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P O'Connell

Publications and source records attributed to P O'Connell.

At least 19 recordsLinked to original sources
PubMed2005

The impact of the draft 2005 recommendations of ICRP on secondary derived regulatory values being considered by the US Department of Energy.

The US Department of Energy, Office of Environment, Safety and Health, Office of Health is responsible for maintaining the Department of Energy's occupational radiation protection rule, Title 10 Code of Federal Regulations, Part 835, Occupational Radiation Protection. The Department of Energy is evaluating amending its rule to include the dose assessment methodology recommended in International Commission on Radiological Protection (ICRP) Publications 60 and 68. On 21 June 2004 the ICRP posted their draft, Recommendations of the International Commission on Radiological Protection 2005, which included revisions to the recommended dose assessment methodology. The Department of Energy compared the draft recommendations to determine their effect on the changes the Department of Energy is currently considering.

Government Agencies↗
PubMed2003

Reduced and standard target concentration tacrolimus with sirolimus in renal allograft recipients.

We report 6-month results of renal allograft recipients enrolled in seven Australian centers as part of a worldwide, multicenter, randomized, open-label, concentration-controlled trial comparing standard tacrolimus (sTAC) with reduced tacrolimus (rTAC) both with sirolimus (SRL) and steroids. Patients were randomized 1:1 to either rTAC (n = 33) with a target maintenance concentration of SRL of 8 to 15 ng/mL and TAC of 3 to 7 ng/mL, or sTAC (n = 31) with SRL target of 5 to 10 ng/mL and TAC of 8 to 12 ng/mL. Antibody induction was prohibited. Adult recipients of a first or second cadaveric or non-HLA-identical living donor renal graft were eligible for enrollment. Recipients with a panel-reactive antibody level of >50% and recipients of regrafts who had lost their first graft from rejection within the first 6 months were ineligible. The groups were compared for graft function, incidence of rejection, and patient and graft survival at 6 months. There were no differences in demographics. There were 30% and 29% discontinuations in the rTAC and sTAC groups mainly due to adverse events in the first month. The 6-month patient and graft survival by intention-to-treat analysis was 94% and 91% for rTAC and 100% and 97% for sTAC (P = NS), respectively. Incidence and severity of biopsy-proven acute rejection was not different between the two groups, being 21% for rTAC and 19% for sTAC. The mean serum creatinine was 121 micromol/L and 148 micromol/L for rTAC and sTAC groups (P =.09), respectively. Glomerular filtration rate (GFR) was 68 mL/min and 62 mL/min (P =.23), respectively. Adverse events, infections, and antihypertensive and antilipidemic agent usage were similar. Of interest is that the overall incidence of thrombotic microangiopathy was 14%. These results support the safety and efficacy of SRL + TAC. Reduced TAC is associated with a trend toward improved renal function.

Adult↗
PubMed2001

Loss of heterozygosity events impeding breast cancer metastasis contain the MTA1 gene.

Breast cancer mortality is seldom attributable to the primary tumor, but rather to the presence of systemic (metastatic) disease. Axillary lymph node dissection can identify the presence of metastatic breast cancer cells and serves as a marker for systemic disease. Previous work in our laboratory determined that rates of loss of heterozygosity (LOH) of a 1.6-Mb region of chromosome 14q 31.2 is much higher in axillary lymph node-negative primary breast tumors than in axillary lymph node-positive primary breast tumors (P. O'Connell et al., J. NATL: Cancer INST:, 91: 1391-1397, 1999.). This unusual observation suggests that, whereas the LOH of this region promotes primary breast cancer formation, some gene(s) mapping to this 1.6-Mb region is rate-limiting for breast cancer metastasis. Thus, if primary breast cancers delete this region, their ability to metastasize decreases. To identify this gene(s), we have physically mapped this area of chromosome 14q, confirmed the position of two known genes and 13 other expressed sequence tags into this 1.6-Mb region. One of these, the metastasis-associated 1 (MTA1) gene, previously identified as a metastasis-promoting gene (Y. Toh et al., J. BIOL: CHEM:, 269: 22958-22963, 1994.), mapped to the center of our 1.6-Mb target region. Thus, MTA1 represents a strong candidate for this breast cancer metastasis-promoting gene.

Breast Neoplasms↗
PubMed2001

A major locus for fasting insulin concentrations and insulin resistance on chromosome 6q with strong pleiotropic effects on obesity-related phenotypes in nondiabetic Mexican Americans.

Insulin resistance and hyperinsulinemia are strong correlates of obesity and type 2 diabetes, but little is known about their genetic determinants. Using data on nondiabetics from Mexican American families and a multipoint linkage approach, we scanned the genome and identified a major locus near marker D6S403 for fasting "true" insulin levels (LOD score 4.1, empirical P<.0001), which do not crossreact with insulin precursors. Insulin resistance, as assessed by the homeostasis model using fasting glucose and specific insulin (FSI) values, was also strongly linked (LOD score 3.5, empirical P<.0001) with this region. Two other regions across the genome were found to be suggestively linked to FSI: a location on chromosome 2q, near marker D2S141, and another location on chromosome 6q, near marker D6S264. Since several insulin-resistance syndrome (IRS)-related phenotypes were mapped independently to the regions on chromosome 6q, we conducted bivariate multipoint linkage analyses to map the correlated IRS phenotypes. These analyses implicated the same chromosomal region near marker D6S403 (6q22-q23) as harboring a major gene with strong pleiotropic effects on obesity and on lipid measures, including leptin concentrations (e.g., LOD(eq) for traits-specific insulin and leptin was 4.7). A positional candidate gene for insulin resistance in this chromosomal region is the plasma cell-membrane glycoprotein PC-1 (6q22-q23). The genetic location on chromosome 6q, near marker D6S264 (6q25.2-q26), was also identified by the bivariate analysis as exerting significant pleiotropic influences on IRS-related phenotypes (e.g., LOD(eq) for traits-specific insulin and leptin was 4.1). This chromosomal region harbors positional candidate genes, such as the insulin-like growth factor 2 receptor (IGF2R, 6q26) and acetyl-CoA acetyltransferase 2 (ACAT2, 6q25.3-q26). In sum, we found substantial evidence for susceptibility loci on chromosome 6q that influence insulin concentrations and other IRS-related phenotypes in Mexican Americans.

Adult↗
PubMed2001

High rates of loss of heterozygosity on chromosome 19p13 in human breast cancer.

We have recently discovered that the nuclear matrix protein SAFB is an oestrogen receptor corepressor. Since it has become clear that many steroid receptor cofactors play important roles in breast tumorigenesis, we investigated whether SAFB could also be involved in breast cancer. To address this question, the gene locus was examined for structural alterations in breast cancer tissue. Laser capture microdissection was used for isolating DNA from paired primary breast tumour and normal tissue specimens, and the loss of heterozygosity (LOH) at chromosome 19p13.2-3 was determined by use of microsatellite markers. LOH was detected at the marker D19S216, which colocalizes with the SAFB locus, in specimens from 29 (78.4%) of 37 informative patients. The peak LOH rate occurred at D19S216 near the SAFB locus, with LOH frequencies ranging from 21.6% to 47.2% at other markers. The finding of a very high LOH rate at the marker D19S216 strongly indicates the presence of a breast tumour-suppressor gene locus. While preliminary findings of mutations in SAFB suggest that this indeed may be a promising candidate, other potential candidate genes are located at this locus.

Antigens, Nuclear↗
PubMed2001

Prevalence of fibromyalgia, anxiety and depression in chronic hepatitis C virus infection: relationship to RT-PCR status and mode of acquisition.

BACKGROUND: Musculoskeletal complaints, dry eyes, fatigue and anxiety are common symptoms in patients with hepatitis C virus (HCV) infection, but there are few controlled data evaluating this. AIM: To assess the prevalence of rheumatological disease, fatigue and anxiety in different groups of patients with chronic HCV infection. PATIENTS AND METHODS: Seventy-seven patients with HCV were evaluated. Of these, 49 (64%) had been infected via contaminated anti-D immunoglobulin, 25 (33%) were intravenous drug users (IVDUs), and three were transfusion related; 78% were female. Twenty-five age- and sex-matched controls were also evaluated. Assessment was performed by history, physical examination, the Fibromyalgia Impact Questionnaire (FIQ) and the Hospital Anxiety and Depression Score (HADS). RESULTS: Four (5%) patients fulfilled the criteria for fibromyalgia. All were infected via anti-D immunoglobulin, and three were PCR positive. The mean number of tender points in anti-D patients was 5.0 (+/- 4.07) compared with 2.8 (+/- 2.7) in controls (P= 0.028) and 2.5 (+/- 2.2) in IVDUs (P< 0.004). There was no significant difference in the number of tender points between PCR-positive and PCR-negative patients (P= 0.23). Anxiety and depression scores were significantly higher in anti-D patients (P= 0.0001) and IVDUs (P= 0.005) compared with controls. Forty per cent of the HCV patients had a positive Schirmer test. Forty-two per cent of PCR-positive patients had a positive rheumatoid factor (RF, > 1/80). CONCLUSION: This study reveals a moderate increase in prevalence of fibromyalgia in HCV patients. The number of tender points was related to mode of acquisition but not to PCR status. Anxiety and depression levels are also increased in HCV patients compared with controls. Prevalence of RF was higher in PCR-positive patients compared with controls and those who had cleared the virus.

Adult↗
PubMed2000

A hypersensitive estrogen receptor-alpha mutation in premalignant breast lesions.

The best current model of breast cancer evolution suggests that most cancers arise from certain premalignant lesions. We have identified a common (34%) somatic mutation in the estrogen receptor (ER)-alpha gene in a series of 59 typical hyperplasias, a type of early premalignant breast lesion. The mutation, which affects the border of the hinge and hormone binding domains of ER-alpha, showed increased sensitivity to estrogen as compared with wild-type ER-alpha in stably transfected breast cancer cells, including markedly increased proliferation at subphysiological levels of estrogen. The mutated ER-alpha exhibits enhanced binding to the TIF-2 coactivator at low levels of hormone, which may partially explain its increased estrogen responsiveness. These data suggest that this mutation may promote or accelerate the development of cancer from premalignant breast lesions.

Breast↗
PubMed2000

A major susceptibility locus influencing plasma triglyceride concentrations is located on chromosome 15q in Mexican Americans.

Although several genetic forms of rare or syndromic hypertriglyceridemia have been reported, little is known about the specific chromosomal regions across the genome harboring susceptibility genes for common forms of hypertriglyceridemia. Therefore, we conducted a genomewide scan for susceptibility genes influencing plasma triglyceride (TG) levels in a Mexican American population. We used both phenotypic and genotypic data from 418 individuals distributed across 27 low-income, extended Mexican American families. For the analyses, TG values were log transformed (ln TG). We used a variance-components technique to conduct multipoint linkage analyses for localizing susceptibility genes that determine variation in TG levels. We used an approximately 10-15-cM map, which was made on the basis of information from 295 microsatellite markers. After accounting for the effects of sex and sex-specific age terms, we found significant evidence for linkage (LOD = 3.88) of ln TG levels to a genetic location between the markers GABRB3 and D15S165 on chromosome 15q. This putative locus explains 39.7+/-7% (P=.000012) of total phenotypic variation in ln TG levels. Suggestive evidence was found for linkage of ln TG levels to two different locations on chromosome 7, which are approximately 85 cM apart from each other. Also, there is some evidence for linkage of high-density lipoprotein cholesterol concentrations to a genetic location near one of the regions on chromosome 7. In conclusion, we found strong evidence for linkage of ln TG levels to a genetic location on chromosome 15q in a Mexican American population, which is prone to disease conditions such as type 2 diabetes and the insulin-resistance syndrome that are associated with hypertriglyceridemia. This putative locus appears to have a major influence on ln TG variation.

Adult↗
PubMed2000

Identification of two distinct regions of allelic imbalance on chromosome 18Q in metastatic prostate cancer.

Like most cancers, prostate cancer (CaP) is believed to be the result of the accumulation of genetic alterations within cells. Previous studies have implicated numerous chromosomal regions with elevated rates of allelic imbalance (AI), using mostly primary CaPs with an unknown disease outcome. These regions of AI are proposed sites for tumor suppressor genes. One of the regions previously implicated as coding for at least one tumor suppressor gene is the long arm of chromosome 18 (18q). To confirm this observation, as well as to narrow the critical region for this putative tumor suppressor, we analyzed 32 metastatic CaP specimens for AI on chromosome 18q. Thirty-one of these 32 specimens (96.8%) exhibited AI at one or more loci on chromosome 18q. Our analysis using 17 polymorphic markers revealed statistically significant AI on chromosome 18q at 3 markers, D18S35, D18S64 and D18S461. Using these markers as a guide, we have been able to identify 2 distinct minimum regions of AI on 18q. The first region is between the genetic markers D18S1119 and D18S64. The second region lies more distal on the long arm of the chromosome and is between the genetic markers D18S848 and D18S58. To determine if 18q loss is a late event in the progression of CaP, we also examined prostatic intraepithelial neoplasia (PIN) and primary prostate tumors from 17 patients for AI with a subset of 18q markers. We found significantly higher AI in the metastatic samples. Our results are consistent with 18q losses occurring late in CaP progression.

Carcinoma in Situ↗
PubMed1999

Race-specific HIV-1 disease-modifying effects associated with CCR5 haplotypes.

Genetic variation in CC chemokine receptor 5 (CCR5), the major HIV-1 coreceptor, has been shown to influence HIV-1 transmission and disease progression. However, it is generally assumed that the same CCR5 genotype (or haplotype) has similar phenotypic effects in different populations. To test this assumption, we used an evolutionary-based classification of CCR5 haplotypes to determine their associated HIV-1 disease-modifying effects in a large well-characterized racially mixed cohort of HIV-1-seropositive individuals. We demonstrate that the spectrum of CCR5 haplotypes associated with disease acceleration or retardation differs between African Americans and Caucasians. Also, we show that there is a strong interactive effect between CCR5 haplotypes with different evolutionary histories. The striking population-specific phenotypic effects associated with CCR5 haplotypes emphasize the importance of understanding the evolutionary context in which disease susceptibility genes are expressed.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Hippocampal volume reduction in schizophrenia: effects of genetic risk and pregnancy and birth complications.

BACKGROUND: Hippocampal volume reduction has been repeatedly demonstrated in schizophrenia. The relative contribution of genetic and environmental factors to this is unclear. METHODS: To address this question, we compared volumetric measurements of the left and right hippocampus, obtained using stereological methods from brain MRI scans, from two groups of patients with schizophrenia as well as healthy controls (n = 26). Patients (n = 27) in the first group, had no family history of schizophrenia and had experienced severe pregnancy and birth complications (PBCs). The second group comprised of patients (n = 21) without a history of severe PBCs from families multiply affected with schizophrenia. RESULTS: Reduction of the left hippocampal volume was associated with the diagnosis of schizophrenia but was present only in patients with a history of severe PBCs; in this group the smaller hippocampal volume, the earlier the onset of psychosis. CONCLUSIONS: Our findings suggest that environmental factors, in this case severe PBCs, make a significant contribution to hippocampal abnormalities in schizophrenia.

Adult↗
PubMed1999

Loss of heterozygosity at D14S62 and metastatic potential of breast cancer.

BACKGROUND: In breast cancer progression, the prevalence of damage at specific genetic loci often increases with the stage of the lesion (i.e., from noninvasive to invasive to metastatic). By use of genetic markers and analysis of allelic imbalances (loss of heterozygosity [LOH]) to compare DNA samples from paired normal and breast tumor tissues, we examined whether specific genetic changes in primary breast cancers can serve as biomarkers of metastatic potential. METHODS: DNA samples from 76 patients with primary breast cancer (42 with axillary lymph node-negative disease and 34 with axillary lymph node-positive disease) were genotyped with four genetic markers spanning chromosome 14q31-q32. The intensity ratios of the two genetic alleles in normal-tumor DNA pairs were examined in genetically informative individuals. LOH was scored when the tumor allele intensity ratio (tumor allele 1/tumor allele 2) divided by the normal allele intensity ratio (normal allele 1/normal allele 2) was either less than 0.71 (tumor allele 1 LOH) or greater than 1. 4 (tumor allele 2 LOH). RESULTS/CONCLUSIONS: Contrary to our expectations, we found statistically significantly more LOH events at markers D14S62 (two-sided P =.001) and D14S51 (two-sided P =.02) in primary breast cancers from patients with lymph node-negative disease versus lymph node-positive disease, suggesting the presence of a gene in this region that affects metastatic potential. Analysis of small interstitial or terminal deletions in the tumors of six especially informative patients with lymph node-negative disease places the putative metastasis-related gene in a 1490-kilobase region near D14S62. IMPLICATIONS: LOH in the D14S62 region may impede the process of metastasis. Therefore, the D14S62 region LOH profile may have prognostic implications, and the isolation of the metastasis-related gene(s) in this region may lead to better diagnosis and treatment of breast cancer.

Biomarkers, Tumor↗
PubMed1999

Genetic pattern of prostate cancer progression.

Genetic alterations in primary prostate cancer (CaP) have been extensively studied, yet little is known about the genetic mechanisms underlying progression of primary CaP to metastatic prostate cancer. As a result, it is not possible to distinguish clinically indolent localized disease from potentially life-threatening tumors with high metastatic potential. To address this question, we collected tissue from 34 autopsy-derived metastases, samples rarely analyzed in previous studies. These were compared to a separate set of 17 prostatectomy specimens containing 22 foci of CaP associated with 49 examples of high-grade prostatic intraepithelial neoplasia (PIN), a histological precursor of CaP. We compared the loss of heterozygosity (LOH) profiles of high-grade PIN, primary CaP and metastases by analyzing 33 microsatellite markers previously found to have high frequencies of LOH in primary CaP. These markers were on chromosomes 5q, 6q, 7q, 8p, 9p, 10q, 11p, 13q, 16q, 17, 18q and 21q. In addition, markers on chromosomes 4p, 11q, 14q and 20q with no reported LOH in primary CaP were analyzed to determine the frequency of background LOH. In PIN lesions, the rate of LOH was significant only at D5S806 (20%) and D16S422 (29%). In addition, different PIN lesions within the same prostate gland were genetically diverse, indicating divergent evolution of synchronous neoplastic precursor lesions. LOH frequency was progressively higher in primary CaP and metastatic lesions. In primary CaP, significant losses occurred at the 8p, 10q, 11p, 16q, 17p, 18q and 21q loci (range 17-43%). Distinct patterns of LOH frequencies were observed in primary CaP compared with metastases. Although some loci (D16S422, D17S960, D21S156) showed similar frequencies of LOH in primary CaP and metastatic CaP, most other loci showed up to 7-fold metastasis-related increases. The metastatic samples revealed previously unrecognized prostate cancer LOH at D5S806, D6S262, D9S157, D13S133 and D13S227. These significant stage-specific differences in LOH frequency specify genetic loci that may play key roles in CaP progression and could represent clinically useful biomarkers for CaP aggressiveness.

Adenocarcinoma↗
PubMed1999

Statistical analysis of array expression data as applied to the problem of tamoxifen resistance.

BACKGROUND: Although the emerging complementary DNA (cDNA) array technology holds great promise to discern complex patterns of gene expression, its novelty means that there are no well-established standards to guide analysis and interpretation of the data that it produces. We have used preliminary data generated with the CLONTECH Atlas human cDNA array to develop a practical approach to the statistical analysis of these data by studying changes in gene expression during the development of acquired tamoxifen resistance in breast cancer. METHODS: For hybridization to the array, we prepared RNA from MCF-7 human breast cell tumors, isolated from our athymic nude mouse xenograft model of acquired tamoxifen resistance during estrogen-stimulated, tamoxifen-sensitive, and tamoxifen-resistant growth. Principal components analysis was used to identify genes with altered expression. RESULTS AND CONCLUSIONS: Principal components analysis yielded three principal components that are interpreted as 1) the average level of gene expression, 2) the difference between estrogen-stimulated gene expression and the average of tamoxifen-sensitive and tamoxifen-resistant gene expression, and 3) the difference between tamoxifen-sensitive and tamoxifen-resistant gene expression. A bivariate (second and third principal components) 99% prediction region was used to identify outlier genes that exhibit altered expression. Two representative outlier genes, erk-2 and HSF-1 (heat shock transcription factor-1), were chosen for confirmatory study, and their predicted relative expression levels were confirmed in western blot analysis, suggesting that semiquantitative estimates are possible with array technology. IMPLICATIONS: Principal components analysis provides a useful and practical method to analyze gene expression data from a cDNA array. The method can identify broad patterns of expression alteration and, based on a small simulation study, will likely provide reasonable power to detect moderate-sized alterations in clinically relevant genes.

Animals↗
PubMed1999

Peer involvement in bullying: insights and challenges for intervention.

The purpose of this research was to examine the peer processes that occur during bullying episodes on the school playground. These processes were examined from a social learning perspective, allowing us to consider the effects of various types of reinforcement among bullies, victims, and peers. Fifty-three segments of video tape were examined. Each segment contained a peer group (two or more peers) that viewed bullying on the school playground. Peers were coded for actively joining or passively reinforcing the bully, and for actively intervening on behalf of the victim. On average, four peers viewed the schoolyard bullying, with a range from two to 14 peers. Averaged across all episodes, peers spent 54% of their time reinforcing bullies by passively watching, 21% of their time actively modelling bullies, and 25% of their time intervening on behalf of victims. Older boys (grades 4-6) were more likely to actively join with the bully than were younger boys (grades 1-3) and older girls. Both younger and older girls were more likely to intervene on behalf of victims than were older boys. The results were interpreted as confirming peers' central roles in the processes that unfold during playground bullying episodes. We discuss the results in terms of the challenges posed to peer-led interventions. Peers' anti-bullying initiatives must be reinforced by simultaneous whole-school interventions.

Aggression↗
PubMed1999

Gene expression patterns in cell lines from patients with 18q- syndrome.

Some studies have suggested that for trisomies, some genes are expressed far in excess of the expected 150% level and that this "dysregulation" is one of the mechanisms for the pathogenesis of trisomies. In an attempt to generalize this result to a monosomy, we examined mRNA isolated from lymphoblastoid cell lines derived from patients with 18q- syndrome, a deletion syndrome involving loss of the distal long arm of chromosome 18. Expression levels of ten chromosome 18 genes were compared between cell lines from eight patients with 18q- syndrome and four diploid controls. Gene expression was investigated by a quantitative reverse-transcription polymerase chain reaction (RT-PCR) method. With the exception of the transcription factor NFATC1, which shows a tendency towards gene dosage compensation (the expression pattern correlates with IgA deficiency), all of the other genes were expressed at a level proportional to their gene copy number. This was true regardless of mRNA abundance or different patterns of gene expression (ubiquitous versus tissue-specific gene expression). These results indicate that, unlike dysregulated gene expression apparent in some trisomies, this monosomic syndrome is largely due to consequences of reduced gene expression.

Blotting, Northern↗
PubMed1999

Linkage of type 2 diabetes mellitus and of age at onset to a genetic location on chromosome 10q in Mexican Americans.

Since little is known about chromosomal locations harboring type 2 diabetes-susceptibility genes, we conducted a genomewide scan for such genes in a Mexican American population. We used data from 27 low-income extended Mexican American pedigrees consisting of 440 individuals for whom genotypic data are available for 379 markers. We used a variance-components technique to conduct multipoint linkage analyses for two phenotypes: type 2 diabetes (a discrete trait) and age at onset of diabetes (a truncated quantitative trait). For the multipoint analyses, a subset of 295 markers was selected on the basis of optimal spacing and informativeness. We found significant evidence that a susceptibility locus near the marker D10S587 on chromosome 10q influences age at onset of diabetes (LOD score 3.75) and is also linked with type 2 diabetes itself (LOD score 2.88). This susceptibility locus explains 63.8%+/-9.9% (P=. 000016) of the total phenotypic variation in age at onset of diabetes and 65.7%+/-10.9% (P=.000135) of the total variation in liability to type 2 diabetes. Weaker evidence was found for linkage of diabetes and of age at onset to regions on chromosomes 3p, 4q, and 9p. In conclusion, our strongest evidence for linkage to both age at onset of diabetes and type 2 diabetes itself in the Mexican American population was for a region on chromosome 10q.

Age Factors↗