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J D Barry

Publications and source records attributed to J D Barry.

At least 19 recordsLinked to original sources
PubMed2005

Prognostic significance of alarm symptoms in patients with gastric cancer.

BACKGROUND: The aim of this study was to determine the incidence and spectrum of alarm symptoms in patients with newly diagnosed gastric cancer, and to examine the relationship between symptoms and outcome. METHODS: Three hundred consecutive patients with gastric adenocarcinoma were studied prospectively. The outcomes of 40 patients (13.3 per cent) without alarm symptoms (21 men; median age 69 years) were compared with those of the 260 patients (86.7 per cent) with alarm symptoms (175 men; median age 72 years). RESULTS: It was possible to perform an R0 gastrectomy more often in patients without alarm symptoms (21 patients; 52 per cent) than in those with alarm symptoms (71 patients; 27.3 per cent) (chi(2) = 10.35, 1 d.f., P = 0.001). The cumulative survival rate at 5 years was 38 per cent for patients without alarm symptoms versus 15.0 per cent for those with alarm symptoms (chi(2) = 10.18, 1 d.f., P = 0.001). In a multivariate analysis, distant metastasis (hazard ratio (HR) 2.73 (95 per cent confidence interval (c.i.) 2.04 to 3.66); P < 0.001), overall stage of cancer (HR 1.83 (95 per cent c.i. 1.53 to 2.19); P < 0.001) and persistent vomiting at diagnosis (HR 1.66 (95 per cent c.i. 1.26 to 2.18); P < 0.001) were independently associated with length of survival. CONCLUSION: Alarm symptoms are absent in a significant minority of patients with gastric cancer at diagnosis; these patients stand a better chance of curative surgery and long-term survival than those with alarm symptoms.

Adenocarcinoma↗
PubMed2005

What the genome sequence is revealing about trypanosome antigenic variation.

African trypanosomes evade humoral immunity through antigenic variation, whereby they switch expression of the gene encoding their VSG (variant surface glycoprotein) coat. Switching proceeds by duplication of silent VSG genes into a transcriptionally active locus. The genome project has revealed that most of the silent archive consists of hundreds of subtelomeric VSG tandem arrays, and that most of these are not functional genes. Precedent suggests that they can contribute combinatorially to the formation of expressed, functional genes through segmental gene conversion. These findings from the genome project have major implications for evolution of the VSG archive and for transmission of the parasite in the field.

Animals↗
PubMed2004

Prospective comparison of D1 vs modified D2 gastrectomy for carcinoma.

To compare the outcomes after D1 gastrectomy with those after modified D2 gastrectomy (preserving pancreas and spleen) performed by specialist surgeons for gastric cancer in a large UK NHS Trust. In all, 118 consecutive patients with gastric adenocarcinoma were referred by postcode, to undergo either a D1 gastrectomy (North Gwent (RJ), n=36, median age 76 years, 21 m) or a modified D2 gastrectomy (South Gwent (WL), n=82, 70 years, 57 m). Operative mortality in the two groups of patients was similar (D1 8.3% vs D2 7.3%, chi2 0.286, DF 1, P=0.593). Overall cumulative survival at 5 years was 32% after D1 gastrectomy compared to 59% after D2 gastrectomy (chi2 4.25, DF 1, P=0.0392). In patients with stage III cancers, survival was 8% after D1, compared with 33% after D2 gastrectomy (chi2 6.43, DF 1, P=0.0112). In a multivariate analysis, T stage (hazard ratio 2.339, 95% CI 1.683-2.995, P=0.01), N stage (hazard ratio 4.026, 95% CI 3.536-4.516, P=0.0001) and the extent of lymphadenectomy (hazard ratio 0.258, 95% CI -0.426-0.942, P=0.0001) were independently associated with durations of survival. In conclusion, modified D2 gastrectomy can improve survival four-fold for patients with stage III gastric cancer, without significantly increasing morbidity and mortality when compared with a D1 gastrectomy.

Adenocarcinoma↗
PubMed2003

Why are parasite contingency genes often associated with telomeres?

Contingency genes are common in pathogenic microbes and enable, through pre-emptive mutational events, rapid, clonal switches in phenotype that are conducive to survival and proliferation in hosts. Antigenic variation, which is a highly successful survival strategy employed by eubacterial and eukaryotic pathogens, involves large repertoires of distinct contingency genes that are expressed differentially, enabling evasion of host acquired immunity. Most, but not all, antigenic variation systems make extensive use of subtelomeres. Study of model systems has shown that subtelomeres have unusual properties, including reversible silencing of genes mediated by proteins binding to the telomere, and engagement in ectopic recombination with other subtelomeres. There is a general theory that subtelomeric location confers a capacity for gene diversification through such recombination, although experimental evidence is that there is no increased mitotic recombination at such loci and that sequence homogenisation occurs. Possible benefits of subtelomeric location for pathogen contingency systems are reversible gene silencing, which could contribute to systems for gene switching and mutually exclusive expression, and ectopic recombination, leading to gene family diversification. We examine, in several antigenic variation systems, what possible benefits apply.

Animals↗
PubMed2003

Surgical time and motion: the intermediate equivalent revisited.

The relationship between operative time, the intermediate equivalent value (IEV) and the complexity of common general surgical operations was examined. Correlation was found between the BUPA schedule values for procedures categorized as intermediate and major, but complex major vascular reconstruction and oesophagogastric resection for cancer occupied significantly more theatre time than the four intermediate equivalents allocated by the Collins or BUPA schedule. Moreover, anaesthetic preparation time for complex major surgery in the latter surgical subspecialities contributed at least one further intermediate value. Re-evaluation of the ideal IEV weighting of all surgical operations including anaesthetic input from larger similar audits would allow more accurate audits of surgeons' work-load, and also facilitate transparent intensive management of operating theatre resource.

Consultants↗
PubMed2002

Special interest radiology improves the perceived preoperative stage of gastric cancer.

AIM: The aim of this study was to compare the accuracy of spiral computed tomography (CT) performed by a specialist radiologist within a multi disciplinary team (MDT) framework with that of radiologists working outside of this framework. MATERIALS AND METHODS: One hundred and ten patients [median age 70 (35-86)yr, 71m] underwent either a preoperative CT performed by the MDT specialist consultant radiologist (n=60) or a CT performed by one of 13 other consultant radiologists (n=50). The strength of the agreement between the CT stage and the histopathological stage was determined by the weighted Kappa statistic (Kw). RESULTS: Sensitivity for T, N and M stage were 64%, 65% and 25% for MDT specialist CT, compared with 24%, 24% and 5% for control CT. Specificity for T, N and M stage were 68%, 59% and 95% for MDT specialist CT compared with 79%, 94% and 93% for control CT. Kw for T, N and M stage were 0.314, 0.350 and 0.255 for MDT specialist CT compared with 0.088, 0.102 and -0.019 for control CT. Unsuspected metastases were found in 12 patients staged by MDT specialist CT compared with 19 patients staged by control CT (Chi2=4.366, df=1,p =0.037). CONCLUSION: Improved patient selection for surgery should maximize use of limited resource.

Adenocarcinoma↗
PubMed2001

Antigenic variation in trypanosomes: enhanced phenotypic variation in a eukaryotic parasite.

African trypanosomes are unicellular, eukaryotic parasites that live extracellularly in a wide range of mammals, including humans. They have a surface coat, composed of variant surface glycoprotein (VSG), which probably is essential and acts as a defence against general innate immunity and against acquired immunity directed at invariant surface antigens. In effect, the VSG is the only antigen that the host can target, and each trypanosome expresses only one VSG. To counter specific antibodies against the VSG, trypanosomes periodically undergo antigenic variation, the change to expression of another VSG. Antigenic variation belongs to the general survival strategy of enhanced phenotypic variation, where a subset of 'contingency' genes of viruses, bacteria and parasites hypermutate, allowing rapid adaptation to hostile or changing environments. A fundamental feature of antigenic variation is its link with the population dynamics of trypanosomes within the single host. Antigenic variants appear hierarchically within the mammalian host, with a mixture of order and randomness. The underlying mechanisms of this are not understood, although differential VSG gene activation may play a prominent part. Trypanosome antigenic variation has evolved a second arm in which the infective metacyclic population in the tsetse fly expresses a defined mixture of VSGs, although again each trypanosome expresses a single VSG. Differential VSG expression enhances transmission to new hosts, in the case of bloodstream trypanosomes by prolonging infection, and in the metacyclic population by generating diversity that may counter existing partial immunity in reservoir hosts. Antigenic variation employs a huge repertoire of VSG genes. Only one is expressed at a time in bloodstream trypanosomes, as a result of transcription being restricted to a set of about 20 bloodstream expression sites (BESs), which are at chromosome telomeres. Only one BES is active at a time, probably through transcriptional elongation being inhibited in the silent BESs. Although transcriptional switching between BESs can effect a VSG switch, the most prolific switch route involves homologous recombination of deoxyribonucleic acid, usually by the copying of a silent gene into a BES. Hierarchical expression of VSGs may be dictated in part by the different types of locus occupied by VSG genes. The VSG genes expressed in the metacyclic population also occupy telomeric sites, which appear to be derived from BESs but have a simpler structure. Their differential expression is achieved by random transcriptional activation; the detailed story requires direct study of the metacyclic stage itself. Available evidence suggests that the VSG originated as a surface receptor, and it can be proposed that a number of selective events have contributed to the evolution of the complex, multisystem phenomenon that antigenic variation has become.

Animals↗
PubMed2001

An update on antigenic variation in African trypanosomes.

African trypanosomes can spend a long time in the blood of their mammalian host, where they are exposed to the immune system and are thought to take advantage of it to modulate their own numbers. Their major immunogenic protein is the variant surface glycoprotein (VSG), the gene for which must be in one of the 20--40 specialized telomeric expression sites in order to be transcribed. Trypanosomes escape antibody-mediated destruction through periodic changes of the expressed VSG gene from a repertoire of approximately 1000. How do trypanosomes exclusively express only one VSG and how do they switch between them?

Animals↗
PubMed2001

Oesophagogastric cancer and surgical subspecialisation: how much work?

The aim of this study was to assess the volume of work generated by one consultant (out of a surgical unit of seven) managing all the upper gastrointestinal malignancy in a district general hospital serving a population of 480,000. A 3-year period was prospectively audited and the volume of out-patient and in-patient workload assessed with particular reference to resource management and levels of surgical staffing. Oesophagogastric cancer accounted for a mean of 61 new cases per year, representing 5.3% of new patient referrals. Assuming that a complex major operation for an oesophagogastric cancer equates to four intermediate equivalent values (IEVs), then this translated to a mean operative workload of 186 IEVs per year, representing 16.7% of the total elective operative workload of 1140 IEVs per year. Thus, all the oesophagogastric cancer was managed by a single firm as a speciality in a district general hospital over this 3-year period, though a relatively small proportion of new patients with oesophagogastric cancer translated into a significantly greater burden on the resources of consultant manpower and operating theatre time.

Esophageal Neoplasms↗
PubMed2000

Characterisation of the loci encoding the glutamic acid and alanine rich protein of Trypanosoma congolense.

We have characterised the organisation of genes encoding the glutamate and alanine rich protein (GARP) surface coat of the procyclic and epimastigote stages of Trypanosoma congolense in the tsetse fly. The GARP genes are arranged at two, possibly physically linked, loci, one of which exhibits allelic variation. One locus contains a single GARP gene, whilst both alleles of the other have a large tandem array of polycistronically transcribed GARP genes. Sequence analysis has revealed that there are very few coding differences between different GARP genes. A sequence related to the Trypanosoma brucei expression site associated gene 4 (encoding a transmembrane protein with a cytoplasmic adenylate cyclase domain) has been identified within a region at the downstream flank of one locus. There is no evidence that, within the single trypanosome, GARP genes are as diverse as the procyclin genes that encode a corresponding coat in T. brucei.

Amino Acid Sequence↗
PubMed1999

A role for RAD51 and homologous recombination in Trypanosoma brucei antigenic variation.

Antigenic variation is an immune evasion strategy used by African trypanosomes, in which the parasites periodically switch the expression of VSG genes that encode their protective variant surface glycoprotein coat. Two main routes exist for VSG switching: changing the transcriptional status between an active and an inactive copy of the site of VSG expression, called the bloodstream VSG expression site, or recombination reactions that move silent VSGs or VSG copies into the actively transcribed expression site. Nothing is known about the proteins that control and catalyze these switching reactions. This study describes the cloning of a trypanosome gene encoding RAD51, an enzyme involved in DNA break repair and genetic exchange, and analysis of the role of the enzyme in antigenic variation. Trypanosomes genetically inactivated in the RAD51 gene were shown to be viable, and had phenotypes consistent with lacking functional expression of an enzyme of homologous recombination. The mutants had an impaired ability to undergo VSG switching, and it appeared that both recombinational and transcriptional switching reactions were down-regulated, indicating that RAD51 either catalyzes or regulates antigenic variation. Switching events were still detectable, however, so it appears that trypanosome factors other than RAD51 can also provide for antigenic variation.

Amino Acid Sequence↗
PubMed1999

Identification of promoter elements of parasite nematode genes in transgenic Caenorhabditis elegans.

Transformation of the free-living nematode Caenorhabditis elegans with promoter/reporter gene constructs is a very powerful technique to examine and dissect gene regulatory mechanisms. No such transformation system is available for parasitic nematode species. We have exploited C. elegans as a heterologous transformation system to examine activity and specificity of parasitic nematode gene promoters. Using three different parasite promoter/lac Z reporter constructs strict tissue-specific expression is observed. Upstream sequences of the Haemonchus contortus gut pepsinogen gene pep-1 and cysteine protease gene AC-2 direct expression exclusively in gut cells, while promoter sequence of the Ostertagia circumcincta cuticular collagen gene colost-1 directs hypodermal-specific expression. Mutation analysis indicates that AC-2 promoter function is dependent on a GATA-like motif close to the translation start site, similar to our findings with the C. elegans cpr-1 cysteine protease gene. While the spatial expression of these parasite promoters in C. elegans correlates with their expression in the parasite, the exact timing of expression does not. This suggests that regulatory mechanisms influencing the timing of expression may have evolved more rapidly than those controlling spatial expression of structural genes.

Animals↗
PubMed1999

A structural and transcription pattern for variant surface glycoprotein gene expression sites used in metacyclic stage Trypanosoma brucei.

African trypanosomes first express the variant surface glycoprotein (VSG) at the metacyclic stage in the tsetse fly vector, in preparation for transfer into the mammal. Metacyclic (M)VSGs comprise a specific VSG repertoire subset and their expression is regulated differently from that of bloodstream VSGs, involving exclusively transcriptional regulation during the life cycle. To identify basic structural and functional features that may be common to MVSG telomeric transcription units, we have characterized the anatomy and transcription of the telomere containing the ILTat 1.61 MVSG gene. This telomere contains pseudogenes of the ESAG1 and ESAG9 families found in bloodstream VSG transcription units. The 1.61 MVSG occupies a monocistronic transcription unit and is transcriptionally controlled through the life cycle. The 1.61, and also the 1.22, MVSG transcription initiation site sequences resemble eukaryotic initiator elements. Sequence comparison reveals that four out of five characterized MVSG expression sites have a conserved region 2.0-4.7 kb long upstream of the MVSG. In some cases, this region contains not only the transcription initiation site that we have observed to be active in fly-transmitted trypanosomes but also, upstream, another sequence, described elsewhere as a 'putative promoter' for the MVAT set of M/VSGs (Nagoshi YL, Alarcon CM, Donelson JE. A monocistronic transcript for a trypanosome variant surface glycoprotein, Mol Biochem Parasitol 1995;72:33-45). In fly-transmitted trypanosomes, the latter element is transcriptionally silent. Our analysis of the structure of MVSG telomeres suggests that metacyclic expression sites arose from bloodstream expression sites.

Animals↗
PubMed1999

ELT-3: A Caenorhabditis elegans GATA factor expressed in the embryonic epidermis during morphogenesis.

We have identified a gene encoding a new member of the Caenorhabditis elegans GATA transcription factor family, elt-3. The predicted ELT-3 polypeptide contains a single GATA-type zinc finger (C-X2-C-X17-C-X2-C) along with a conserved adjacent basic region. elt-3 mRNA is present in all stages of C. elegans development but is most abundant in embryos. Reporter gene analysis and antibody staining show that elt-3 is first expressed in the dorsal and ventral hypodermal cells, and in hypodermal cells of the head and tail, immediately after the final embryonic cell division that gives rise to these cells. No expression is seen in the lateral hypodermal (seam) cells. elt-3 expression is maintained at a constant level in the epidermis until the 2(1/2)-fold stage of development, after which reporter gene expression declines to a low level and endogenous protein can no longer be detected by specific antibody. A second phase of elt-3 expression in cells immediately anterior and posterior to the gut begins in pretzel-stage embryos. elt-1 and lin-26 are two genes known to be important in specification and maintenance of hypodermal cell fates. We have found that elt-1 is required for the formation of most, but not all, elt-3-expressing cells. In contrast, lin-26 function does not appear necessary for elt-3 expression. Finally, we have characterised the candidate homologue of elt-3 in the nematode Caenorhabditis briggsae. Many features of the elt-3 genomic and transcript structure are conserved between the two species, suggesting that elt-3 is likely to perform an evolutionarily significant function during development.

Amino Acid Sequence↗
PubMed1999

Predominance of duplicative VSG gene conversion in antigenic variation in African trypanosomes.

A number of mechanisms have been described by which African trypanosomes undergo the genetic switches that differentially activate their variant surface glycoprotein genes (VSGs) and bring about antigenic variation. These mechanisms have been observed mainly in trypanosome lines adapted, by rapid syringe passaging, to laboratory conditions. Such "monomorphic" lines, which routinely yield only the proliferative bloodstream form and do not develop through their life cycle, have VSG switch rates up to 4 or 5 orders of magnitude lower than those of nonadapted lines. We have proposed that nonadapted, or pleomorphic, trypanosomes normally have an active VSG switch mechanism, involving gene duplication, that is depressed, or from which a component is absent, in monomorphic lines. We have characterized 88 trypanosome clones from the first two relapse peaks of a single rabbit infection with pleomorphic trypanosomes and shown that they represent 11 different variable antigen types (VATs). The pattern of appearance in the first relapse peak was generally reproducible in three more rabbit infections. Nine of these VATs had activated VSGs by gene duplication, the tenth possibly also had done so, and only one had activated a VSG by the transcriptional switch mechanism that predominates in monomorphic lines. At least 10 of the donor genes have telomeric silent copies, and many reside on minichromosomes. It appears that trypanosome antigenic variation is dominated by one, relatively highly active, mechanism rather than by the plethora of pathways described before.

Animals↗
PubMed1998

A trypanosome metacyclic VSG gene promoter with two functionally distinct, life cycle stage-specific activities.

In the mammalian bloodstream, African trypanosomes express the variant surface glycoprotein (VSG), continual switching of which allows evasion of the host immune response. Bloodstream VSG genes are transcribed from polycistronic bloodstream expression sites with promoters which are located 45-60 kb upstream. These promoters are not exclusively stage-regulated, being active in the insect midgut stage where VSG is not expressed. However, the metacyclic VSG (M-VSG) genes, a small subset activated when VSG synthesis begins in the metacyclic stage in the tsetse fly salivary glands, are transcriptionally activated specifically in that stage from promoters <3 kb upstream. Using deletion mapping and transient transfection, we show that the entire 1.22 M-VSG gene promoter region (171 bp) is required for full activity in metacyclic-derived trypanosomes. However, a subsidiary, bloodstream stage-specific activity is present in its 5' half which directs transcription initiation very close to the initiation site used in metacyclic-derived trypanosomes. Our results imply that the M-VSG gene promoter is longer and more complex than other VSG gene promoters.

Animals↗