effect of ultrasonic debridement using a chlorhexidine irrigant on circulating levels of lipopolysaccharides and interleukin-6.

Aim: Transient bacteraemia and endotoxaemia, and elevated levels of systemic cytokines have been reported following subgingival debridement. This study aimed to investigate the effect of chlorhexidine (CHX) solution on circulating levels of lipopolysaccharide (LPS) and interleukin-6 (IL-6) when used as an irrigant during ultrasonic debridement in patients with periodontitis.

Material And Methods: Eighteen patients with moderate to advanced chronic periodontitis were treated in a split-mouth, crossover, single-masked study.

The management of wounds following primary lower limb arthroplasty: a prospective, randomised study comparing hydrofibre and central pad dressings.

Wound care following lower limb arthroplasty has not been subject to in-depth clinical research, primarily because such wounds usually heal without complication. However, when prosthetic implants are used, serious wound problems can be disastrous (Whitehouse et al. Infect Control Hosp Epidemiol 2002;23:183-9; Lindwell OM.

Investigation of periodontal destruction patterns in smokers and non-smokers.

Background: Previous work has suggested that tobacco smoking has a local as well as a systemic effect on the severity of periodontal disease.

Objective: To test the hypothesis that smokers have more disease in the upper anterior region.

Methods: A retrospective stratified random sample of 49 non-smokers and 39 heavy smokers (>or=20 cigarettes/day) was obtained from a total of 3678 referred patients with adult periodontitis.

The effect of a commercially available chlorhexidine mouthwash product on human osteoblast cells.

Chlorhexidine mouthwash (CMW) is used for decontamination of tooth, implant or prosthetic surfaces to treat or prevent local infection. A cell culture model was used to investigate cytotoxicity of CMW employing an MTT assay to record cell activity. Human osteoblast-like cells (HOS TE 85) were seeded.