Inhibition of 11β-HSD1 is viewed as a potential target for the treatment of obesity and other elements of the metabolic syndrome. We report here the optimization of a carboxylic acid class of ...inhibitors from AZD4017 (1) to the development candidate AZD8329 (27). A structural change from pyridine to pyrazole together with structural optimization led to an improved technical profile in terms of both solubility and pharmacokinetics. The extent of acyl glucuronidation was reduced through structural optimization of both the carboxylic acid and amide substituents, coupled with a reduction in lipophilicity leading to an overall increase in metabolic stability.
Guidelines to improve the ease and safety of chest drain insertion recommend using the fifth intercostal space, around the midaxillary line (MAL). This study aimed to assess whether compliance with ...published guidelines reliably ensured such placement and avoided the potentially serious complications of subdiaphragmatic insertion and peripheral nerve injury.
Three international guidelines were assessed by identifying the intercostal space for chest drain insertion using 16 cadavers (32 sides) at a point 1 cm anterior to MAL. The European Trauma Course method was compared with the British Thoracic Society's 'safe triangle' and the ATLS course technique.
The level most commonly found was the sixth intercostal space (43%; 41 of 96 sides). Overall the sixth space or below was found in 83% of insertions (80 of 96 sides). In the fifth intercostal space, the long thoracic nerve ran posterior to the marker placed in all cases and the lateral cutaneous branches of intercostal nerves arose anteriorly to the marker in all but one case.
The results suggest these guidelines may result in insertion of chest drains below the fifth intercostal space, potentially risking injury to subdiaphragmatic structures. Peripheral nerves of the lateral thoracic wall appear safe from incisions 1 cm anterior to MAL.
Background Sarcopenia, the loss of muscle mass and function with age, is associated with increased morbidity and mortality. Current understanding of the underlying mechanisms is limited. ...Glucocorticoids (GC) in excess cause muscle weakness and atrophy. We hypothesized that GC may contribute to sarcopenia through elevated circulating levels or increased glucocorticoid receptor (GR) signaling by increased expression of either GR or the GC-amplifying enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) in muscle. Methods There were 82 participants; group 1 comprised 33 older men (mean age 70.2years, SD 4.4) and 19 younger men (22.2years, 1.7) and group 2 comprised 16 older men (79.1years, 3.4) and 14 older women (80.1years, 3.7). We measured muscle strength, mid-thigh cross-sectional area, fasting morning plasma cortisol, quadriceps muscle GR and 11betaHSD1 mRNA, and urinary glucocorticoid metabolites. Data were analysed using multiple linear regression adjusting for age, gender and body size. Results Muscle strength and size were not associated with plasma cortisol, total urinary glucocorticoids or the ratio of urinary 5beta-tetrahydrocortisol +5alpha-tetrahydrocortisol to tetrahydrocortisone (an index of systemic 11betaHSD activity). Muscle strength was associated with 11betaHSD1 mRNA levels (beta -0.35, p = 0.04), but GR mRNA levels were not significantly associated with muscle strength or size. Conclusion Although circulating levels of GC are not associated with muscle strength or size in either gender, increased cortisol generation within muscle by 11betaHSD1 may contribute to loss of muscle strength with age, a key component of sarcopenia. Inhibition of 11betaHSD1 may have therapeutic potential in sarcopenia.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Separable discrete preferences Bradley, W. James; Hodge, Jonathan K.; Kilgour, D. Marc
Mathematical social sciences,
05/2005, Letnik:
49, Številka:
3
Journal Article
Recenzirano
An ordering of multidimensional alternatives is separable on a set of dimensions if fixing values on the complementary dimensions always produces the same induced ordering. Most often, studies of ...separability assume continuous alternative spaces; as we show, separability has different properties when alternative spaces are discrete. For instance, two well-known theorems of Gorman—that common set operations preserve separability and that separable preferences are additive—fail for binary alternative spaces. Intersection is the only set operation that preserves separability. For binary alternative spaces, separability is equivalent to additivity if and only if there are four or fewer dimensions.
Inhibition of 11β-HSD1 is viewed as a potential target for the treatment of obesity and other elements of the metabolic syndrome. We report here the optimisation of a carboxylic acid class of ...inhibitors from AZD4017 (
1
) to the development candidate AZD6925 (
11
). A central aim of this optimisation campaign was the modulation of clearance mechanism to reduce the extent of acyl glucuronidation. This was achieved by modulation of the acid substructure together with a redistribution of lipophilicity in order to achieve the desired profile.
Acyl glucuronidation was reduced by modulation of acid substructure together with a redistribution of lipophilicity.
Chemical Detection Using the Receptor Density Algorithm Hilder, J. A.; Owens, N. D. L.; Neal, M. J. ...
IEEE transactions on systems, man and cybernetics. Part C, Applications and reviews,
11/2012, Letnik:
42, Številka:
6
Journal Article
This paper describes the application of the receptor density algorithm, an artificial immune system, as used to detect chemicals from data provided by various spectrometers. The system creates ...chemical signatures which are matched to a library of known chemicals, allowing the positive identification of hazardous substances. The performance of the system is tested against a publicly available mass-spectrometry dataset, against which it has previously been demonstrated as an effective anomaly detection algorithm. An autonomous chemical-detection device is then discussed, in which the algorithm is running on hardware embedded in a Pioneer robot carrying a portable chemical agent monitor.
Tetrazole Analogues of Glutamic Acid Elwood, James K.; Herbst, Robert M.; Kilgour, Gordon L.
The Journal of biological chemistry,
05/1965, Letnik:
240, Številka:
5
Journal Article
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