HadISD data format description

This document provides data format information for the Met Office Hadley Centre (MOHC) HadISD data. The document contains information on the NetCDF structure, the variable abbreviations and corresponding names and the global attributes

Intravital Multiphoton Microscopy with Fluorescent Bile Salts in Rats as an In Vivo Biomarker for Hepatobiliary Transport Inhibition

The bile salt export pump (BSEP) is expressed at the canalicular domain of hepatocytes, where it mediates the elimination of monovalent bile salts into the bile. Inhibition of BSEP is considered a susceptibility factor for drug-induced liver injury that often goes undetected during nonclinical testing. Although in vitro assays exist for screening BSEP inhibition, a reliable and specific method for confirming Bsep inhibition in vivo would be a valuable follow up to a BSEP screening strategy, helping to put a translatable context around in vitro inhibition data, incorporating processes such as metabolism, protein binding, and other exposure properties that are lacking in most in vitro BSEP models. Here, we describe studies in which methods of quantitative intravital microscopy were used to identify dose-dependent effects of two known BSEP/Bsep inhibitors, 2-[4-[4-(butylcarbamoyl)-2-[(2,4-dichlorophenyl)sulfonylamino]phenoxy]-3-methoxyphenyl]acetic acid (AMG-009) and bosentan, on hepatocellular transport of the fluorescent bile salts cholylglycyl amidofluorescein and cholyl-lysyl-fluorescein in rats. Results of these studies demonstrate that the intravital microscopy approach is capable of detecting Bsep inhibition at drug doses well below those found to increase serum bile acid levels, and also indicate that basolateral efflux transporters play a significant role in preventing cytosolic accumulation of bile acids under conditions of Bsep inhibition in rats. Studies of this kind can both improve our understanding of exposures needed to inhibit Bsep in vivo and provide unique insights into drug effects in ways that can improve our ability interpret animal studies for the prediction of human drug hepatotoxicity

Postjunctional Vascular Alpha-2 Adrenoceptors: Modulation and Interactions

The work presented herein represents an examination of the alpha-adrenoceptors mediating contractions in isolated vascular preparations from the rabbit and the factors involved in modulating these responses. 1) The alpha-adrenoceptor population in the rabbit isolated lateral saphenous vein, based upon agonist and antagonist potency profiles, could not be ascribed to be either a homogeneous population of either postjunctional alpha1- or alpha2-adrenoceptors, but had characteristics of both. 2) A homogeneous population of postjunctional alpha2-adrenoceptors could be isolated in the lateral saphenous vein using receptor protection experiments with the combination of rauwolscine and phenoxybenzamine. 3) Only limited success was achieved in attempting to isolate a homogeneous population of postjunctional alpha1-adrenoceptors in the lateral saphenous vein using receptor protection experiments with the combination of YM 12617 and phenoxybenzamine. The residual response to NA remaining after this procedure had characteristics of a mixed population of both postjunctional alpha1- and alpha2-adrenoceptors. 4) A comparison of the effects of angiotensin II and Bay K 8644 revealed marked differences in their ability to modulate responses to NA mediated via postjunctional alpha1- and alpha2-adrenoceptors. AII produced a selective enhancement of responses mediated via postjunctional alpha2-adrenoceptors, while the action of Bay K 8644 was not dependent upon receptor subtype. 5) In the lateral saphenous vein after isolation of postjunctional alpha2-adrenoceptors, both Bay K 8644 enhanced responses to NA. The mechanism of this potentiation also appears to differ for these agents. Bay K 8644 enhanced responses mediated via voltage-dependent Ca2+ channels, while AII inhibited the influx of Ca2+ mediated via these channels. 6) The effects of A II on responses mediated via postjunctional alpha2-adrenoceptors, was mimicked by its physiological precursor angiotensin I, suggesting that local vascular production of A II may be important for the facilitatory action of this peptide. 7) Nifedipine, like Bay K 8644, had a non-differential effect on responses to NA mediated via postjunctional alpha1 and alpha2-adrenoceptors in a number of isolated vascular preparations. 8) Under normal experimental conditions, based upon agonist and antagonist potencies, the rabbit isolated distal saphenous artery contains a homogeneous population of postjunctional alpha1-adrenoceptors. 9) In the presence of A II, there was a marked increase in the responsiveness of the distal saphenous artery to UK-14304, which was prazosin-resistant, rauwolscine-sensitive, and so mediated via postjunctional alpha2-adrenoceptors. 10) After attempted isolation of postjunctional alpha2-adrenoceptors in the distal saphenous artery using receptor protection experiments, with the combination of rauwolscine and phenoxybenzamine, no responses were observed. 11) AII uncovered responses to alpha-adrenoceptor agonists after the combination of rauwolscine and phenoxybenzamine. The agonist and antagonist potencies after this protocol were consistent with a homogeneous population of postjunctional alpha2-adrenoceptors. 12) Some of the results in the present study indicate an interaction between postjunctional alpha1- and alpha2-adrenoceptors in vascular smooth muscle. The implications for such an interaction is discussed in detail. Furthermore, evidence is presented demonstrating an interaction between postjunctional alpha2-adrenoceptors and a number of vasoactive agents. 13) Sympathetic neurotransmission in the rabbit isolated distal saphenous artery is the resultant of an interaction between three receptor systems, postjunctional alpha1-and alpha2-adrenoceptors and purinoceptors. alpha1-adrenoceptors are of principal importance, although a role for the two other receptor systems can be demonstrated under the appropriate experimental conditions

Rugby and cervical spine injuries

At the time of writing, a Cape newspaper reported on a 21-year-old rugby player who died on the field following a presumed spine injury. This highlights the ongoing concerns regarding safety in this contact sport. Although the physicality of rugby is a large part of its attraction, both to spectators and players, no one wishes serious harm. Two papers in this issue of SAMJ review rugby-related injuries to the spine and spinal cord

Company unions today

https://stars.library.ucf.edu/prism/1244/thumbnail.jp

Six Amazing Years

In only six years—1958–63, an era when the Navy operated some of the most challenging new aircraft in its history—the service cut its major-mishap rate in more than half. How