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P Sutton

Publications and source records attributed to P Sutton.

At least 19 recordsLinked to original sources
PubMed2005

Lung cancer in Teesside (UK) and Varese (Italy): a comparison of management and survival.

BACKGROUND: The survival of lung cancer patients in the UK is lower than in other similar European countries. The reasons for this are unclear. METHODS: Two areas were selected with a similar incidence of lung cancer: Teesside in Northern England and Varese in Northern Italy. Data were collected prospectively on all new cases of lung cancer diagnosed in the year 2000. Comparisons were made of basic demographic characteristics, management, and survival. RESULTS: There were 268 cases of lung cancer in Teesside and 243 in Varese. Patients in Teesside were older (p<0.05), were more likely to have smoked (p<0.001), had a higher occupational risk (p<0.001), higher co-morbidity (p<0.05), and poorer performance status (p<0.001). Fewer patients in Teesside presented as an incidental finding (p<0.001) and the histological confirmation rate was lower than in Varese (p<0.01). In Teesside there were more large cell carcinomas (p<0.001), more small cell carcinomas (p<0.05), and fewer early stage non-small cell lung cancers (p<0.05). The resection rate was lower in Teesside (7% v 24%; p<0.01) and more patients received no specific anti-cancer treatment (50% v 25%; p<0.001). Overall 3 year survival was lower in Teesside (7% v 14%; p<0.001). Surgical resection was the strongest multivariate survival predictor in Varese (HR = 0.46) and Teesside (HR = 0.31). Co-morbidity in Teesside resulted in a significantly lower resection rate (p<0.001). CONCLUSIONS: Patients with lung cancer in Teesside presented at a later stage, with more aggressive types of tumour, and had higher co-morbidity than patients in Varese. As a result, the resection rate was significantly lower and survival was worse.

Carcinoma, Non-Small-Cell Lung↗
PubMed2003

Helicobacter pylori vaccines spiral into the new millennium.

This article reviews the current situation regarding research towards an effective human vaccine against Helicobacter pylori, with particular emphasis on developments in the new millennium. The mechanism(s) by which immunisation of mice can affect helicobacter colonisation of mice remains a mystery, but may be related to immune mediated environmental changes. In particular, it is proposed that severe gastritis and T-cell mediated changes in mucin production can significantly impact upon H. pylori colonisation. Despite the potential influence of environmental factors, significant progress towards a truly effective vaccine may depend upon the induction of specific immune targeting of this pathogen. This would probably be best achieved by the generation of an appropriate antibody response, something which has not yet been accomplished. An overview of previous and current H. pylori vaccine clinical trials is also presented.

Animals↗
PubMed2001

Helicobacter-induced expression of Bcl-X(L) in B lymphocytes in the mouse model: a possible step in the development of gastric mucosa-associated lymphoid tissue (MALT) lymphoma.

Primary gastric mucosa-associated lymphoid tissue (MALT) lymphoma may develop from chronic infection with Helicobacter sp. in the mouse model. The mechanisms of pathogenesis remain unclear. Regulation of B-cell proliferation and death are important features to investigate. Proteins encoded by bcl-2 family genes, e.g., Bcl-X(L), regulate apoptosis; and alterations in the expression of these genes can contribute to the development of cancer. Our aim was to determine the role of Bcl-X(L) in B lymphocytes in the development of gastric MALT lymphoma associated with Helicobacter infection using the BALB/c mouse model. We analyzed 37 animals with Helicobacter-associated MALT (n = 25), low-grade MALT lymphoma (n = 10) and high-grade lymphoma (n = 2), investigating the in vivo distribution of Bcl-X(L) in B cells/B-lymphoma cells using immunohistochemical analysis. In vitro cultivation of B cells/B-lymphoma cells was employed to perform RT-PCR analysis of Bcl-X(L) mRNA expression after cell stimulation with Helicobacter antigen. We found significant Bcl-X(L) protein expression in B lymphocytes within MALT and low-grade MALT lymphoma, whereas there was no and minimal expression, respectively, of Bcl-X(L) in the 2 high-grade MALT lymphoma cases. Expression of bcl-X(L) mRNA in B lymphocytes was up-regulated in vitro upon Helicobacter-antigen stimulation and associated with prolonged cell survival. These findings support the hypothesis that Bcl-X(L) plays a role in the pathogenesis of B-cell MALT lymphoma by providing cell-survival signals and by triggering the acquisition of MALT.

Animals↗
PubMed2001

Progress in vaccination against Helicobacter pylori.

This review discusses recent progress in the development of a vaccine against Helicobacter pylori. This progress includes demonstration that: effective immunisation is independent of antibodies but dependent upon CD4+ T helper cells, although their role remains unknown; the immunisation regime can be improved to increase efficacy; successful immunisation against H. pylori is possible using a live vector; a strain of H. pylori suitable for experimental infection of humans has been developed. Important issues that remain to be addressed include incomplete protection, non-availability of suitable mucosal adjuvants and post-immunisation gastritis. Significantly, commercial development of products for clinical trial is underway.

Adjuvants, Immunologic↗
PubMed2001

Helicobacter pylori vaccines and mechanisms of effective immunity: is mucus the key?

In this theoretical article, the hypothesis is proposed that immunization against gastric helicobacter infection is mediated by CD4+ T-cell induced changes in mucus production. Vaccine development for the gastric pathogen Helicobacter pylori has encountered several problems. Resolving these problems is impeded by our lack of understanding of the mechanisms by which the immune response influences bacterial colonization. Protective immunity requires CD4+ T cells, but the majority of helicobacters are located in the mucus of the gastric lumen, away from the epithelial surface. Evidence suggests that this mechanism functions independently of antibodies, so how this is achieved is unknown. Clues to this mechanism may be provided by immune clearance of nematode infection. Similar to H. pylori, expulsion of the intestinal nematode, Nippostrongylus brasiliensis, in rodents is mediated by CD4+ T-cell changes in the numbers of goblet cells and the type of mucins secreted into the gut. Immune-mediated changes in secretion of gastric mucins could similarly be responsible for the reductions in helicobacter colonization seen in immunized animals. Helicobacter pylori are highly motile bacteria that have evolved to inhabit their specialized niche. Alterations in their mucus environment could influence their motility, such that the bacteria cannot remain efficiently within the mucus and are flushed away.

Animals↗
PubMed2001

Post-immunisation gastritis and Helicobacter infection in the mouse: a long term study.

BACKGROUND AND AIMS: Helicobacter pylori is a major cause of peptic ulcers and gastric cancer. Vaccine development is progressing but there is concern that immunisation may exacerbate Helicobacter induced gastritis: prophylactic immunisation followed by challenge with H felis or H pylori can induce a more severe gastritis in mice than seen with infection alone. The aim of this study was to investigate the relationship between immunity to Helicobacter infection and post-immunisation gastritis. METHODS: (1) C57BL/6 mice were prophylactically immunised before challenge with either H felis or H pylori. Histopathology and colonisation were assessed one month post-challenge. (2) C57BL/6 mice were prophylactically immunised against H felis infection and gastritis assessed up to 18 months post-challenge. RESULTS: Prophylactic immunisation induced a reduction in bacterial colonisation following H felis challenge which was associated with increased severity of active gastritis with neutrophil infiltration and atrophy. However, immunised mice challenged with H pylori SS1 had little evidence of pathology. Long term follow up showed that post-immunisation gastritis was evident at three months. However, from six months onwards, although immunised/challenged mice still developed gastritis, there was no significant difference between inflammation in these mice and infected controls. Post-immunisation gastritis was not associated with the serum antibody response. Immunisation prevented the formation of secondary lymphoid aggregates in the gastric tissue. CONCLUSION: The H felis mouse model of post-immunisation gastritis is the most extreme example of this type of pathology. We have shown in this model that post-immunisation gastritis is a transient event which does not produce long term exacerbation of pathology.

Analysis of Variance↗
PubMed2001

Iron deficiency associated with higher blood lead in children living in contaminated environments.

The evidence that iron deficiency increases lead child exposure is based primarily on animal data and limited human studies, and some of this evidence is contradictory. No studies of iron status and blood lead levels in children have accounted for environmental lead contamination and, therefore, the source of their exposure. Thus, no studies have directly determined whether iron deficiency modifies the relationship of environmental lead and blood lead. In this study, we compared blood lead levels of iron-deficient and iron-replete children living in low, medium, or highly contaminated environments. Measurements of lead in paint, soil, dust, and blood, age of housing, and iron status were collected from 319 children ages 1-5. We developed two lead exposure factors to summarize the correlated exposure variables: Factor 1 summarized all environmental measures, and Factor 2 was weighted for lead loading of house dust. The geometric mean blood lead level was 4.9 microg/dL; 14% exceeded 10 microg/dL. Many of the children were iron deficient (24% with ferritin < 12 ng/dL). Seventeen percent of soil leads exceeded 500 microg/g, and 23% and 63% of interior and exterior paint samples exceeded 5,000 microg/g. The unadjusted geometric mean blood lead level for iron-deficient children was higher by 1 microg/dL; this difference was greater (1.8 microg/dL) after excluding Asians. Blood lead levels were higher for iron-deficient children for each tertile of exposure as estimated by Factors 1 and 2 for non-Asian children. Elevated blood lead among iron-deficient children persisted after adjusting for potential confounders by multivariate regression; the largest difference in blood lead levels between iron-deficient and -replete children, approximately 3 microg/dL, was among those living in the most contaminated environments. Asian children had a paradoxical association of sufficient iron status and higher blood lead level, which warrants further investigation. Improving iron status, along with reducing exposures, may help reduce blood lead levels among most children, especially those living in the most contaminated environments.

Child Welfare↗
PubMed2000

A mesoscale phytoplankton bloom in the polar Southern Ocean stimulated by iron fertilization.

Changes in iron supply to oceanic plankton are thought to have a significant effect on concentrations of atmospheric carbon dioxide by altering rates of carbon sequestration, a theory known as the 'iron hypothesis'. For this reason, it is important to understand the response of pelagic biota to increased iron supply. Here we report the results of a mesoscale iron fertilization experiment in the polar Southern Ocean, where the potential to sequester iron-elevated algal carbon is probably greatest. Increased iron supply led to elevated phytoplankton biomass and rates of photosynthesis in surface waters, causing a large drawdown of carbon dioxide and macronutrients, and elevated dimethyl sulphide levels after 13 days. This drawdown was mostly due to the proliferation of diatom stocks. But downward export of biogenic carbon was not increased. Moreover, satellite observations of this massive bloom 30 days later, suggest that a sufficient proportion of the added iron was retained in surface waters. Our findings demonstrate that iron supply controls phytoplankton growth and community composition during summer in these polar Southern Ocean waters, but the fate of algal carbon remains unknown and depends on the interplay between the processes controlling export, remineralisation and timescales of water mass subduction.

Atmosphere↗
PubMed2000

Combined lesions of hippocampus and subiculum Do not produce deficits in a nonspatial social olfactory memory task.

Rats transmit information to each other about which foods are safe to eat. If a rat smells a food odor on the breath of another rat, it is subsequently more likely to eat that food than an alternative. Work by Galef et al. (1988) has shown that the observer rat forms an association between two olfactory stimuli on the breath of the demonstrator rat that has eaten the food, the food odor and carbon disulphide, which is normally present in the rat breath. Bunsey and Eichenbaum (1995) claimed that the hippocampus/subicular region is required for the long-term retention of this nonspatial form of associative memory on the basis that combined lesions of the hippocampus and subiculum produced a deficit, but lesions of either structure alone did not. We report here a failure to repeat this finding. Rats with either combined lesions of the hippocampus and subiculum or with amygdala lesions were tested on their ability to remember this association either immediately (testing short-term memory) or after a 24 hr delay (testing long-term memory). Neither lesion group exhibited significant memory deficits on this nonspatial associative task at either test interval. In contrast, a deficit was observed on a spatial memory task (forced-choice alternation t-maze) for animals with combined lesions of the hippocampus and subiculum. These results contradict the findings of Bunsey and Eichenbaum (1995) and support the idea that the hippocampus/subicular region is not required for this nonspatial associative memory.

Amygdala↗
PubMed2000

Further development of the Helicobacter pylori mouse vaccination model.

Immunisation against Helicobacter infection in mouse models has thus far produced neither complete protection against the bacteria, nor a complete prevention of the associated gastritis. This study aimed firstly to compare the sensitivities of the various methods used to assess H. pylori infection in the mouse model, and secondly to develop the experimental design to induce a more effective immunity, aimed at further reducing bacterial burden in the gastric tissue. Various mouse strains were prophylactically immunised with whole bacterial sonicate and cholera toxin before challenge with H. pylori-SS1. The relative sensitivities of the urease assay, histological assessment and the colony forming assay to detect levels of H. pylori colonisation were compared. Comparisons of different antigen doses and different timecourses of immunisation were performed. The colony forming assay was found to be far more sensitive than either the urease assay or histological assessment for determining the protective efficacies of immunisation. Mice which had 10(5) H. pylori per gram of stomach by colony assay were negative by histology and urease. Lower doses of whole cell sonicate were more protective than high doses and more effective immunisation was achieved by leaving at least 3 weeks between immunisation instead of weekly immunisations. In conclusion, for assessment of H. pylori colonisation in the mouse model, the colony forming assay should be used. The experimental protocol for immunisation has been altered to produce a significant improvement in protection. However, full protection has still not yet been achieved and more work is still required.

Animals↗
PubMed2000

Review article: Helicobacter pylori vaccines-the current status.

In this review, we take a look at the current status in the development of a vaccine against the human pathogenic bacterium, Helicobacter pylori, a major aetiological factor in peptic ulcer disease and gastric adenocarcinoma. Various animal models are now in use from mice infected with H. pylori, through gnotobiotic pigs and primates to ferrets naturally infected with their own Helicobacter, H. mustelae. A significant problem remains the requirement for a suitable mucosal adjuvant. Detoxification or the use of low doses of adjuvants already available may provide a solution and new immune stimulating compounds have been tested with some success. New approaches include the delivery of Helicobacter antigens by DNA immunization, microparticles or live vectors such as attenuated salmonella and the examination of alternative routes of vaccine administration. The phenomenon of post-immunization gastritis and improvements in vaccine efficacy are also discussed. A major area of interest is the mechanism by which immunization actually influences Helicobacter colonization. This remains a mystery: antibodies appear to be unimportant whereas CD4+ T-cells essential. Finally, a viewpoint is given on whom should be immunized when a final vaccine becomes available.

Animals↗
PubMed2000

Therapeutic immunization against Helicobacter pylori infection in the absence of antibodies.

Helicobacter pylori is an important human pathogen. Prophylactic immunization with bacterial antigen plus an adjuvant protects mice against challenge with live H. pylori. Surprisingly, it was found that immunizations of mice already infected with Helicobacter also influenced bacterial colonization. This concept of therapeutic immunization is a novel phenomenon. Because H. pylori lives in the lumen of the stomach, it was initially hypothesized that the protective mechanism would involve induction of secretory IgA. However, work with knockout mice has demonstrated that prophylactic immunization is equally effective in mice deficient in IgA and even in microMT mice lacking B lymphocytes. Currently nothing is known about therapeutic vaccination and the effect of immunizing a host with an ongoing ineffective immune response. To address this, we infected B-cell deficient, microMT mice with H. pylori and therapeutically immunized them four times in 3 weeks with bacterial sonicate and cholera toxin adjuvant. These immunizations significantly reduced colonization by H. pylori. The antibody- negative status of the microMT mice was confirmed by ELISA. Thus, therapeutic immunization stimulates an immune response, which reduces H. pylori infection via a mechanism that is antibody independent. How this is achieved remains to be determined, but may well involve a novel immune mechanism.

Adjuvants, Immunologic↗
PubMed2000

Dominant nonresponsiveness to Helicobacter pylori infection is associated with production of interleukin 10 but not gamma interferon.

Helicobacter pylori-induced gastritis is an essential precursor lesion for the development of peptic ulcers or gastric adenocarcinoma. We demonstrate that nonresponsiveness to H. pylori SS1 infection is dominantly inherited in mice. F(1) hybrid crosses between a nonresponder mouse and three responder strains all possessed the nonresponder phenotype. Secretion of interleukin-10 but not gamma interferon was associated with nonresponsiveness to infection.

Adenocarcinoma↗
PubMed1999

Dose escalation of chart in non-small cell lung cancer: is three-dimensional conformal radiation therapy really necessary?

PURPOSE: To evaluate, preclinically, the potential for dose escalation of continuous, hyperfractionated, accelerated radiation therapy (CHART) for non small-cell lung cancer (NSCLC), we examined the strategy of omission of elective nodal irradiation with and without the application of three-dimensional conformal radiation technology (3DCRT). METHODS AND MATERIALS: 2D, conventional therapy plans were designed according to the specifications of CHART for 18 patients with NSCLC (Stages Ib, IIb, IIIa, and IIIb). Further plans were generated with the omission of elective nodal irradiation (ENI) from the treatment portals (2D minus ENI plans [2D-ENI plans]). Both sets were inserted in the patient's planning computed tomographies (CTs). These reconstructed plans were then compared to alternative, three-dimensional treatment plans which had been generated de novo, with the omission of ENI: 3D minus elective nodal irradiation (3D-ENI plans). Dose delivery to the planning target volumes (PTVs) and to the organs at risk were compared between the 3 sets of corresponding plans. The potential for dose escalation of each patient's 2D-ENI and 3D-ENI plan beyond 54 Gy, standard to CHART, was also determined. RESULTS: PTV coverage was suboptimal in the 2D CHART and the 2D-ENI plans. Only in the 3D-ENI plans did 100% of the PTV get > or = 95% of the dose prescribed (i.e., 51.5 Gy [51.3-52.2]). Using 3D-ENI plans significantly reduced the dose received by the spinal cord, the mean and median doses to the esophagus and the heart. It did not significantly reduce the lung dose when compared to 2D-ENI plans. Escalation of the dose (minimum > or = 1 Gy) with optimal PTV coverage was possible in 55.5% of patients using 3D-ENI, but was possible only in 16.6% when using the 2D-ENI planning strategy. CONCLUSIONS: 3DCRT is fundamental to achieving optimal PTV coverage in NSCLC. A policy of omission of elective nodal irradiation alone (and using 2D technology) will not achieve optimal PTV coverage or dose escalation. 3DCRT with omission of ENI can achieve true escalation of CHART in 55.5% of tumors, depending on their site and N-stage.

Aged↗
PubMed1999

Immunogenicity of recombinant BCG producing the GRA1 antigen from Toxoplasma gondii.

Toxoplasmosis is a major parasitic disease, responsible for foetopathy in humans and domestic animals, especially sheep. Toxoplasma gondii infection generally protects immunocompetent hosts against subsequent reinfection, suggesting that efficacious vaccines can be developed against this disease. Excreted/secreted T. gondii antigens have previously been shown to provide immunoprotection in small rodents, and protective immunity is thought to be cell-mediated. Mycobacterium bovis BCG is known to be a good inducer of cellular immunity. In this study, we have developed a BCG strain which produces and secretes GRA1, one of the major excreted/secreted T. gondii antigens. This strain does not carry antibiotic-resistance determinants and is therefore safe for the environment. The intraperitoneal immunisation of OF1 outbred mice with this BCG strain failed to induce GRA1-specific humoral or cellular immune responses and only conferred a very limited degree of protection against challenge with virulent T. gondii. However, in sheep immunised subcutaneously and boosted intravenously, this recombinant BCG strain induced GRA1-specific cell-mediated responses, as evidenced by the proliferation of peripheral blood mononuclear cells and by the production of IFN-gamma, although it failed to elicit GRA1-specific antibody responses. Following oocyst challenge infection, sheep immunised with recombinant BCG exhibited an abbreviated temperature response compared with controls, suggesting partial protection.

Animals↗
PubMed1999

Different manifestations of Toxoplasma gondii infection in F344 and LEW rats.

There is evidence that not only the immune status, but also the genetic predisposition of certain hosts influence the clinical outcome of Toxoplasma gondii infection. By far the majority of our knowledge on genetic and immunological mechanisms involved in control of T. gondii infection has been obtained by studying mouse models, which in terms of clinical outcome of infection differ considerably from humans. Rats which show a rather similar course of infection in comparison to humans have not so far been investigated for effects of genetic differences on course of the infection. In this study we show that, like mice, different strains of rats exhibit a remarkable variation in the number of brain cysts arising from chronic infection. LEW rats seem to be highly resistant to cyst formation, in contrast to F344 rats that are susceptible. In addition, F344 rats express high numbers of gammadelta T cells during the acute phase of infection, whereas LEW rats express elevated but comparably low numbers of gammadelta T cells. The RT1 (rat MHC) haplotypes of both strains are identical in the RT1A and RT1B/D regions, which encode the restriction elements for conventional peptide antigens. Consequently, rat strain-specific differences may be useful to define MHC-independent mechanisms of resistance against T. gondii, which may also act in humans.

Animals↗
PubMed1999

A genetic basis for atrophy: dominant non-responsiveness and helicobacter induced gastritis in F(1) hybrid mice.

BACKGROUND: The importance of host factors in helicobacter induced gastritis has been shown in animal models. Infection of most mouse strains with Helicobacter felis results in a functional atrophic gastritis, while other strains remain gastritis free. AIMS: To investigate these host factors further by using genetic crosses of responder and non-responder mice. METHODS: F(1) hybrids of the non-responder CBA/Ca strain and three strains of mice known to develop H felis induced gastritis were infected for three months with H felis. Gastritis was assessed by histopathology and serum antibody responses by ELISA. RESULTS: Infection of CBA/Ca mice and F(1) hybrids induced little or no gastritis. Analyses of the antibody responses in these mice revealed virtually undetectable anti-helicobacter antibody levels despite colonisation with high numbers of H felis. In contrast, infection of H felis responsive strains induced gastritis and a significant humoral immune response. CONCLUSIONS: The non-responsiveness of CBA/Ca mice to H felis infection is dominantly inherited. The lack of gastritis in CBA mice and their offspring is probably due to active suppression of the immune response normally mounted against H felis. Investigation of these mechanisms will provide important insights relevant to induction of gastric atrophy and cancer in humans.

Animals↗