scispace - formally typeset
Search or ask a question

Showing papers by "McGill University published in 2005"


Journal ArticleDOI
John W. Belmont1, Andrew Boudreau, Suzanne M. Leal1, Paul Hardenbol  +229 moreInstitutions (40)
27 Oct 2005
TL;DR: A public database of common variation in the human genome: more than one million single nucleotide polymorphisms for which accurate and complete genotypes have been obtained in 269 DNA samples from four populations, including ten 500-kilobase regions in which essentially all information about common DNA variation has been extracted.
Abstract: Inherited genetic variation has a critical but as yet largely uncharacterized role in human disease. Here we report a public database of common variation in the human genome: more than one million single nucleotide polymorphisms (SNPs) for which accurate and complete genotypes have been obtained in 269 DNA samples from four populations, including ten 500-kilobase regions in which essentially all information about common DNA variation has been extracted. These data document the generality of recombination hotspots, a block-like structure of linkage disequilibrium and low haplotype diversity, leading to substantial correlations of SNPs with many of their neighbours. We show how the HapMap resource can guide the design and analysis of genetic association studies, shed light on structural variation and recombination, and identify loci that may have been subject to natural selection during human evolution.

5,479 citations


Journal ArticleDOI
TL;DR: Elotinib can prolong survival in patients with non-small-cell lung cancer after first-line or second-line chemotherapy, and five percent of patients discontinued erlot inib because of toxic effects.
Abstract: Patients with stage IIIB or IV non–small-cell lung cancer, with performance status from 0 to 3, were eligible if they had received one or two prior chemotherapy regimens. The patients were stratified according to center, performance status, response to prior chemotherapy, number of prior regimens, and prior platinum-based therapy and were randomly assigned in a 2:1 ratio to receive oral erlotinib, at a dose of 150 mg daily, or placebo. results The median age of the 731 patients who underwent randomization was 61.4 years; 49 percent had received two prior chemotherapy regimens, and 93 percent had received platinum-based chemotherapy. The response rate was 8.9 percent in the erlotinib group and less than 1 percent in the placebo group (P<0.001); the median duration of the response was 7.9 months and 3.7 months, respectively. Progression-free survival was 2.2 months and 1.8 months, respectively (hazard ratio, 0.61, adjusted for stratification categories; P<0.001). Overall survival was 6.7 months and 4.7 months, respectively (hazard ratio, 0.70; P<0.001), in favor of erlotinib. Five percent of patients discontinued erlotinib because of toxic effects. conclusions Erlotinib can prolong survival in patients with non–small-cell lung cancer after firstline or second-line chemotherapy.

5,157 citations


Journal ArticleDOI
TL;DR: One year of treatment with trastuzumab after adjuvant chemotherapy significantly improves disease-free survival among women with HER2-positive breast cancer.
Abstract: background Trastuzumab, a recombinant monoclonal antibody against HER2, has clinical activity in advanced breast cancer that overexpresses HER2. We investigated its efficacy and safety after excision of early-stage breast cancer and completion of chemotherapy. methods This international, multicenter, randomized trial compared one or two years of trastuzumab given every three weeks with observation in patients with HER2-positive and either node-negative or node-positive breast cancer who had completed locoregional therapy and at least four cycles of neoadjuvant or adjuvant chemotherapy. results Data were available for 1694 women randomly assigned to two years of treatment with trastuzumab, 1694 women assigned to one year of trastuzumab, and 1693 women assigned to observation. We report here the results only of treatment with trastuzumab for one year or observation. At the first planned interim analysis (median follow-up of one year), 347 events (recurrence of breast cancer, contralateral breast cancer, second nonbreast malignant disease, or death) were observed: 127 events in the trastuzumab group and 220 in the observation group. The unadjusted hazard ratio for an event in the trastuzumab group, as compared with the observation group, was 0.54 (95 percent confidence interval, 0.43 to 0.67; P<0.0001 by the log-rank test, crossing the interim analysis boundary), representing an absolute benefit in terms of disease-free survival at two years of 8.4 percentage points. Overall survival in the two groups was not significantly different (29 deaths with trastuzumab vs. 37 with observation). Severe cardiotoxicity developed in 0.5 percent of the women who were treated with trastuzumab. conclusions One year of treatment with trastuzumab after adjuvant chemotherapy significantly improves disease-free survival among women with HER2-positive breast cancer. (clinicaltrials.gov number, NCT 00045032.)

4,815 citations


Journal ArticleDOI
TL;DR: The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them as mentioned in this paper.
Abstract: The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in ∼50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.

4,258 citations


Journal ArticleDOI
Takashi Matsumoto1, Jianzhong Wu1, Hiroyuki Kanamori1, Yuichi Katayose1  +262 moreInstitutions (25)
11 Aug 2005-Nature
TL;DR: A map-based, finished quality sequence that covers 95% of the 389 Mb rice genome, including virtually all of the euchromatin and two complete centromeres, and finds evidence for widespread and recurrent gene transfer from the organelles to the nuclear chromosomes.
Abstract: Rice, one of the world's most important food plants, has important syntenic relationships with the other cereal species and is a model plant for the grasses. Here we present a map-based, finished quality sequence that covers 95% of the 389 Mb genome, including virtually all of the euchromatin and two complete centromeres. A total of 37,544 non-transposable-element-related protein-coding genes were identified, of which 71% had a putative homologue in Arabidopsis. In a reciprocal analysis, 90% of the Arabidopsis proteins had a putative homologue in the predicted rice proteome. Twenty-nine per cent of the 37,544 predicted genes appear in clustered gene families. The number and classes of transposable elements found in the rice genome are consistent with the expansion of syntenic regions in the maize and sorghum genomes. We find evidence for widespread and recurrent gene transfer from the organelles to the nuclear chromosomes. The map-based sequence has proven useful for the identification of genes underlying agronomic traits. The additional single-nucleotide polymorphisms and simple sequence repeats identified in our study should accelerate improvements in rice production.

3,423 citations


Journal ArticleDOI
TL;DR: A systematic review of the literature regarding how activity in diverse brain regions creates and modulates the experience of acute and chronic pain states, emphasizing the contribution of various imaging techniques to emerging concepts is presented in this paper.

2,686 citations


Journal ArticleDOI
K. Adcox1, S. S. Adler2, Serguei Afanasiev3, Christine Angela Aidala2  +550 moreInstitutions (48)
TL;DR: In this paper, the results of the PHENIX detector at the Relativistic Heavy Ion Collider (RHIC) were examined with an emphasis on implications for the formation of a new state of dense matter.

2,572 citations


Journal ArticleDOI
TL;DR: This tutorial presents the CE methodology, the basic algorithm and its modifications, and discusses applications in combinatorial optimization and machine learning.
Abstract: The cross-entropy (CE) method is a new generic approach to combinatorial and multi-extremal optimization and rare event simulation. The purpose of this tutorial is to give a gentle introduction to the CE method. We present the CE methodology, the basic algorithm and its modifications, and discuss applications in combinatorial optimization and machine learning.

2,367 citations


Journal ArticleDOI
TL;DR: A strain of C. difficile that was resistant to fluoroquinolones and had binary toxin and a partial deletion of the tcdC gene was responsible for this outbreak ofC.difficile-associated diarrhea.
Abstract: Background In March 2003, several hospitals in Quebec, Canada, noted a marked increase in the incidence of Clostridium difficile–associated diarrhea. Methods In 2004 we conducted a prospective study at 12 Quebec hospitals to determine the incidence of nosocomial C. difficile–associated diarrhea and its complications and a case–control study to identify risk factors for the disease. Isolates of C. difficile were typed by pulsed-field gel electrophoresis and analyzed for binary toxin genes and partial deletions in the toxin A and B repressor gene tcdC. Antimicrobial susceptibility was evaluated in a subgroup of isolates. Results A total of 1703 patients with 1719 episodes of nosocomial C. difficile–associated diarrhea were identified. The incidence was 22.5 per 1000 admissions. The 30-day attributable mortality rate was 6.9 percent. Case patients were more likely than matched controls to have received fluoroquinolones (odds ratio, 3.9; 95 percent confidence interval, 2.3 to 6.6) or cephalosporins (odds rati...

1,902 citations


Journal ArticleDOI
TL;DR: In this paper, a double-blind placebo-controlled phase II study was done to assess the efficacy of a prophylactic quadrivalent vaccine targeting the human papillomavirus (HPV) types associated with 70% of cervical cancers (types 16 and 18) and with 90% of genital warts (types 6 and 11).
Abstract: Summary Background A randomised double-blind placebo-controlled phase II study was done to assess the efficacy of a prophylactic quadrivalent vaccine targeting the human papillomavirus (HPV) types associated with 70% of cervical cancers (types 16 and 18) and with 90% of genital warts (types 6 and 11). Methods 277 young women (mean age 20·2 years [SD 1·7]) were randomly assigned to quadrivalent HPV (20 μg type 6, 40 μg type 11, 40 μg type 16, and 20 μg type 18) L1 virus-like-particle (VLP) vaccine and 275 (mean age 20·0 years [1·7]) to one of two placebo preparations at day 1, month 2, and month 6. For 36 months, participants underwent regular gynaecological examinations, cervicovaginal sampling for HPV DNA, testing for serum antibodies to HPV, and Pap testing. The primary endpoint was the combined incidence of infection with HPV 6, 11, 16, or 18, or cervical or external genital disease (ie, persistent HPV infection, HPV detection at the last recorded visit, cervical intraepithelial neoplasia, cervical cancer, or external genital lesions caused by the HPV types in the vaccine). Main analyses were done per protocol. Findings Combined incidence of persistent infection or disease with HPV 6, 11, 16, or 18 fell by 90% (95% CI 71–97, p Interpretation A vaccine targeting HPV types 6, 11, 16, 18 could substantially reduce the acquisition of infection and clinical disease caused by common HPV types. Published online April 7, 2005 DOI 10.1016/S1470-2045(05)70101-7

1,627 citations


Journal ArticleDOI
TL;DR: These data definitively implicate perturbation of TGFβ signaling in many common human phenotypes, including craniosynostosis, cleft palate, arterial aneurysms, congenital heart disease and mental retardation, and suggest that comprehensive mechanistic insight will require consideration of both primary and compensatory events.
Abstract: We report heterozygous mutations in the genes encoding either type I or type II transforming growth factor β receptor in ten families with a newly described human phenotype that includes widespread perturbations in cardiovascular, craniofacial, neurocognitive and skeletal development. Despite evidence that receptors derived from selected mutated alleles cannot support TGFβ signal propagation, cells derived from individuals heterozygous with respect to these mutations did not show altered kinetics of the acute phase response to administered ligand. Furthermore, tissues derived from affected individuals showed increased expression of both collagen and connective tissue growth factor, as well as nuclear enrichment of phosphorylated Smad2, indicative of increased TGFβ signaling. These data definitively implicate perturbation of TGFβ signaling in many common human phenotypes, including craniosynostosis, cleft palate, arterial aneurysms, congenital heart disease and mental retardation, and suggest that comprehensive mechanistic insight will require consideration of both primary and compensatory events.

Journal ArticleDOI
08 Apr 2005-Science
TL;DR: A novel nonverbal task is used to examine 15-month-old infants' ability to predict an actor's behavior on the basis of her true or false belief about a toy's hiding place, supporting the view that, from a young age, children appeal to mental states—goals, perceptions, and beliefs—to explain the behavior of others.
Abstract: For more than two decades, researchers have argued that young children do not understand mental states such as beliefs. Part of the evidence for this claim comes from preschoolers' failure at verbal tasks that require the understanding that others may hold false beliefs. Here, we used a novel nonverbal task to examine 15-month-old infants' ability to predict an actor's behavior on the basis of her true or false belief about a toy's hiding place. Results were positive, supporting the view that, from a young age, children appeal to mental states--goals, perceptions, and beliefs--to explain the behavior of others.

Journal ArticleDOI
TL;DR: Increased acid-to-pulp ratio reduced the dimensions of the nanocrystals thus produced and the critical concentration was increased and the biphasic range became narrower; a suspension made from a bleached kraft eucalyptus pulp gave very similar properties to the softwood nanocrystal suspension when prepared under similar hydrolysis conditions.

Journal ArticleDOI
TL;DR: The innovations in block copolymer synthesis, polymeric micelle preparation and characterization, as well as the relevance of these developments to the field of biomedical research are proposed.

Journal ArticleDOI
TL;DR: Two representative models are examined, the regulation of eukaryotic initiation factor-2α by phosphorylation and internal ribosome initiation through the internal Ribosome-entry site, which illustrate the importance of translational control in the cellular stress response and apoptosis.
Abstract: Cells respond to stress stimuli through coordinated changes in gene expression. The regulation of translation is often used under these circumstances because it allows immediate and selective changes in protein levels. There are many examples of translational control in response to stress. Here we examine two representative models, the regulation of eukaryotic initiation factor-2alpha by phosphorylation and internal ribosome initiation through the internal ribosome-entry site, which illustrate the importance of translational control in the cellular stress response and apoptosis.

Journal ArticleDOI
TL;DR: Forest transitions have occurred in two, sometimes overlapping circumstances: economic development and scarcity of forest products have prompted governments and landowners to plant trees in some fields as mentioned in this paper, and these transitions do little to conserve biodiversity, but they do sequester carbon and conserve soil, so governments should place a high priority on promoting them.
Abstract: Places experience forest transitions when declines in forest cover cease and recoveries in forest cover begin. Forest transitions have occurred in two, sometimes overlapping circumstances. In some places economic development has created enough non-farm jobs to pull farmers off of the land, thereby inducing the spontaneous regeneration of forests in old fields. In other places a scarcity of forest products has prompted governments and landowners to plant trees in some fields. The transitions do little to conserve biodiversity, but they do sequester carbon and conserve soil, so governments should place a high priority on promoting them. C 2005 Elsevier Ltd. All rights reserved.

Journal ArticleDOI
TL;DR: Despite the potential bias caused by the unblinding of the P-1 trial, the magnitudes of all beneficial and undesirable treatment effects of tamoxifen were similar to those initially reported, with notable reductions in breast cancer and increased risks of thromboembolic events and endometrial cancer.
Abstract: Background: Initial fi ndings from the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial (P-1) demonstrated that tamoxifen reduced the risk of estrogen receptor – positive tumors and osteoporotic fractures in women at increased risk for breast cancer. Side effects of varying clinical signifi cance were observed. The trial was unblinded because of the positive results, and follow-up continued. This report updates our initial fi ndings. Methods: Women (n = 13 388) were randomly assigned to receive placebo or tamoxifen for 5 years. Rates of breast cancer and other events were compared by the use of risk ratios (RRs) and 95% confi dence intervals (CIs). Estimates of the net benefi t from 5 years of tamoxifen therapy were compared by age, race, and categories of predicted breast cancer risk. Statistical tests were two-sided. Results: After 7 years of follow-up, the cumulative rate of invasive breast cancer was reduced from 42.5 per 1000 women in the placebo group to 24.8 per 1000 women in the tamoxifen group (RR = 0.57, 95% CI = 0.46 to 0.70) and the cumulative rate of noninvasive breast cancer was reduced from 15.8 per 1000 women in the placebo group to 10.2 per 1000 women in the tamoxifen group (RR = 0.63, 95% CI = 0.45 to 0.89). These reductions were similar to those seen in the initial report. Tamoxifen led to a 32% reduction in osteoporotic fractures (RR = 0.68, 95% CI = 0.51 to 0.92). Relative risks of stroke, deep-vein thrombosis, and cataracts (which increased with tamoxifen) and of ischemic heart disease and death (which were not changed with tamoxifen) were also similar to those initially reported. Risks of pulmonary embolism were approximately 11% lower than in the original report, and risks of endometrial cancer were about 29% higher, but these differences were not statistically signifi cant. The net benefi t achieved with tamoxifen varied according to age, race, and level of breast cancer risk. Conclusions: Despite the potential bias caused by the unblinding of the P-1 trial, the magnitudes of all benefi cial and undesirable treatment effects of tamoxifen were similar to those initially reported, with notable reductions in breast cancer and increased risks of thromboem bolic events and endometrial cancer. Readily identifi able sub sets of individuals comprising 2.5 million women could derive a net benefi t from the drug. [J Natl Cancer Inst 2005;97:1652 – 62]

Journal ArticleDOI
TL;DR: A multilevel, longitudinal approach to better explain resistance to information technology implementation was used, finding that the bottom-up process by which group resistance behaviors emerge from individual behaviors is not the same in early versus late implementation.
Abstract: To better explain resistance to information technology implementation, we used a multilevel, longitudinal approach We first assessed extant models of resistance to IT Using semantic analysis, we identified five basic components of resistance: behaviors, object, subject, threats, and initial conditions We further examined extant models to (1) carry out a preliminary specification of the nature of the relationships between these components and (2) refine our understanding of the multilevel nature of the phenomenon Using analytic induction, we examined data from three case studies of clinical information systems implementations in hospital settings, focusing on physicians' resistance behaviors The resulting mixed-determinants model suggests that group resistance behaviors vary during implementation When a system is introduced, users in a group will first assess it in terms of the interplay between its features and individual and/or organizational-level initial conditions They then make projections about the consequences of its use If expected consequences are threatening, resistance behaviors will result During implementation, should some trigger occur to either modify or activate an initial condition involving the balance of power between the group and other user groups, it will also modify the object of resistance, from system to system significance If the relevant initial conditions pertain to the power of the resisting group vis-a-vis the system advocates, the object of resistance will also be modified, from system significance to system advocates Resistance behaviors will follow if threats are perceived from the interaction between the object of resistance and initial conditions We also found that the bottom-up process by which group resistance behaviors emerge from individual behaviors is not the same in early versus late implementation In early implementation, the emergence process is one of compilation, described as a combination of independent, individual behaviors In later stages of implementation, if group level initial conditions have become active, the emergence process is one of composition, described as the convergence of individual behaviors

Journal ArticleDOI
25 Mar 2005-Science
TL;DR: It is found that protein production rates fluctuate over a time scale of about one cell cycle, while intrinsic noise decays rapidly, which can form a basis for quantitative modeling of natural gene circuits and for design of synthetic ones.
Abstract: The quantitative relation between transcription factor concentrations and the rate of protein production from downstream genes is central to the function of genetic networks. Here we show that this relation, which we call the gene regulation function (GRF), fluctuates dynamically in individual living cells, thereby limiting the accuracy with which transcriptional genetic circuits can transfer signals. Using fluorescent reporter genes and fusion proteins, we characterized the bacteriophage lambda promoter P_R in Escherichia coli. A novel technique based on binomial errors in protein partitioning enabled calibration of in vivo biochemical parameters in molecular units. We found that protein production rates fluctuate over a time scale of about one cell cycle, while intrinsic noise decays rapidly. Thus, biochemical parameters, noise, and slowly varying cellular states together determine the effective single-cell GRF. These results can form a basis for quantitative modeling of natural gene circuits and for design of synthetic ones.

Journal ArticleDOI
TL;DR: The Gastrointestinal Quality of Life Index (GIQLI) is ready to be used in clinical practice and research and validated against other generic measures of quality of life.
Abstract: At present, an instrument for measuring the quality of life, specifically for patients with gastrointestinal disease, is not available. A new instrument for gastrointestinal disorders that is system-specific has been developed in three phases. In the first phase, questions were collated and then tested on 70 patients with gastrointestinal diseases and those that worked well were retained. In the second phase, the questions were modified and tested on 204 patients and the results verified by international experts. The instrument was also validated against other generic measures of quality of life. During the third phase, the instrument was validated with 168 normal individuals. Reproducibility was tested on 25 patients with stable gastrointestinal disease and responsiveness was tested on 194 patients undergoing laparoscopic cholecystectomy. The result is a bilingual (German and English) questionnaire containing 36 questions each with five response categories. The responses to questions are summed to give a numerical score. It is concluded that the Gastrointestinal Quality of Life Index (GIQLI) is ready to be used in clinical practice and research.

Journal ArticleDOI
TL;DR: Recent insights into the molecular processes regulated by arginine methylation in normal and diseased cells are described.

Journal ArticleDOI
TL;DR: A growing body of evidence suggests that biological mechanisms underlie a bidirectional link between mood disorders and many medical illnesses and there is evidence to suggest that mood disorders affect the course of medical illnesses.

Journal ArticleDOI
03 Feb 2005-Nature
TL;DR: A family of proteins that through a shared sequence regulate cap-dependent translation are described, which affects such processes as cell growth, development, oncogenic transformation and perhaps even axon pathfinding and memory consolidation.
Abstract: Eukaryotic messenger RNAs contain a modified guanosine, termed a cap, at their 5' ends. Translation of mRNAs requires the binding of an initiation factor, eIF4E, to the cap structure. Here, we describe a family of proteins that through a shared sequence regulate cap-dependent translation. The biological importance of this translational regulation is immense, and affects such processes as cell growth, development, oncogenic transformation and perhaps even axon pathfinding and memory consolidation.

Journal ArticleDOI
21 Dec 2005-JAMA
TL;DR: The use of acid-suppressive therapy, particularly proton pump inhibitors, is associated with an increased risk of community-acquired C difficile and the unexpected increase in risk with nonsteroidal anti-inflammatory drug use should be investigated further.
Abstract: ContextRecent reports suggest an increasing occurrence and severity of Clostridium difficile–associated disease. We assessed whether the use of gastric acid–suppressive agents is associated with an increased risk in the community.ObjectiveTo determine whether the use of gastric acid–suppressive agents increases the risk of C difficile–associated disease in a community population.Design, Setting, and PatientsWe conducted 2 population-based case-control studies using the United Kingdom General Practice Research Database (GPRD). In the first study, we identified all 1672 cases of C difficile recorded between 1994 and 2004 among all patients registered for at least 2 years in each practice. Each case was matched to 10 controls on calendar time and the general practice. In the second study, a subset of these cases defined as community-acquired, that is, not hospitalized in the prior year, were matched on practice and age with controls also not hospitalized in the prior year.Main Outcome MeasuresThe incidence of C difficile and risk associated with gastric acid–suppressive agent use.ResultsThe incidence of C difficile in patients diagnosed by their general practitioners in the General Practice Research Database increased from less than 1 case per 100 000 in 1994 to 22 per 100 000 in 2004. The adjusted rate ratio of C difficile–associated disease with current use of proton pump inhibitors was 2.9 (95% confidence interval [CI], 2.4-3.4) and with H2-receptor antagonists the rate ratio was 2.0 (95% CI, 1.6-2.7). An elevated rate was also found with the use of nonsteroidal anti-inflammatory drugs (rate ratio, 1.3; 95% CI, 1.2-1.5).ConclusionsThe use of acid-suppressive therapy, particularly proton pump inhibitors, is associated with an increased risk of community-acquired C difficile. The unexpected increase in risk with nonsteroidal anti-inflammatory drug use should be investigated further.

Journal ArticleDOI
TL;DR: For patients with high-risk breast cancer treated with modified radical mastectomy, treatment with radiation therapy and adjuvant chemotherapy leads to better survival outcomes than chemotherapy alone, and it is well tolerated, with acceptable long-term toxicity.
Abstract: Background The British Columbia randomized radiation trial was designed to determine the survival impact of locoregional radiation therapy in premenopausal patients with lymph node-positive breast cancer treated by modified radical mastectomy and adjuvant chemotherapy. Three hundred eighteen patients were assigned to receive no further therapy or radiation therapy (37.5 Gy in 16 fractions). Previous analysis at the 15-year follow-up showed that radiation therapy was associated with a statistically significant improvement in breast cancer survival but that improvement in overall survival was of only borderline statistical significance. We report the analysis of data from the 20-year follow-up. Methods Survival was analyzed by the Kaplan-Meier method. Relative risk estimates were calculated by the Wald test from the proportional hazards regression model. All statistical tests were two-sided. Results At the 20 year follow up (median follow up for live patients: 249 months) chemotherapy and radiation therapy, compared with chemotherapy alone, were associated with a statistically significant improvement in all end points analyzed, including survival free of isolated locoregional recurrences (74% versus 90%, respectively; relative risk [RR] = 0.36, 95% confidence interval [CI] = 0.18 to 0.71; P = .002), systemic relapse-free survival (31% versus 48%; RR = 0.66, 95% CI = 0.49 to 0.88; P = .004), breast cancer-free survival (48% versus 30%; RR = 0.63, 95% CI = 0.47 to 0.83; P = .001), event-free survival (35% versus 25%; RR = 0.70, 95% CI = 0.54 to 0.92; P = .009), breast cancer-specific survival (53% versus 38%; RR = 0.67, 95% CI = 0.49 to 0.90; P = .008), and, in contrast to the 15-year follow-up results, overall survival (47% versus 37%; RR = 0.73, 95% CI = 0.55 to 0.98; P = .03). Long-term toxicities, including cardiac deaths (1.8% versus 0.6%), were minimal for both arms. Conclusion For patients with high-risk breast cancer treated with modified radical mastectomy, treatment with radiation therapy (schedule of 16 fractions) and adjuvant chemotherapy leads to better survival outcomes than chemotherapy alone, and it is well tolerated, with acceptable long-term toxicity.

Journal ArticleDOI
TL;DR: In this article, the authors used functional and effective connectivity analyses to show that listening to music strongly modulates activity in a network of mesolimbic structures involved in reward processing including the nucleus accumbens and the ventral tegmental area (VTA), as well as the hypothalamus and insula, which are thought to be involved in regulating autonomic and physiological responses to rewarding and emotional stimuli.

Journal ArticleDOI
TL;DR: It is reported that methionine infusion reverses the effect of maternal behavior on DNA methylation, nerve growth factor-inducible protein-A binding to the exon 17 promoter, GR expression, and hypothalamic-pituitary-adrenal and behavioral responses to stress, suggesting a causal relationship among epigenomic state, GRexpression, and stress responses in the adult offspring.
Abstract: Stress responses in the adult rat are programmed early in life by maternal care and associated with epigenomic marking of the hippocampal exon 17 glucocorticoid receptor (GR) promoter. To examine whether such epigenetic programming is reversible in adult life, we centrally infused the adult offspring with the essential amino acid l-methionine, a precursor to S-adenosyl-methionine that serves as the donor of methyl groups for DNA methylation. Here we report that methionine infusion reverses the effect of maternal behavior on DNA methylation, nerve growth factor-inducible protein-A binding to the exon 17 promoter, GR expression, and hypothalamic-pituitary-adrenal and behavioral responses to stress, suggesting a causal relationship among epigenomic state, GR expression, and stress responses in the adult offspring. These results demonstrate that, despite the inherent stability of the epigenomic marks established early in life through behavioral programming, they are potentially reversible in the adult brain.

Journal ArticleDOI
TL;DR: A detailed review of the signaling process of rhizobia (iPGPR), including plant-to-bacteria signal molecules, followed by bacterial perception and consequent production of bacteria- to-plant signals, is provided.
Abstract: Plant growth promoting bacteria (PGPR) associations range in degree of bacterial proximity to the root and intimacy of association. In general, these can be separated into extracellular PGPR (ePGPR), existing in the rhizosphere, on the rhizoplane or in the spaces between cells of the root cortex, and intracellular PGPR (iPGPR), which exist inside root cells, generally in specialized nodular structures. The latter includes rhizobia and Frankia species, both of which fix nitrogen in symbiosis with higher plants. There has been considerable development in understanding signaling mechanisms of rhizobia (iPGPR) during the establishment of the rhizobia–legume symbiosis, and this may serve as a model of knowledge regarding cross-talk and plant growth promoting mechanisms. We provide a detailed review of this process, including plant-to-bacteria signal molecules, followed by bacterial perception and consequent production of bacteria-to-plant signals. A history of PGPR discovery is also provided, indicating progress in understanding each of the PGPR groups. Recent advances in understanding plant growth responses to microbial signals are reviewed, along with the research areas that require attention. Based on new understandings of signaling mechanisms in the iPGPR (rhizobia) and recent findings with ePGPR we are able to speculate regarding general patterns of signaling in the ePGPR.

Journal ArticleDOI
TL;DR: It is highlighted that a goal of decreased documentation time in an EHR project is not likely to be realized and how the selection of bedside or central station desktop EHRs may influence documentation time for the two main user groups, physicians and nurses is identified.

Journal ArticleDOI
TL;DR: Breeding patch isolation via limited dispersal and/or strong site fidelity was the most frequently implicated or tested metapopulation condition, however there is strong evidence that amphibian dispersal is not as uniformly limited as is often thought.
Abstract: Amphibians are frequently characterized as having limited dispersal abilities, strong site fidelity and spatially disjunct breeding habitat. As such, pond-breeding species are often alleged to form metapopulations. Amphibian species worldwide appear to be suffering population level declines caused, at least in part, by the degradation and fragmentation of habitat and the intervening areas between habitat patches. If the simplification of amphibians occupying metapopulations is accurate, then a regionally based conservation strategy, informed by metapopulation theory, is a powerful tool to estimate the isolation and extinction risk of ponds or populations. However, to date no attempt to assess the class-wide generalization of amphibian populations as metapopulations has been made. We reviewed the literature on amphibians as metapopulations (53 journal articles or theses) and amphibian dispersal (166 journal articles or theses for 53 anuran species and 37 salamander species) to evaluate whether the conditions for metapopulation structure had been tested, whether pond isolation was based only on the assumption of limited dispersal, and whether amphibian dispersal was uniformly limited. We found that in the majority of cases (74%) the assumptions of the metapopulation paradigm were not tested. Breeding patch isolation via limited dispersal and/or strong site fidelity was the most frequently implicated or tested metapopulation condition, however we found strong evidence that amphibian dispersal is not as uniformly limited as is often thought. The frequency distribution of maximum movements for anurans and salamanders was well described by an inverse power law. This relationship predicts that distances beneath 11–13 and 8–9 km, respectively, are in a range that they may receive one emigrating individual. Populations isolated by distances approaching this range are perhaps more likely to exhibit metapopulation structure than less isolated populations. Those studies that covered larger areas also tended to report longer maximum movement distances – a pattern with implications for the design of mark-recapture studies. Caution should be exercised in the application of the metapopulation approach to amphibian population conservation. Some amphibian populations are structured as metapopulations – but not all.