PubMed Health⌕ Search

Biomedical subjects

James Gallagher

Publications and source records attributed to James Gallagher.

11 recordsLinked to original sources
PubMed2006

The in vitro metabolism of irinotecan (CPT-11) by carboxylesterase and beta-glucuronidase in human colorectal tumours.

AIMS: Irinotecan (CPT-11) is a prodrug that is used to treat metastatic colorectal cancer. It is activated to the topoisomerase poison SN-38 by carboxylesterases. SN-38 is metabolized to its inactive glucuronide, SN-38 glucuronide. The aim of this study was to determine, the reactivation of SN-38 from SN-38 glucuronide by beta-glucuronidase may represent a significant pathway of SN-38 formation. METHODS: The production of SN-38 from irinotecan and SN-38 glucuronide (2.4, 9.6 and 19.2 microm) was measured in homogenates of human colorectal tumour, and matched normal colon mucosa from 21 patients). RESULTS: The rate of conversion of irinotecan (9.6 microm) was lower in tumour tissue than matched normal colon mucosa samples (0.30+/-0.14 pmol min-1 mg-1 protein and 0.77+/-0.59 pmol min-1 mg-1 protein, respectively; P<0.005). In contrast, no significant difference was observed in beta-glucuronidase activity between tumour and matched normal colon samples (4.56+/-6.9 pmol min-1 mg-1 protein and 3.62+/-2.95 pmol min-1 mg-1 protein, respectively, using 9.6 microm SN-38 glucuronide; P>0.05). beta-Glucuronidase activity in tumour correlated to that observed in matched normal tissue (r2>0.23, P<0.05), whereas this was not the case for carboxylesterase activity. At equal concentrations of irinotecan and SN-38 glucuronide, the rate of beta-glucuronidase-mediated SN-38 production was higher than that formed from irinotecan in both tumour and normal tissue (P<0.05). However, at concentrations that reflect the relative plasma concentrations observed in patients, the rate of SN-38 production via these two pathways was comparable. CONCLUSIONS: Tumour beta-glucuronidase may play a significant role in the exposure of tumours to SN-38 in vivo.

Antineoplastic Agents, Phytogenic↗
PubMed2004

The significance of "nonsignificance" in randomized controlled studies: a discussion inspired by a double-blinded study on St. John's wort (Hypericum perforatum L.) for premenstrual symptoms.

OBJECTIVES: This study aimed to investigate the efficacy of St. John's wort extract (SJW) as a treatment for premenstrual symptoms. DESIGN: The study was a randomized, double-blinded, placebo-controlled trial, with two parallel treatment groups. After a no-treatment baseline cycle, volunteers were randomized to either SJW or placebo for a further two menstrual cycles. SETTINGS/LOCATION: A postal trial conducted from The University of Reading, Berkshire, England. SUBJECTS: One hundred and sixty-nine (169) normally menstruating women who experienced recurrent premenstrual symptoms were recruited onto the study. One hundred and twenty-five (125) completed the protocol and were included in the analysis. INTERVENTIONS: Six hundred milligrams (600) mg of SJW (standardized to contain 1800 microg of hypericin) or placebo (containing lactose and cellulose). OUTCOME MEASURE: A menstrual diary was used to assess changes in premenstrual symptoms. The anxiety-related subgroup of symptoms of this instrument was used as the primary outcome measure. RESULTS: After averaging the effects of treatment over both treatment cycles it was found that there was a trend for SJW to be superior to placebo. However, this finding was not statistically significant. CONCLUSION: The possibility that this nonsignificant finding resulted from insufficient statistical power in the study, rather than a lack of efficacy of SJW, is discussed. Following this discussion the recommendation is made that, in future, similar studies should be powered to detect a minimum clinically relevant difference between treatments.

Adult↗
PubMed2004

A practical approach to a multi-level analysis with a sparse binary outcome within a large surgical trial.

OBJECTIVES: To assess the potential source of variation that surgeon may add to patient outcome in a clinical trial of surgical procedures. METHODS: Two large (n = 1380) parallel multicentre randomized surgical trials were undertaken to compare laparoscopically assisted hysterectomy with conventional methods of abdominal and vaginal hysterectomy; involving 43 surgeons. The primary end point of the trial was the occurrence of at least one major complication. Patients were nested within surgeons giving the data set a hierarchical structure. A total of 10% of patients had at least one major complication, that is, a sparse binary outcome variable. A linear mixed logistic regression model (with logit link function) was used to model the probability of a major complication, with surgeon fitted as a random effect. Models were fitted using the method of maximum likelihood in SAS. RESULTS: There were many convergence problems. These were resolved using a variety of approaches including; treating all effects as fixed for the initial model building; modelling the variance of a parameter on a logarithmic scale and centering of continuous covariates. The initial model building process indicated no significant 'type of operation' across surgeon interaction effect in either trial, the 'type of operation' term was highly significant in the abdominal trial, and the 'surgeon' term was not significant in either trial. CONCLUSIONS: The analysis did not find a surgeon effect but it is difficult to conclude that there was not a difference between surgeons. The statistical test may have lacked sufficient power, the variance estimates were small with large standard errors, indicating that the precision of the variance estimates may be questionable.

Humans↗
PubMed2003

Endovascular stent-graft placement for nonaneurysmal infrarenal aortic rupture: a case report and review of the literature.

Penetrating atheromatous ulceration of the infrarenal aorta is a rare entity. There are few reported cases of this lesion, and most of the published data is in regards to the thoracic aorta. Spontaneous rupture of a nonaneurysmal noninfected atherosclerotic infrarenal aorta is a rare event. We report the eleventh case of this occurrence and present the first reported case of endovascular stent-graft placement in treating this entity. We review the literature regarding ulcerative disease of the aorta and specifically discuss the published data on spontaneous rupture of the nondilated, noninfected infrarenal aorta secondary to penetrating atheromatous ulceration.

Aged↗
PubMed2002

Efficacy and toxicity of adjuvant chemotherapy in elderly patients with colon carcinoma: a 10-year experience of the Geisinger Medical Center.

BACKGROUND: Although the benefit from adjuvant chemotherapy has been established clearly in patients with Stage III colon carcinoma, the degree to which elderly patients with colon carcinoma can tolerate such therapy generally has remained unknown. METHODS: The authors reviewed all patients in their Tumor Registry with Stage II and Stage III adenocarcinoma of the colon who underwent potentially curative resection for their disease at the Geisinger Medical Center between January 1990 and September 2000. One hundred twenty patients underwent complete resection of their colon carcinoma and received 5-fluorouracil-based (5-FU) adjuvant chemotherapy. RESULTS: The 5-year disease free survival rate for patients age > or =65 years (Group A) was 70% compared with 56% for patients age < 65 years (Group B) (P = 0.085). The 5-year overall survival rate for patients in Group B was 77% compared with 62% for the patients in Group A (P = 0.143). In a Cox regression model, age was not a predictor of disease free survival (P = 0.633) or overall survival (P = 0.900) when it was analyzed as a continuous variable. Only 19 patients were age > 75 years, and the disease free and overall survival rates for this group were similar but were underpowered compared with the rates for the patients ages between 65-75 years. When gender and disease stage were included in the model, age remained a nonsignificant variable (P = 0.400 for disease free survival; P = 0.615 for overall survival). Nine of 56 patients in Group A (16%) experienced Grade 3-4 toxicity compared with 14 of 64 patients in Group B (22%) (P = 0.420). The lack of a correlation between toxicity and age was maintained after controlling for disease stage and patient gender (P = 0.343). There were no correlations between preoperative carcinoembryonic antigen level, tumor grade, or lymph node involvement and patient age (P = 0.258, P = 0.256, and P = 0.519, respectively). CONCLUSIONS: Elderly patients with Stage II and Stage III colon carcinoma benefit from 5-FU-based adjuvant therapy without a significant increase in toxicity compared with their younger counterparts. Adjuvant chemotherapy should be presented to elderly patients with high-risk, resected colon carcinoma. The data regarding age cannot be generalized to patients age > 75 years.

Adenocarcinoma↗
PubMed2002

Molecular pathogenesis of primary hyperparathyroidism.

This article will primarily focus on the molecular pathogenesis of common, sporadic (nonfamilial) parathyroid adenomas; two genes currently have established roles in the development of these tumors. The cyclin D1/PRAD1 gene was identified as a clonally activated oncogene in parathyroid adenomas and has subsequently been established as a major contributor to human neoplasia. Overexpression of cyclin D1, a key regulator of the cell cycle, has been implicated in the pathogenesis of 20-40% of sporadic parathyroid adenomas. That such cyclin D1 overexpression indeed constitutes a stimulus to excessive parathyroid cell proliferation has been confirmed experimentally by the development of a transgenic mouse model with parathyroid-targeted overexpression of cyclin D1. Parathyroid hormone (PTH)-cyclin D1 transgenic mice develop parathyroid hypercellularity, biochemical hyperparathyroidism, and a shifted in vivo parathyroid-calcium setpoint; these mice constitute an animal model of human hyperparathyroidism in which aspects of tumorigenesis, parathyroid secretory setpoint control, and the pathophysiology of the chronic hyperparathyroid state can be further investigated. The MEN1 tumor suppressor is the only other gene to date with an established role in the pathogenesis of sporadic parathyroid adenomatosis. Specific clonal alterations involving somatic mutation and/or deletion of both MEN1 alleles have been demonstrated in about 15-20% of sporadic parathyroid adenomas. Allelic losses on 11q occur in roughly twice this number of adenomas, raising the still-unresolved possibility that an additional tumor suppressor gene on 11q may be the functional target of many of these acquired deletions. A mouse model of MEN1 deficiency causes a phenotype that includes parathyroid hypercellularity albeit unaccompanied by biochemical hyperparathyroidism, and additional mouse models in which menin deficiency is targeted to the parathyroids will likely provide additional important insights. The MEN1 gene product menin may have a role in transcriptional regulation involving JunD; several other menin-interacting proteins have also been identified. The in vivo mechanism of menin's actions, with special attention to its role as a parathyroid oncosuppressor, will be important to establish, as will the potential interrelationships between these pathways and those involving cyclin D1. A number of genes, put forth as candidate tumor suppressors based on their genomic locations, roles in familial disease, and/or other relevant biological functions, have been examined for pathogenetic mutations in sporadic parathyroid tumors with negative results; these include the calcium-sensing receptor protein (CaR), vitamin-D receptor (VDR), and RET. However, the CaR, which when partially or markedly deficient because of germline mutation can cause familial hypocalciuric hypercalcemia or neonatal severe hyperparathyroidism, must still be considered as having a potentially important secondary role in the manifestations of sporadic parathyroid tumors. Future goals include identifying additional parathyroid oncogenes and tumor suppressor genes; exploiting tools of complex trait genetics to ascertain whether development of "sporadic" hyperparathyroidism might be influenced by predisposing polymorphic alleles in the population; obtaining molecular insights into the relationship between proliferative and hormone regulatory abnormalities of hyperparathyroidism; and obtaining molecular insights into the observed association of parathyroid neoplasia with exposure to ionizing irradiation and with the postmenopausal state.

Adenoma↗
PubMed1998

Chemical Nuclease Activity of 1,10-Phenanthroline-Copper. Isotopic Probes of Mechanism.

The chemical nuclease 1,10-phenanthroline-copper cleaves DNA by oxidative attack on the deoxyribose moiety yielding 3'- and 5'-phosphomonoesters, free purine and pyrimidine, and 5-methylenefuranone as stable products. Kinetic isotope effects associated with deuterium substitution have been measured in an attempt to analyze the chemical mechanism of the scission reaction. A kinetic isotope effect of 2.7 is observed with completely perdeuterated DNA, which is substituted in the oxidatively sensitive deoxyribose moiety as well as in the bases. Surprisingly, no isotope effect is found upon cleavage of DNA deuterated in the thymidines at either C-1', C-2',2", or C-4', all positions from which hydrogen is lost during the course of the reaction, by either the 2:1 or the 1:1 1,10-phenanthroline-cuprous complexes. These results suggest that perdeuteration of DNA alters the ligand binding and/or conformational flexibility of the nucleic acid.

Journal Article↗
PubMedDate not supplied

Arterial vascular conduits in adult orthotopic liver transplant recipients.

BACKGROUND: Vascular conduits may be required to gain arterial inflow to the donor hepatic artery in orthotopic liver transplantation. METHODS: From January 1986 to December 2003, arterial conduits were required in 31/582 (5.3%) adult liver transplant procedures. RESULTS: Indications for the conduit included recipient hepatic artery problems (20); hepatic artery thrombosis previous allograft (7) and other (4). The conduits used in 28/31 cases (90%) were deceased donor iliac arteries and the remainder prosthetic grafts. Patients requiring conduits were more likely to be already hospitalized (P = 0.038) or undergoing a retransplant procedure (P = 0.001) than patients not requiring conduits. Both sepsis and haemorrhage caused death in 8/31 (26%) patients requiring conduits versus 42/551 (7.6%) patients not requiring conduits. Death from thrombosis of the iliac artery conduit occurred in two cases and from bacterial infection of a prosthetic conduit in one case. For retransplant procedures, allograft loss was seen in 11/13 (84%) conduit cases versus 11/28 (39%) non-conduit cases (P = 0.016). Overall allograft survival was significantly lower in the conduit cases than in the non-conduit cases (P = 0.0001), with 12/31 (39%) allografts being lost within the first 3 months post-transplantation for the conduit cases. CONCLUSION: Arterial vascular conduits are more commonly required in adult liver transplant recipients who are hospitalized or undergoing retransplant procedures. Allograft survival is poorer in the conduit cases and is associated with complications, particularly sepsis and haemorrhage, following retransplantation procedures.

Adolescent↗
PubMedDate not supplied

Clinical impact of chronic renal insufficiency on endovascular aneurysm repair.

Endovascular aneurysm repair of abdominal aortic aneurysms has become a viable alternative to open repair. A significant proportion of this patient population has chronic renal insufficiency. The surgical outcomes associated with endovascular repair in 342 patients, with and without chronic renal insufficiency, are reported. Perioperative mortality, length of admission, length of intensive care unit admission, and rates of acute renal failure, congestive heart failure, myocardial infarction, conversion to open surgery, progression to hemodialysis, and incidence of endoleaks were retrospectively reviewed and analyzed. Endovascular repair demonstrated higher rates of acute renal failure, longer length of stay, and longer intensive care unit admissions in patients with chronic renal insufficiency. Patients with severe renal dysfunction demonstrated markedly elevated mortality and morbidity. These results indicate that chronic renal insufficiency is not an absolute contraindication to endovascular repair in patients with moderate renal dysfunction, but patients with severe renal dysfunction perform poorly after aortic reconstruction.

Acute Kidney Injury↗
PubMedDate not supplied

Endovascular abdominal aortic aneurysm repair at hartford hospital: a six year experience.

INTRODUCTION AND OBJECTIVES: Endograft repair of abdominal aortic aneurysms (AAA) has become a viable alternative to open surgical repair in the last decade. We report here our experience and analysis of the surgical outcomes associated with endograft AAA repair. METHODS: Patients suffering from significant abdominal aortic aneurysms (> 5cm in diameter) underwent endovascular repair. We report our experience with 342 consecutive patients from June 1998 to December 2004. Outcomes such as perioperative mortality, length of admission, length of ICU admission, operative blood loss, rates of transfusion postoperatively, rates of postoperative myocardial infarction (MI), rates of lower extremity ischemia, rates of conversion to open surgery, and the incidence of postoperative endoleaks were reviewed and analyzed. These results were compared to our patients undergoing open AAA repair during the same time period. Differences in the rates of perioperative mortality (2.0% vs 5.3%, NS) were not significant. However, the length of admission (4.8 vs 11.6 days, P=<0.001), length of ICU admission (0.6 vs 3.8 days, P=<0.001), blood transfusion (0.27 vs 1.83 units, P=<0.001), rates of postoperative MI (0.9% vs 5.0%, P=<0.001), and the incidence of postoperative renal insufficiency (4.1% vs 22.2%, P=<0.001) were superior in our endovascular group as compared to our open subset. In addition, most of our results were comparable to those results reported in recent major trials of endograft AAA repair. CONCLUSIONS: Endograft repair of AAA demonstrated superior outcomes when compared to our patients undergoing open AAA repair. However, these results must be weighed against the risk of endoleaks, secondary interventions, and routine radiographic surveillance required for the endovascular approach.

Aged↗