Cholesterol is eliminated from neurons by oxidization, which generates oxysterols. Cholesterol oxidation is mediated by the enzymes cholesterol 24-hydroxylase (CYP46A1) and cholesterol 27-hydroxylase (CYP27A1). Immunocytochemical studies show that CYP46A1 and CYP27A1 are expressed in neurons and some astrocytes in the normal brain, and CYP27A1 is present in oligodendrocytes. In Alzheimer's disease (AD), CYP46A1 shows prominent expression in astrocytes and around amyloid plaques, whereas CYP27A1 expression decreases in neurons and is not apparent around amyloid plaques but increases in oligodendrocytes. Although previous studies have examined the effects of synthetic oxysterols on the processing of amyloid precursor protein (APP), the actions of the naturally occurring oxysterols have yet to be examined. To understand the role of cholesterol oxidation in AD, we compared the effects of 24(S)-and 27-hydroxycholesterol on the processing of APP and analyzed the cell-specific expression patterns of the two cholesterol hydroxylases in the human brain. Both oxysterols inhibited production of A␤ in neurons, but 24(S)-hydroxycholesterol was ϳ1000-fold more potent than 27-hydroxycholesterol. The IC 50 of 24(S)-hydroxycholesterol for inhibiting A␤ secretion was ϳ1 nM. Both oxysterols induced ABCA1 expression with IC 50 values similar to that for inhibition of A␤ secretion, suggesting the involvement of liver X receptor. Oxysterols also inhibited protein kinase C activity and APP secretion following stimulation of protein kinase C. The selective expression of CYP46A1 around neuritic plaques and the potent inhibition of APP processing in neurons by 24(S)-hydroxycholesterol suggests that CYP46A1 affects the pathophysiology of AD and provides insight into how polymorphisms in the CYP46A1 gene might influence the pathophysiology of this prevalent disease.

DJD is a common disease of domesticated cats that requires further investigation of its associated clinical signs.

Angiotensin-converting enzyme-related carboxypeptidase (ACE2) is a recently identified zinc metalloprotease with carboxypeptidase activity that was identified using our genomics platform. We implemented a rational design approach to identify potent and selective ACE2 inhibitors. To this end, picomolar inhibitors of ACE2 were designed and synthesized.

Results suggest that EIPH is associated with impaired performance in Thoroughbred racehorses not medicated with furosemide and not using nasal dilator strips.

Background Among asymptomatic patients with severe carotid artery stenosis but no recent stroke or transient cerebral ischaemia, either carotid artery stenting (CAS) or carotid endarterectomy (CEA) can restore patency and reduce long-term stroke risks. However, from recent national registry data, each option causes about 1% procedural risk of disabling stroke or death. Comparison of their long-term protective effects requires large-scale randomised evidence.Methods ACST-2 is an international multicentre randomised trial of CAS versus CEA among asymptomatic patients with severe stenosis thought to require intervention, interpreted with all other relevant trials. Patients were eligible if they had severe unilateral or bilateral carotid artery stenosis and both doctor and patient agreed that a carotid procedure should be undertaken, but they were substantially uncertain which one to choose. Patients were randomly allocated to CAS or CEA and followed up at 1 month and then annually, for a mean 5 years. Procedural events were those within 30 days of the intervention. Intention-to-treat analyses are provided. Analyses including procedural hazards use tabular methods. Analyses and meta-analyses of non-procedural strokes use Kaplan-Meier and log-rank methods. The trial is registered with the ISRCTN registry, ISRCTN21144362.

Results indicated that interobserver reliability of tracheobronchoscopic assessment of EIPH in Thoroughbred racehorses is high when the examination is conducted by experienced veterinarians. Concordance among investigators is sufficient to justify use of this grading system for further studies and clinical descriptions of EIPH.

Behaviors relating to activity were substantially different between healthy cats and cats with signs of DJD-associated pain. Fifteen items were identified as being potentially useful, and the preferred instrument design was identified. This information could be used to construct an owner-based questionnaire to assess feline DJD-associated pain. Once validated, such a questionnaire would assist in evaluating potential analgesic treatments for these patients.

SummaryReasons for performing study: Risk factors for occult exerciseinduced pulmonary haemorrhage (EIPH) are poorly defined or quantified. Objectives: To investigate the importance of putative risk factors for EIPH amongst Thoroughbred racehorses in Australia. Methods: Tracheobronchoscopy was used to determine EIPH status of 744 Thoroughbred racehorses after flat racing in Melbourne, Australia. Horses were identified for study before racing, and over 50% of horses racing during the study period were examined. Statistical analysis included use of bivariate and multivariate logistic regression analysis to account for simultaneous effects of a large number of variables. Results: The only risk factor identified as associated with both EIPH Ն1 or Ն2 was ambient temperature, with horses racing at temperatures <20°C being at~2 times risk of occult EIPH. There was no association of EIPH with age, sex, weight carried, track hardness, speed of racing, or air quality. Conclusions: There do not appear to be individual risk factors, amongst those examined in this study, that are strongly associated with EIPH. Potential relevance: The risk of developing EIPH cannot be readily determined from a combination of age, race speed, race distance, track hardness or air quality. This study does not provide support for the hypotheses that racing on hard surfaces or in polluted air contributes to the development of EIPH.