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J Kerr

Publications and source records attributed to J Kerr.

At least 37 records · Page 2Linked to original sources
PubMed1998

No evidence for microsatellite instability from allelotype analysis of benign and low malignant potential ovarian neoplasms.

UNLABELLED: The genetic events that lead to the development of benign and low malignant potential (LMP) tumors from normal ovarian surface epithelium are not well understood. In contrast to invasive ovarian neoplasms, loss of heterozygosity (LOH) is not common in these tumors except on the X chromosome, but one report has suggested that an alternative genetic mechanism, microsatellite instability (MSI), might be an important pathogenic mechanism for LMP ovarian tumors. OBJECTIVE: To determine the frequency of MSI in LMP tumors and to detect novel regions of LOH in benign and LMP ovarian tumors. METHODS: Sixty-nine microsatellite markers were analyzed in 23 benign and 31 LMP ovarian tumors. RESULTS: No evidence of MSI was found in any of the tumors studied, nor were any novel regions of LOH identified. CONCLUSIONS: This suggests that new approaches may be necessary to understand the genetic basis of benign and LMP ovarian neoplasms since neither LOH nor MSI appears to play a major role.

Cystadenoma↗
PubMed1998

A comparison of ocular blood flow in untreated primary open-angle glaucoma and ocular hypertension.

PURPOSE: To compare ocular blood flow in untreated primary open-angle glaucoma and ocular hypertension using scanning laser Doppler flowmetry and pulsatile ocular blood flow. METHOD: Fourteen ocular hypertensive subjects and 10 patients with primary open-angle glaucoma were matched for intraocular pressure, mean arterial blood pressure, and age. They had scanning laser Doppler flowmetry images taken centered on the optic disk. Pulsatile ocular blood flow readings were performed in sitting, standing, and supine positions. No subjects were receiving topical antiglaucoma treatment, systemic beta-blockers, calcium antagonists, or nitrates at the time of measurement. RESULTS: Laser Doppler flowmetry results showed a significant reduction in blood velocity, volume, and flow at the lamina cribrosa and the temporal neuroretinal rim in glaucoma compared to ocular hypertension (P < .05). No difference was found between the groups at the nasal neuroretinal rim or the nasal juxtapapillary retina. There was a significant increase in minimum velocity (P = .03) at the temporal juxtapapillary retina in glaucoma compared to ocular hypertension. The ocular pulse amplitude, pulse volume, and pulsatile ocular blood flow were significantly lower (P < .05) in the glaucoma group compared to ocular hypertension in sitting and standing positions. CONCLUSION: Having controlled for factors known to affect perfusion pressure, we found evidence of reduced ocular blood flow in primary open-angle glaucoma compared with ocular hypertension. Our findings indicate a reduction in choroidal and short posterior ciliary artery circulation in primary open-angle glaucoma. Whether these changes in blood flow are a cause or a consequence of glaucomatous optic atrophy is still unknown.

Aged↗
PubMed1998

Response bias in visual serial order memory.

The recency-to-primacy shift represents a major challenge for all theories that attempt to explain the effects of serial order on memory. At short retention intervals, strong recency and no primacy effects occur, but as the retention interval increases, recency is attenuated and primacy increases. In 2 experiments, 24 participants were presented with sets of 4 unfamiliar faces and were asked to state the serial position of a probe face after 0 or 10 s. The predicted recency-to-primacy shift was obtained with accuracy responses. However, the distribution of responses also showed that there was a change in response bias with retention interval. When this was corrected for, the recency-to-primacy shift was eliminated. Response bias is suggested as the underlying cause of the recency-to-primacy shift in this task.

Adult↗
PubMed1998

Male pelvic anatomy reconstructed from the visible human data set.

PURPOSE: To improve understanding of the male pelvic anatomy pertinent to urological surgery we performed computer generated, 3-dimensional reconstruction of the male pelvis from the Visible Human data set. MATERIALS AND METHODS: A total of 18 discrete anatomical structures, including the prostate, bladder, urethra, rectum and pelvic musculature, was segmented from the Visible Human cross-sectional data obtained from the National Library of Medicine. Using high speed computing and rendering software, 3-dimensional models of each structure were generated and assembled into composite figures. RESULTS: These reconstructions offer a revised view of pelvic anatomy as it has been traditionally depicted. The lateral surfaces of the levator ani muscle are oriented vertically in the pelvis and directly applied to the entire lateral surface of the prostate. The bladder rests primarily anterior to the prostate rather than directly above it, as has been commonly depicted. In the cross-sectional data and reconstructions the trigone and anterior fibromuscular stroma of the prostate appear as a single unit in continuity, which may have functional implications for understanding the mechanisms of continence at the bladder neck. The striated urethral sphincter appears circular with abundant tissue posteriorly. This sphincteric muscle has greater length anteriorly than posteriorly. CONCLUSIONS: These 3-dimensional reconstructions provide unique insights into male pelvic anatomy. They are a useful teaching tool for investigation and virtual reality modeling of the male pelvis.

Adult↗
PubMed1997

Warfarin analog inhibition of human CYP2C9-catalyzed S-warfarin 7-hydroxylation.

Human metabolism of the S-warfarin enantiomer is catalyzed primarily by cytochrome P4502C9 (CYP2C9), which, because of the enzyme's broad drug substrate specificity, leads to drug-S-warfarin interactions. Several warfarin analogs have been synthesized and used to determine whether they exhibit diminished interactions with CYP2C9. The kinetics of the warfarin analogs' inhibition of human liver microsomal CYP2C9 catalyzed metabolism of S-warfarin to S-7-hydroxywarfarin have been investigated. R- and S-7-fluorowarfarin were both predominantly competitive inhibitors, whereas racemic 6-fluorowarfarin and racemic 6,7,8-trifluorowarfarin were predominantly mixed inhibitors with some competitive inhibition. For the alcohols produced by reductive methylation of the side chain of R- and S-warfarin, the R-enantiomer did not inhibit S-warfarin metabolism, whereas the S-enantiomer was primarily a competitive inhibitor. The fluorine substituted warfarins and the S-warfarin alcohol apparently bind with high affinity to CYP2C9. Thus their use clinically (if efficacious) would not prevent CYP2C9 associated warfarin-drug interactions. The R-warfarin alcohol did not inhibit CYP2C9 catalyzed metabolism of S-warfarin and is less likely than warfarin to participate in CYP2C9 associated warfarin-drug interactions.

Aryl Hydrocarbon Hydroxylases↗
PubMed1997

Rare mutations and no hypermethylation at the CDKN2A locus in epithelial ovarian tumours.

The tumour-suppressor gene CDKN2A (p16, MTS1, CDK4I) encodes a cell cycle-regulatory protein and is located on chromosome 9p21, a region deleted in a wide variety of human cancers. To determine the role of the CDKN2A gene in the development of ovarian adenocarcinomas, we examined a large series of benign, low malignant potential (LMP) and invasive ovarian neoplasms for evidence of loss of heterozygosity (LOH), homozygous deletions, point mutations and hypermethylation of the CDKN2A locus. We have previously reported LOH on 9p in 45% of malignant ovarian neoplasms and a smaller percentage of benign and LMP tumours. In the current study, 6 malignant tumours were identified with partial deletions of 9p21. In 5 of these, the CDKN2A gene lays within the minimal deleted region. Homozygous deletions of CDKN2A were observed in only 2/88 invasive ovarian tumours and in 5/11 ovarian cancer cell lines. Of 15 primary ovarian tumours analyzed, one nonsense mutation was identified in a mucinous LMP tumour. No evidence of hypermethylation of the CDKN2A gene was found in 50 primary ovarian adenocarcinomas nor in 3 ovarian cancer cell lines. In conclusion, homozygous deletions, mutations and the de novo methylation of 5' CpG island are not frequent modes of inactivation of the CDKN2A gene in ovarian cancer. The target of 9p LOH in ovarian adenocarcinomas is therefore unknown.

Blotting, Southern↗
PubMed1997

Analysis of loss of heterozygosity and KRAS2 mutations in ovarian neoplasms: clinicopathological correlations.

The molecular events that give rise to ovarian epithelial neoplasms are not well understood. In particular, it is not known whether adenocarcinomas arise from benign or low malignant potential (LMP) precursors. We have examined a large series of benign (25) and LMP (31) ovarian tumors for loss of heterozygosity (LOH) at multiple loci on 17 chromosomes. LOH was observed in benign tumors on chromosomes 6 (14%) and 9 (5%) and on the X chromosome (33%) only. LOH on these chromosomes was also detected in a small number of LMP neoplasms, suggesting that these may derive sometimes from benign precursors. In addition, we examined LOH in 93 adenocarcinomas. Analysis of associations between LOH events showed that LOH on chromosomes 5 and 17 (P = 0.0002) and on chromosomes 17 and 18 (P = 0.00007) were associated significantly with each other, which suggests that these may represent cooperative, progressive events. No novel significant associations were identified between LOH events and stage, grade, or histology, which would indicate the existence of genetic heterogeneity in ovarian neoplasms. KRAS2 mutations were detected more often in LMP neoplasms than in malignant tumors (P = 0.004) and were detected more often in Stage I/II malignant tumors than in Stage III/IV malignant tumors (P = 0.033), suggesting that LMP tumors with KRAS2 mutations are unlikely to progress to frank malignancy. Univariate (but not multivariate) survival analysis showed that LOH of chromosomes 11 (P = 0.039) and 17 (P = 0.04) was associated with a significantly worse prognosis. Replication of these novel findings is necessary, and the identification, isolation, and characterization of the critical genes affected by LOH will determine their importance in the pathogenesis of ovarian malignancies.

Chromosome Deletion↗
PubMed1997

Prophylaxis for venous thromboembolism in head and neck surgery: the practice of otolaryngologists.

Deep venous thrombosis (DVT) and pulmonary embolism (PE) are an important cause of morbidity and mortality in the surgical patient. The first guideline produced by the Scottish Intercollegiate Guidelines Network was for the prophylaxis of venous thromboembolism. Patients undergoing major head and neck cancer surgery commonly exhibit risk factors for venous thromboembolism. Currently, however, there are no data on its incidence in these patients. A questionnaire survey was performed to assess the current practice of consultant otolaryngologists regarding DVT prophylaxis in patients undergoing head and neck cancer surgery. Of those respondents who managed these patients, 57 per cent did not use routine DVT prophylaxis while 43 per cent did. A wide variety of techniques were employed among those practising DVT prophylaxis. A consensus is needed concerning the use of thromboembolism prophylaxis in head and neck surgery patients.

Head and Neck Neoplasms↗
PubMed1997

PACE BOM chemotherapy: a 12-week regimen for advanced Hodgkin's disease.

BACKGROUND: This study was designed to evaluate the efficacy and toxicity of a 12-week alternating weekly chemotherapy regimen for advanced Hodgkin's disease. Consolidative irradiation of residual masses was used in selected cases. PATIENTS AND METHODS: Eighty-three patients with newly diagnosed advanced Hodgkin's disease (bulky stage IIA, stage IIB-IVB) or with progressive disease after extended field radiotherapy for early stage disease were included in this study. The patients were treated for 12 weeks with PACE BOM comprising oral prednisolone together with intravenous doxorubicin, cyclophosphamide and etoposide alternating weekly with intravenous bleomycin, vincristine and methotrexate. Limited field adjuvant radiotherapy was also given to 21 patients with localised persistent radiological abnormalities visible on chest X-ray after chemotherapy. The study end points were overall survival, failure free survival (FFS) and toxicity, particularly with respect to reproductive function. RESULTS: With a median post treatment follow up of 52 months the actuarial 5-year overall survival is 90% (confidence interval 81%-95%) and FFS is 64% (52%-74%). This treatment was well tolerated and fertility was maintained in a high proportion of young adults. CONCLUSIONS: The brief duration PACE BOM regimen with or without radiotherapy appears to be comparable in efficacy to other doxorubicin containing regimens, with a favourable toxicity profile. Randomised clinical trials are now needed to evaluate the role of this and comparable initial treatment approaches to advanced Hodgkin's disease.

Adolescent↗
PubMed1997

A state-based immunization campaign: the New Mexico experience.

Hepatitis B prophylaxis in the form of immunization has become an increasingly effective protective measure across the United States. Various cohorts have been targeted and methodologies used by public health officials to attain optimal coverage of the population. New Mexico is in its third year of school-based hepatitis B immunization programs. New Mexico's approach to this issue is characterized by significant rates of participation (66% in middle schools and 56% in high schools), high vaccination series completion (88% in middle schools and 89% in high schools), and minimal financial investment (cost of vaccine). The "Roll Up Your Sleeves" campaign was piloted, modified, and adapted to New Mexico's multi-lingual and multi-cultural environment, resulting in these successes.

Adolescent↗
PubMed1997

Single-colony derived strains of human marrow stromal fibroblasts form bone after transplantation in vivo.

Populations of marrow stromal fibroblasts (MSFs) can differentiate into functional osteoblasts and form bone in vivo. It is not known, however, what proportion of MSF precursor cells, colony forming units-fibroblast (CFU-Fs), have osteogenic potential. In the present study, analysis of bone formation in vivo by single-colony derived strains of human marrow stromal fibroblasts (HMSFs) has been performed for the first time. Each strain originated from an individual CFU-F and underwent four passages in vitro prior to subcutaneous implantation into immunodeficient mice within vehicles containing hydroxyapatite-tricalcium phosphate ceramic. Multicolony derived HMSF strains were also transplanted to serve as positive controls. After 8 weeks, abundant bone formation was found in the transplants of all multicolony derived HMSF strains, whereas 20 out of 34 (58.8%) single-colony derived strains from four donors formed bone. Immunostaining with antibody directed against human osteonectin and in situ hybridization for human-specific alu sequences demonstrated that cells forming new bone were of human origin and were vital for at least 45 weeks post-transplantation. Both the incidence of bone-forming colonies and the extent of bone formation by single-colony derived HMSF strains were increased by cultivation with dexamethasone and ascorbic acid phosphate. Other factors, including type of transplantation vehicle, morphology, size, and structure of the original HMSF colonies showed no obvious correlation with the incidence or extent of bone formation. Hematopoietic tissue within the newly formed bone was developed in the transplants exhibiting exuberant bone formation. These results provide evidence that individual human CFU-Fs have osteogenic potential and yet differ from each other with respect to their osteogenic capacity.

Animals↗
PubMed1997

Loss of heterozygosity at chromosome segment Xq25-26.1 in advanced human ovarian carcinomas.

To determine whether a tumor suppressor gene of importance to epithelial ovarian cancer resides on the X chromosome, we examined loss of heterozygosity (LOH) in 123 epithelial ovarian cancer cases. In 54 such cases, we examined LOH at 26 loci on the human X chromosome. In eight cases, we examined LOH in 14 loci and in 61 cases we examined LOH in 13 loci. Matched DNA samples from tumors and corresponding normal tissues were analyzed by polymerase chain reaction (PCR) amplification of microsatellite markers. Frequent losses were found in epithelial carcinomas at the Xq25-26.l region, including DXS1206 (34.5% loss in informative cases), DXS1047 (27.7%), HPRT (24.1%), and DXS1062 (33.3%). The minimum overlapping region of LOH was approximately 5 megabases (Mb), flanked by DXS1206 (Xq25) and HPRT (Xq26.1). The methylation status of the remaining allele of the androgen receptor gene in the tumors exhibiting LOH at the Xq25-26.1 region suggested that the loss was exclusively in the inactive X chromosome. We next determined whether a significant relationship exists between Xq LOH and other parameters, including histologic grade and/or clinical stage of the tumors and LOH at TP53. The Xq LOH had a significant association with grade 2 to 3 tumors at stages II to IV. Sixteen of 18 cases that showed Xq LOH revealed LOH at the TP53 locus, and 45% of tumors exhibiting LOH at TP53 showed Xq LOH. These results suggest that there may be a tumor suppressor gene or genes which escape inactivation of the X chromosome at Xq25-26.1, and that the loss of the gene(s) at Xq25-26.1 is frequently accompanied by loss of the TP53 or loss of another gene on chromosome 17. These losses may contribute to the progression from a well-differentiated to a more poorly differentiated state or to metastatic aggressiveness.

Carcinoma↗
PubMed1997

Attachment characteristics and involvement of integrins in adhesion of breast cancer cell lines to extracellular bone matrix components.

Evidence is mounting that changes in the ability of cancer cells to adhere to extracellular matrices play a decisive role in metastatic spread. The mechanism underlying the preference of breast cancer cells to metastasize to bone is, however, poorly understood. We investigated the expression and involvement of integrin adhesion receptors in the adhesion of breast cancer cells to bone matrix (constituents) in two in vitro attachment assays using RGD peptides and anti-integrin antibodies. Breast cancer cells adhered rapidly to extracellular bone matrix. Adhesion of most cells to vitronectin, fibronectin, thrombospondin, osteopontin, and the fairly bone-specific bone sialoprotein was inhibited by the 200 micrograms/ml GRGDS peptide. These data suggest that integrin adhesion receptors can modulate the attachment of breast cancer cells to bone matrix molecules. In accordance with these findings, we found that alpha 1-alpha 5(beta 1) and alpha v(beta 3) integrins were expressed by mammary carcinoma cells. Highly tumorigenic MDA-MB-231 cells, which form osteolytic metastases in vivo, expressed relatively high levels of alpha 2 beta 1, alpha 3 beta 1, alpha 5 beta 1, alpha v beta 3 integrins, when compared to MCF-7, T47D, and ZR75-1 breast cancer cells. Addition of function-blocking anti-alpha 2 beta 1, -alpha 3 beta 1, -alpha 5 beta 1, and -alpha v beta 3 antibodies significantly inhibited the adhesion of MDA-MB-231 breast cancer cells to bone matrices. In conclusion, our data suggest a possible role for beta 1 and beta 3 integrin subfamily members in the establishment of skeletal metastases in advanced breast cancer patients. Clearly, functional evidence is required to understand the mechanisms involved in the development of skeletal metastases in breast cancer patients.

Bone and Bones↗
PubMed1996

Allelic loss on chromosome 7q in ovarian adenocarcinomas: two critical regions and a rearrangement of the PLANH1 locus.

The presence of a tumour suppressor gene on chromosome 7q is indicated by cytogenetic, loss of heterozygosity (LOH) and chromosome transfer studies. One candidate gene in this region is Plasminogen Activator Inhibitor-1 (PAI-1). The PAI-1 gene product is involved in proteolysis and may therefore influence tumour spread and invasion. We have analysed a series of 139 ovarian epithelial tumours at four loci in the region 7q21-q31 which includes the PAI-1 gene. The highest rates of loss were found in malignant tumours (FIGO stages I-IV) at markers D7S471 (38%, 20/52 informative cases) and D7S522 (34%, 15/44). No loss was seen in benign tumours and only one out of 27 (4%) informative LMP tumours demonstrated LOH. The smallest region of overlap (SRO) lies between D7S471 and PAI-1. We also identified a rearrangement in one tumour in the PAI-1 gene, suggesting that this may be the inactivated gene in this region. In addition LOH at the more distal marker, D7S522, which lies outside the SRO, shows significant association with stage (P=0.0343) and with LOH on chromosome 13 (P=0.0024). This is in contrast to all other markers examined. These data suggest the presence of two critical regions on 7q which may be important in subsets of epithelial ovarian tumours.

Adenocarcinoma↗
PubMed1996

Somatic and germline mutations of the BRCA2 gene in sporadic ovarian cancer.

The breast and ovarian cancer susceptibility gene BRCA2 has recently been isolated. A role for BRCA2 in sporadic breast and ovarian cancer has been suggested by loss of heterozygosity (LOH) studies which show frequent LOH in the BRCA2 region at chromosome 13q12. In addition, the observation of nonrandom loss of the wild-type chromosome in a breast/ovarian cancer family which shows linkage to BRCA2 suggests it may act as a tumor suppressor gene. To determine the extent of somatic alteration involving BRCA2 in sporadic ovarian cancer, 50 tumors were analyzed for mutations throughout the entire BRCA2 coding region. Mutations predicted to result in truncation of the BRCA2 protein were detected in four tumors. Analysis of germline DNA revealed two of these alterations to be of somatic origin. In addition, all four tumors exhibited loss of the second BRCA2 allele as predicted by Knudson's hypothesis for a tumor suppressor gene. These results suggest that, as is the case with BRCA1, somatic mutations of BRCA2 are infrequent in sporadic ovarian cancer, despite the relatively high frequency of LOH detected around the BRCA2 locus.

BRCA2 Protein↗
PubMed1996

The crossover femoropopliteal bypass: a useful option for unilaterial iliofemoral occlusive disease.

OBJECTIVE: To study the outcome of treating critical limb ischaemia due to concurrent, unilateral iliac and femoral arterial occlusive disease by the placement of a crossover femoropopliteal bypass graft. DESIGN: Retrospective study of 10 patients unfit for aortic reconstruction whose disease was not amenable to endovascular therapy who were treated with this graft. MATERIALS: Seven grafts originated from the common femoral artery, two from aortobifemoral graft limbs and one from the common iliac artery. There was not direct revascularisation of the profunda femoris artery. The distal anastomosis was to the above-knee popliteal artery in nine cases and to the below-knee popliteal artery in one. OUTCOME MEASURES: Follow-up after discharge from hospital consisted of regular ankle-brachial index measurement and Duplex ultrasound scan assessment to record graft patency and limb salvage. RESULTS: The median duration of secondary patency was 52.5 months (range 14-84). During follow-up, there were four occlusive events. One graft had its patency restored, but in the other three patients, graft occlusion was associated with limb loss (at 18, 51 and 83 months respectively). In one of this latter group, surveillance had identified a failing graft and a jump graft prolonged patency for a further 34 months. CONCLUSION: This experience demonstrates that the crossover femoropopliteal bypass achieves satisfactory limb salvage in patients with extensive iliofemoral occlusive disease who are not suitable for major aortic reconstruction.

Aged↗