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Showing papers by "University of Utah published in 1995"


Journal ArticleDOI
15 Dec 1995-Cell
TL;DR: This research presents a new probabilistic procedure called ‘spot-spot analysis’ to characterize the response of the immune system to the presence of E.coli.

6,818 citations


Journal ArticleDOI
TL;DR: The results suggest that the definition of improvement presented is statistically powerful and does not identify a large percentage of placebo-treated patients as being improved, which the authors hope will be used widely in RA trials.
Abstract: Objective. Trials of rheumatoid arthritis (RA) treatments report the average response in multiple outcome measures for treated patients. It is more clinically relevant to test whether individual patients improve with treatment, and this identifies a single primary efficacy measure. Multiple definitions of improvement are currently in use in different trials. The goal of this study was to promulgate a single definition for use in RA trials. Methods. Using the American College of Rheumatology (ACR) core set of outcome measures for RA trials, we tested 40 different definitions of improvement, using a 3-step process. First, we performed a survey of rheumatologists, using actual patient cases from trials, to evaluate which definitions corresponded best to rheumatologists' impressions of improvement, eliminating most candidate definitions of improvement. Second, we tested 20 remaining definitions to determine which maximally discriminated effective treatment from placebo treatment and also minimized placebo response rates. With 8 candidate definitions of improvement remaining, we tested to see which were easiest to use and were best in accord with rheumatologists' impressions of improvement. Results. The following definition of improvement was selected: 20% improvement in tender and swollen joint counts and 20% improvement in 3 of the 5 remaining ACR core set measures: patient and physician global assessments, pain, disability, and an acutephase reactant. Additional validation of this definition was carried out in a comparative trial, and the results suggest that the definition is statistically powerful and does not identify a large percentage of placebo-treated patients as being improved. Conclusion. We present a definition of improvement which we hope will be used widely in RA trials.

2,593 citations


Journal ArticleDOI
21 Apr 1995-Cell
TL;DR: The finding that HERG encodes IKr channels provides a mechanistic link between certain forms of inherited and acquired LQT, and that an additional subunit may be required for drug sensitivity.

2,375 citations


Journal ArticleDOI
10 Mar 1995-Cell
TL;DR: In this article, the authors investigated patients with long QT syndrome (LQT), an inherited disorder causing sudden death from a ventricular tachyarrythmia, torsade de pointes.

2,207 citations


Book ChapterDOI
TL;DR: In this article, the authors assessed whether cross-cultural variations in the strength of associations were related to societal dimensions including income and individualism, and found that life satisfaction and self-esteem were clearly discriminable constructs.
Abstract: College students in 31 nations (N = 13,118) completed measures of self-esteem, life satisfaction, and satisfaction with specific domains (friends, family, and finances). The authors assessed whether cross-cultural variations in the strength of associations were related to societal dimensions including income and individualism. At the national level, individualism correlated −0.24 (ns) with heterogeneity and 0.71 (p<0.001) with wealth. At the individual level, self-esteem and life satisfaction were correlated 0.47 for the entire sample. This relation, however, was moderated by the individualism of the society. The associations of financial, friend, and family satisfactions with life satisfaction and with self-esteem also varied across nations. Financial satisfaction was a stronger correlate of life satisfaction in poorer countries. It was found that life satisfaction and self-esteem were clearly discriminable constructs. Satisfaction ratings, except for financial satisfaction, varied between slightly positive and fairly positive.

1,785 citations


Journal ArticleDOI
TL;DR: Subjective well-being in 55 nations, reported in probability surveys and a large college student sample, was correlated with social, economic, and cultural characteristics of the nations and only individualism persistently correlated with SWB when other predictors were controlled.
Abstract: Subjective well-being (SWB) in 55 nations, reported in probability surveys and a large college student sample, was correlated with social, economic, and cultural characteristics of the nations. The SWB surveys, representing nations that include three fourths of the earth's population, showed strong convergence. Separate measures of the predictor variables also converged and formed scales with high reliability, with the exception of the comparison variables. High income, individualism, human rights, and societal equality correlated strongly with each other, and with SWB across surveys. Income correlated with SWB even after basic need fulfillment was controlled. Only individualism persistently correlated with SWB when other predictors were controlled. Cultural homogeneity, income growth, and income comparison showed either low or inconsistent relations with SWB.

1,617 citations


Journal ArticleDOI
10 Mar 1995-Cell
TL;DR: Genetic linkage between LQT3 and polymorphisms within SCN5A, the cardiac sodium channel gene, and single strand conformation polymorphism and DNA sequence analyses suggest that mutations in SCN 5A cause chromosome 3-linked LQt and indicate a likely cellular mechanism for this disorder.

1,550 citations


Journal ArticleDOI
TL;DR: The meaning and significance of the empowerment concept and problems associated with the proliferation of interest in empowerment are reviewed and synopses of each article are presented along with some of the themes and lessons cutting across the frameworks, studies, and applications.
Abstract: This introduction to the special issue briefly reviews the meaning and significance of the empowerment concept and problems associated with the proliferation of interest in empowerment. We identify some of the topics not included in this issue and relate those to the many broad and diverse areas of psychological empowerment theory and community-based research and intervention that are covered. We present synopses of each article along with some of the themes and lessons cutting across the frameworks, studies, and applications. These include a wide diversity of settings, fairly representative of empowerment interventions, and, at the same time, improved clarity (if not unanimity) of definitions and measurement, which has been a problem in much empowerment research and intervention.

1,128 citations


Journal ArticleDOI
TL;DR: The results do not support routine treatment of myocarditis with immunosuppressive drugs, but long-term mortality was high and patients with a vigorous inflammatory response had less severe disease.
Abstract: Background Myocarditis is a serious disorder, and treatment options are limited. This trial was designed to determine whether immunosuppressive therapy improves left ventricular function in patients with myocarditis. Methods We randomly assigned 111 patients with a histopathological diagnosis of myocarditis and a left ventricular ejection fraction of less than 0.45 to receive conventional therapy alone or combined with a 24-week regimen of immunosuppressive therapy. Immunosuppressive therapy consisted of prednisone with either cyclosporine or azathioprine. The primary outcome measure was a change in the left ventricular ejection fraction at 28 weeks. Results In the group as a whole, the mean (±SE) left ventricular ejection fraction improved from 0.25±0.01 at base line to 0.34±0.02 at 28 weeks (P<0.001). The mean change in the left ventricular ejection fraction at 28 weeks did not differ significantly between the group of patients who received immunosuppressive therapy (a gain of 0.10; 95 percent confidenc...

1,105 citations


Journal ArticleDOI
TL;DR: It is inferred that a major expansion of the human population occurred during the late Pleistocene, because a simple model of population history that assumes that a population grows (or shrinks) suddenly from female size N0 toFemale size N1 is studied.
Abstract: Expansions of population size leave characteristic signatures in mitochondrial "mismatch distributions." Consequently, these distributions can inform us about the history of changes in population size. Here, I study a simple model of population history that assumes that, t generations before the present, a population grows (or shrinks) suddenly from female size N0 to female size N1 . Although this model is simple, it often provides an accurate description of data generated by complex population histories. I develop statistical methods that estimate θ0 = 2uN0 , θ1 = 2uN1 , and τ = 2ut (where u is the mutation rate), and place a confidence region around these estimates. These estimators are well behaved, and insensitive to simplifying assumptions. Finally, I apply these methods to published mitochondrial data, and infer that a major expansion of the human population occurred during the late Pleistocene.

1,048 citations


Journal ArticleDOI
M. K. Ridd1
TL;DR: In this paper, a vegetation-impervious surface-soil (V-I-S) model is presented as a possible basis for standardization of urban environment parameters, which may serve as a foundation for characterizing urban/near-urban environments universally, and for comparison of urban morphology within and between cities.
Abstract: Growing interest in urban systems as ecological entities calls for some standards in parameterizing biophysical composition of urban environments. A vegetation-impervious surface-soil ( V-I-S) model is presented as a possible basis for standardization. The V-I-S model may serve as a foundation for characterizing urban/near-urban environments universally, and for comparison of urban morphology within and between cities. Inasmuch as the model may be driven by satellite digital data, it may serve as a global model of urban ecosystem analysis and comparison world-wide. The V-I-S model may prove useful for urban change detection and growth modelling, for environmental impact analysis from urbanization, for energy- and water-related investigations, and for certain dimensions of human ecosystem analysis of the city as well.

Journal ArticleDOI
TL;DR: In a study of mothers 13 to 24 years old who had the characteristics of most white, middle-class Americans, a younger age conferred an increased risk of adverse pregnancy outcomes that was independent of important confounding sociodemographic factors.
Abstract: Background Pregnancy in adolescence is associated with an excess risk of poor outcomes, including low birth weight and prematurity. Whether this association simply reflects the deleterious sociodemographic environment of most pregnant teenagers or whether biologic immaturity is also causally implicated is not known. Methods To determine whether a young age confers an intrinsic risk of adverse outcomes of pregnancy, we performed stratified analyses of 134,088 white girls and women, 13 to 24 years old, in Utah who delivered singleton, first-born children between 1970 and 1990. Relative risk for subgroups of this study population was examined to eliminate the confounding influence of marital status, educational level, and the adequacy of prenatal care. The adjusted relative risk for the entire study group was calculated as the weighted average of the stratum-specific risks. Results Among white married mothers with educational levels appropriate for their ages who received adequate prenatal care, younger teen...

Journal ArticleDOI
TL;DR: Under basal conditions HDL serves an anti-inflammatory role but during APR displacement and/or exchange of proteins associated with HDL results in a pro-inflammatory molecule.
Abstract: We previously reported that high density lipoprotein (HDL) protects against the oxidative modification of low density lipoprotein (LDL) induced by artery wall cells causing these cells to produce pro-inflammatory molecules. We also reported that enzyme systems associated with HDL were responsible for this anti-inflammatory property of HDL. We now report studies comparing HDL before and during an acute phase response (APR) in both humans and a croton oil rabbit model. In rabbits, from the onset of APR the protective effect of HDL progressively decreased and was completely lost by day three. As serum amyloid A (SAA) levels in acute phase HDL (AP-HDL) increased, apo A-I levels decreased 73%. Concomitantly, paraoxonase (PON) and platelet activating factor acetylhydrolase (PAF-AH) levels in HDL declined 71 and 90%, respectively, from days one to three. After day three, there was some recovery of the protective effect of HDL. AP-HDL from human patients and rabbits but not normal or control HDL (C-HDL) exhibited increases in ceruloplasmin (CP). This increase in CP was not seen in acute phase VLDL or LDL. C-HDL incubated with purified CP and re-isolated (CP-HDL), lost its ability to inhibit LDL oxidation. Northern blot analyses demonstrated enhanced expression of MCP-1 in coculture cells treated with AP-HDL and CP-HDL compared to C-HDL. Enrichment of human AP-HDL with purified PON or PAF-AH rendered AP-HDL protective against LDL modification. We conclude that under basal conditions HDL serves an anti-inflammatory role but during APR displacement and/or exchange of proteins associated with HDL results in a pro-inflammatory molecule.

Journal ArticleDOI
TL;DR: This is the first study to demonstrate differential responses of LQTS patients to interventions targeted to their specific genetic defect, and it is suggested that LQT3 patients may be more likely to benefit from Na+ channel blockers and from cardiac pacing because they would be at higher risk of arrhythmia at slow heart rates.
Abstract: Background The genes for the long QT syndrome (LQTS) linked to chromosomes 3 (LQT3) and 7 (LQT2) were identified as SCN5A, the cardiac Na+ channel gene, and as HERG, a K+ channel gene. These findings opened the possibility of attempting gene-specific control of ventricular repolarization. We tested the hypothesis that the QT interval would shorten more in LQT3 than in LQT2 patients in response to mexiletine and also in response to increases in heart rate. Methods and Results Fifteen LQTS patients were studied. Six LQT3 and 7 LQT2 patients were treated with mexiletine, and its effects on QT and QTc were measured. Mexiletine significantly shortened the QT interval among LQT3 patients (QTc from 535±32 to 445±31 ms, P<.005) but not among LQT2 patients (QTc from 530±79 to 503±60 ms, P=NS). LQT3 patients (n=7) shortened their QT interval in response to increases in heart rate much more than LQT2 patients (n=4) and also more than 18 healthy control subjects (9.45±3.3 versus 3.95±1.97 and 2.83±1.33, P<.05; data e...

Book
29 Jun 1995
TL;DR: Almost two thirds of adult ADHD patients experience moderate-to-marked improvement with psychoeducational management and stimulant drug therapy.
Abstract: Attention-deficit hyperactivity disorder (ADHD) is probably the most common chronic undiagnosed psychiatric disorder in adults. It is characterized by inattention and distractibility, restlessness, labile mood, quick temper, overactivity, disorganization, and impulsivity. It is always preceded by the childhood diagnosis, a disorder that is rarely inquired about, and usually overlooked. Treatment can be dramatically effective. Approximately two thirds of adult ADHD patients experience moderate-to-marked improvement with psychoeducational management and stimulant drug therapy.



Journal ArticleDOI
Anoop Madhok1
TL;DR: In this article, the authors argue that overemphasis on the outcome has resulted in a neglect of the social processes underlying the outcome, and argue that a shift in focus from ownership to relational dynamics is encouraged.
Abstract: In spite of the increasing popularity of international joint ventures, managers express a high level of dissatisfaction with them. This paper argues that overemphasis on the outcome has resulted in a neglect of the social processes underlying the outcome. The paper elaborates upon the rationale for a cooperative approach towards interorganizational collaborative relationships based on trust, and discusses it in the context of joint ventures. This is then applied towards understanding multinational ownership preferences and tolerance for joint ventures. It is argued that trust-centered logic is largely consistent with approaches that emphasize the issue of ownership, and deepens and enriches the insights provided by the latter. A shift in focus from ownership to relational dynamics is encouraged.

Journal ArticleDOI
29 Jun 1995-Nature
TL;DR: Double mutants are generated which have dramatic phenotypes not apparent in mice homozygous for the individual mutations, and suggest that paralogous Hoxgenes function together to specify limb outgrowth and patterning along the proximodistal axis.
Abstract: MICE with targeted disruptions1 in Hoxgenes have been generated to evaluate the role of the Hox complex in determining the mammalian body plan. This complex of 38 genes encodes transcription factors that specify regional information along the embryonic axes. Early in vertebrate evolution an ancestral complex shared with invertebrates was duplicated twice to give rise to the four linkage groups (Hox A, B, C and D)2,3. As a consequence, corresponding genes on the separate linkage groups, called paralogues, are most closely related to each other. Based on sequence similarities, the Hox genes have been subdivided into 13 paralogous groups. The five most 5′ groups (Hox9–13) pattern the posterior region of the vertebrate embryo and the appendicular skeleton4–18. Mice with individual mutations in the paralogous genes hoxa-11 and hoxd-11 have been described15–18. By breeding these two strains together we have generated double mutants which have dramatic phenotypes not apparent in mice homozygous for the individual mutations. The radius and the ulna of the forelimb are almost entirely eliminated, the axial skeleton shows homeotic transformations, and there are severe kidney defects not present in either single mutant. The limb and axial phenotypes are quantitative: as more mutant alleles are added to the genotype, the phenotype becomes progressively more severe. The appendicular skeleton defects suggest that paralogous Hoxgenes function together to specify limb outgrowth and patterning along the proximodistal axis.

Journal ArticleDOI
TL;DR: Three separate genetic loci for the long QT syndrome including mutations in two cardiac ionic channel genes were associated with different phenotypic T-wave patterns on the ECG, providing insight into the influence of genetic factors on ECG manifestations of ventricular repolarization.
Abstract: Background The long QT syndrome is an inherited disorder with prolonged ventricular repolarization and a propensity to ventricular tachyarrhythmias and sudden arrhythmic death. Recent linkage studies have demonstrated three separate loci for this disorder on chromosomes 3, 7, and 11, and specific mutated genes for long QT syndrome have been identified on two of these chromosomes. We investigated ECG T-wave patterns (phenotypes) in members of families linked to three genetically distinct forms of the long QT syndrome. Methods and Results Five quantitative ECG repolarization parameters, ie, four Bazett-corrected time intervals (QTonset-c, QTpeak-c, QTc, and Tduration-c, in milliseconds) and the absolute height of the T wave (Tamplitude, in millivolts), were measured in 153 members of six families with long QT syndrome linked to markers on chromosomes 3 (n=47), 7 (n=30), and 11 (n=76). Genotypic data were used to define each family member as being affected or unaffected with long QT syndrome. Affected member...

Journal ArticleDOI
TL;DR: This study examined the effectiveness of a social skills training program for normal-IQ adolescents with autism and demonstrated meaningful change in the treatment group's performance on several false belief tasks, but no improvement in the control sample.
Abstract: This study examined the effectiveness of a social skills training program for normal-IQ adolescents with autism. Five boys participated in the 4 1/2-month treatment condition; four boys matched on age, IQ, and severity of autism constituted the no-treatment control group. In addition to teaching specific interactional and conversational skills, the training program provided explicit and systematic instruction in the underlying social-cognitive principles necessary to infer the mental states of others (i.e., theory of mind). Pre- and post-intervention assessment demonstrated meaningful change in the treatment group's performance on several false belief tasks, but no improvement in the control sample. No changes, however, were demonstrated on general parent and teacher ratings of social competence for either group.

Journal ArticleDOI
TL;DR: The striking similarities between clinical and hemodynamic findings in amniotic fluid embolism and both anaphylaxis and septic shock suggest a common pathophysiologic mechanism for all these conditions.

Journal ArticleDOI
06 Apr 1995-Nature
TL;DR: Recombinant PAF acetylhydrolase has the sub-strate specificity and lipoprotein association of the native enzyme, and blocks inflammation in vivo: it markedly decreases vascular leakage in pleurisy and paw oedema, suggesting that PAFacetylHydrolase might be a useful therapy for severe acute inflammation.
Abstract: Platelet-activating factor (PAF) is a potent pro-inflammatory phospholipid that activates cells involved in inflammation. The biological activity of PAF depends on its structural features, namely an ether linkage at the sn-1 position and an acetate group at the sn-2 position. The actions of PAF are abolished by hydrolysis of the acetyl residue, a reaction catalysed by PAF acetylhydrolase. There are at least two forms of this enzyme--one intracellular and another that circulates in plasma and is likely to regulate inflammation. Here we report the molecular cloning and characterization of the human plasma PAF acetylhydrolase. The unique sequence contains a Gly-Xaa-Ser-Xaa-Gly motif commonly found in lipases. Recombinant PAF acetylhydrolase has the substrate specificity and lipoprotein association of the native enzyme, and blocks inflammation in vivo: it markedly decreases vascular leakage in pleurisy and paw oedema, suggesting that PAF acetylhydrolase might be a useful therapy for severe acute inflammation.

Patent
05 Jun 1995
TL;DR: Positive-negative selector (PNS) as discussed by the authors vectors are provided for modifying a target DNA sequence contained in the genome of a target cell capable of homologous recombination, which includes organisms such as non-human transgenic animals and plants.
Abstract: Positive-negative selector (PNS) vectors are provided for modifying a target DNA sequence contained in the genome of a target cell capable of homologous recombination. The vector comprises a first DNA sequence which contains at least one sequence portion which is substantially homologous to a portion of a first region of a target DNA sequence. The vector also includes a second DNA sequence containing at least one sequence portion which is substantially homologous to another portion of a second region of a target DNA sequence. A third DNA sequence is positioned between the first and second DNA sequences and encodes a positive selection marker which when expressed is functional in the target cell in which the vector is used. A fourth DNA sequence encoding a negative selection marker, also functional in the target cell, is positioned 5' to the first or 3' to the second DNA sequence and is substantially incapable of homologous recombination with the target DNA sequence. The invention also includes transformed cells containing at least one predetermined modification of a target DNA sequence contained in the genome of the cell. In addition, the invention includes organisms such as non-human transgenic animals and plants which contain cells having predetermined modifications of a target DNA sequence in the genome of the organism.

Journal ArticleDOI
13 Jan 1995-Cell
TL;DR: A novel autoregulatory mechanism enables modulation of frameshifting according to the cellular concentration of polyamines, which binds to, and destabilizes, ornithine decarboxylase, a key enzyme in polyamine synthesis, thus completing a regulatory circuit.

Journal ArticleDOI
TL;DR: Results stress the importance of severity-chronicity of parental illness in the study of depression and early attachment relations, and that differences between children with and without coherent, organized attachment strategies are as clinically informative as are differences between secure and insecure children.
Abstract: Relations between maternal depression and attachment security among 50 infant-mother and 54 preschool child-mother dyads were examined using the classification system of M.D.S. Ainsworth, M.C. Blehar, E. Waters, and S. Wall (1979) and M. Main and J. Solomon (1990) for infants and the Preschool Assessment (P.M. Crittenden, 1992b) for preschoolers. Attachment insecurity was significantly associated with maternal depression among infants and preschoolers. Futhermore, children without unitary, coherent attachment strategies tended to have more chronically impaired mothers than did children with coherent, organzed attachment strategies. Results stress the importance of severity-chronicity of parental illness in the study of depression and early attachment relations, and that differences between children with and without coherent, organized attachment strategies are as clinically informative as are differences between secure and insecure children

Journal ArticleDOI
TL;DR: The particles of dust introduce into space a privileged system of coordinates that allows the supermomentum constraint to be solved explicitly and yields a formally conserved inner product that can be written in terms of either the instantaneous state functionals or the solutions of constraints.
Abstract: The coupling of the metric to an incoherent dust introduces into spacetime a privileged dynamical reference frame and time foliation. The comoving coordinates of the dust particles and the proper time along the dust worldlines become canonical coordinates in the phase space of the system. The Hamiltonian constraint can be resolved with respect to the momentum that is canonically conjugate to the dust time. Formal imposition of the resolved constraint as an operator restriction on the quantum states yields a functional Schr\"odinger equation. The ensuing Hamiltonian density has an extraordinary feature: it depends only on the geometric variables, not on the dust coordinates or time. This has three important consequences. First, the functional Schr\"odinger equation can be solved by separating the dust time from the geometric variables. Second, disregarding the standard factor-ordering difficulties, the Hamiltonian densities strongly commute and therefore can be simultaneously defined by spectral analysis. Third, the standard constraint system of vacuum gravity is cast into a form in which it generates a true Lie algebra. The particles of dust introduce into space a privileged system of coordinates that allows the supermomentum constraint to be solved explicitly. The Schr\"odinger equation yields a formally conserved inner product that can be written in terms of either the instantaneous state functionals or the solutions of constraints. Gravitational observables admit a similar dual representation. Examples of observables are given, though neither the intrinsic metric nor the extrinsic curvature are observables. This comes as close as one can reasonably expect to a satisfactory phenomenological quantization scheme that is free of most of the problems of time.

Journal ArticleDOI
TL;DR: It appears that the loss of Hoxa-3 affects the intrinsic capacity of this neural crest cell population to differentiate and/or to induce proper differentiation of the surrounding pharyngeal arch and pouch tissues.
Abstract: Targeted disruption of Hoxa-3 results in a number of regionally restricted defects in tissues and structures derived from or patterned by mesenchymal neural crest. However, analysis of mutant embryos with injections of a carbocyanine dye or with molecular markers that label these cells indicates that neither the amount nor the migration patterns of this neural crest population are grossly affected. Therefore, it appears that the loss of Hoxa-3 affects the intrinsic capacity of this neural crest cell population to differentiate and/or to induce proper differentiation of the surrounding pharyngeal arch and pouch tissues. Hoxa-3 mutant mice are athymic and show thyroid hypoplasia. Thymus development is first evident as an expansion of mesenchymal neural crest in the posterior part of the 3rd pharyngeal pouch. Prior to this expansion, a marked reduction in pax-1 expression is observed in these cells in the mutant embryos. As pax-1 mutant mice also show thymic hypoplasia, these results suggest that Hoxa-3 may be required to maintain pax-1 expression in these cells and that the reduction of pax-1 expression is part of the athymic teleology in Hoxa-3 mutant mice. The thyroid gland is formed from the fusion of two structures of separate embryonic origin, the thyroid diverticulum, which is formed from endodermal epithelium in the floor of the pharynx, and the ultimobranchial body, formed from mesenchymal neural crest in the 4th pharyngeal pouch. Both of these sites express Hoxa-3 and are defective in mutant mice. Often a vesicle is observed in mutant mice that is exclusively composed of calcitonin-producing cells, suggesting the persistence of an ultimobranchial body. Both aspects of the thyroid phenotype show variable expressivity among mutant animals, even on the two sides of the same mutant animal. This variability suggests the presence of a compensating gene or genes, whose utilization is stochastic. A reasonable candidate for providing this compensatory function is the paralogous gene Hoxb-3.

Journal ArticleDOI
15 Feb 1995-JAMA
TL;DR: The high frequency of protein-terminating mutations and the observation of many recurrent mutations found in a diverse set of samples could lead to a relatively simple diagnostic test for BRCA1 mutations.
Abstract: Objectives. —To report the initial experience of an international group of investigators in identifying mutations in theBRCA1breast and ovarian cancer susceptibility gene, to assess the spectrum of such mutations in samples from patients with different family histories of cancer, and to determine the frequency of recurrent mutations. Design. —Nine laboratories in North America and the United Kingdom tested forBRCA 1mutations in DNA samples obtained from a total of 372 unrelated patients with breast or ovarian cancer largely chosen from high-risk families. Three of these laboratories also analyzed a total of 714 additional samples from breast or ovarian cancer cases, including 557 unselected for family history, for two specific mutations that had been found to recur in familial samples. Participants. —A total of 1086 women with either breast or ovarian cancer. Main Outcome Measure. —The detection of sequence variation in patients' DNA samples that is not found in sets of control samples. Results. —BRCA 1mutations have now been identified in a total of 80 patient samples. Thirty-eight distinct mutations were found among 63 mutations identified through a complete screen of theBRCA 1gene. Three specific mutations appeared relatively common, occurring eight, seven, and five times, respectively. When specific tests for the two most common mutations were performed in larger sets of samples, they were found in 17 additional patients. Mutations predicted to result in a truncated protein accounted for 86% of the mutations detected by complete screening. Conclusions. —The high frequency of protein-terminating mutations and the observation of many recurrent mutations found in a diverse set of samples could lead to a relatively simple diagnostic test forBRCA 1mutations. More data must be accumulated to address specifically the sensitivity and specificity of such a diagnostic testing procedure and to better estimate the age-specific risk for breast and ovarian cancer associated with such mutations. (JAMA. 1995;273:535-541)

Journal ArticleDOI
TL;DR: In this article, the classic concept of centrality discovered by Camille Jordan in the 19th century is introduced as a model for social network analysis and generalized to include the path center of a graph.