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R Bell

Publications and source records attributed to R Bell.

At least 145 records · Page 8Linked to original sources
PubMed1996

The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds.

Breast carcinoma is the most common malignancy among women in developed countries. Because family history remains the strongest single predictor of breast cancer risk, attention has focused on the role of highly penetrant, dominantly inherited genes in cancer-prone kindreds (1). BRCA1 was localized to chromosome 17 through analysis of a set of high-risk kindreds (2), and then identified four years later by a positional cloning strategy (3). BRCA2 was mapped to chromosomal 13q at about the same time (4). Just fifteen months later, Wooster et al. (5) reported a partial BRCA2 sequence and six mutations predicted to cause truncation of the BRCA2 protein. While these findings provide strong evidence that the identified gene corresponds to BRCA2, only two thirds of the coding sequence and 8 out of 27 exons were isolated and screened; consequently, several questions remained unanswered regarding the nature of BRCA2 and the frequency of mutations in 13q-linked families. We have now determined the complete coding sequence and exonic structure of BRCA2 (GenBank accession #U43746), and examined its pattern of expression. Here, we provide sequences for a set of PCR primers sufficient to screen the entire coding sequence of BRCA2 using genomic DNA. We also report a mutational analysis of BRCA2 in families selected on the basis of linkage analysis and/or the presence of one or more cases of male breast cancer. Together with the specific mutations described previously, our data provide preliminary insight into the BRCA2 mutation profile.

BRCA2 Protein↗
PubMed1996

Low incidence of BRCA2 mutations in breast carcinoma and other cancers.

Inherited mutant alleles of familial tumour suppressor genes predispose individuals to particular types of cancer. In addition to an involvement in inherited susceptibility to cancer, these tumour suppressor genes are targets for somatic mutations in sporadic cancers of the same type found in the familial forms. An exception is BRCA1, which contributes to a significant fraction of familial breast and ovarian cancer, but undergoes mutation at very low rates in sporadic breast and ovarian cancers. This finding suggests that other genes may be the principal targets for somatic mutation in breast carcinoma. A second, recently identified familial breast cancer gene, BRCA2 (refs 5-8), accounts for a proportion of breast cancer roughly equal to BRCA1. Like BRCA1, BRCA2 behaves as a dominantly inherited tumour suppressor gene. Individuals who inherit one mutant allele are at increased risk for breast cancer, and the tumours they develop lose the wild-type allele by heterozygous deletion. The BRCA2 coding sequence is huge, composed of 26 exons that span 10,443 bp. Here we investigate the rate of BRCA2 mutation in sporadic breast cancers and in a set of cell lines that represent twelve other tumour types. Surprisingly, mutations in BRCA2 are infrequent in cancers including breast carcinoma. However, a probable germline mutation in a pancreatic tumour cell line suggests a role for BRCA2 in susceptibility to pancreatic cancer.

BRCA2 Protein↗
PubMed1996

Nutritional effect of calcium supplementation by skim milk powder or calcium tablets on total nutrient intake in postmenopausal women.

The effect of different types of calcium supplements on total nutrient intake has not been studied. The effect of dietary calcium supplementation (calcium tablets or skim milk powder) on nutrient intake in 64 postmenopausal women was studied in a 4-y longitudinal study consisting of 2 y of intervention and 2 y of follow-up. Subjects also received advice on how to reduce their consumption of high-fat and cholesterol-rich foods. Analysis of 4-d weighed diet records at 1 y showed that calcium intakes from the milk-powder supplement (1618 +/- 213 mg) and calcium tablets (1718 +/- 257 mg) were above recommended dietary intakes (RDI), and dietary fat intake and plasma cholesterol were significantly reduced compared with baseline values. The subjects supplemented with milk powder had higher intakes of several nutrients, including protein and zinc, compared with the subjects given calcium tablets. A greater proportion of subjects using the milk-powder supplement achieved > or = 70% of the RDI for zinc compared with tablet-supplemented subjects during the intervention study. Subjects were advised to continue with supplementation at the end of the intervention study. Thirty-nine subjects were available for follow-up. The mean (+/- SD) calcium intake for the milk-powder group (942 +/- 434 mg) was below the RDI and significantly lower than that of the calcium-tablet group (1346 +/- 512 mg). These data suggest that advice on dietary calcium supplementation and fat reduction had a beneficial effect on the nutrient intakes of postmenopausal women but compliance outside of a control trial by women taking calcium tablets was higher than that by women taking milk powder. Thus, strategies to encourage women to increase calcium intake can be introduced without significant deleterious effects on other aspects of the diet.

Administration, Oral↗
PubMed1996

Locations of herpes simplex virus type 2 glycoprotein B epitopes recognized by human serum immunoglobulin G antibodies.

Herpes simplex virus type 2 (HSV-2) glycoprotein B (gB-2) gene segments were expressed as recombinant proteins in Escherichia coli. gB-2 recombinant proteins were reacted with human serum immunoglobulin G (IgG) antibodies in Western immunoblot assays. Initially, samples were tested for the presence of HSV-1-specific antibodies and HSV-2-specific antibodies by using HSV-infected cell lysates as antigen targets in Western blot assays. Serum samples that contained HSV-2-specific IgG (n = 58), HSV-1-specific IgG (n = 33), or no detectable HSV antibodies (n = 31) were tested for reactivities with the gB-2 recombinant proteins. In 58 of 58 samples that contained HSV-2-specific IgG, antibodies were present that reacted strongly with a gB-2 amino-proximal segment between amino acids (aa) 18 and 75. Three of 33 serum samples that contained HSV-1- and not HSV-2-specific IgG (as defined by the HSV lysate Western blot assay) reacted with this segment. Both HSV-2 antibodies and HSV-1 antibodies reacted strongly with a carboxy-terminal gB-2 segment between aa 819 and 904; a second minor cross-reactive region was mapped to a gB-2 segment between aa 564 and 626. The gB-2 segment from aa 18 to 75 may constitute a useful reagent for the virus type-specific serodiagnosis of HSV-2 infections. Further studies will be required to determine the relative sensitivities and specificities of the assay for gB-2 aa 18 to 75, HSV gG assays, and HSV lysate Western blot assays for detecting virus type-specific antibody responses in acute and chronic HSV-2 infections.

Amino Acid Sequence↗
PubMed1996

Residual disease following unplanned excision of soft-tissue sarcoma of an extremity.

Sixty-five patients who had been referred to our unit for additional management after an unplanned excision of a soft-tissue sarcoma of an extremity at another institution were studied retrospectively to determine the prevalence of residual tumor and to identify factors that predict which patients will have a tumor following such an excision. Unplanned excision was defined as excisional biopsy or unplanned resection of the lesion without benefit of preoperative imaging and without regard for the necessity to resect the lesion with a margin of normal tissue. In each patient, histological evaluation of the specimen removed at the unplanned excision had demonstrated positive resection margins, but postoperative physical examination on our unit revealed no gross evidence of residual tumor and no tumor was identified on cross-sectional imaging of the local site. Patients who had evidence of residual disease on physical examination or on imaging were thought to have definite evidence of sarcoma at the site of the operative wound and were therefore excluded from the study. After multidisciplinary consultation, all patients had a repeat resection at our cancer center. Extensive pathological sampling of the specimen from this second procedure was carried out, with sections obtained at mean intervals of 1.2 +/- 0.7 centimeters. Nodules initially thought to indicate disease were identified grossly in twenty-seven (42 percent) of the sixty-five patients, but histological evaluation confirmed the presence of tumor in only sixteen (59 percent). Histological evidence of sarcoma was identified in seven additional patients in whom gross nodules were not apparent in the specimen. Thus, sarcoma was identified in a total of twenty-three (35 percent) of the sixty-five patients. The mean duration of follow-up was forty-six months (range, twenty-four to eighty months; median, thirty-nine months). The margins of the second resection were positive in nine (39 percent) of the twenty-three patients who had residual sarcoma. Five (22 percent) of the twenty-three had a local recurrence. Four of the five patients who had a local recurrence had positive margins on repeat resection. This rate of local recurrence (five of twenty-three patients) was significantly higher than that in the remainder of our patients who had a soft-tissue sarcoma of an extremity (sixteen [7 percent] of 227) (p = 0.03). There was no association between the detection of sarcoma at the second procedure and the initial size or grade of the tumor, the use of irradiation preoperatively, or the interval between the initial, unplanned excision and referral to our cancer center. These data indicate that it is not possible to predict which patients will have residual tumor at the site of the operative wound. Therefore, it is prudent to advise repeat excision for all patients who have had an unplanned excision of a soft-tissue sarcoma of an extremity. Unplanned excision complicates decision-making in the treatment of this disease and should be avoided.

Biopsy↗
PubMed1995

Long-term follow-up of efficacy and safety of megavoltage radiotherapy in high-risk giant cell tumors of bone.

PURPOSE: Giant cell tumors of the bone are rare and have variable presentations and natural history. There may be significant functional sequelae as a result of their locally aggressive nature or as a result of treatment. We reviewed the long-term results of radiotherapy for high risk giant cell tumors to assess: the efficacy of radiotherapy and the potential late toxicity of treatment, and to determine indications for radiation treatment. METHODS AND MATERIALS: This report is a retrospective review of 21 localized giant cell tumors of the bone treated with radiotherapy between 1959 and 1991. Radiation was used in the primary management of 13 cases and for recurrent disease in eight cases. In the primary cases, two received radiotherapy as the sole modality (including a massive pelvic lesion and an advanced maxillary sinus tumor with orbital and pterygoid invasion), and in the other 11, 3 had gross residual disease following surgery and 8 had microscopic residual disease. Of eight recurrent cases, five were treated with radiotherapy alone and three with combined surgery and radiation. Sites of origin included extremity bones in nine cases, pelvis in six, spine in four, and skull in two. Extraosseous disease was apparent in 18 tumors and extended to contiguous structures in 14 (including four cases of spinal cord compression, three cases of sacral plexopathy, and one patient with temporal lobe invasion). The most common dose regimen was 35 Gy/15 fractions/3 weeks (14 cases), with varying schedules for the remainder. RESULTS: Mean follow-up time was 15.4 years (2 to 35 years). Local control was achieved in 19 of 21 patients with radiotherapy. The two failures were subsequently salvaged for an ultimate control rate of 100%. One of the two radiotherapy failures was a marginal failure and was subsequently salvaged with combined surgery and radiotherapy. No patient died of giant cell tumor. Radiotherapy was well tolerated, with no serious late toxicity. There were no cases of malignant transformation or radiation-induced cancer. CONCLUSION: Long-term results in this series indicate that radiotherapy in modest doses (35 Gy in 15 fractions or equivalent) is a safe and effective option for primary and recurrent giant cell tumors of the bone. Radiotherapy should be used if surgery would result in significant functional morbidity and should be considered in select sites where the probability of recurrence is high and there is potential for significant morbidity from tumor relapse or subsequent surgery.

Adolescent↗
PubMed1995

No evidence for linkage between the X-chromosome marker DXS7 and schizophrenia.

DeLisi et al. (1994b) have examined the X and Y chromosomes for linkage to schizophrenia in 126 small families and report a small positive LOD score for the marker DXS7, adjacent to the MAO locus at Xp11.4-11.3. Because of this, we have examined the DXS7 for linkage to schizophrenia using 17 pedigrees in which male-to-male transmission of schizophrenia was absent. Alleles at DXS7 were genotyped using the PCR and LOD scores calculated using five models of inheritance, including classical dominant recessive and intermediate models. LOD scores were substantially negative for all models examined and analysis for linkage heterogeneity using the LOD2 method showed no significance. Analysis by the nonparametric affected sib-pair method likewise indicated no linkage. We conclude that DXS7 is not a major locus for schizophrenia in our collection of pedigrees.

Family↗
PubMed1995

New spiropiperidines as potent and selective non-peptide tachykinin NK2 receptor antagonists.

The synthesis of a series of 2-(5-fluoro-1H-indol-3-yl)ethyl spiropiperidines is described together with their tachykinin NK2 receptor affinities measured in a rat colon binding assay. Equivalent NK2 receptor binding affinity was observed for the spirooxazolidinone 3-benzyl-8-[2-(5-fluoro-1H-indol-3-yl)ethyl]-1-oxa-3,8-diazaspiro[4.5] decan-2-one (3a), the imidazolidinone 3-benzyl-8-[2-(5-fluoro-1H-indol-3-yl)ethyl]-1,3,8-triazaspiro[4.5 ] decan-2-one (3s), and the pyrrolidinone 2-benzyl-8-[2-(5-fluoro-1H-indol-3-yl)ethyl]-2,8-diazaspiro[4.5]decan -3 - one (3t). Substitution in the phenyl ring of compound 3a produced no significant enhancement in NK2 binding affinity. Replacement of the phenyl ring in 3a with other aromatic rings resulted in a significant loss in binding affinity. Compound 3a was shown to be a potent NK2 receptor antagonist in guinea pig trachea where it also demonstrated 1000-fold selectivity for NK2 receptors over NK1. In the anesthetized guinea pig, compound 3a administered by the intravenous or oral route displayed potent and long-lasting antagonist activity against NK2 receptor agonist induced bronchoconstriction.

Animals↗
PubMed1995

Outcome following radiation treatment for high-risk pigmented villonodular synovitis.

PURPOSE: Pigmented villonodular synovitis (PVNS) is a rare proliferative process involving synovial membranes. It has a variable course, and while usually benign, may be destructive, resulting in major symptoms and loss of function leading to amputation. Optimum treatment is not always clear, and little information exists with respect to the role of radiotherapy. The purpose was to review our experience with radiotherapy in cases at high risk for recurrence with functional loss including instances where amputation was the sole alternative for symptomatic disease. METHODS AND MATERIALS: The records of all patients registered between 1972 and 1992 with a diagnosis of PVNS were identified (21 cases). The records of 14 cases who received radiotherapy after referral were reviewed retrospectively for demographic information, radiotherapy treatment parameters, and tumor outcome. RESULTS: All cases had confirmation of pathologic diagnosis. Six patients had primary and eight had recurrent disease (with a mean of 2.5 prior surgical procedures). All cases had both intra- and extraarticular disease and, without exception, the poorer prognosis diffuse subtype of the disease. The majority had one or more additional risk factors including skin, bone, tendon, neurovascular, or muscle group extension. With a mean follow-up time of 69 months (range 13-250 months), only one patient has shown persistence of disease. With the exception of that single case, all those with measurable disease had obvious disease until at least 12 months and, subsequently, manifested complete responses. The single case was lost from the clinic after 8 months from the initiation of radiotherapy to a dose of 30 Gy in 15 fractions and had a palpable mass at the time. He subsequently was noted to have a persisting mass and an excisional biopsy 9 years later showed PVNS. He remains well 21 years after treatment with good function. Eleven patients enjoyed excellent or good function from the affected limb and three had fair function. All patients had greater use of limb than at the time of treatment. No patient required amputation, and none had evidence of serious radiotherapy complications. CONCLUSIONS: These results demonstrate that moderate dose radiotherapy is an effective modality in the treatment of a subset of cases with this rare condition. Its use has permitted avoidance of amputation in very advanced cases with acceptable function preservation. When treatment is indicated we currently recommend gross total removal of PVNS. This is followed by moderate dose radiotherapy (35 Gy in 15 fractions) for residual disease where salvage of subsequent recurrence may compromise function.

Adolescent↗
PubMed1995

Monitoring the efficacy of hybrid selection during positional cloning: the search for BRCA1.

Positional cloning often requires isolation of candidate genes from a large, genetically defined region. Hybrid selection (direct cDNA selection, solution hybrid capture) is a rapid, simple procedure that has been used to identify expressed sequence tags (ESTs) from cloned genomic DNA. We used hybrid selection to screen a 600-kb region that includes the BRCA1 gene. From a set of 931 sequenced clones, we obtained 118 nonoverlapping candidate ESTs from ovary and lymphocyte cDNA. We analyzed the results of our hybrid selection experiments with particular attention to the overall completeness, efficiency, and background noise of the experiment. We introduce simple parameters that serve as measures of important aspects of the hybrid selection process in the context of positional cloning.

BRCA1 Protein↗
PubMed1995

The Beck Anxiety Inventory in a non-clinical sample.

This study investigated the properties of the Beck Anxiety Inventory (BAI) in a sample of 326 undergraduate students. Scores on the BAI were compared with data from the State-Trait Anxiety Inventory and the Beck Depression Inventory. The BAI demonstrated good psychometric properties, with a high level of internal consistency. Relatively low test-retest correlations, in comparison with the STAI-Trait, suggested that the scale was functioning as a state measure. Factor analysis revealed a unifactorial solution on the first administration (a time of low stress), but a two factor solution similar to that proposed initially by Beck, Epstein, Brown and Steer (Journal of Consulting and Clinical Psychology, 56, 893-897, 1988) at the second administration (hypothesised to be a time of increased stress). Thus, the two factor structure of the BAI (characterised by physical and cognitive symptoms) may not be distinguishable in the normal population in the absence of an external stressor. An apparent strength of the BAI was its superior ability in differentiating anxiety from depression when compared with the STAI. A combined factor analysis of the BAI and STAI-State revealed two distinct factors, suggesting that the scales may actually be measuring separate, although not necessarily independent, constructs. It is suggested that the high discriminant validity demonstrated by the BAI may have been achieved at the expense of some construct validity.

Adolescent↗
PubMed1995

Differential effects of CGS 12066B and CP-94,253 on murine social and agonistic behaviour.

Although it has been previously proposed that 5-HT1B agonism specifically attenuates rodent agonistic behaviour, more recent investigations have indicated that such influences may be ancillary to an anxiogenic effect. The present study examined the influences of two 5-HT1B agonists, CGS 12066B and CP-94,253, on murine agonistic behaviour. In a resident-intruder paradigm, CGS 12066B (0.5-5.0 mg/kg) decreased resident offensive aggression, social interest, and exploration while dose-dependently enhancing defensive behaviours across the dose range tested. CP-94,253 (2.5-10.0 mg/kg) also reduced elements of resident offensive behaviour whereas defensive behaviours were largely unchanged. Some elements of resident nonsocial and social behaviour were enhanced at 2.5 and 5.0 mg/kg but decreased at 10.0 mg/kg. The behavioural profile of CP-94,253, but not CGS 12066B, supports the proposal that 5-HT1B receptors inhibit agonistic behaviour without concomitant sedative or anxiogenic effects. Findings are discussed in relation to 5-HT1A/1B/2C receptors involved in agonistic behaviour and anxiety.

Agonistic Behavior↗
PubMed1995

Aggressive fibromatosis: optimisation of local management with a retrospective failure analysis.

The records of 40 consecutive patients treated at the Princess Margaret Hospital (PMH) between 1979 and 1988 for aggressive fibromatosis were reviewed. The median follow-up was 86 months (range 21-167 months). All surgery was performed at the referring hospitals. Thirty-six underwent an attempt at excision, four were biopsied. Thirty-one had no overt disease after surgery and 26 of these received adjuvant irradiation. Eight were treated with radiotherapy alone, and another was treated with azathioprine and prednisone. Twenty-four (60%) presented with recurrent disease. The overall relapse free rate was 63% at 5 and 10 years. Combined surgery and irradiation had a higher relapse rate than irradiation alone (46% vs. 25%), and a high proportion of failures in the combined group were marginal failures (36%). Relapses following surgery alone were 1/5 (20%), and chemotherapy 0/1. Tumour size greater than 8 cm predicted for relapse (p = 0.002), but tumour site, status of surgical margins, and presence or absence of a history of relapse were not statistically significant. Twelve with subsequent treatment failure underwent successful salvage surgery, and 37/40 (92%) were disease free at last follow-up. A functional assessment (modified Johnstone scale) revealed 11/24 patients (46%) with poor functional outcomes (grade 2 or less) after all treatment compared with 6/24 (25%) at referral. Ten of 11 (91%) with grade of 2 or less had a history of recurrence, and 4/5 amputations were for treatment of a painful recurrence. Treatment planning in this study was hampered by inadequate information on tumour location since few patients had clinically apparent disease when seen by the radiation oncologist (only 35% of cases) and fewer had preoperative cross-sectional imaging available (12% of cases).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

Short-term and long-term outcome following renovascular reconstruction.

Experience with renovascular reconstruction at the authors' institution over the past 16 years has been reviewed. A total of 76 patients underwent surgical intervention for renovascular disease during that time. This included 62 patients with atherosclerosis and 11 with fibromuscular hyperplasia. Indications for intervention were uncontrolled hypertension in 42 patients and to restore renal impairment in eight. The procedure was performed for both indications in 26 patients. Ten patients (13%) died in the perioperative interval, which correlated strongly with comorbidity. With the exception of one patient, all deaths occurred in the elderly (> 65 years). While an increased mortality rate (P < 0.05) was observed in those undergoing concomitant surgical procedures (20%) as opposed to those undergoing renovascular reconstruction alone (6%), this was not an independent risk factor. Both the short term and long term response of hypertension control to renovascular reconstruction were favourable, with age < 60 years, shorter duration of hypertension (< 5 years) and diagnosis of fibromuscular hyperplasia predictive of a better response. Renovascular reconstruction, while successful in stabilizing or even improving renal function in the short term, was poor at restoring function long term, especially in the subgroup of patients whose serum creatinine was > 200 mumol/l at the time of reconstruction.

Adolescent↗