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

Psychosocial outcome and family burden after traumatic brain injury

The persistence of psychosocial symptoms after severe head injury has been identified as one of the main long-term difficulties facing such patients and their families. Not only have such problems proved persistent, they have been found to present particular problems for community re-entry including return to work. They have been associated in particular with stress on carers and also with disruption of family activities and health. Given that so many survivors of severe head injury rely on their families for long-term support, this topic has attracted increasing attention. The present study described the psychosocial problems after severe head injury and their relationship to various "burdens" on carers and the wider family based on a group of 54 patients studied at 3, 6, and 12 months post-injury. Replication and extension of some findings is made through study of a multi-centre internationally collected group of 562 survivors of severe head injury. Thepersistence of psychosocial problems is noted alongside their differing relationships to various aspects of "burden". Aspects of burden, and especially of social isolation, present challenges especially for those working in rehabilitation and community re-entry programme

Spatial aspects of the reproductive and feeding biology of the striped robber, Brycinus lateralis (Pisces: Characidae), in the Okavango Delta, Botswana

The Okavango Delta is a vast inland wetland system situated in northern Botswana. High rainfall is received in early summer in the southern Angolan highlands and throughout the Delta with the flood waters reaching the upper riverine floodplain between March and May where it percolates through to the lower drainage rivers between July and September. Aspects of the reproductive and feeding biology of two allopatric populations of the striped robber, Brycinus lateralis, a small characin species inhabiting the northern riverine floodplain and southern drainage rivers, were investigated. Both populations were similar in the biological aspects studied, with the flood cycle having little influence on the timing of reproduction, sexual maturity and dietary composition. Female fish from both populations matured sexually at 57mmSL, breeding over a protracted period during the warm, summer months. In both populations, the sex ratio was female-dominated at 4.8:1 (riverine floodplain) and 2.2:1 (drainage rivers). The striped robber is an opportunistic micro-carnivore with immature fish feeding predominantly on Daphnia spp. and adults being largely insectivorous

Wavelet Decomposition of Forced Turbulence: Applicability of the Iterative Donoho-Johnstone Threshold

We examine the decomposition of forced Taylor-Green and Arn’old-Beltrami- Childress (ABC) flows into coherent and incoherent components using an orthonormal wavelet decomposition. We ask whether wavelet coefficient thresh- olding based on the Donoho-Johnstone criterion can extract a coherent vortex signal while leaving behind Gaussian random noise. We find that no threshold yields a strictly Gaussian incoherent component, and that the most Gaussian incoherent flow is found for data compression lower than that achieved with the fully iterated Donoho-Johnstone threshold. Moreover, even at such low compression, the incoherent component shows clear signs of large-scale spatial correlations that are signatures of the forcings used to drive the flows

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

Blood lead level and dental caries in school-age children.

The association between blood lead level and dental caries was evaluated in cross-sectional analyses of baseline data for 543 children 6-10 years old screened for enrollment in the Children's Amalgam Trial, a study designed to assess potential health effects of mercury in silver fillings. Approximately half of the children were recruited from an urban setting (Boston/Cambridge, MA, USA) and approximately half from a rural setting (Farmington, ME, USA). Mean blood lead level was significantly greater among the urban subgroup, as was the mean number of carious tooth surfaces. Blood lead level was positively associated with number of caries among urban children, even with adjustment for demographic and maternal factors and child dental practices. This association was stronger in primary than in permanent dentition and stronger for occlusal, lingual, and buccal tooth surfaces than for mesial or distal surfaces. In general, blood lead was not associated with caries in the rural subgroup. The difference between the strength of the associations in the urban and rural settings might reflect the presence of residual confounding in the former setting, the presence of greater variability in the latter setting in terms of important caries risk factors (e.g., fluoride exposure), or greater exposure misclassification in the rural setting. These findings add to the evidence supporting a weak association between children's lead exposure and caries prevalence. A biologic mechanism for lead cariogenicity has not been identified, however. Our data are also consistent with residual confounding by factors associated with both elevated lead exposure and dental caries

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