The Future of Trimethoprim

From a dissertation read before the Society on 11th February, 1981.Co-trimoxazole became available for medical use towards the end of 1968 and represented a successful marriage of the old and the new, being a combination of a sulphonamide and a new drug called trimethoprim. Today it is one of the most widely prescribed drugs in the United Kingdom, and is used extensively in urinary and respiratory tract infections. More recently, however, trimethoprim has been released for use on its own, and this has raised considerable controversy as to which is the drug of choice.Three original claims for co-trimoxazoleSimple laboratory tests suggest that a combination of trimethoprim and a sulphonamide will inhibit bacterial growth at concentrations lower than either drug on its own. More formal assays which compare the drugs over a range of concentrations confirm that the antibacterial effect of the combination greatly exceeds a purely additive response. The drugs' interaction is said to be synergistic, although no single definition of the term synergy has ever been universally accepted

Gamma-ray bursts and terrestrial planetary atmospheres

We describe results of modeling the effects on Earth-like planets of long-duration gamma-ray bursts (GRBs) within a few kiloparsecs. A primary effect is generation of nitrogen oxide compounds which deplete ozone. Ozone depletion leads to an increase in solar UVB radiation at the surface, enhancing DNA damage, particularly in marine microorganisms such as phytoplankton. In addition, we expect increased atmospheric opacity due to buildup of nitrogen dioxide produced by the burst and enhanced precipitation of nitric acid. We review here previous work on this subject and discuss recent developments, including further discussion of our estimates of the rates of impacting GRBs and the possible role of short-duration bursts.Comment: 12 pages including 5 figures (4 in color). Added discussion of GRB rates and biological effects. Accepted for publication in New Journal of Physics, for special issue "Focus on Gamma-Ray Bursts

Late-time draining of a thin liquid film on the outer surface of a circular cylinder

A combination of analytical and numerical techniques is used to give a complete description of the late-time draining of a two-dimensional thin liquid film on the outer surface of a stationary horizontal circular cylinder. In this limit three regions of qualitatively different behaviour emerge, namely a draining region on the upper part of the cylinder and a pendant-drop region on the lower part of the cylinder joined by a narrow inner region. In the draining region, capillarity is negligible and the film thins due to gravity. In the pendant-drop region (which, to leading order, contains all of the liquid initially on the cylinder), there is a quasi-static balance between gravity and capillarity. The matching between the draining and pendant-drop regions occurs via the inner region in which the film has a capillary-ripple structure consisting of an infinite sequence of alternating dimples and ridges. Gravity is negligible in the dimples, which are all thinner than the film in the draining region. On the other hand, gravity and capillarity are comparable in the ridges, which are all thicker than the film in the draining region. The dimples and the ridges are all asymmetric: specifically, the leading-order thickness of the dimples grows quadratically in the downstream direction but linearly in the upstream direction, whereas the leading-order film thickness in the ridges goes to zero linearly in the downstream direction but quadratically in the upstream direction. The dimples and ridges become apparent in turn as the draining proceeds, and only the first few dimples and ridges are likely to be discernible for large but finite times. However, there is likely to be a considerable period of time during which the present asymptotic solution provides a good description of the flow

Population health and the economy: Mortality and the Great Recession in Europe

We analyze the evolution of mortality‐based health indicators in 27 European countries before and after the start of the Great Recession. We find that in the countries where the crisis has been particularly severe, mortality reductions in 2007–2010 were considerably bigger than in 2004–2007. Panel models adjusted for space‐invariant and time‐invariant factors show that an increase of 1 percentage point in the national unemployment rate is associated with a reduction of 0.5% (p < .001) in the rate of age‐adjusted mortality. The pattern of mortality oscillating procyclically is found for total and sex‐specific mortality, cause‐specific mortality due to major causes of death, and mortality for ages 30–44 and 75 and over, but not for ages 0–14. Suicides appear increasing when the economy decelerates—countercyclically—but the evidence is weak. Results are robust to using different weights in the regression, applying nonlinear methods for detrending, expanding the sample, and using as business cycle indicator gross domestic product per capita or employment‐to‐population ratios rather than the unemployment rate. We conclude that in the European experience of the past 20 years, recessions, on average, have beneficial short‐term effects on mortality of the adult population.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142224/1/hec3495_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142224/2/hec3495.pd

TWEAK-FN14 signaling induces lysosomal degradation of a cIAP1–TRAF2 complex to sensitize tumor cells to TNFα

Synthetic inhibitor of apoptosis (IAP) antagonists induce degradation of IAP proteins such as cellular IAP1 (cIAP1), activate nuclear factor κB (NF-κB) signaling, and sensitize cells to tumor necrosis factor α (TNFα). The physiological relevance of these discoveries to cIAP1 function remains undetermined. We show that upon ligand binding, the TNF superfamily receptor FN14 recruits a cIAP1–Tnf receptor-associated factor 2 (TRAF2) complex. Unlike IAP antagonists that cause rapid proteasomal degradation of cIAP1, signaling by FN14 promotes the lysosomal degradation of cIAP1–TRAF2 in a cIAP1-dependent manner. TNF-like weak inducer of apoptosis (TWEAK)/FN14 signaling nevertheless promotes the same noncanonical NF-κB signaling elicited by IAP antagonists and, in sensitive cells, the same autocrine TNFα-induced death occurs. TWEAK-induced loss of the cIAP1–TRAF2 complex sensitizes immortalized and minimally passaged tumor cells to TNFα-induced death, whereas primary cells remain resistant. Conversely, cIAP1–TRAF2 complex overexpression limits FN14 signaling and protects tumor cells from TWEAK-induced TNFα sensitization. Lysosomal degradation of cIAP1–TRAF2 by TWEAK/FN14 therefore critically alters the balance of life/death signals emanating from TNF-R1 in immortalized cells

Have Anglo-Saxon concepts really influenced the development of European qualifications policy?

This paper considers how far Anglo-Saxon conceptions of have influenced European Union vocational education and training policy, especially given the disparate approaches to VET across Europe. Two dominant approaches can be identified: the dual system (exemplified by Germany); and output based models (exemplified by the NVQ ‘English style’). Within the EU itself, the design philosophy of the English output-based model proved in the first instance influential in attempts to develop tools to establish equivalence between vocational qualifications across Europe, resulting in the learning outcomes approach of the European Qualifications Framework, the credit-based model of European VET Credit System and the task-based construction of occupation profiles exemplified by European Skills, Competences and Occupations. The governance model for the English system is, however, predicated on employer demand for ‘skills’ and this does not fit well with the social partnership model encompassing knowledge, skills and competences that is dominant in northern Europe. These contrasting approaches have led to continual modifications to the tools, as these sought to harmonise and reconcile national VET requirements with the original design. A tension is evident in particular between national and regional approaches to vocational education and training, on the one hand, and the policy tools adopted to align European vocational education and training better with the demands of the labour market, including at sectoral level, on the other. This paper explores these tensions and considers the prospects for the successful operation of these tools, paying particular attention to the European Qualifications Framework, European VET Credit System and European Skills, Competences and Occupations tool and the relationships between them and drawing on studies of the construction and furniture industries

Deletion at ITPR1 Underlies Ataxia in Mice and Spinocerebellar Ataxia 15 in Humans

We observed a severe autosomal recessive movement disorder in mice used within our laboratory. We pursued a series of experiments to define the genetic lesion underlying this disorder and to identify a cognate disease in humans with mutation at the same locus. Through linkage and sequence analysis we show here that this disorder is caused by a homozygous in-frame 18-bp deletion in Itpr1 (Itpr1Δ18/Δ18), encoding inositol 1,4,5-triphosphate receptor 1. A previously reported spontaneous Itpr1 mutation in mice causes a phenotype identical to that observed here. In both models in-frame deletion within Itpr1 leads to a decrease in the normally high level of Itpr1 expression in cerebellar Purkinje cells. Spinocerebellar ataxia 15 (SCA15), a human autosomal dominant disorder, maps to the genomic region containing ITPR1; however, to date no causal mutations had been identified. Because ataxia is a prominent feature in Itpr1 mutant mice, we performed a series of experiments to test the hypothesis that mutation at ITPR1 may be the cause of SCA15. We show here that heterozygous deletion of the 5′ part of the ITPR1 gene, encompassing exons 1–10, 1–40, and 1–44 in three studied families, underlies SCA15 in humans