The effect of -difluorination on the conformation and properties of a model macrocyclic system.

Conformational control of drug candidates to engineer improved potency and ADME properties is an ongoing area of research. Macrocyclic rings tend to offer a greater degree of rigidity than non-cyclised small molecules, and, as a result they are perfect platforms to instil conformational controls. In this study, the difluoroalkoxyphenyl moiety is examined as a tool to alter the conformation of macrocycles.

Timing of Surgery for Proximal Humeral Fracture Treated with Shoulder Hemiarthroplasty, Best Results with Surgery Within 2 Weeks.

Background: Preoperative delay may affect the outcome of proximal humerus fractures treated with shoulder hemiarthroplasty. There is currently no consensus for the recommended preoperative time interval. The aim was to examine how the time to surgery with shoulder hemiarthroplasty after a proximal humerus fracture affected the patient-reported outcome.

Fundamental units of numerosity estimation.

Humans can approximately enumerate a large number of objects at a single glance. While several mechanisms have been proposed to account for this ability, the fundamental units over which they operate remain unclear. Previous studies have argued that estimation mechanisms act only on topologically distinct units or on units formed by spatial grouping cues such as proximity and connectivity, but not on units grouped by similarity.

Cattle Cleanliness from the View of Swedish Farmers and Official Animal Welfare Inspectors.

Dirty cattle have been commonly recorded in official animal welfare inspections in Sweden for years. The relevant authorities have initiated work to better understand the causes of dirty cattle, in order to improve compliance and standardize the grounds for categorizing a farm as non-compliant with welfare legislation when dirty animals are present. This study investigated the occurrence of dirty cattle in official animal welfare controls, on Swedish cattle farms, and examined farmers' views on the reasons for non-compliance and on key factors in keeping animals clean.

Protease-activated receptor-2 ligands reveal orthosteric and allosteric mechanisms of receptor inhibition.

Protease-activated receptor-2 (PAR2) has been implicated in multiple pathophysiologies but drug discovery is challenging due to low small molecule tractability and a complex activation mechanism. Here we report the pharmacological profiling of a potent new agonist, suggested by molecular modelling to bind in the putative orthosteric site, and two novel PAR2 antagonists with distinctly different mechanisms of inhibition. We identify coupling between different PAR2 binding sites.

Food-symptom diaries can generate personalized lifestyle advice for managing gastrointestinal symptoms: A pilot study.

Background: Gastrointestinal (GI) symptoms have a heterogeneous pathophysiology. Yet, clinical management uses group-level strategies. There is a need for studies exploring personalized management options in patients with GI symptoms.

Discovery of retinoic acid receptor agonists as proliferators of cardiac progenitor cells through a phenotypic screening approach.

Identification of small molecules with the potential to selectively proliferate cardiac progenitor cells (CPCs) will aid our understanding of the signaling pathways and mechanisms involved and could ultimately provide tools for regenerative therapies for the treatment of post-MI cardiac dysfunction. We have used an in vitro human induced pluripotent stem cell-derived CPC model to screen a 10,000-compound library containing molecules representing different target classes and compounds reported to modulate the phenotype of stem or primary cells. The primary readout of this phenotypic screen was proliferation as measured by nuclear count.

Neuropeptide 26RFa (QRFP) is a key regulator of glucose homeostasis and its activity is markedly altered in obese/hyperglycemic mice.

Recent studies have shown that the hypothalamic neuropeptide 26RFa regulates glucose homeostasis by acting as an incretin and increasing insulin sensitivity. In this study, we further characterized the role of the 26RFa/GPR103 peptidergic system in the global regulation of glucose homeostasis using a 26RFa receptor antagonist and also assessed whether a dysfunction of the 26RFa/GPR103 system occurs in obese hyperglycemic mice. First, we demonstrate that administration of the GPR103 antagonist reduces the global glucose-induced incretin effect and insulin sensitivity whereas, conversely, administration of exogenous 26RFa attenuates glucose-induced hyperglycemia.

Mineralocorticoid Receptor Antagonists.

Two mineralocorticoid receptor antagonists, spironolactone and eplerenone, are currently approved by the FDA. Several non-steroid based ligands are in clinical trials for indications including heart failure, hypertension and diabetic kidney disease, and even more structurally distinct chemical series are reported in the literature with preclinical data from animal models. Design of new ligands that are both selective over the other oxosteroid receptors (GR, PR and AR) and possess properties compatible with oral dosing, despite the overall lipophilic binding pocket of MR, remains a challenge.

Identification of Mineralocorticoid Receptor Modulators with Low Impact on Electrolyte Homeostasis but Maintained Organ Protection.

The mechanism-based risk for hyperkalemia has limited the use of mineralocorticoid receptor antagonists (MRAs) like eplerenone in cardio-renal diseases. Here, we describe the structure and property-driven lead generation and optimization, which resulted in identification of MR modulators ( S)-1 and ( S)-33. Both compounds were partial MRAs but still demonstrated equally efficacious organ protection as eplerenone after 4 weeks of treatment in uni-nephrectomized rats on high-salt diet and aldosterone infusion.

Structural Characterization of Agonist Binding to Protease-Activated Receptor 2 through Mutagenesis and Computational Modeling.

Protease-activated receptor 2 (PAR2) is a G-protein-coupled receptor that is activated by proteolytic cleavage of its N-terminus. The unmasked N-terminal peptide then binds to the transmembrane bundle, leading to activation of intracellular signaling pathways associated with inflammation and cancer. Recently determined crystal structures have revealed binding sites of PAR2 antagonists, but the binding mode of the peptide agonist remains unknown.

Phenotypic Screen for Cardiac Regeneration Identifies Molecules with Differential Activity in Human Epicardium-Derived Cells versus Cardiac Fibroblasts.

Activation and proliferation of resident cardiac progenitor cells has therapeutic potential to repair the heart after injury. However, research has been impeded by a lack of well-defined and characterized cell sources and difficulties in translation to screening platforms. Here, we describe the development, validation, and use of a 384-well phenotypic assay in primary human epicardium-derived cells (EPDCs) to identify compounds that induce proliferation while maintaining the progenitor phenotype.

Structure-Based Drug Design of Mineralocorticoid Receptor Antagonists to Explore Oxosteroid Receptor Selectivity.

The mineralocorticoid receptor (MR) is a nuclear hormone receptor involved in the regulation of body fluid and electrolyte homeostasis. In this study we explore selectivity triggers for a series of nonsteroidal MR antagonists to improve selectivity over other members of the oxosteroid receptor family. A biaryl sulfonamide compound was identified in a high-throughput screening (HTS) campaign.

Predicting the relative binding affinity of mineralocorticoid receptor antagonists by density functional methods.

In drug discovery, prediction of binding affinity ahead of synthesis to aid compound prioritization is still hampered by the low throughput of the more accurate methods and the lack of general pertinence of one method that fits all systems. Here we show the applicability of a method based on density functional theory using core fragments and a protein model with only the first shell residues surrounding the core, to predict relative binding affinity of a matched series of mineralocorticoid receptor (MR) antagonists. Antagonists of MR are used for treatment of chronic heart failure and hypertension.

GPR103 antagonists demonstrating anorexigenic activity in vivo: design and development of pyrrolo[2,3-c]pyridines that mimic the C-terminal Arg-Phe motif of QRFP26.

GPR103, a G-protein coupled receptor, has been reported to have orexigenic properties through activation by the endogenous neuropeptide ligands QRFP26 and QRFP43. Recognizing that central administration of QRFP26 and QRFP43 increases high fat food intake in rats, we decided to investigate if antagonists of GPR103 could play a role in managing feeding behaviors. Here we present the development of a new series of pyrrolo[2,3-c]pyridines as GPR103 small molecule antagonists with GPR103 affinity, drug metabolism and pharmacokinetics and safety parameters suitable for drug development.

New Hits as Antagonists of GPR103 Identified by HTS.

Preclinical data indicate that GPR103 receptor and its endogenous neuropeptides QRFP26 and QRFP43 are involved in appetite regulation. A high throughput screening (HTS) for small molecule GPR103 antagonists was performed with the clinical goal to target weight management by modulation of appetite. A high hit rate from the HTS and initial low confirmation with respect to functional versus affinity data challenged us to revise the established screening cascade.

Patients with shoulder impingement remain satisfied 6 years after arthroscopic subacromial decompression: a prospective study of 46 patients.

Background: Although arthroscopic subacromial decompression (ASD) is a common procedure for treatment of shoulder impingement, few long term results have been published. In this prospective study, we determined whether the high degree of patient satisfaction at 6 months postoperatively reported by us earlier remained at the 6-year follow-up.

Patients And Methods: We originally reported high patient satisfaction 6 months after ASD for shoulder impingement in 50 prospectively studied patients using the Disability of the Arm Shoulder and Hand questionnaire (DASH) and the Visual Analog Scale (VAS).

Synthesis of functionalized cinnamaldehyde derivatives by an oxidative Heck reaction and their use as starting materials for preparation of Mycobacterium tuberculosis 1-deoxy-D-xylulose-5-phosphate reductoisomerase inhibitors.

Cinnamaldehyde derivatives were synthesized in good to excellent yields in one step by a mild and selective, base-free palladium(II)-catalyzed oxidative Heck reaction starting from acrolein and various arylboronic acids. Prepared α,β-unsaturated aldehydes were used for synthesis of novel α-aryl substituted fosmidomycin analogues, which were evaluated for their inhibition of Mycobacterium tuberculosis 1-deoxy-D-xylulose 5-phosphate reductoisomerase. IC(50) values between 0.

Comminuted fractures of the radial head.

Background: There have been few reports on the long-term outcome of comminuted radial head fractures in adults.

Method: 10 women and 9 men with a mean age of 45 (21-65) years when they sustained a comminuted fracture of the radial head were re-evaluated after 15-25 years. 6 patients had been nonoperatively (NO) treated while 13 had had a radial head excision.

Mason type IV fractures of the elbow: a 14- to 46-year follow-up study.

A total of 14 women and seven men with a mean age of 43 years (18 to 68) who sustained a Mason type IV fracture of the elbow, without an additional type II or III coronoid fracture, were evaluated after a mean of 21 years (14 to 46). Primary treatment included closed elbow reduction followed by immobilisation in a plaster in all cases, with an additional excision of the radial head in 11, partial resection in two and suturing of the annular ligament in two. Delayed radial head excision was performed in two patients and an ulnar nerve transposition in one.

Functionalized 3-amino-imidazo[1,2-a]pyridines: a novel class of drug-like Mycobacterium tuberculosis glutamine synthetase inhibitors.

3-Amino-imidazo[1,2-a]pyridines have been identified as a novel class of Mycobacterium tuberculosis glutamine synthetase inhibitors. Moreover, these compounds represent the first drug-like inhibitors of this enzyme. A series of compounds exploring structural diversity in the pyridine and phenyl rings have been synthesized and biologically evaluated.

Long-term outcome of displaced radial neck fractures in adulthood: 16-21 year follow-up of 5 patients treated with radial head excision.

Background: There have been no reports on the long-term outcome of radial neck Mason type IIIb fractures in adults.

Methods: 3 women and 2 men, aged 46 (22-69) years when they sustained a radial neck Mason type IIIb fracture, were evaluated after an average of 18 (16-21) years. All had been treated with radial head excision.

Physical activity, muscle function, falls and fractures.

Study Design: A thematic review.

Objectives: To evaluate if physical activity enhances muscle strength, improves balance, and reduces the fall frequency and the fracture incidence.

Background: One of the major medical problems of today is the increasing incidence of fragility fractures.

Physical activity increases bone mass during growth.

Background: The incidence of fragility fractures has increased during the last half of the 1990's. One important determinant of fractures is the bone mineral content (BMC) or bone mineral density (BMD), the amount of mineralised bone. If we could increase peak bone mass (the highest value of BMC reached during life) and/or decrease the age-related bone loss, we could possibly improve the skeletal resistance to fracture.