Targeted monitoring for human pharmaceuticals in vulnerable source and final waters

A range of pharmaceuticals has been detected in soils, surface waters and groundwaters across the world. While the reported concentrations are generally low (i.e. sub μg l-1 in surface waters), the substances have been observed throughout the year across a variety of hydrological, climatic and land-use settings. As a result, questions have been raised over the potential for pharmaceuticals in surface waters to enter drinking water supplies and to affect consumers. In a previous Drinking Water Inspectorate (DWI) funded study, results from a simple exposure model were used alongside information on therapeutic doses of pharmaceuticals to identify pharmaceuticals that are likely to be of most concern in UK drinking water sources. However, this previous study was entirely desk-based and did not involve any experimental measurements of pharmaceutical concentrations. The current study was therefore performed to generate actual measurements on the occurrence of pharmaceuticals in source and treated waters in England. The study considered a range of pharmaceutical compounds and their metabolites that have either a) high predicted exposure concentrations; b) toxicological concerns; or c) a low predicted exposure to therapeutic dose ratio. An illicit drug and its major metabolite were also investigated. The study compounds (in total 17) covered a range of chemical classes and varied in terms of their physico-chemical properties. The study was done at four sites where concentrations in source water at the drinking water treatment abstraction point were predicted to be some of the greatest in England. The study therefore is likely to provide a ‘worst case’ assessment of potential human exposure to pharmaceuticals in drinking water in England and Wales. Ten of the 17 study compounds were detected in untreated source waters at sub-μg/l concentrations. Six of these compounds (namely, benzoylecgonine (a metabolite of cocaine), caffeine, carbamazepine (an antiepileptic medicine), carbamazepine epoxide (a metabolite of carbamazepine), ibuprofen and naproxen (both non-steroidal anti-inflammatory drugs) were also detected in treated drinking water. With the exception of carbamazepine epoxide, concentrations in treated drinking water were generally significantly lower than in source water. Even though England is a densely populated country and in some regions there is limited dilution of wastewater effluents, these observations, made at sites that were predicted to have some of the highest concentrations of pharmaceuticals in England and Wales, are in line with results from similar studies performed in other countries. Comparison of measured concentrations of the study compounds in drinking waters with information on therapeutic doses demonstrated that levels of these compounds in drinking water in England are many orders of magnitude lower than levels that are given to patients therapeutically. It would therefore appear that the low or non-detectable levels of pharmaceuticals and illicit drugs present in drinking waters in England and Wales do not pose an appreciable risk to human health

α_1L-adrenoceptors mediate contraction of human erectile tissue

α1-adrenoceptor antagonists can impact upon sexual function and have potential in the treatment of erectile dysfunction. Human erectile tissue contains predominantly α1A-adrenoceptors, and here we examined whether contractions of this tissue are mediated by the functional phenotype, the α1L-adrenoceptor. Functional experiments using subtype selective agonists and antagonists, along with radioligand ([3H]tamsulosin) binding assays, were used to determine the α1-adrenoceptor population. A61603, a α1A-adrenoceptor agonist, was a full agonist with a potency 21-fold greater than that of noradrenaline. The α1A- and α1D-adrenoceptor antagonist tamsulosin antagonized noradrenaline responses with high affinity (pKD = 9.7 ± 0.3), whilst BMY7378 (100 nM) (α1D-adrenoceptor antagonist) failed to antagonize responses. In contrast, relatively low affinity estimates were obtained for both prazosin (pKD = 8.2 ± 0.1) and RS17053 (pKD = 6.9 ± 0.2), antagonists which discriminate between the α1A- and α1L-adrenoceptors. [3H]Tamsulosin bound with high affinity to the receptors of human erectile tissue (pKD = 10.3 ± 0.1) with a receptor density of 28.1 ± 1.4 fmol mg−1 protein. Prazosin displacement of [3H]tamsulosin binding revealed a single homogenous population of binding sites with a relatively low affinity for prazosin (pKi = 8.9). Taken together these data confirm that the receptor mediating contraction in human erectile tissue has the pharmacological properties of the α1L-adrenoceptor. Keywords: Erectile tissue, α1-adrenoceptor subtypes, α1L-adrenoceptor, Tamsulosin, Prazosi

The Effect of Thermal History on Microstructural Evolution, Cold-Work Refinement and {\alpha}/\b{eta} Growth in Ti-6Al-4V Wire + Arc AM

Wire + arc additive manufacture (WAAM) is an attractive method for manufacturing large-scale aerospace components, however the microstructural changes that occur and the effect of interpass rolling are poorly understood. Therefore two fundamental studies were conducted: the first involved temperature measurement of a wrought dummy wall so that the microstructural changes in the heat affected zone (HAZ) could be related to the thermal cycle. This demonstrated that the white band in the microstructure corresponded to 825 C well below the beta-transus temperature and above this boundary the bi-modal substrate material was converted to lamellar. The second involved peening WAAM material along the side of a deposited wall before applying a typical WAAM thermal heat treatment. This showed that refinement occurred up to the first layer band in the microstructure and the smallest grains were observed just above this boundary at higher temperatures significant grain growth occurred. This study has provided the foundational understanding of microstructural changes that will facilitate future process developments.Comment: 15 Figures, 25 pages, Journal publicatio

Uncoupling clutch size, prolactin, and luteinizing hormone using experimental egg removal

Clutch size is a key avian fitness and life history trait. A physiological model for clutch size determination CSD), involving an anti-gonadal effect of prolactin (PRL) via suppression of luteinizing hormone (LH),was proposed over 20 years ago, but has received scant experimental attention since. The few studies looking at a PRL-based mechanistic hypothesis for CSD have been equivocal, but recent experiments utilizing a pharmacological agent to manipulate PRL in the zebra finch (Taeniopygia guttata) found no support for a role of this hormone in clutch size determination. Here, we take a complementary approach by manipulating clutch size through egg removal, examining co-variation in PRL and LH between two breeding attempts, as well as through experimentally-extended laying. Clutch size increased for egg removal females, but not controls, but this was not correlated with changes in PRL or LH. There were also no differences in PRL between egg removal females and controls, nor did PRL levels during early, mid- or late-laying of supra-normal clutches predict clutch size. By uncoupling PRL, LH and clutch size in our study, several key predictions of the PRL-based mechanistic model for CSD were not supported. However,a positive correlation between PRL levels late in laying and days relative to the last egg (clutch completion) provides an alternative explanation for the equivocal results surrounding the conventional PRL-based physiological model for CSD. We suggest that females coordinate PRL-mediated incubation onset with clutch completion to minimize hatching asynchrony and sibling hierarchy, a behavior that is amplified in females laying larger clutches

Institutions, identities and lesser-used languages in Wales and Brittany

In this article we compare and contrast the very different approaches adopted towards ‘regional’ languages in Wales and the French region of Brittany. Consistent with our interest in the dynamics of devolution, decentralisation and regional governance, we focus principally upon the interplay between institutions, actors and opinion at the meso-level, using structured interviews, documentary evidence and survey material to back up our findings. In their own way, the Breton and Welsh cases both demonstrate the resilience of national paths and the effects of institutions on political outcomes