PubMed Health⌕ Search

Biomedical subjects

B M Ryan

Publications and source records attributed to B M Ryan.

At least 19 recordsLinked to original sources
PubMed2006

Survivin expression in breast cancer predicts clinical outcome and is associated with HER2, VEGF, urokinase plasminogen activator and PAI-1.

BACKGROUND: Survivin, a novel inhibitor of apoptosis, is one of the most cancer-specific proteins identified to date. In this study we (a) evaluated the association between survivin and HER2, vascular endothelial growth factor (VEGF) and uPA/PAI-1 expression and (b) defined its effect on clinical outcome in a large breast cancer patient cohort. PATIENTS AND METHODS: Survivin expression was measured by ELISA in primary breast cancer tissue extracts from 420 patients with long-term clinical follow-up. RESULTS: Survivin was detected in 378 (90%) of the 420 primary breast cancer cases. Increased survivin levels were significantly associated with high nuclear grade (P < 0.0001), negative hormone receptor status (P = 0.0028), HER2 overexpression (P = 0.0094), VEGF expression (P < 0.0001), high uPA (P = 0.0002) and PAI-1 levels (P = 0.0002). Using the 25th percentile (1.4 ng/mg) as a cut-off point, patients expressing elevated survivin had a significantly worse disease-free survival (DFS: P = 0.0007, RR 1.97) and overall survival (OS: P = 0.0009, RR 2.11) compared with patients expressing lower levels of survivin. In multivariate analysis, this prognostic value of survivin was independent of both traditional and novel clinicopathologic factors for both DFS (P = 0.0076, RR 1.72) and OS (P = 0.0155, RR 1.76). CONCLUSIONS: The independent prognostic relevance of survivin, when combined with previous data from model systems implicating survivin in the inhibition of apoptosis, suggests that survivin may be a suitable target for future therapeutic strategies.

Breast Neoplasms↗
PubMed2005

Cirrhosis related chylous ascites successfully treated with TIPS.

We describe a patient with chylous ascites, who was extensively investigated for the cause. No malignant or lymphatic disease could be found, but a liver biopsy revealed liver cirrhosis. The chylous ascites was unsuccessfully treated with a sodium restriction diet, diuretics and a medium chain triglyceride diet. After the placement of a transjugular intrahepatic portosystemic shunt the ascites disappeared.

Aged↗
PubMed2004

Effect of antitumour necrosis factor-alpha therapy on bone turnover in patients with active Crohn's disease: a prospective study.

BACKGROUND AND AIMS: Patients with Crohn's disease are at increased risk of osteoporosis. Disease activity and circulating proinflammatory cytokines are thought to play a role in this process. Infliximab, a chimaeric antitumour necrosis factor-alpha antibody is effective in the treatment of Crohn's disease. The aim of this study was to investigate the impact of treatment with infliximab on bone turnover in Crohn's disease patients. METHODS: This was a prospective trial. Twenty-four patients with active Crohn's disease were treated with infliximab (5 mg/kg). Bone markers were assayed pre- and post-treatment. Bone formation was measured using serum bone-specific alkaline phosphatase and total osteocalcin and bone resorption using serum N-telopeptide cross-linked type 1 collagen. RESULTS: Infliximab therapy caused a significant increase in both markers of bone formation in patients with active Crohn's disease. No significant change in the bone resorption marker serum N-telopeptide cross-linked type 1 was found. CONCLUSION: Infliximab therapy had a significant beneficial effect on bone metabolism in patients with active Crohn's disease. These findings further support the theory that active ongoing inflammation and high levels of circulating cytokines play a pivotal role in the pathogenesis of bone loss in patients with Crohn's disease.

Adult↗
PubMed2003

Aminosalicylates and colorectal cancer in IBD: a not-so bitter pill to swallow.

Inflammatory bowel disease (IBD) is associated with an increased risk of developing intestinal cancer at sites of chronic inflammation. Aminosalicylates, including both sulfasalazine and mesalamine, are the most commonly prescribed anti-inflammatory agents prescribed in IBD. On balance, the body of literature to date suggests that aminosalicylates confer some protection against the development of colonic neoplasia in patients with IBD and in a variety of models, including in the noninflamed gut. This latter observation implies that aminosalicylates may be of chemopreventive value in normal as well as IBD individuals. The current review examines and gives an overview of the evidence from a variety of sources, including epidemiological, in vivo and in vitro studies that have investigated the potential anticancer effects of aminosalicylates.

Aminosalicylic Acids↗
PubMed2003

A prospective study of circulating mutant KRAS2 in the serum of patients with colorectal neoplasia: strong prognostic indicator in postoperative follow up.

BACKGROUND AND AIMS: Mutant tumour derived DNA has been detected in the sera of colorectal cancer patients. We investigated if mutant serum KRAS2 was detectable preoperatively in a large group of patients with colorectal neoplasia. A prospective study of 94 patients who underwent putative curative resection for colorectal carcinoma (CRC) was performed to ascertain if serum mutant KRAS2 could be used postoperatively as a disease marker. METHODS: Preoperative sera from 78 patients were analysed (group A). Sera from 94 patients were obtained three monthly for up to three years during the postoperative period (group B). Codon 12 and 13 KRAS2 mutations were analysed in matched tumour and serum samples. RESULTS: In the preoperative group (group A), KRAS2 mutation was found in 41/78 (53%) tumours and in 32/78 (41%) preoperative sera. Of 41 tumour KRAS2 mutation positive cases, 31/41 (76%) had an identical serum mutation detectable. In group B, the postoperative follow up group, 60/94 cases were primary tumour KRAS2 mutation positive. Of these 60, 16/60 (27%) became persistently serum mutant KRAS2 positive postoperatively. Ten of 16 (63%) of these developed a recurrence compared with only 1/44 (2%) patients who remained serum mutant negative (odds ratio 71.7 (95% confidence interval 7.7-663.9; p=0.0000). None of 34 tumour mutation negative cases became serum mutant KRAS2 positive postoperatively, despite recurrence in 9/34 patients. The relative hazard of disease recurrence in postoperative serum mutant KRAS2 positive patients was 6.37 (2.26-18.0; p=0.000). CONCLUSIONS: Serum mutant KRAS2 can be detected preoperatively in all stages of colorectal neoplasia. Postoperatively, serum mutant KRAS2 is a strong predictor of disease recurrence, stronger even than Dukes' stage of disease, and thus shows potential for use in clinical practice as a marker of preclinical disease recurrence.

Aged↗
PubMed2003

Insurance problems among inflammatory bowel disease patients: results of a Dutch population based study.

BACKGROUND AND AIMS: The majority of patients with inflammatory bowel disease (IBD) have a normal life expectancy and therefore should not be weighted when applying for life assurance. There is scant literature on this topic. In this study our aim was to document and compare the incidence of difficulties in application for life and medical insurance in a population based cohort of IBD patients and matched population controls. METHODS: A population based case control study of 1126 IBD patients and 1723 controls. Based on a detailed questionnaire, the frequency and type of difficulties encountered when applying for life and medical insurance in matched IBD and control populations were appraised. RESULTS: In comparison with controls, IBD patients had an 87-fold increased risk of encountering difficulties when applying for life assurance (odds ratio (OR) 87 (95% confidence interval (CI) 31-246)), with a heavily weighted premium being the most common problem. Patients of high educational status, with continuous disease activity, and who smoked had the highest odds of encountering such problems. Medical insurance difficulties were fivefold more common in IBD patients compared with controls (OR 5.4 (95% CI 2.3-13)) although no specific disease or patient characteristics were identified as associated with such difficulties. CONCLUSIONS: This is the first detailed case control study that has investigated insurance difficulties among IBD patients. Acquiring life and medical insurance constituted a major problem for IBD patients in this study. These results are likely to be more widely representative given that most insurance companies use international guidelines for risk assessment. In view of the recent advances in therapy and promising survival data on IBD patients, evidence based guidelines for risk assessment of IBD patients by insurance companies should be drawn up to prevent possible discriminatory practices.

Adolescent↗
PubMed2002

Comparison of the bactericidal activities and post-antibiotic effects of the Des-F(6)-quinolone BMS-284756, levofloxacin, and ciprofloxacin against methicillin-susceptible and methicillin-resistant Staphylococcus aureus.

The bactericidal activities and post-antibiotic effects of BMS-284756 (T-3811ME), levofloxacin, and ciprofloxacin were evaluated against a methicillin-susceptible and a methicillin-resistant Staphylococcus aureus strain. Minimum inhibitory concentrations (MICs), minimum bactericidal concentrations, post-antibiotic effects, and post-antibiotic sub-MIC effects were determined and time-kill studies were performed for BMS-284756, levofloxacin, and ciprofloxacin. At 4-times and 10-times the MIC, time-kill kinetics over 3 h and over 24 h were similar for all three quinolones when effects were considered as multiples of the MIC. All three quinolones achieved a 3 log10 reduction in cfu/ml within 2 h. At 10-times the MIC, the post-antibiotic effects of BMS-284756, levofloxacin, and ciprofloxacin were 1.6-2.6 h for the methicillin-susceptible Staphylococcus aureus strain and 1.5-1.9 h for the methicillin-resistant Staphylococcus aureus strain. When actual concentrations were considered, BMS-284756 achieved results comparable to levofloxacin and ciprofloxacin at concentrations nearly 10-fold less. When relating the pharmacokinetic properties of the three quinolones to their in vitro activities, the resulting Cmax/MIC and AUC/MIC ratios were. respectively, 120-240.7 and 1,321.7-2,643 for BMS-284756, 22.8 and 190 for levofloxacin, and 5.9-11.9 and 54.8-109.6 for ciprofloxacin. The greater in vitro activity and favorable human pharmacokinetics of BMS-284756 may translate to improved clinical effectiveness of this agent compared to currently marketed quinolones.

Anti-Infective Agents↗
PubMed2001

A common p73 polymorphism is associated with a reduced incidence of oesophageal carcinoma.

The incidence of oesophageal adenocarcinoma is rising; to date, no susceptibility genes have been identified. p73, a novel p53 homologue, maps to chromosome 1p36, a region commonly deleted in oesophageal cancers. p73 shares some p53-like activity, but in addition, may also play a role in gastrointestinal epithelial inflammatory responses. A non-coding p73 polymorphism (denoted AT or GC) may be functionally significant. We investigated whether this polymorphism might play a role in the aetiopathogenesis of oesophageal cancer. This was a case-control, retrospective study. 84 cases of oesophageal cancer (25 squamous and 59 adenocarcinoma) and 152 normal population controls were genotyped for this polymorphism. Informative cases were examined for p73 LOH within the tumour. AT/AT homozygotes were significantly less prevalent in the oesophageal cancer population (1/84 = 1.2%) compared to controls (15/152 = 9.9%) (P < 0.02), corresponding to an odds ratio of 0.11 (95% C.I. 0.02-0.6, P < 0.02), or 9-fold reduced risk. Moreover, AT/AT homozygotes were significantly less frequent in the cancer population than would be expected under the Hardy-Weinberg hypothesis (P = 0.0099). LOH at the p73 locus was observed in 37.8% (14/37) of the AT/GC heterozygotes studied; in all cases there was loss of the AT allele. Our findings indicate that p73 AT/AT homozygotes appear to be protected against the development of oesophageal cancer. Clinically, this observation could have implications in aiding identification of high-risk Barrett's oesophagus patients.

Adenocarcinoma↗
PubMed2001

Relevance of folate metabolism in the pathogenesis of colorectal cancer.

The purpose of this review is to outline the principal mechanisms involved in folate metabolism and how they may relate to the pathogenesis of colorectal cancer (CRC). In recent years, mild folate depletion (low normal level) has been associated with an increased risk of developing certain cancers, in particular colorectal neoplasia. The epidemiologic and mechanistic evidence linking folate deficiency with carcinogenesis is reviewed, with a particular emphasis on colorectal neoplasia. Methylenetetrahydrofolate reductase (MTHFR) is a critical folate metabolizing enzyme, and a functional polymorphic variant of this enzyme, the so-called thermolabile variant, caused by a C677T transition in the MTHFR gene, is common in the general population. This review critically examines the evidence that suggests that carriers of this C677T variant may be at increased risk of developing colorectal neoplasia. Although folate depletion may predispose to the initiation of the neoplastic process, folate supplementation, on the other hand, might potentiate the progression of an already established early neoplastic clone (eg, a colorectal adenoma). This could have potential public health implications, given an increasingly widespread policy of folate supplementation of food staples.

Adenoma↗
PubMed2001

The methylenetetrahydrofolate reductase (MTHFR) gene in colorectal cancer: role in tumor development and significance of allelic loss in tumor progression.

BACKGROUND AND AIM: Folate deficiency predisposes to sporadic colorectal cancer (CRC). Methylenetetrahydrofolate reductase (MTHFR) is a critical folate-metabolising enzyme and a polymorphism at position 677 (C677T), is associated with reduced enzyme activity. We investigated whether this functional polymorphism modulates the risk of developing CRC. METHODS: This was a retrospective case-control study. 136 unselected cases of sporadic CRC and 848 normal population controls were genotyped for the MTHFR C677T polymorphism. Tumor tissue was genotyped to assess loss of heterozygosity (LOH). RESULTS: MTHFR CT heterozygotes had a significantly increased risk of developing CRC (53.7% of CRC cases vs 38.4% of controls), odds ratio 1.86 (95% CI 1.3-2.7, p < 0.005). No increased cancer risk was observed in TT homozygotes. The MTHFR 'T' allele frequency was significantly higher in the cancer group (0.3713) as compared to controls (0.2900, p < 0.008). LOH at the MTHFR locus was observed in 18% of informative cancers, with exclusive loss of the variant 'T' allele, in all cases. CONCLUSION: In this study of a homogenous northern European population, MTHFR CT heterozygotes had an almost two-fold increased risk of developing sporadic CRC. The exclusive pattern of MTHFR allele loss in cases of LOH, suggest that functional MTHFR activity within a tumor might play an important role in the survival and progression of a colonic neoplasm.

Adenocarcinoma↗
PubMed2001

Efflux in bacteria: what do we really know about it?

Efflux is the process in which bacteria transport compounds outside the cell which are potentially toxic, such as drugs or chemicals or compounds. Efflux pumps can be identified not only by biochemical, microbiological, or molecular means but with the availability of microbial genomic sequences, by the application of bioinformatics analysis of DNA sequences for key conserved structure motifs. Efflux has been identified as a relevant contributor to bacterial resistance in the clinic and is now recognised as one of the most important causes of intrinsic antibiotic resistance in bacteria, especially in Pseudomonas aeruginosa. With the recognition of efflux as a major factor in bacterial resistance, several companies have invested in the identification and development of bacterial efflux pump inhibitors. Among those, Microcide, Pfizer, Paratek and several academic laboratories are in the process of exploring efflux pump inhibitors from synthetic, natural products and peptidomimetics. Inhibiting bacterial efflux with a non-antibiotic inhibitor would restore activity of an antibiotic subject to efflux (similar to the use of beta-lactamase inhibitors to combat beta-lactamase production by bacteria). The feasibility of such an approach has been experimentally demonstrated in vitro and in vivo for efflux reversal of levofloxacin.

Bacteria↗
PubMed2000

Phenylsilsesquioxane fluid: developmental toxicity studies in rats and rabbits following oral administration.

Phenylsilsesquioxane fluid (PSF) is used widely in the personal care industry and is a common component of skin and oral care products. The potential developmental toxicity of PSF was evaluated in rats and rabbits. Groups of 25 sperm-positive Sprague-Dawley rats (Taconic Farms) and 15 sperm-positive New Zealand White rabbits (HRP) were administered dose levels of 50, 500, or 1000 mg/kg PSF in corn oil. Vehicle control groups of equal size were administered corn oil alone. Rats were dosed daily (5 ml/kg) on gestation d 6-15 and sacrificed on gestation d 20, while rabbits were dosed daily (1.5 ml/kg) on gestation d 6-18 and sacrificed on gestation d 29. The fetuses were removed by cesarean section and examined for gross external, visceral, cephalic, and skeletal anomalies. No treatment-related clinical signs of toxicity were observed. No marked effects upon maternal food consumption, body weight, body weight gain, or uterus or liver weight were detected. Fetal viability and body weight, as well as developmental endpoints, were unaffected by treatment. Accordingly, exposure of pregnant rats or rabbits to 50, 500, or 1000 mg/kg of PSF during the period of major organogenesis did not result in any biologically significant adverse or teratogenic effects in the dams or fetuses.

Administration, Oral↗
PubMed2000

Refractory celiac disease.

Celiac disease is a gluten-sensitive enteropathy, characterized by villous atrophy, which is reversed by gluten withdrawal. A minority of patients with celiac-like enteropathy are resistant to gluten-free diet, so-called refractory sprue, or unclassified sprue. Refractory sprue is a diagnosis of exclusion; all other causes of a celiac-like enteropathy must be eliminated before a diagnosis of refractory sprue can be made. Recent evidence suggests that refractory sprue comprises a heterogenous group of patients with diverse underlying causes. A small proportion of these patients seem to have an adult form of autoimmune enteropathy, characterized by the presence of antienterocyte antibodies. However, a larger group of patients with refractory sprue now seem to have a cryptic intestinal T-cell lymphoma, characterized by the presence of phenotypically abnormal, monoclonal intraepithelial lymphocytes, despite benign cytology. Current therapeutic options include nutritional support and immunosuppressive therapy, but response is variable. The prognosis of refractory sprue may be poor; patients may die of severe malabsorption, or through synchronous or metachronous development of an enteropathy-associated T-cell lymphoma. Based on this recent evidence, patients with refractory sprue should be screened for antienterocyte antibodies and have T-cell receptor and monoclonal antibody studies performed; this could facilitate identification of cases of adult-onset autoimmune enteropathy and those of cryptic T-cell lymphoma. Moreover, early recognition of the malignant nature of the intestinal infiltrate in some cases of refractory sprue could permit the development of novel chemotherapeutic regimens for this condition.

Autoimmune Diseases↗
PubMed2000

Evaluation of the developmental toxicity of 60 Hz magnetic fields and harmonic frequencies in Sprague-Dawley rats.

Experimental data suggest that exposure to the 50 and 60 Hz sinusoidal components of power-frequency magnetic fields (MFs) does not have an adverse impact on fetal development. However, the possible developmental toxicity of MF harmonics has not been investigated. This study was designed to determine whether exposure to 180 Hz MFs (third harmonic), alone or in combination with 60 Hz MFs, induces birth defects in Sprague-Dawley rats. Groups of sperm-positive dams (> or =20/group) were exposed for 18.5 h per day from gestation days 6 through 19 to (1) ambient MFs only (<0.0001 mT; sham controls); (2) 60 Hz MFs at 0.2 mT; (3) 180 Hz MFs at 0.2 mT; or (4) 60 Hz + 180 Hz MFs (10% third harmonic; total field strength = 0.2 mT). Litter size, litter weight, percentage live births, sex ratio, and number of resorption sites were determined for each dam, and gross external, visceral, cephalic and skeletal examinations were performed on all fetuses. MF exposure had no significant effects on litter size, litter weight, or fetal development. With the exception of common rib variants, the incidence of fetal anomalies was comparable in all groups. A small increase in the incidence of rib variants was seen in the group exposed to 60 Hz + 180 Hz MFs; however, the incidence of rib variants in this group was similar to that in historical controls from our laboratory. These data extend the existing database on developmental toxicity of MFs by demonstrating that exposure to 180 Hz MFs, either alone or superimposed on an underlying 60 Hz signal, does not induce biologically significant developmental toxicity. These data do not support the hypothesis that exposure to power-frequency MFs is an important risk factor for fetal development.

Animals↗
PubMed1999

Multigeneration reproductive toxicity assessment of 60-Hz magnetic fields using a continuous breeding protocol in rats.

Male and female reproductive functions have been proposed as possibly sensitive targets for the biological effects of 60-Hz (power frequency) magnetic fields (MF). However, experimental data relevant to this hypothesized association are very limited. In the present study, the "reproductive assessment by continuous breeding" design was used to identify possible effects of MF exposure on reproductive performance, fetal development, and early postnatal growth in rats. Groups of age-matched Sprague-Dawley rats (40 breeding pairs/group) were exposed continuously (18.5 hr per day) to linearly polarized, transient-free 60-Hz MF at field strengths of 0 Gauss (G; sham control), 0.02 G, 2.0 G, or 10.0 G. An additional group of 40 breeding pairs received intermittent (1 hr on/1 hr off) exposure to 10.0 G fields. F0 breeding pairs were exposed to MF or sham fields for 1 week prior to mating, during a 14-week period of cohabitation, and during a 3-week holding period after cohabitation. The duration of the cohabitation period was selected to be sufficient for the delivery of five litters in the sham control group. Pups from the final F1 litter from each breeding pair were exposed to MF or sham fields until sexual maturity, were cohabitated in MF or sham fields for 7 days with nonsiblings from the same exposure group, and were held in the MF or sham fields for 22 days to permit delivery of F2 pups for evaluation. No evidence of exposure-related toxicity was identified in any rat in the F0, F1, or F2 generations. Fetal viability and body weights in all litters of groups exposed to MF were comparable to those of sham controls. No significant differences between sham controls and MF-exposed groups were seen in any measure of reproductive performance (litters/breeding pair, percent fertile pairs, latency to parturition, litter size, or sex ratio) in either the F0 or F1 generation. Exposure of Sprague-Dawley rats to 60-Hz MF strengths of up to 10.0 G either during their peak reproductive period (F0) or during gestation and throughout their life span (F1) has no biologically significant effects on reproductive performance. These results do not support the hypothesis that exposure to pure, linearly polarized 60-Hz MF is a significant reproductive or developmental toxicant.

Animals↗
PubMed1998

A highly conserved intraspecies homolog of the Saccharomyces cerevisiae elongation factor-3 encoded by the HEF3 gene.

A paralog (intraspecies homolog) of the Saccharomyces cerevisiae YEF3 gene, encoding elongation factor-3, has been sequenced in the course of the yeast genome project, and identified by database searching; this gene has been designated HEF3. Bioinformatic and Northern blot analysis indicate that the HEF3 gene is not expressed during vegetative growth. Deletion of the HEF3 gene reveals no growth defects, nor any defects in mating or sporulation. A high copy 2 mu clone of HEF3 was constructed, and was shown to be unable to complement a null allele of yef3. Finally, an in vitro assay for ribosome-stimulated ATPase activity was performed with isogenic HEF3 and delta hef3 strains; no difference in biochemical activity could be detected in these strains. From these results, we conclude that the HEF3 gene does not encode a functional homolog of YEF3.

Adenosine Triphosphatases↗