Showing papers by "University of Nottingham published in 1997"
TL;DR: Of the many factors examined that might affect the relation between breast cancer risk and use of HRT, only a woman's weight and body-mass index had a material effect: the increase in the relative risk of breast cancer diagnosed in women using HRT and associated with long durations of use in current and recent users was greater for women of lower than of higher weight or body- mass index.
2,343 citations
TL;DR: In this article, the authors analyse the behaviour of two possible tests, and of modifications of these tests designed to circumvent shortcomings in the original formulations, and make a recommendation for one particular testing approach for practical applications.
1,760 citations
TL;DR: The ability of CV026 to respond to a series of synthetic AHL and N-acylhomocysteine thiolactone (AHT) analogues is explored, greatly extending the ability to detect a wide spectrum of AHL signal molecules.
Abstract: Quorum sensing relies upon the interaction of a diffusible signal molecule with a transcriptional activator protein to couple gene expression with cell population density. In Gram-negative bacteria, such signal molecules are usually N-acylhomoserine lactones (AHLs) which differ in the structure of their N-acyl side chains. Chromobacterium violaceum, a Gram-negative bacterium commonly found in soil and water, produces the characteristic purple pigmen violacein. Previously the authors described a violacein-negative, mini-Tn5 mutant of C. violaceum (CV026) in which pigment production can be restored by incubation with supernatants from the wild-type strain. To develop this mutant as a general biosensor for AHLs, the natural C. violaceum AHL molecule was first chemically characterized. By using solvent extraction, HPLC and mass spectrometry, a single AHL, N-hexanoyl-L-homoserine lactone (HHL), was identified in wild-type C. violaceum culture supernatants which was absent from CV026. Since the production of violacein constitutes a simple assay for the detection of AHLs, we explored the ability of CV026 to respond to a series of synthetic AHL and N-acylhomocysteine thiolactone (AHT) analogues. In CV026, violacein is inducible by ail the AHL and AHT compounds evaluated with N-acyl side chains from C4 to C8 in length, with varying degrees of sensitivity. Although AHL compounds with N-acyl side chains from C10 to C14 are unable to induce violacein production, if an activating AHL (e.g. HHL) is incorporated into the agar, these long-chain AHLs can be detected by their ability to inhibit violacein production. The versatility of CV026 in facilitating detection of AHL mixtures extracted from culture supernatants and separated by thin-layer chromatography is also demonstrated. These simple bioassays employing CV026 thus greatly extend the ability to detect a wide spectrum of AHL signa molecules.
1,617 citations
TL;DR: This paper examined the relationship between per capita income and a wide range of environmental indicators using cross-country panel sets and found that meaningful EKCs exist only for local air pollutants whilst indicators with a more global, or indirect, impact either increase monotonically with income or or else have predicted turning points at high per- capita income levels with large standard errors, unless they have been subjected to a multilateral policy initiative.
Abstract: This paper examines the relationship between per capita income and a wide range of environmental indicators using cross-country panel sets. The manner in which this has been done overcomes several of the weaknesses asscociated with the estimation of environmental Kuznets curves (EKCs). outlined by Stern et al. (1996). Results suggest that meaningful EKCs exist only for local air pollutants whilst indicators with a more global, or indirect, impact either increase monotonically with income or else have predicted turning points at high per capita income levels with large standard errors – unless they have been subjected to a multilateral policy initiative. Two other findings are also made: that concentration of local pollutants in urban areas peak at a lower per capita income level than total emissions per capita; and that transport-generated local air pollutants peak at a higher per capita income level than total emissions per capita. Given these findings, suggestions are made regarding the necessary future direction of environmental policy.
942 citations
TL;DR: Tissue in situ hybridization studies on human embryos from days 26 to 52 of gestation reveal expression of TBXS in heart and limb, consistent with a role in human embryonic development.
Abstract: Holt-Oram syndrome is a developmental disorder affecting the heart and upper limb, the gene for which was mapped to chromosome 12 two years ago. We have now identified a gene for this disorder (HOS1). The gene (TBX5) is a member of the Brachyury (T) family corresponding to the mouse TbxS gene. We have identified six mutations, three in HOS families and three in sporadic HOS cases. Each of the mutations introduces a premature stop codon in the TBXS gene product. Tissue in situ hybridization studies on human embryos from days 26 to 52 of gestation reveal expression of TBXS in heart and limb, consistent with a role in human embryonic development.
908 citations
TL;DR: This poster presents a poster presented at the 2016 American Academy of Medical Oncology Congress on Wednesday, 3 March 2016 calling for awareness of the importance of informed consent in the selection of patients for cancer treatment.
747 citations
TL;DR: A growing understanding of the mechanisms regulating leukocyte apoptosis and of the molecules mediating safe phagocytic clearance of dying cells may yield new insights into the pathogenesis and therapy of inflammatory diseases.
Abstract: The last few years have seen the accumu- lation of compelling evidence that apoptosis (pro- grammed cell death) plays a major role in promoting resolution of the acute inflammatory response. Neutro- pulls are constitutively programmed to undergo apop- tosis, which limits their pro-inflammatory potential and leads to rapid, specific, and non-phlogistic recognition
694 citations
TL;DR: H. pylori strains of vacA signal sequence type s1a are associated with enhanced gastric inflammation and duodenal ulceration and vacA s2 strains areassociated with less inflammation and lower ulcer prevalence.
637 citations
TL;DR: Persistence of bowel symptoms commonly occurs after bacterial gastroenteritis and is responsible for considerable morbidity and health care costs.
Abstract: Objective: To measure the prevalence of gastrointestinal symptoms six months after bacterial gastroenteritis and determine risk factors and associations with postdysenteric symptoms. Design: Postal questionnaire. Setting: Nottingham Health Authority. Subjects: 544 people with microbiologically confirmed bacterial gastroenteritis between July 1994 and December 1994. Main outcome measures: Prevalence of gastrointestinal symptoms and relative risks for development of the irritable bowel syndrome and self reported altered bowel habit. Results: A quarter of subjects reported persistence of altered bowel habit six months after an episode of infective gastroenteritis. Increasing duration of diarrhoea, younger age, and female sex increased this risk, whereas vomiting as part of the illness reduced the risk. One in 14 developed the irritable bowel syndrome with an increased risk seen in women (relative risk 3.4; 95% confidence interval 1.2 to 9.8) and with duration of diarrhoea (6.5; 1.3 to 34 for 15-21 days). Conclusions: Persistence of bowel symptoms commonly occurs after bacterial gastroenteritis and is responsible for considerable morbidity and health care costs.
603 citations
TL;DR: The data indicate that IRPs constitute part of the execution machinery of mammalian apoptosis induced by deregulated oncogenes, DNA damage, or Bak but that they act after the point at which cells become committed to apoptosis or can be rescued by survival factors.
Abstract: There is increasing evidence for a central role in mammalian apoptosis of the interleukin-1 beta-converting enzyme (ICE) family of cysteine proteases, homologues of the product of the nematode "death" gene, ced-3. Ced-3 is thought to act as an executor rather than a regulator of programmed cell death in the nematode. However, it is not known whether mammalian ICE-related proteases (IRPs) are involved in the execution or the regulation of mammalian apoptosis. Moreover, an absolute requirement for one or more IRPs for mammalian apoptosis has yet to be established. We have used two cell-permeable inhibitors of IRPs, Z-Val-Ala-Asp.fluoromethylketone (ZVAD.fmk) and t-butoxy carbonyl-Asp.fluoromethylketone (BD.fmk), to demonstrate a critical role for IRPs in mammalian apoptosis induced by several disparate mechanisms (deregulated oncogene expression, ectopic expression of the Bcl-2 relative Bak, and DNA damage-induced cell death). In all instances, ZVAD.fmk and BD.fmk treatment inhibits characteristic biochemical and morphological events associated with apoptosis, including cleavage of nuclear lamins and poly-(ADP-ribose) polymerase, chromatin condensation and nucleosome laddering, and external display of phosphatidylserine. However, neither ZVAD.fmk nor BD.fmk inhibits the onset of apoptosis, as characterized by the onset of surface blebbing; rather, both act to delay completion of the program once initiated. In complete contrast, IGF-I and Bcl-2 delay the onset of apoptosis but have no effect on the kinetics of the program once initiated. Our data indicate that IRPs constitute part of the execution machinery of mammalian apoptosis induced by deregulated oncogenes, DNA damage, or Bak but that they act after the point at which cells become committed to apoptosis or can be rescued by survival factors. Moreover, all such blocked cells have lost proliferative potential and all eventually die by a process involving cytoplasmic blebbing.
577 citations
TL;DR: In this paper, the authors consider epidemics with removal (SIR) in populations that mix at two levels: global and local, and develop a general modelling framework for such processes, which allows them to analyze the conditions under which a large outbreak is possible, the size of such outbreaks when they can occur and the implications for vaccination strategies, in each case comparing their results with the simpler homogeneous mixing case.
Abstract: We consider epidemics with removal (SIR epidemics) in populations that mix at two levels: global and local. We develop a general modelling framework for such processes, which allows us to analyze the conditions under which a large outbreak is possible, the size of such outbreaks when they can occur and the implications for vaccination strategies, in each case comparing our results with the simpler homogeneous mixing case. More precisely, we consider models in which each infectious individual i has a global probability $p_G$ for infecting each other individual in the population and a local probability $p_L$, typically much larger, of infecting each other individual among a set of neighbors $\mathscr{N}(i)$. Our main concern is the case where the population is partitioned into local groups or households, but our approach also applies to cases where neighborhoods do not form a partition, for instance, to spatial models with a mixture of local (e.g., nearest-neighbor) and global contacts. We use a variety of theoretical approaches: a random graph framework for the initial exposition of the simple case where an individual's contacts are independent; branching process approximations for the general threshold result; and an embedding representation for rigorous results on the final size of outbreaks. From the applied viewpoint the key result is that, compared with the homogeneous mixing model in which individuals make contacts simply with probability $p_G$, the local infectious contacts have an "amplification" effect. The basic reproductive ratio of the epidemic is increased from its individual-to-individual value $R_G$ in the absence of local infections to a group-to-group value $R_* = \mu R_G$, where $\mu$ is the mean size of an outbreak, started by a randomly chosen individual, in which only local infections count. Where the groups are large and the within-group epidemics are above threshold, this amplification can permit an outbreak in the whole population at very low levels of $p_G$, for instance, for $p_G = O(1/Nn)$ in a population of N divided into groups of size n. The implication of these results for control strategies is that vaccination should be directed preferentially toward reducing $\mu$; we discuss the conditions under which the equalizing strategy, aimed at leaving unvaccinated sets of neighbors of equal sizes, is optimal. We also discuss the estimation of our threshold parameter $R_*$ from data on epidemics among households.
TL;DR: A model for the DSF system is proposed, which represents a novel mechanism for regulating virulence factor synthesis in response to physiological or environmental changes and is confined to certain xanthomonads.
Abstract: Mutations in the seven clustered rpf genes cause downregulated synthesis of extracellular enzymes and reduced virulence of Xanthomonas campestris pathovar campestris (Xcc). The phenotype of mutants in one of the genes, rpfF, can be restored by a diffusible extracellular factor (DSF) produced by all Xcc strains tested, apart from rpfF and rpfB mutants. DSF accumulates in early stationary phase (when synthesis of enzymes is maximal), but levels decline subsequently. Addition of DSF to exponentially-growing wild-type bacteria does not cause precocious enzyme synthesis. rpfB and rpfF are expressed throughout growth, but the rate increases in early stationary phase. RpfB is predicted to be a long-chain fatty acyl CoA ligase, and RpfF shows some relatedness to enoyl CoA hydratases. The properties of DSF suggest that it may be a fatty-acid derivative, and certain lipid preparations possess DSF activity at higher concentrations. These include lipid extracts and acid-hydrolysed lipoplysaccharide and lipid A from Xcc, and purified dodecanoic and hydroxydodecanoic acid. DSF production is confined to certain xanthomonads. We propose a model for the DSF system, which represents a novel mechanism for regulating virulence factor synthesis in response to physiological or environmental changes.
TL;DR: Downstream of both ahyI and asaI is a gene with close homology to iciA, an inhibitor of chromosome replication in Escherichia coli, a finding which implies that in Aeromonas, cell division may be linked to quorum sensing.
Abstract: Spent culture supernatants from both Aeromonas hydrophila and Aeromonas salmonicida activate a range of biosensors responsive to N-acylhomoserine lactones (AHLs). The genes for a quorum sensing signal generator and a response regulator were cloned from each Aeromonas species and termed ahyRI and asaRI, respectively. Protein sequence homology analysis places the gene products within the growing family of LuxRI homologs. ahyR and asaR are transcribed divergently from ahyI and asaI, respectively, and in both Aeromonas species, the genes downstream have been identified by DNA sequence and PCR analysis. Downstream of both ahyI and asaI is a gene with close homology to iciA, an inhibitor of chromosome replication in Escherichia coli, a finding which implies that in Aeromonas, cell division may be linked to quorum sensing. The major signal molecule synthesized via both AhyI and AsaI was purified from spent culture supernatants and identified as N-(butanoyl)-L-homoserine lactone (BHL) by thin-layer chromatography, high-pressure liquid chromatography analysis, and mass spectrometry. In addition, a second, minor AHL, N-hexanoyl-L-homoserine lactone, was identified. Transcriptional reporter studies with ahyI::luxCDABE fusions indicate that AhyR and BHL are both required for ahyI transcription. For A. salmonicida, although the addition of exogenous BHL gives only a small stimulation of the production of serine protease with comparison to the control culture, the incorporation of a longer-chain AHL, N-(3-oxodecanoyl)-L-homoserine lactone, reduced the final level (by approximately 50%) and delayed the appearance (from an A650 of 0.9 in the control to an A650 of 1.2 in the test) of protease in the culture supernatant. These data add A. hydrophila and A. salmonicida to the growing family of gram-negative bacteria now known to control gene expression through quorum sensing.
TL;DR: Theoretical arguments on neural development support the limited evidence here for the increased benefit for child and family associated with very early identification, and there are areas for further research and service development.
Abstract: Background This review was commissioned because of the increasing doubt about the ability of existing screening programmes (mainly the health visitor distraction test (HVDT) at 7-8 months) to identify children with congenital hearing impairment, and technological advances which have made neonatal hearing screening an alternative option. Objectives To review the available literature on the screening of permanent childhood hearing impairment. To provide commissioners and providers of health care with information about how to deliver a more uniform service, better outcomes, and more cost-effective screening. To identify areas for further research and service development. How the research was conducted The research involved a review of the available published and unpublished literature, and a comprehensive survey of current pre-school hearing screening provision in the UK coupled with a health economics study of hearing screening costs. The research also included a number of focus groups and visits to key centres in the UK and North America. Research findings EPIDEMIOLOGY OF PERMANENT CHILDHOOD HEARING IMPAIRMENT: There are approximately 840 children a year born in the UK with significant permanent hearing impairment likely to affect their own and their family's quality of life. Present services will miss about 400 of these children by 1 1/2 years of age, and about 200 of these children by 3 1/2 years of age. Such late identification of hearing impairment greatly reduces the responsiveness of the services for individual children. Evidence for improved outcomes with earlier identification Hearing-impaired children identified late are at risk of substantial delay in their acquisition of language and communication skills, with consequent longer-term risk to education achievement, mental health and quality of life. Theoretical arguments on neural development support the limited evidence here for the increased benefit for child and family associated with very early identification. In general, parents and professionals want very early identification, which, if implemented properly, does not cause undue anxiety. Current uk practice The survey of current practice indicated a major problem with poor information systems. This problem was further highlighted as a major concern by the multi-disciplinary focus groups. Practice varies. There are two District-wide programmes in which all newborn babies are neonatally screened, a large number of ad hoc programmes for neonatal screening of 'at-risk' babies, a variety of early surveillance programmes, and widespread use of the HVDT. Intervention and habilitation for the majority of those screened neonatally is routinely undertaken within 6 months of birth. For those screened only by the health visitor, identification was on average at about 26 months of age with intervention at about 32 months on average. (ABSTRACT TRUNCATED)
TL;DR: It is shown that Rho family small G proteins such as Rac1 and Cdc42hs, which activate the JNK/SAPK pathway, cooperate with Raf‐1 to activate the ERK pathway which causes activation of ternary complex factors, which regulate c‐fos gene expression through the serum response element.
Abstract: Mitogens promote cell growth through integrated signal transduction networks that alter cellular metabolism, gene expression and cytoskeletal organization. Many such signals are propagated through activation of MAP kinase cascades partly regulated by upstream small GTP-binding proteins. Interactions among cascades are suspected but not defined. Here we show that Rho family small G proteins such as Rac1 and Cdc42hs, which activate the JNK/SAPK pathway, cooperate with Raf-1 to activate the ERK pathway. This causes activation of ternary complex factors (TCFs), which regulate c-fos gene expression through the serum response element. Examination of ERK pathway kinases shows that neither MEK1 nor Ras will synergize with Rho-type proteins, and that only MEK1 is fully activated, indicating that MEKs are a focal point for cross-cascade regulation. Rho family proteins utilize PAKs for this effect, as expression of an active PAK1 mutant can substitute for Rho family small G proteins, and expression of an interfering PAK1 mutant blocks Rho-type protein stimulation of ERKs. PAK1 phosphorylates MEK1 on Ser298, a site important for binding of Raf-1 to MEK1 in vivo. Expression of interfering PAK1 also reduces stimulation of TCF function by serum growth factors, while expression of active PAK1 enhances EGF-stimulated MEK1 activity. This demonstrates interaction among MAP kinase pathway elements not previously recognized and suggests an explanation for the cooperative effect of Raf-1 and Rho family proteins on cellular transformation.
TL;DR: Results indicate that the positional analysis can account for a mean of 60% of all the children's multiword utterances and that the great majority of all other utterances are defined as frozen by the analysis.
Abstract: Pine & Lieven (1993) suggest that a lexically-based positional analysis can account for the structure of a considerable proportion of children's early multiword corpora. The present study tests this claim on a second, larger sample of eleven children aged between 1;0 and 3;0 from a different social background, and extends the analysis to later in development. Results indicate that the positional analysis can account for a mean of 60% of all the children's multiword utterances and that the great majority of all other utterances are defined as frozen by the analysis. Alternative explanations of the data based on hypothesizing underlying syntactic or semantic relations are investigated through analyses of pronoun case marking and of verbs with prototypical agent-patient roles. Neither supports the view that the children's utterances are being produced on the basis of general underlying rules and categories. The implications of widespread distributional learning in early language development are discussed.
TL;DR: Placental apoptosis increases significantly as pregnancy progresses, suggesting that it may play a role in the normal development and aging of the placenta.
TL;DR: A single 5 mg/kg infusion of CDP571 reduced disease activity in Crohn's disease at 2 weeks, suggesting that antibody neutralisation of TNFα is a potentially effective strategy in the management of Crohn't disease.
TL;DR: Colloidal particles in the nanometre size range (less than 1 micron in diameter) can be engineered to provide opportunities for the site-specific delivery of drugs after injection into the general circulation or lymphatic systems.
TL;DR: In this paper, the authors compared the rates of asthma symptoms and atopy in urban populations in Jimma, southwest Ethiopia, at an early stage of economic development with those among the population of remote, rural, subsistence areas, and assessed the potential role of environmental aetiological factors leading to the differences.
TL;DR: This work investigates the binding of the protein catalase to gold surfaces modified by self-assembled monolayers (SAMs) of 3-mercaptopropanoic acid, 3-MPA, 11-MUA, and a mixture of the two acid thiols.
Abstract: The attachment of biomolecules, in particular proteins, onto solid supports is fundamental in the development of advanced biosensors, bioreactors, affinity chromatographic separation materials, and many diagnostic techniques. In addition, the effective investigation of biomolecular structure and function with scanning probe microscopy often requires a strong attachment of the biomolecule to a substrate. Here, we investigate the binding of the protein catalase to gold surfaces modified by self-assembled monolayers (SAMs). The chemical and physical adsorption of the protein molecules onto SAMs of 3-mercaptopropanoic acid (3-MPA), 11-mercaptoundecanoic acid (11-MUA), and a mixture of the two acid thiols (mixed) was investigated by utilizing tapping mode atomic force microscopy, scanning tunneling microscopy, surface plasmon resonance (SPR), static secondary ion mass spectrometry, and X-ray photoelectron spectroscopy. The surface concentration of catalase adsorbed on the SAMs decreased in the following order:...
TL;DR: A system of nonlinear partial differential equations is proposed as a model for the growth of an avascular-tumour spheroid, revealing two phases of growth retardation from the initial exponential growth, the first of which is due to nutrient-diffusion limitations and the second to contraction during necrosis.
Abstract: A system of nonlinear partial differential equations is proposed as a model for the growth of an avascular-tumour spheroid. The model assumes a continuum of cells in two states, living or dead, and, depending on the concentration of a generic nutrient, the live cells may reproduce (expanding the tumour) or die (causing contraction). These volume changes resulting from cell birth and death generate a velocity field within the spheroid. Numerical solutions of the model reveal that after a period of time the variables settle to a constant profile propagating at a fixed speed. The travelling-wave limit is formulated and analytical solutions are found for a particular case. Numerical results for more general parameters compare well with these analytical solutions. Asymptotic techniques are applied to the physically relevant case of a small death rate, revealing two phases of growth retardation from the initial exponential growth, the first of which is due to nutrient-diffusion limitations and the second to contraction during necrosis. In this limit, maximal and "linear' phase growth speeds can be evaluated in terms of the model parameters.
TL;DR: The results suggest that apoptosis may play a role in the pathophysiologic mechanisms of intrauterine growth restriction.
TL;DR: Preliminary evidence is found that beta 2-adrenoceptor polymorphism is associated with altered beta 1-adRenoceptor expression in asthma patients, and the homozygous Gly-16 form was significantly more prone to bronchodilator desensitisation than Arg 16, with the influence of Gly 16 dominating over any putative protective effects of Glu 27.
TL;DR: A full understanding of this complexity will require definition of recognition mechanisms which operate in vivo in higher organisms as well as specific evidence in vitro for involvement of phagocyte receptors.
Abstract: In vivo, the normal fate of cells undergoing apoptosis is recognition, uptake and degradation of the intact dying cell by phagocytes. Cell clearance by this mechanism is fast, efficient and injury-limiting, being mediated by macrophages and semi-professional phagocytes. Apoptotic cells are marked for disposal by mechanisms which remain poorly understood, although in some circumstances surface sugar changes and exposure of phosphatidylserine lead to recognition by uncharacterised phagocyte receptors. Furthermore, there is specific evidence in vitro for involvement of phagocyte receptors including the thrombospondin receptors alpha v beta 3 and CD36, scavenger receptors, the 61D3 antigen and the ABC 1 transporter. It is conceivable that recognition mechanisms may be ordered in a hierarchy of 'back ups', each recognising cells at different stages of the death program. Nevertheless, a full understanding of this complexity will require definition of recognition mechanisms which operate in vivo in higher organisms.
TL;DR: Topical GTN provides rapid, sustained relief of pain in patients with anal fissure and over two-thirds of patients treated in this way avoided surgery which would otherwise have been required for healing.
TL;DR: The finding that antiarrhythmic treatment was a significant predictor of increased mortality in ibopamine-treated patients may be important, but exploratory analyses must be interpreted with caution.
TL;DR: An extended pedigree of 92 current and historically important long-, medium- and short-grain US rice cultivars representing the efforts of many breeders over more than 80 years found a single nucleotide polymorphism could explain 79.7% of the variation in the apparent amylose content of the 89 non-glutinous cultivars tested.
Abstract: The Waxy gene (Wx) encodes the granule-bound starch synthase responsible for the synthesis of amylose in rice (Oryza sativa). Recently, a polymorphic microsatellite sequence closely linked to the Wx gene was reported. To determine whether polymorphism in this sequence correlates with variation in apparent amylose content, we tested an extended pedigree of 92 current and historically important long-, medium- and short-grain US rice cultivars representing the efforts of many breeders over more than 80 years. Seven Wx microsatellite alleles were identified which together explained 82.9% of the variation in apparent amylose content of the 89 non-glutinous rice cultivars tested. Similar results were also obtained with 101 progenyof a cross between low- and intermediate-amylose breeding lines. An additional, unique microsatelliteallele, (CT)16, was detected in one glutinous cultivar,CI 5309. However, the other glutinous cultivars,Calmochi 101 and Tatsumi mochi, were in the (CT)17 class along with three other cultivars that contained15–16.5% amylose.