Design and Evaluation of [F]CHDI-650 as a Positron Emission Tomography Ligand to Image Mutant Huntingtin Aggregates.

Therapeutic interventions are being developed for Huntington's disease (HD), a hallmark of which is mutant huntingtin protein (mHTT) aggregates. Following the advancement to human testing of two [C]-PET ligands for aggregated mHTT, attributes for further optimization were identified. We replaced the pyridazinone ring of CHDI-180 with a pyrimidine ring and minimized off-target binding using brain homogenate derived from Alzheimer's disease patients.

Imaging Mutant Huntingtin Aggregates: Development of a Potential PET Ligand.

Mutant huntingtin (mHTT) protein carrying the elongated N-terminal polyglutamine (polyQ) tract misfolds and forms protein aggregates characteristic of Huntington's disease (HD) pathology. A high-affinity ligand specific for mHTT aggregates could serve as a positron emission tomography (PET) imaging biomarker for HD therapeutic development and disease progression. To identify such compounds with binding affinity for polyQ aggregates, we embarked on systematic structural activity studies; lead optimization of aggregate-binding affinity, unbound fractions in brain, permeability, and low efflux culminated in the discovery of compound , which exhibited target engagement in autoradiography (ARG) studies in brain slices from HD mouse models and postmortem human HD samples.

Glaucoma spectrum and age-related prevalence of individuals with FOXC1 and PITX2 variants.

Variation in FOXC1 and PITX2 is associated with Axenfeld-Rieger syndrome, characterised by structural defects of the anterior chamber of the eye and a range of systemic features. Approximately half of all affected individuals will develop glaucoma, but the age at diagnosis and the phenotypic spectrum have not been well defined. As phenotypic heterogeneity is common, we aimed to delineate the age-related penetrance and the full phenotypic spectrum of glaucoma in FOXC1 or PITX2 carriers recruited through a national disease registry.

Time trends of gender-based differences in lipid goal attainments during secondary prevention of coronary artery disease: results of a 5-year survey.

Coronary artery disease is the leading cause of death in both men and women worldwide. Little is known about gender-based differences in lipid goal attainment during secondary prevention of coronary artery disease. We conducted this study to analyze gender differences in low-density lipoprotein cholesterol target attainment in secondary prevention after acute myocardial infarction over a 5-year period.

Suboccipital decompression enhances heart rate variability indices of cardiac control in healthy subjects.

Objectives: Osteopathic manipulative treatment (OMT) focused on the upper cervical spine is theorized to affect the function of the vagus nerve and thereby influence the parasympathetic branch of the autonomic nervous system. This study was designed to determine the acute effect of upper cervical spine manipulation on cardiac autonomic control as measured by heart rate variability.

Design: Nineteen healthy, young adult subjects underwent three different experimental interventions administered in random order: cervical OMT, sham manipulation, and time control.

Controlling lipids in a high-risk population with documented coronary artery disease for secondary prevention: are we doing enough?

Background: The prevalence of high-density lipoprotein cholesterol (HDL-C) in patients who have achieved low-density lipoprotein cholesterol (LDL-C) targets in the current era of universal statin therapy remains unknown. We conducted a study to determine the prevalence of low HDL-C in patients with documented coronary artery disease, and to determine the lipid-lowering treatment patterns in secondary prevention of coronary artery disease.

Methods: In this retrospective cohort analysis, data were obtained from the electronic database of a cardiology clinic.

Antagonists of the human adenosine A2A receptor. Part 2: Design and synthesis of 4-arylthieno[3,2-d]pyrimidine derivatives.

We describe herein the discovery and development of a series of 4-arylthieno[3,2-d]pyrimidines which are potent adenosine A(2A) receptor antagonists. These novel compounds show high degrees of selectivity against the human A(1), A(2B) and A(3) receptor sub-types. Moreover, a number of these compounds show promising activity in vivo, suggesting potential utility in the treatment of Parkinson's disease.

Antagonists of the human adenosine A2A receptor. Part 1: Discovery and synthesis of thieno[3,2-d]pyrimidine-4-methanone derivatives.

The (-)-(11R,2'S)-enantiomer of the antimalarial drug mefloquine has been found to be a reasonably potent and moderately selective adenosine A(2A) receptor antagonist. Further investigation of this compound has led to the discovery of a series of keto-aryl thieno[3,2-d]pyrimidine derivatives, which are potent and selective antagonists of the adenosine A(2A) receptor. These derivatives show selectivity against the A(1) receptor.

Formula estimation of glomerular filtration rate: have we gone wrong?

and argue that the introduction of estimated glomerular filtration rate to screen for chronic kidney disease in primary care will lead to pressure on specialist services and create patient anxiety without clear proof of benefit