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Biomedical subjects

J Boyd

Publications and source records attributed to J Boyd.

At least 19 recordsLinked to original sources
PubMed2001

The hairpin structure of the (6)F1(1)F2(2)F2 fragment from human fibronectin enhances gelatin binding.

The solution structure of the (6)F1(1)F2(2)F2 fragment from the gelatin-binding region of fibronectin has been determined (Protein Data Bank entry codes 1e88 and 1e8b). The structure reveals an extensive hydrophobic interface between the non-contiguous (6)F1 and (2)F2 modules. The buried surface area between (6)F1 and (2)F2 ( approximately 870 A(2)) is the largest intermodule interface seen in fibronectin to date. The dissection of (6)F1(1)F2(2)F2 into the (6)F1(1)F2 pair and (2)F2 results in near-complete loss of gelatin-binding activity. The hairpin topology of (6)F1(1)F2(2)F2 may facilitate intramolecular contact between the matrix assembly regions flanking the gelatin-binding domain. This is the first high-resolution study to reveal a compact, globular arrangement of modules in fibronectin. This arrangement is not consistent with the view that fibronectin is simply a linear 'string of beads'.

Binding Sites↗
PubMed2001

The androgen receptor and genetic susceptibility to ovarian cancer: results from a case series.

Our objectives were to test whether polymorphic variation in the (CAG)n repeat of the androgen receptor (AR) gene affects penetrance of germ-line BRCA mutations for ovarian cancer or age of diagnosis for ovarian cancer. Using a case-series study design, 179 consecutive Ashkenazi Jewish ovarian cancer patients were genotyped for AR repeat length and BRCA mutation status. There was no association between AR repeat length and presence of a BRCA mutation. However, ovarian cancer patients from both groups (with or without BRCA mutation) who carried a short AR allele were diagnosed an average of 7.2 (95% confidence interval, 2.3-12.1) years earlier than patients who did not carry a short allele (P = 0.004). These data suggest that AR allele length affects age of diagnosis of ovarian cancer, irrespective of BRCA mutation status.

Adult↗
PubMed2001

Risk of endometrial carcinoma associated with BRCA mutation.

OBJECTIVE: Inherited mutations in the BRCA1 or BRCA2 genes are associated with a greatly increased lifetime risk of breast and ovarian cancers and a modestly increased risk of several other cancer types. Several case reports of endometrial carcinoma in women with a BRCA mutation have led to speculation regarding the effect of these genes on the risk of endometrial cancer. The purpose of this study was to test the hypothesis that germline mutation of a BRCA gene is associated with an increased risk of endometrial carcinoma. METHODS: A retrospective cohort of 199 consecutive Ashkenazi Jewish patients with endometrial carcinoma was identified from a 12-year period at this institution. All were genotyped for the three BRCA founder mutations (185delAG and 5382insC in BRCA1 and 6174delT in BRCA2) that exist in this population, and the case frequency was compared to the known population frequency of these mutations. Additionally, endometrial carcinomas occurring in patients with BRCA mutations were assessed for somatic loss of the wild-type BRCA allele. RESULTS: Germline BRCA mutations were identified in 3 (1 in BRCA1 and two in BRCA2) of 199 (1.5%) patients, compared to a frequency of 2.0% in this population generally. A relative risk of endometrial carcinoma associated with BRCA mutation, as estimated by the odds ratio, was calculated as 0.75 (95% CI = 0.24--2.34; P = 0.6). Loss of the wild-type BRCA allele was observed in two of three tumors associated with a BRCA mutation. CONCLUSIONS: For individuals with a germline BRCA mutation, the lifetime risk of endometrial carcinoma is not increased.

Aged↗
PubMed2001

Psychopathology and young people with Down's syndrome: childhood predictors and adult outcome of disorder.

There is a scarcity of follow-up studies into adult life of psychiatric disorder in young people with intellectual disability. The key aims of the present study were: (1) to determine the outcome of psychopathology present in childhood in individuals with Down's syndrome (DS); and (2) to look at childhood predictors of adult psychiatric disorder. Fifty-two young people with DS were identified from a sample of 193 subjects examined in childhood and adolescence for psychiatric and behaviour disorder. These young adults were interviewed for the presence of psychiatric disorder. No significant relationship was found between childhood mental disorder and psychiatric disorder in adult life for those individuals with DS. Early childhood factors of psychiatric disorder, challenging behaviour and family environment, except social background, did not predict adult psychopathology in young people with DS. Childhood disorder in individuals with DS has a good early prognosis with little evidence of continuity of the disorder into adult life.

Adolescent↗
PubMed2001

A refined solution structure of hen lysozyme determined using residual dipolar coupling data.

A high resolution NMR structure of hen lysozyme has been determined using 209 residual 1H-15N dipolar coupling restraints from measurements made in two different dilute liquid crystalline phases (bicelles) in conjunction with a data set of 1632 NOE distance restraints, 110 torsion angle restraints, and 60 hydrogen bond restraints. The ensemble of 50 low-energy calculated structures has an average backbone RMSD of 0.50+/-0.13A to the mean structure and of 1.49+/-0.10A to the crystal structure of hen lysozyme. To assess the importance of the dipolar coupling data in the structure determination, the final structures are compared with an ensemble calculated using an identical protocol but excluding the dipolar coupling restraints. The comparison shows that structures calculated with the dipolar coupling data are more similar to the crystal structure than those calculated without, and have better stereochemical quality. The structures also show improved quality factors when compared with additional dipolar coupling data that were not included in the structure calculations, with orientation-dependent 15N chemical shift changes measured in the bicelle solutions, and with T1/T2 values obtained from 15N relaxation measurements. Analysis of the ensemble of NMR structures and comparisons with crystal structures, 15N relaxation data, and molecular dynamics simulations of hen lysozyme provides a detailed description of the solution structure of this protein and insights into its dynamical behavior.

Animals↗
PubMed2001

The ICCD benchmarks for clubhouses: a practical approach to quality improvement in psychiatric rehabilitation.

OBJECTIVE: The study evaluated whether the average performance of clubhouses certified by the International Center for Clubhouse Development (ICCD) should be considered valid benchmarks for clubhouse programs. METHODS: A representative sample of clubhouses more than three years old that were based on the Fountain House model participated in a 1998 mail survey. To verify that ICCD certification is a valid indicator of program quality for use in setting benchmark performance rates, 71 certified and 48 noncertified programs were compared on a variety of organizational variables. RESULTS: Even though certified and noncertified clubhouses were similar in organizational structure and resources, findings from a logistic regression analysis confirmed that certified clubhouses provided a wider array of rehabilitation services and achieved higher rates of employment. CONCLUSIONS: The findings suggest that ICCD certification is a valid indicator of program quality. The ICCD has therefore proposed that the average performance of certified U.S. clubhouses in specific domains be adopted as benchmarks for organizational performance. When tailored for programs in particular regions and with specific levels of funding, the ICCD benchmarks for clubhouse performance set fair and reasonable expectations for clubhouse programs and for the design of performance contracts between departments of mental health and ICCD clubhouses.

Benchmarking↗
PubMed2000

Evidence of improving prognosis in heart failure: trends in case fatality in 66 547 patients hospitalized between 1986 and 1995.

BACKGROUND: Contemporary survival in unselected patients with heart failure and the population impact of newer therapies have not been widely studied. Therefore, we have documented case-fatality rates (CFRs) over a recent 10-year period. METHODS AND RESULTS: In Scotland, all hospitalizations and deaths are captured on a single database. We have studied case fatality in all patients admitted with a principal diagnosis of heart failure from 1986 to 1995. A total of 66 547 patients (47% male) were studied. Median age was 72 years in men and 78 years in women. Crude CFRs at 30 days and at 1, 5, and 10 years were 19.9%, 44.5%, 76.5%, and 87.6%, respectively. Median survival was 1.47 years in men and 1.39 years in women (2.47 and 2. 36 years, respectively, in those surviving 30 days). Age had a powerful effect on survival, and sex, comorbidity, and deprivation had modest effects. One-year CF was 24.2% in those aged <55 years and 58.1% in those aged >84 years. After adjustment, 30-day CFRs fell between 1986 and 1995, by 26% (95% CI 15 to 35, P<0.0001) in men and 17% (95% CI 6 to 26, P<0.0001) in women. Longer term CFRs fell by 18% (95% CI 13 to 24, P<0.0001) in men and 15% (95% CI 10 to 20, P<0.0001) in women. Median survival increased from 1.23 to 1. 64 years. CONCLUSIONS: Heart failure CF is much higher in the general population than in clinical trials, especially in the elderly. Although survival has increased significantly over the last decade, there is still much room for improvement.

Aged↗
PubMed2000

Absence of premalignant histologic, molecular, or cell biologic alterations in prophylactic oophorectomy specimens from BRCA1 heterozygotes.

BACKGROUND: The high mortality associated with ovarian carcinoma is largely a reflection of the inability to diagnose the disease at an early stage; the identification of a histologic lesion or molecular marker associated early stages of transformation would represent an important advance in understanding the natural history of this cancer. The existence of individuals with germline mutations in the ovarian and breast carcinoma susceptibility gene BRCA1 represents a unique opportunity to search for such premalignant alterations in ovarian tissues that are at unusually high risk for tumorigenesis. In this study, the authors addressed the hypothesis that pathologically normal ovaries removed from BRCA1 heterozygotes are likely to display premalignant histologic, molecular, and/or cell biologic alterations that may provide insight into early stages of ovarian tumorigenesis. METHODS: Ovarian tissues from 18 BRCA1 heterozygotes and from 20 age-matched controls were examined in a blinded fashion for histologic evidence of surface epithelial pseudostratification, epithelial inclusion cysts, deep cortical invaginations of surface epithelium, increased stromal cell activity, and surface papillomatosis. Immunohistochemical analyses for expression of BRCA1, p53, and ERBB-2 and quantitation of cell proliferation (Ki-67 expression) and apoptosis (TUNEL assay), were also performed on all specimens. RESULTS: Although histologic alterations were observed, there was no difference in frequency between cases and controls. Analysis of BRCA1 expression revealed ubiquitous nuclear immunoreactivity in the surface epithelial cells of all ovaries. Similarly, no evidence was found of p53 overexpression in any ovarian tissue or of a difference in ERBB-2 expression between cases and controls. Finally, no differences were observed in epithelial cell proliferation or apoptosis. CONCLUSIONS: Clinically, normal ovaries from BRCA1 heterozygotes do not show evidence of premalignant alterations in histology, molecular markers, cell proliferation, or apoptosis, indicating that such changes are likely rare.

Adult↗
PubMed2000

Clinicopathologic features of BRCA-linked and sporadic ovarian cancer.

CONTEXT: Most hereditary ovarian cancers are associated with germline mutations in BRCA1 or BRCA2. Attempts to define the clinical significance of BRCA mutation status in ovarian cancer have produced conflicting results, especially regarding survival. OBJECTIVE: To determine whether hereditary ovarian cancers have distinct clinical and pathological features compared with sporadic (nonhereditary) ovarian cancers. DESIGN AND SETTING: Retrospective cohort study of a consecutive series of 933 ovarian cancers diagnosed and treated at our institution, which is a comprehensive cancer center as designated by the National Cancer Institute, over a 12-year period (December 1986 to August 1998). PATIENTS: The study was restricted to patients of Jewish origin because of the ease of BRCA1 and BRCA2 genotyping in this ethnic group. From the 189 patients who identified themselves as Jewish, 88 hereditary cases were identified with the presence of a germline founder mutation in BRCA1 or BRCA2. The remaining 101 cases from the same series not associated with a BRCA mutation and 2 additional groups (Gynecologic Oncology Group protocols 52 and 111) with ovarian cancer from clinical trials (for the survival analysis) were included for comparison. MAIN OUTCOME MEASURES: Age at diagnosis, surgical stage, histologic cell type and grade, and surgical outcome; and response to chemotherapy and survival for advanced-stage (II and IV) cases. RESULTS: Hereditary cancers were rarely diagnosed before age 40 years and were common after age 60 years, with mean age at diagnosis being significantly younger for BRCA1- vs BRCA2-linked patients (54 vs 62 years; P=.04). Histology, grade, stage, and success of cytoreductive surgery were similar for hereditary and sporadic cases. The hereditary group had a longer disease-free interval following primary chemotherapy in comparison with the nonhereditary group, with a median time to recurrence of 14 months and 7 months, respectively (P<.001). Those with hereditary cancers had improved survival compared with the nonhereditary group (P=.004). For stage III cancers, BRCA mutation status was an independent prognostic variable (P=.03). CONCLUSIONS: Although BRCA-associated hereditary ovarian cancers in this population have surgical and pathological characteristics similar to those of sporadic cancers, advanced-stage hereditary cancer patients survive longer than nonhereditary cancer patients. Age penetrance is greater for BRCA1-linked than for BRCA2-linked cancers in this population.

Adult↗
PubMed2000

Carcinosarcoma of the ovary in a patient with a germline BRCA2 mutation: evidence for monoclonal origin.

BACKGROUND: Themajority of hereditary breast and ovarian cancers are associated with germline mutations in BRCA1 or BRCA2. While the occurrence of breast carcinoma and epithelial ovarian carcinoma in association with BRCA mutations is firmly established, the etiologic role of these genes in the development of other tumor types is less well documented. Carcinosarcoma of the ovary is an uncommon tumor consisting of both malignant epithelial and malignant mesenchymal components. OBJECTIVE: Here we report a patient with an ovarian carcinosarcoma who was found to harbor a germline mutation in BRCA2. We sought to link the BRCA2 mutation to the pathogenesis of this tumor as well as to determine whether both histologic components arose from the same progenitor cell. METHODS: Microdissection and molecular genetic analyses of the carcinomatous and sarcomatous components of this tumor were performed. RESULTS: Clonal loss of the wild-type BRCA2 allele as well as the same somatic mutation of the TP53 gene was evident in both histologic components. CONCLUSIONS: These data indicate that hereditary ovarian carcinosarcoma may result from a mutation in BRCA2 and that both histologic elements of this tumor arose from the same progenitor cell.

Aged↗
PubMed2000

[Does primary melanoma of the bladder exist?].

Primary melanoma of the urinary bladder is a rare neoplasm to which very strict diagnostic criteria apply. Although reports of previous cases exist, these criteria have yet to be met. We report a case of a young lady from whom a malignant melanoma of the bladder was resected. This was presumed to be primary as detailed investigation failed to find any other site from which metastases could have originated. We discuss the diagnostic criteria of this entity and stress the difficulty in conclusively demonstrating that, despite some of these criteria being met, a lesion such as this is primary in origin. This case could be the longest surviving patient with primary melanoma of the bladder, however we will never be able to prove that spontaneous regression of an undiagnosed extravesical primary malignant melanoma did not occur.

Adult↗
PubMed2000

Trends in case-fatality in 117 718 patients admitted with acute myocardial infarction in Scotland.

OBJECTIVES: To analyse short- and long-term case-fatality trends following admission to hospital with a first acute myocardial infarction, in men and women between 1986 and 1995, after adjusting for risk factors known to influence survival. DESIGN: A Scottish-wide retrospective cohort study. SETTING: The Linked Scottish Morbidity Record Database was analysed. This contains accurate data on all hospital admissions since 1981, for the Scottish population of 5.1 million. It is linked to the Registrar General's death certificate data. SUBJECTS: All 117 718 patients admitted to Scottish hospitals with a principal diagnosis of first acute myocardial infarction (ICD-9 code 410) between 1986 and 1995. MAIN OUTCOME MEASURES: The outcome was death, both in and out of hospital, from any cause, at 30 days, 1 year, 5 and 10 years. RESULTS: Overall case-fatality following hospital admission with acute myocardial infarction was 22. 2%, 31.4%, 51.1% and 64.0% at 1 month, 1 year, 5 and 10 years, respectively. Multivariate analyses identified statistically significant independent prognostic factors. Thirty day mortality increased twofold for each decade of increasing age, and increased with any prior admission to hospital. When comparing the most deprived category to that of the most affluent, men had a 10% increased mortality (P<0.01), whilst women had an increased mortality of 4% (not significant). After adjustment for age, sex, deprivation and prior admission to hospital, case-fatality rates fell significantly between 1986 and 1995. Short-term case-fatality fell by 46% in men (27% in women) and long-term by 34% in men (30% in women) (both P<0.001). CONCLUSIONS: Population-based case-fatality rates in Scotland have fallen dramatically since 1986, particularly in men. The increasing survival in patients admitted to hospital suggests that the trial-based efficacy of modern therapies is now translating into population-based effectiveness. However, an individual's life expectancy still halves after a diagnosis of acute myocardial infarction. Of the variables that we could examine, age was the most powerful predictor of prognosis.

Age Distribution↗
PubMed2000

First trimester ultrasound with nuchal translucency measurement for Down syndrome risk estimation using software developed by the Fetal Medicine Foundation, United Kingdom--the first 2000 examinations in Newcastle, New South Wales, Australia.

In September 1997 screening for Down syndrome using first trimester ultrasound to measure nuchal translucency, with risk estimation by the software program developed in the United Kingdom by the Fetal Medicine Foundation, was introduced in Newcastle, New South Wales. In the first 2,000 such risk estimations 134 women (6.7 %) were screen positive (with a risk of greater than 1 in 300 at that gestation for Trisomy 21). In the first 1,000 of these 2,000 fetuses delivered thus far there were 8 cases of Trisomy 21, 2 of Trisomy 18 and 1 of 47 XXX. Nine of these 11 were screen positive, the only false negative results being for 2 cases of Trisomy 21. The detection rate for Trisomy 21 was 6 out of 8 (75%) and for every case of Trisomy 21 (Down Syndrome) detected by this process, 11.3 invasive tests would have been needed to make that diagnosis in a screen positive woman.

Down Syndrome↗
PubMed1999

Breast conservation therapy for invasive breast cancer in Ashkenazi women with BRCA gene founder mutations.

BACKGROUND: Germline mutations in the BRCA1 and BRCA2 genes are associated with an increased risk of breast cancer. Whether women with breast cancer who have inherited mutations in these genes have a different outcome after breast conservation therapy than women with "sporadic" cancer is unresolved. Consequently, we compared the outcomes after breast conservation therapy in Ashkenazi women with or without germline mutations in BRCA1 and/or BRCA2 (hereafter called BRCA). METHODS: We studied 305 women of Ashkenazi Jewish descent undergoing breast-conserving treatment for 329 invasive breast cancers. We reviewed their clinical records, retrieved their archival tissue samples, and tested those samples for the founder mutations BRCA1 185delAG, BRCA1 5382insC, and BRCA2 6174delT. Genetic results were linked to clinical data and outcomes by univariate and multivariate analyses. All Pvalues are two-sided. RESULTS: We detected mutations in BRCA genes in 28 of 305 women. Women with BRCA mutations were more likely to be diagnosed with cancer before the age of 50 years (P<.001) and to have lymph node involvement (P =.04). Ipsilateral breast tumor recurrence was more common in women with BRCA mutations, although this did not reach statistical significance (relative risk [RR] = 1.79; 95% confidence interval [CI] = 0.64-5.03). Women with mutations were more likely to develop contralateral breast cancer (RR = 3.50; 95% CI = 1.78-8.74; P =.001). Distant disease-free survival was shorter in women with mutations (66.2% versus 84.3% at 10 years; P =.05), as was breast cancer-specific survival (71.9% versus 87.2% at 10 years; P =.02). Tumor stage and nodal status, but not mutation status, were predictive of distant disease-free and breast cancer-specific survival in multivariate analysis. CONCLUSIONS: Women with BRCA founder mutations are at increased risk for breast cancer-related events after breast conservation. However, mutation status is not an independent predictor of survival and should not influence decisions regarding adjuvant therapy. The increased contralateral breast cancer risk in women heterozygous for BRCA mutations mandates careful surveillance.

Analysis of Variance↗