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J N Baxter

Publications and source records attributed to J N Baxter.

At least 19 recordsLinked to original sources
PubMed2007

Immunohistochemical study of nuclear factor-kappaB activity and interleukin-8 abundance in oesophageal adenocarcinoma; a useful strategy for monitoring these biomarkers.

AIMS: To determine if immunohistochemistry (IHC) could be used to monitor nuclear factor-kappaB (NF-kappaB) activity in oesophageal adenocarcinoma and pre-malignant (Barrett's) oesophageal tissues, relative to normal oesophageal mucosa. The pro-inflammatory cytokine interleukin-8 (IL-8), a transcriptional target of NF-kappaB, was also studied to better understand NF-kappaB functionality; its RNA and protein levels were assessed in oesophageal tissues. METHODS: IHC was employed using an antibody against the nuclear localisation sequence (NLS) of the p65 subunit as well as an antibody against IL-8. To assess NF-kappaB function, changes in gene expression of NF-kappaB controlled genes (IL-8 and I-kappaB) were also assessed in the histological sequence using real-time PCR. More global expression changes were also studied using membrane arrays. RESULTS: IHC was effective at monitoring overall NF-kappaB activity and IL-8 abundance. This method also allowed NF-kappaB activity and IL-8 abundance to be pinpointed in specific cell types. There were significant increases in nuclear NF-kappaB activity and IL-8 abundance across the histological series. Gene expression analysis also showed consistent up-regulation of IL-8, confirming the IHC data and showing enhanced transcriptional NF-kappaB activity. I-kappaB (another NF-kappaB target) showed down-regulation in dysplastic and adenocarcinoma tissues. Down-regulation of I-kappaB gene expression may partly explain increased NF-kappaB activity. CONCLUSION: IHC, using antibodies against the NLS of p65, may be useful in monitoring overall NF-kappaB activity in oesophageal tissues. As IHC is amenable to high-throughput screening (whereas traditional electrophoretic mobility shift assay methods are not), this may lead to the development of a better screening tool for early cancer risk.

Adenocarcinoma↗
PubMed2007

Severe proctitis, perforation, and fatal rectal bleeding secondary to cytomegalovirus in an immunocompetent patient: report of a case.

Cytomegalovirus (CMV) infection is associated with significant morbidity and mortality in immunocompromised patients. In immunocompetent individuals, the infection is usually subclinical but it can sometimes be life threatening. We describe a case of fatal CMV proctitis in a 71-year-old man following an Ivor-Lewis esophagectomy. After surgery he developed renal failure, methicillin-resistant Staphylococcus aureus pneumonia, and acute respiratory distress syndrome. He recovered but developed melena and massive fresh rectal bleeding. Sigmoidoscopy revealed severe proctitis and a biopsy was consistent with ischemia. Despite undergoing a proctectomy he continued to bleed and died despite every effort. The final histological examination of the rectum revealed a CMV infection.

Adenocarcinoma↗
PubMed2006

Laparoscopic gastric bypass in a patient with malrotation of the intestine.

The increased prevalence of morbid obesity is associated with an increased prevalence of obesity co-morbidities. Bariatric surgery is generally the only effective treatment. Gastric bypasses are the most common bariatric operation in many countries, and more than half are performed laparoscopically. We discuss the challenges encountered in performing laparoscopic gastric bypass and cholecystectomy in a morbidly obese patient who was found to have malrotated small and large bowel when the procedure started. In the absence of past gastrointestinal symptoms and investigations, there is no way of diagnosing this anomaly preoperatively. However, when such a problem is posed at the time of surgery, it is safe to perform the planned operation if the surgeon has experience and skills in advanced laparoscopic techniques.

Adult↗
PubMed2006

Gastro-ileal stenosis and gastroparesis after a biliopancreatic diversion.

Biliopancreatic diversion (BPD) is a very effective bariatric operation particularly for super-obese patients (BMI > or = 50 kg/m(2)). We present the development of a stricture at the gastro-ileal anastomotic site, with subsequent dilatation and aperistalsis of the stomach in a female patient who had undergone a standard open Scopinaro BPD. The patient remained symptomatic and persisted in losing weight, despite endoscopic balloon dilatations of the stricture and surgical revision of the anastomosis. She finally underwent conversion to a standard Roux-en-Y proximal gastric bypass. We describe the development of the stricture after the use of the stapling gun, subsequent gastric dilatation and dysmotility.

Biliopancreatic Diversion↗
PubMed2005

Parathyroid carcinoma.

BACKGROUND: Parathyroid carcinoma is a rare malignancy affecting 0.5-5 per cent of all patients with primary hyperparathyroidism. This article reviews the literature on the pathogenesis, pathology, clinical features, diagnosis and management of parathyroid carcinoma. METHODS: A Medline search was performed and all relevant English language articles published between 1970 and 2005 were retrieved. The search words included 'parathyroid carcinoma', 'pathology', 'genetics', 'management' and 'radiotherapy'. Secondary references were obtained from key articles. RESULTS AND CONCLUSION: The exact aetiology of parathyroid carcinoma remains obscure. Recently, the HRPT2 gene has been implicated in its pathogenesis and may prove to be a genetic target in future. Surgical resection is the accepted 'gold standard'. There is now a growing consensus on the use of adjuvant radiotherapy as it has been shown to provide a survival benefit.

Combined Modality Therapy↗
PubMed2004

Generation of locus-specific probes for interphase fluorescence in situ hybridisation--application in Barrett's esophagus.

Despite the wide range of probes commercially available for interphase fluorescence in situ hybridisation (FISH), the supply of locus-specific probes is limited to genes or chromosomal regions commonly altered in genetic diseases or during carcinogenesis. Generation of these probes is therefore desirable to accommodate individual research requirements. Hence, we detail the methodology required to design and produce custom locus-specific interphase FISH probes for any human genomic region of interest and their application was illustrated in cytogenetic investigations of Barrett's tumourigenesis. Previously utilising FISH, we observed that Barrett's tissues demonstrated chromosome 4 hyperploidy [Gut 52 (2003) 623], but as centromeric probes were used in this analysis, it was not known if the whole chromosome was amplified. We consequently generated single-copy sequence probes for the 4p16.3 and 4q35.1 subtelomeric loci. Multicolour FISH was subsequently performed on interphase preparations originating from patients with Barrett's esophagus at varying histological grades, thus demonstrating the whole region of chromosome 4 was amplified within the tissues. Additionally, probes for the DNA methyltransferase genes were produced to determine if gene dosage alterations were responsible for increasing methylation activity during Barrett's neoplastic progression. No significant alterations at the DNMT1 and DNMT3a loci were detected. An increased copy number of these genes is therefore not the basis for the hypermethylation commonly observed in this premalignant lesion.

Adenocarcinoma↗
PubMed2003

The bile acid deoxycholic acid (DCA) at neutral pH activates NF-kappaB and induces IL-8 expression in oesophageal cells in vitro.

Barrett's oesophagus patients accumulate chromosomal defects during the histological progression to cancer, one of the most prominent of which is the amplification of the whole of chromosome 4. We aimed to study the role that the transcription factor NF-kappaB, a candidate cancer- promoting gene, present on chromosome 4, plays in Barrett's oesophagus, using OE33 cells as a model. Specifically, we wanted to determine if NF-kappaB was activated by exposure to bile acid (deoxycholic acid) in oesophageal cells. We employed pathway specific cDNA microarrays and real-time PCR, to first identify bile acid induced genes and specifically to investigate the role of NF-kappaB. An NF-kappaB reporter system was used, as well as an inhibitor of NF-kappaB (pyrrolidine dithiocarbamate) to confirm the activation of NF-kappaB by bile. We show that physiological levels of DCA (100-300 microM) were capable of activating NF-kappaB in OE33 cells and inducing NF-kappaB target gene expression (particularly IkappaB and IL-8). Other gene expression abnormalities were also shown to be induced by DCA. Importantly, preliminary experiments showed that NF-kappaB activation by bile occurred at neutral pH, but not at acid pH. Acidic bile did however cause over-expression of the c-myc oncogene, as reported previously. Hence, we present data showing that NF-kappaB may be a key mediator of carcinogenesis in bile exposed Barrett's tissues. In addition, neutral bile acids appear to play a significant part in reflux induced gene expression changes. We postulate that the activation of the survival factor NF-kappaB by bile may be linked to the previous cytogenetic data from our laboratory showing the amplification of NF-kappaB's chromosome (chromosome 4), during Barrett's cancer progression. Hence chromosome 4 amplification may provide a survival mechanism for bile exposed oesophageal tissues via NF-kappaB.

Adenocarcinoma↗
PubMed2003

Characterisation of p53 status at the gene, chromosomal and protein levels in oesophageal adenocarcinoma.

p53 mutations and loss of heterozygosity have been commonly associated with oesophageal adenocarcinoma. In this investigation, the p53 status of a Welsh population of Barrett's-associated oesophageal adenocarcinomas were fully characterised at the gene sequence, chromosomal, mRNA and protein levels. In total, 31 tumours were examined for p53 gene sequence mutations using RFLP with sequencing, allelic loss of the gene was characterised by FISH, mRNA expression by p53 pathway signalling arrays and protein levels by p53 immunohistochemistry. In all, 9.6% of adenocarcinomas harboured p53 mutations, 24% displayed p53 allelic loss and 83% exhibited p53 protein accumulation. Point mutations and deletions of the gene did not coexist within the same samples. All samples containing p53 mutations also displayed positive immunostaining; however; in the majority of cases, p53 protein accumulation developed in the absence of mutations. The gene expression analysis demonstrated no differences in p53 and mdm-2 transcription levels between the p53 immunonegative and immunopositive samples, indicating other mechanisms underlie the proteins' overexpression. In conclusion, p53 mutations and deletions do not appear to be frequent events in oesophageal adenocarcinomas; however, abnormal accumulation of the protein is present in a vast majority of cases. P53 gene mutations are not the primary cause of protein overexpression--an alternative mechanism is responsible for the positive p53 immunohistochemistry detected.

Adenocarcinoma↗
PubMed2003

Detection of p53 mutations in precancerous gastric tissue.

Intestinal-type gastric cancer is preceded by gastritis and intestinal metaplasia. There is uncertainty regarding the stage at which genetic alterations in the p53 gene occur. Reactive oxygen species (ROS) may participate in the production of mutations and the inactivation of p53 is due to infection by the bacterium Helicobacter pylori. We have investigated whether alterations of the p53 gene can be detected in gastritis and intestinal metaplasia using the restriction site mutation assay. We also assessed the potential contribution of ROS to p53 inactivation using electron spin resonance spectroscopy (ESR) and correlated with the presence of H. pylori. In all, 35% of the gastritis samples and 45% of the intestinal metaplasia samples were found to contain mutations in exons 5-8 of the p53 gene. Electron spin resonance spectroscopy analysis showed a significant increase in free radical levels in gastritis samples compared with normal, intestinal metaplasia and cancer samples, suggesting that free radicals present in gastritis may contribute to p53 mutations. There was no significant difference in free radical levels between the H. pylori-positive and -negative groups. However, a small subpopulation of the H. pylori-negative patients had much higher levels of free radicals. This suggests a more prominent role for other factors in ROS production.

Acute Disease↗
PubMed2003

Early p53 mutations in nondysplastic Barrett's tissue detected by the restriction site mutation (RSM) methodology.

Barrett's oesophagus is a premalignant condition whose incidence is rising dramatically. Molecular markers are urgently needed to identify Barrett's patients at the highest risk of cancer progression. To this end, we have used a rapid molecular technique, restriction site mutation (RSM), to detect low-frequency mutations in the p53 tumour suppressor gene in premalignant Barrett's tissues of cancer-free patients. In total, 38 endoscopically diagnosed Barrett's patients with a range of histological stages of Barrett's progression, plus four control patients without Barrett's oesophagus, were analysed for early p53 mutations. Tissue samples taken from these patients (93 samples in total) were analysed for the presence of low-frequency p53 mutations at hotspot codons: 175, 213, 248, 249, 282. In total, 13 of the 38 Barrett's patients were shown to possess a p53 mutation in at least one sample (no mutations in the four control patients). Although no statistically significant associations were found, p53 mutations reflected histological progression in Barrett's patients with p53 mutations found in 30% of metaplasia patients (P=0.4) and low-grade dysplasia patients (P=0.33) and 45% of high-grade dysplasia patients (P=0.15). Detected p53 mutations were mainly GC to AT transitions at CpG sites.

Barrett Esophagus↗
PubMed2003

Chromosome 4 hyperploidy represents an early genetic aberration in premalignant Barrett's oesophagus.

BACKGROUND AND AIMS: Characterisation of the underlying molecular mechanisms that promote Barrett's progression may ultimately lead to identification of potential predictive genetic markers that classify patients' malignant risk. In an attempt to understand these causative pathways, fluorescence in situ hybridisation (FISH) was used in this study to determine when specific genetic alterations arise during Barrett's associated neoplastic progression. METHODS: Endoscopic cytology brushings were obtained from 28 patients with Barrett's metaplasia, 28 with dysplasia (20 low grade dysplasia (LGD) and eight with high grade dysplasia (HGD)), and seven with adenocarcinoma, together with paired control brushings from regions of normal proximal squamous cell epithelium. The exfoliated epithelial cells were washed and deposited onto slides. Probes specific for the centromeres of chromosomes 4, 8, 20, and Y, and locus specific probes for the tumour suppressor genes p16, p53, and Rb were subsequently hybridised. RESULTS: Aneuploidy was found early in progression, with metaplastic tissues displaying increased copy numbers of chromosomes 4 and 8. Chromosome 4 hyperploidy was found in 89%, 90%, 88%, and 100% of metaplasias, LGD, HGD, adenocarcinomas, respectively, while chromosome 8 hyperploidy occurred in 71%, 75%, 100%, and 100% of patients with the respective staging. Loss of the p16 tumour suppressor gene also presented in metaplastic epithelium (7%) but most other genetic aberrations were only seen in HGD. CONCLUSIONS: Genetic instability arises well before dysplasia in Barrett's oesophagus, with chromosome 4 and 8 hyperploidy representing the earliest and most common alterations identified. As these aberrations are widespread at all the premalignant stages, there may be genes on chromosomes 4 and 8 that are involved in both the initiation and progression of Barrett's oesophagus.

Adenocarcinoma↗
PubMed2003

Laparoscopic fundoplication: learning curve and patient satisfaction.

AIMS: Laparoscopic fundoplication is now accepted as the optimal surgical option for the management of selected cases of gastro-oesophageal reflux disease. The principal aim of this study was to evaluate the learning curve experience of two consultant surgeons in the technique of laparoscopic fundoplication (LF). Additional variables assessed were total number of cases, preoperative investigations, conversion rate, duration of operation, ASA grade, morbidity, mortality, necessity of further procedures, and patient satisfaction rate. PATIENTS AND METHODS: Retrospective case-note analysis of all adult patients who underwent fundoplication under the care of two consultant general surgeons over a 3-year period from January 1997 to December 1999. RESULTS: A total of 61 patients were included, 31 males and 30 females, with a median age of 46 years (range, 21-73 years). Of the patients, 90% were either ASA 1 or 2. The mean time for which the 24-h pH < 4 was 20.5% (95% CI, 15.3-25.7). Of the 61 patients, 6 were operated on by open technique, for medical reasons and previous abdominal procedures. Out of the remaining 55 patients, 13 had to be converted (23.6%). Mean operating times were 120 min for LF, 85 min for open operation and 142 min for LF plus conversion. There was a significant decline in conversion rate with time (P < 0.002). Mortality was nil. One patient had a perforation of the cricopharyngeus secondary to insertion of a bougie. The mean length of hospital stay following the laparoscopic technique was 3.4 days compared to 8.7 days following the open technique. Overall, 59 patients (96%) were happy with the result, and the operation failed in 2 patients. Five patients (8%) needed endoscopic dilatation in the first few weeks after the operation. CONCLUSIONS: The results show that LF is a safe procedure, takes longer than open procedure, and has an acceptable morbidity. Experience with the technique reduces the need for conversion. The mean length of hospital stay is significantly less and there is a high level of patient satisfaction.

Adult↗
PubMed2002

Restriction enzymes in the analysis of genetic alterations responsible for cancer progression.

BACKGROUND: Molecular approaches are increasingly being employed to dissect the genetic changes accompanying tumour formation. These methods can often be confusing to the non-specialist as they include complex molecular steps. This can reduce the usefulness of such molecular data to clinicians. The authors aim to aid interpretation of molecular studies in general by presenting a comprehensive review of one molecular approach, i.e. the use of restriction enzymes in molecular studies of tumour development. METHOD: A review was made of the molecular studies that have employed restriction enzymes in gastrointestinal cancer research. These studies have used restriction enzymes to analyse point mutation induction, gene methylation status and the deletion of chromosomal loci. In addition, emphasis is placed on some of the important considerations for the molecular analysis of tumours that can affect the molecular data obtained. RESULTS: Restriction enzyme digestion has played, and continues to play, a major role in analysing the genetic changes in cancer. Many adaptations of basic restriction enzyme methodologies have enhanced the application of this approach in cancer genetics. CONCLUSION: The availability of 200 different restriction enzymes, each recognizing different sequences in DNA, has been invaluable in studying cancer genetics. It is hoped that current advances in protein engineering will facilitate the creation of novel restriction enzymes with tailor-made sequence specificities. This will further improve the applicability of restriction enzymes in cancer genetics.

DNA Methylation↗
PubMed2002

Genetic pathways involved in the progression of Barrett's metaplasia to adenocarcinoma.

BACKGROUND: The prediction of which patients with Barrett's metaplasia will develop cancer is difficult. Better genetic characterization of the condition may aid clinicians in devising more effective management and follow-up strategies. METHODS: A review was undertaken of the accumulated genetic data relating to the progression of squamous epithelium to adenocarcinoma. The normal functions of a number of cancer-related genes are described and an explanation is given of how alterations in these genes interfere with normal cell processes and lead to cancer. RESULTS AND CONCLUSION: The main genetic alterations accompanying the progression through dysplasia to adenocarcinoma were collated from 135 papers. The principal genetic changes implicated are the loss of p16 gene expression (by deletion or hypermethylation), the loss of p53 expression (by mutation and deletion), the increase in cyclin D1 expression, the induction of aneuploidy and the losses of the Rb, DCC and APC chromosomal loci.

Adenocarcinoma↗
PubMed2001

The detection of mutations induced in vitro in the human p53 gene by hydrogen peroxide with the restriction site mutation (RSM) assay.

We have analysed five mutation hotspots within the p53 gene (codons 175, 213, 248, 249, and 282) for mutations induced by hydrogen peroxide (H(2)O(2)), employing the restriction site mutation (RSM) assay. In addition, four other restriction sites covering non-hotspot codons of exons 5-9 of the p53 gene (codons 126, 153/54, 189 and the 3' splice site of exon 9) were analysed by the RSM assay for H(2)O(2)-induced mutations. Two cell types were concurrently analysed in this study, i.e. primary fibroblast cells and a gastric cancer cell line. Using the RSM assay, H(2)O(2)-induced mutations were only detected in exon 7 of the p53 gene. This was true for both cell types. These mutations were mainly induced in the Msp I restriction site (codon 247/248) and were predominantly GC to AT transitions (71%). Hence these GC to AT mutations were presumably due to H(2)O(2) exposure, possibly implicating the 5OHdC adduct, which is known to induce C to T mutations upon misreplication. Importantly, this study demonstrates that the RSM methodology is capable of detecting rare oxidative mutations within the hotspot codons of the p53 tumour suppressor gene. Hence, this methodology may allow the detection of early p53 mutations in pre-malignant tissues.

Binding Sites↗
PubMed2001

What effect does the duration of an inguinal hernia have on patient symptoms?

BACKGROUND: Despite the fact that repair of an inguinal hernia is one of the most common operations performed in general surgery, we have very little information on the natural history of the untreated hernia. The aim of this study was to evaluate the association between hernia symptoms and the duration the patients had their hernias before presentation to a surgical outpatient department for an elective or emergency operation. STUDY DESIGN: Data were gathered prospectively on a consecutive series of 699 patients admitted to two University Departments of Surgery for scheduled operations for an inguinal hernia. RESULTS: More than one third (267) of patients had their hernias for 1 year or longer, up to 65 years, before presentation. The most common symptom on presentation was pain or discomfort at the hernia site, which occurred in 457 (66%) patients. The cumulative probability of pain increased with time to almost 90% at 10 years. The hernia had become irreducible in 48 patients (6.9%). The cumulative probability of irreducibility increased from 6.5% (95% confidence interval 4% to 9%) at 12 months to 30% (95% confidence interval 18% to 42%) at 10 years. Leisure activities were affected in 29% of patients although only 13% of patients had to take time off work because of hernia-related symptoms. Only two patients (0.3%) required resection of infarcted bowel or omentum. CONCLUSIONS: Because many patients with an inguinal hernia are asymptomatic or mildly symptomatic, prospective clinical trials to assess the role of operations for such hernias are required.

Aged↗
PubMed2001

Somatostatin analogs in oncology: a look to the future.

In the past 15 years considerable advances have been made in our understanding of the molecular pharmacology of the mechanisms whereby somatostatin and its analogs mediate their direct and indirect antineoplastic effects. However, some important issues remain to be resolved, in particular the functional roles of the individual somatostatin receptors (SSTR-1-5) in tumor tissue and up- or downregulation of the hSSTRs with prolonged administration of somatostatin analogs. Answers to these questions are essential before we can maximize the therapeutic efficacy of somatostatin analogs in cancer. For example, is continuous administration more or less effective than intermittent therapy? The role of somatostatin analogs in the management of acromegaly and to a lesser extent neuroendocrine tumors is firmly established. The development of depot preparations of all 3 somatostatin analogs currently available for clinical use will undoubtedly improve both patient compliance and quality of life in patients with these conditions. There are only likely to be minor differences in the therapeutic efficacy of octreotide, lanreotide and vapreotide since all three analogs exert the majority of their antineoplastic effects via hSSTR-2 and hSSTR-5 and at the end of the day, price may well dictate which of these drugs oncologists use to provide symptomatic palliation of acromegaly and neuroendocrine tumors. Apart from some notable exceptions, somatostatin analog therapy has proven to be very disappointing in the management of advanced malignancy. Improvements in the management of solid tumors are likely to come only from combination therapy of somatostatin analogs with cytotoxic agents or other hormones in both advanced malignancy and in the adjuvant setting. Clinical trials with clear-cut objective outcome measures and health-related quality of life assessment are needed to evaluate the therapeutic efficacy of combination treatment in advanced malignancy and as an adjuvant to surgery. Particular attention needs to be paid to possible adverse effects of somatostatin analog therapy on the immune response to cancer. Further studies are required to establish whether the adverse effects of somatostatin analog therapy alone or in combination with cytotoxics or other hormones can be reversed with appropriate immunomodulatory treatment. Targeted somatostatin analog radiotherapy and chemotherapy are currently being investigated and the results of these studies are awaited with interest. Novel approaches using combinations of somatostatin analogs with antiangiogenic drugs or gene therapy are of particular interest and may provide important advances in the management of cancer in the not too distant future.

Animals↗