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Biomedical subjects

J Kelly

Publications and source records attributed to J Kelly.

At least 199 records · Page 11Linked to original sources
PubMed1998

Immunohistochemical expression of BRCA2 protein and allelic loss at the BRCA2 locus in prostate cancer. CRC/BPG UK Familial Prostate Cancer Study Collaborators.

Many epidemiological studies have reported an association between breast and prostate cancer. BRCA2 functions as a tumour-suppressor gene in about 35% of large familial breast-cancer clusters; its role in the pathogenesis of sporadic breast cancer is less clear. We have evaluated immunohistochemical expression of BRCA2 protein and allelic loss of markers at the BRCA2 locus in tissue derived both from sporadic and from familial cases of prostate cancer. Immunohistochemical analysis was performed in 167 paraffin-embedded archival specimens. Normal prostate and 75% (120/160) of prostate-cancer tissue did not express BRCA2 protein. However, 25% (40/160) of cancer cases did express patchy staining; of these, 17% (2711 60) expressed positive nuclear staining in normal glandular tissue adjacent to tumour (either in addition to, or, independent of tumour). Allelic loss is the hallmark of a tumour-suppressor gene. Markers flanking (D13S267, D13S260) and within (D13S171) the BRCA2 gene indicated allelic loss in at least one locus in 23% (17/73) of tumours analyzed. There was no difference in the rates of allelic loss between sporadic and familial tumours, nor was there any association between immunohistochemical staining and allelic loss. Although immunohistochemical staining provided no useful prognostic information, allelic loss at BRCA2 was shown in univariate analysis to be associated with poorer survival (log-rank test, p = 0.046).

BRCA2 Protein↗
PubMed1998

Inhibitors of farnesyl protein transferase. Synthesis and biological activity of amide and cyanoguanidine derivatives containing a 5,11-dihydro[1]benzthiepin, benzoxepin, and benzazepin [4,3-b]pyridine ring system.

Bioisosteric replacement of the C-6 carbon atom in piperidine I and piperazine II with S, O, and N heteroatoms is described. Amide and cyanoguanidine derivatives of these compounds were evaluated in vitro and found to be good inhibitors of farnesyl-protein transferase. An improved method of preparing the 5,11-dihydro-[1]-benzthiepin nucleus 6 was accomplished in high yield and with excellent regioselectivity using an AlCl3 melt protocol.

Alkyl and Aryl Transferases↗
PubMed1998

Effect of educational leaflets and questions on knowledge of contraception in women taking the combined contraceptive pill: randomised controlled trial.

OBJECTIVE: To assess whether provision of educational leaflets or questions on contraception improves knowledge of contraception in women taking the combined contraceptive pill. DESIGN: Randomisation of women into three groups according to type of educational leaflet on contraceptive information. These groups were subdivided into two on the basis of questions on contraception asked by the doctor or practice nurse. The women were followed up by postal questionnaire 3 months later. SETTING: 15 general practices in South and West region. SUBJECTS: 636 women attending check up appointment for repeat prescription of the combined contraceptive pill. MAIN OUTCOME MEASURES: Knowledge of: factors causing pill failure, subsequent action, emergency contraception, and all the rules (pill rules) that apply to the contraceptive pill. RESULTS: 523 women returned completed questionnaires (response rate 82%). Knowledge of contraception with no intervention was low with only 10 (12%) women knowing all the pill rules. Educational intervention had a highly significant effect on knowledge of: factors causing pill failure (likelihood ratio chi2=22); subsequent action (21); emergency contraception (24); and all the pill rules (22) (P<0.01 in all cases). Improvement in knowledge of all the pill rules occurred with provision of the summary leaflet (28% knew all the rules, adjusted odds ratio 4.04, 95% confidence interval 1.68 to 9.75), the Family Planning Association's leaflet (27%, 3.43, 1.45 to 8.09), and asking questions (26%, 3.03, 1.30 to 7.00). Asking questions in addition to provision of leaflets improved knowledge of contraception further for the summary leaflet (39%, 6.81, 2.85 to 16.27) but not for the Family Planning Association leaflet (21%, 2.58, 1.07 to 6.18). CONCLUSION: Women attending check ups for repeat prescriptions of the contraceptive pill should be provided with educational leaflets on contraception or asked relevant questions to help improve their knowledge of contraception. Asking questions in addition to providing a summary leaflet is time consuming, but results in the most knowledge gained.

Adolescent↗
PubMed1998

Affinity selection from peptide libraries to determine substrate specificity of protein tyrosine phosphatases.

Affinity selection from peptide libraries is a powerful tool that has been used for determining the sequence specificities of a number of enzymes and protein binding domains, including protein kinases, src homology 2 domains, and PDZ domains. We have extended this approach to protein tyrosine phosphatases using peptide libraries containing a nonhydrolyzable phosphotyrosine analog, difluorophosphonomethylphenylalanine. A size-exclusion method is used to separate enzyme-peptide complexes from free peptide, providing several advantages over the traditional immobilized protein affinity column approach. In addition, the feasibility of using mass spectrometric detection to quantitate peptides rapidly and reproducibly is demonstrated as an alternative to quantitation by peptide sequencing. The validity of this analysis is demonstrated by synthesizing individual peptides and comparing their affinity for enzyme with the predictions from the affinity selection process. As a model for these studies the protein tyrosine phosphatase PTP1B is used, providing additional insights into the sequence specificity of this enzyme. In particular, a selection for aromatic amino acids at the pY - 1 position (immediately N-terminal to the phosphotyrosine), as well as a broad pY + 1 selectivity, is observed in addition to the general preference for acidic residues N-terminal to the phosphotyrosine. The approach described here should prove applicable to protein tyrosine phosphatases in general as well as for the study of nonpeptidyl combinatorial libraries.

Amino Acid Sequence↗
PubMed1998

Colorectal sarcoma: analysis of failure patterns.

BACKGROUND AND OBJECTIVES: Colorectal sarcomas (CRS) are rare and their treatment remains controversial, especially for those located in the rectum. The aim of this paper is to evaluate our experience, with special emphasis on the failure pattern after surgical therapy alone or combined with postoperative radiotherapy. MATERIALS AND METHODS: The medical records and histological slides of 13 CRS patients treated between 1986 and 1996 were reviewed retrospectively. RESULTS: The patients included eight males and five females, with a median age of 54 years; nine of their primary tumors were located in the rectum, and four in the colon. The histologies were leiomyosarcoma in nine cases and malignant fibrous histiocytoma in four cases. Surgical treatment consisted of anatomical colectomy (four); local excision (three); abdominoperineal resection (APR)(two); low anterior resection (LAR)(two); LAR en bloc with the prostate (one), and total pelvic exenteration (one). One operative death occurred. The median size of the tumors was 8 cm (range, 5-40). The tumors were graded as low, three, and high, ten. The median follow-up was 24 months. Eight patients in the overall group developed recurrences as follows: local, three; local and distant, three, and distant, two. Five out of nine patients with rectal sarcoma received adjuvant postoperative radiotherapy (PRT). Local recurrence occurred in 20% (1/5) of those who received PRT, and in 100% (3/3) of those who did not. The overall 5-year survival was 40%, and the 5-year survival for patients with low-grade tumors was 66%, as compared with 22% for those with high-grade tumors. CONCLUSIONS: The patterns of failure in CRS are combined in both local and distant sites. However, our results suggest that in rectal sarcoma, the use of surgery + PRT may reduce the local recurrence rate; in selected patients, it may allow for anal sphincter preservation.

Adult↗
PubMed1998

Fas ligand expression in primary colon adenocarcinomas: evidence that the Fas counterattack is a prevalent mechanism of immune evasion in human colon cancer.

Fas ligand (FasL) kills sensitive Fas receptor (FasR)-bearing cells by inducing apoptosis. FasL expressed by non-lymphoid cells within the eye and the testis mediates immune privilege by inducing apoptosis of Fas-sensitive infiltrating pro-inflammatory immune effector cells. It has previously been demonstrated by the present authors that the colon cancer cell SW620 expresses FasL and can kill lymphoid cells by Fas-mediated apoptosis in vitro. This 'Fas counterattack' was subsequently confirmed by others as a potential mechanism of immune privilege in various malignancies. The aim of the present study was to ascertain the prevalence of FasL expression in human colon cancer and to confirm that neoplastic colonic epithelial cells express FasL in vivo. The study of FasL expression by colon cancer cell lines was extended: it was shown that seven of eight colon adenocarcinoma cell lines expressed FasL mRNA, using reverse transcription-polymerase chain reaction (RT-PCR). Prevalent expression of FasL was confirmed in vivo: all the resected colonic tumours examined (31/31) were found to express FasL. In the tumours, FasL were co-localized to neoplastic colonic epithelial cells, using immunohistochemistry and in situ hybridization, respectively. FasL expression was independent of Dukes' stage, suggesting that it may occur throughout colon cancer progression. These results suggest that FasL is a common mediation of immune privilege in colon cancer.

Adenocarcinoma↗
PubMed1998

Herniation of cerebellar tonsils following supratentorial shunt placement.

Acquired Chiari 1 following ventriculoperitoneal shunting is an extremely unusual event. We report the case of an 8-year-old boy who presented with clinical and radiological signs of cerebellar tonsil herniation shortly after the placement of a cystoperitoneal shunt. Quantitative analysis of posterior fossa volumes (PFV) revealed that the patient had a smaller posterior fossa than age-matched normal controls. This abnormality, expressed as a decreased ratio between the posterior fossa and the supratentorial cavities (PFR), had already been present when the preoperative MRI was done. Our results suggest that preexisting structural abnormalities in the posterior fossa may constitute an important factor in the development tonsillar herniation following supratentorial shunts.

Arnold-Chiari Malformation↗
PubMed1998

Leptin activates hypothalamic CART neurons projecting to the spinal cord.

The adipocyte-derived hormone leptin decreases body weight in part by activating the sympathetic nervous system, resulting in increased thermogenesis and energy expenditure. We investigated hypothalamic pathways underlying leptin's effects on stimulating the sympathetic nervous system. We found that leptin activates neurons in the retrochiasmatic area (RCA) and lateral arcuate nucleus (Arc) that innervate the thoracic spinal cord and also contain cocaine- and amphetamine-regulated transcript (CART). We also found that most CART-containing neurons in the RCA and Arc of the hypothalamus also contain proopiomelanocortin (POMC) mRNA. The finding that leptin activates CART/POMC neurons innervating sympathetic preganglionic neurons in the thoracic spinal cord suggests that this pathway may contribute to the increased thermogenesis and energy expenditure and decreased body weight observed following leptin administration.

Animals↗
PubMed1998

Synthesis of isomeric 3-piperidinyl and 3-pyrrolidinyl benzo[5,6]cyclohepta[1,2-b]pyridines: sulfonamido derivatives as inhibitors of Ras prenylation.

Blocking farnesylation of oncogenic Ras proteins is a mechanism based therapeutic approach that is of current interest for the development of antitumor agents to treat ras associated tumors. As part of a SAR study on the lead farnesyl protein transferase (FPT) inhibitor I, we report here the synthesis of novel geometric isomers II and III and the FPT inhibition activity of their N-acyl and N-sulfonamido derivatives 15-65. The N-acyl derivatives are markedly less active than the lead inhibitor I thereby demonstrating that the spatial location of the N-acyl group in I is critical for binding of the compound to FPT. In contrast to I, the N-sulfonamido-II series is a novel lead of non-sulfhydryl, nonpeptidic compounds that are dual FPT/GGPT inhibitors. In light of recent reports on the alternative prenylation of N- and K-Ras, dual FPT/GGPT inhibitors may be required to control cell proliferation in tumors containing activated Ras.

Alkyl and Aryl Transferases↗
PubMed1998

Allelic imbalance in familial and sporadic prostate cancer at the putative human prostate cancer susceptibility locus, HPC1. CRC/BPG UK Familial Prostate Cancer Study Collaborators. Cancer Research Campaign/British Prostate Group.

A recent report has provided strong evidence for a major prostate cancer susceptibility locus (HPC1) on chromosome 1q24-25 (Smith et al, 1996). Most inherited cancer susceptibility genes function as tumour-suppressor genes (TSGs). Allelic loss or imbalance in tumour tissue is often the hallmark of a TSG. Studies of allelic loss have not previously implicated the chromosomal region 1q24-25 in prostate cancer. However, analysis of tumour DNA from cases in prostate cancer families has not been reported. In this study, we have evaluated DNA from tissue obtained from small families [3-5 affected members (n = 17)], sibling pairs (n = 15) and sporadic (n = 40) prostate tumours using the three markers from Smith et al (1996) that defined the maximum multipoint linkage lod score. Although widely spaced (12-50 cM), each marker showed evidence of allelic imbalance in only approximately 7.5% of informative tumours. There was no difference between the familial and sporadic cases. We conclude that the incidence of allelic imbalance at HPC1 is low in both sporadic tumours and small prostate cancer families. In this group of patients, HPC1 is unlikely to be acting as a TSG in the development of prostate cancer.

Aged↗
PubMed1998

Platinum concentrations in urban road dust and soil, and in blood and urine in the United Kingdom.

Increasing Pt concentrations from vehicle catalysts have been reported from a number of countries. Analysis of Pt and Pd in soils and road dusts taken from areas of high and low traffic flows in SE England show concentrations of Pt in the range < 0.30-40.1 ng g-1 and Pd in the range < 2.1-57.9 ng g-1. Higher concentrations of Pt are associated with high traffic densities. Samples taken from streets of lower traffic flows were found to contain the lower concentrations of the ranges. Pilot studies of Pt concentrations in blood and urine using ICP-MS have been carried out. Platinum concentrations in whole blood were: precious metal workers, 780-2170, mean 1263 pmol l-1 (0.152-0.423, mean 0.246 microgram l-1); motorway maintenance workers, 645-810, mean 744 pmol l-1 (0.126-0.158, mean 0.145 microgram l-1); Imperial College staff, 590-713, mean 660 pmol l-1 (0.115-0.139, mean 0.129 microgram l-1). Platinum concentrations in urine in pmol Pt per mmol creatinine were: precious metal workers, 122-682, mean 273 [0.21-1.18, mean 0.47 microgram Pt (g creatinine)-1]; motorway maintenance workers, 13-78, mean 33.7 [0.022-0.135, mean 0.058 microgram Pt (g creatinine)-1]; Imperial College staff, 28-130, mean 65.6 [0.048-0.224, mean 0.113 microgram Pt (g creatinine)-1]. Detection limits were 0.03 microgram l-1 for both blood and urine. The possible health effects of increasing Pt in the environment are discussed. Platinum provides an excellent example of the significance of speciation in metal toxicity. Platinum allergy is confined to a small group of charged compounds that contain reactive ligand systems, the most effective of which are chloride ligand systems. Metallic Pt is considered to be biologically inert and non allergenic and since the emitted Pt is probably in the metallic or oxide form, the sensitising potential is probably very low. Platinum from road dusts, however, can be solubilised, and enter waters, sediments, soils and the food chain. There is at present no evidence for any adverse health effects from Pt in the general environment, particularly allergic reactions.

Air Pollutants↗
PubMed1998

Vesico-vaginal and recto-vaginal fistulae.

In a series of 1138 patients with vesico-vaginal and/or recto-vaginal fistulae, the main cause in the developing world was obstructed labour, and in the developed world was surgery and/or malignancy. Most repairs were performed by a vaginal approach; there was dedicated nursing care; 85% were cured at the first attempt. In the developing world, prevention will require improved access to good obstetric care.

Journal Article↗
PubMed1998

A follow-up of repair of ruptured uterus in Ethiopia.

The uterus was conserved and repaired in 238 of 245 mothers admitted with ruptured uterus to a rural hospital in Ethiopia between 1991 and 1995. The patients have been followed for intervals varying from 6 years and 3 months to 1 year and 11 months since treatment of their rupture. One hundred and eleven mothers have given birth to 117 healthy babies. All mothers are well. Repair of uterine rupture is medically safe and culturally acceptable to the population served, provided the mothers are willing to spend the latter months of subsequent pregnancies in the maternity waiting area.

Journal Article↗
PubMed1998

Facilitating care management through computerized clinical pathways.

The development and implementation of clinical pathways at New York University Medical Center and the transition to a computerized multidisciplinary documentation system took place between 1995 and 1998. Both the computerized system and the pathway program evolved simultaneously over this 3-year period. The article describes the process of creating the clinical pathways and the automated documentation system to support the clinical pathways. Migration from the paper pathway to the automated system required the efforts of an interdisciplinary team, which focused on issues such as translation of written pathway detail into language that could be loaded into the automated system. The advantages, pitfalls, and lessons learned in this integration experience are also described.

Automation↗
PubMed1998

The contribution of classical (beta1/2-) and atypical beta-adrenoceptors to the stimulation of human white adipocyte lipolysis and right atrial appendage contraction by novel beta3-adrenoceptor agonists of differing selectivities.

The role of beta3- and other putative atypical beta-adrenoceptors in human white adipocytes and right atrial appendage has been investigated using CGP 12177 and novel phenylethanolamine and aryloxypropanolamine beta3-adrenoceptor (beta3AR) agonists with varying intrinsic activities and selectivities for human cloned betaAR subtypes. The ability to demonstrate beta1/2AR antagonist-insensitive (beta3 or other atypical betaAR-mediated) responses to CGP 12177 was critically dependent on the albumin batch used to prepare and incubate the adipocytes. Four aryloxypropanolamine selective beta3AR agonists (SB-226552, SB-229432, SB-236923, SB-246982) consistently elicited beta1/2AR antagonist-insensitive lipolysis. However, a phenylethanolamine (SB-220646) that was a selective full beta3AR agonist elicited full lipolytic and inotropic responses that were sensitive to beta1/2AR antagonism, despite it having very low efficacies at cloned beta1- and beta2ARs. A component of the response to another phenylethanolamine selective beta3AR agonist (SB-215691) was insensitive to beta1/2AR antagonism in some experiments. Because no [corrected] novel aryloxypropanolamine had a beta1/2AR antagonist-insensitive inotropic effect, these results establish more firmly that beta3ARs mediate lipolysis in human white adipocytes, and suggest that putative 'beta4ARs' mediate inotropic responses to CGP 12177. The results also illustrate the difficulty of predicting from studies on cloned betaARs which betaARs will mediate responses to agonists in tissues that have a high number of beta1- and beta2ARs or a low number of beta3ARs.

Adipose Tissue↗
PubMed1998

Arteriovenous malformation presenting as a complex pelvic mass with ureteral obstruction. A case report.

BACKGROUND: Arteriovenous malformations (AVMs) are an abnormal communication between arterial and venous structures. Pelvic AVMs have been infrequently described in the literature and represent an uncommon cause of a palpable pelvic mass. CASE: A case of pelvic AVM with ureteral obstruction occurred. The location and radiologic appearance of the AVM suggested a complex adnexal mass. During exploration and resection of the mass, significant bleeding was encountered. The diagnosis of AVM was made only retrospectively, with histologic examination of the specimen. CONCLUSION: AVMs are an uncommon and unique cause of pelvic pathology. Preoperative diagnosis will alert the surgeon as to the technically difficult resection that may be encountered and to the massive bleeding that can be associated with their removal.

Adult↗