tbuckley/cabot-search huggingface dataset:
Late local recurrences in a randomised trial comparing conservative treatment with total mastectomy in early breast cancer patients
Authors: R. Arriagada, M.G. Lê, J.-M. Guinebretière, A. Dunant, F. Rochard, T. Tursz
Journal: Annals of Oncology (2003)

BackgroundA randomised trial was conducted comparing wide lumpectomy and breast irradiation with modified radical mastectomy. As the follow-up was long (mean duration 22 years), we analysed the variation in the effect of treatment over time.Patients and methodsThe trial included 179 patients with a breast cancer measuring ≤2 cm at macroscopic examination. Eighty-eight patients had breast-conserving surgery and radiotherapy, and 91 underwent mastectomy. All patients had axillary dissection. The analyses were based on Cox models with time-dependent treatment effects.ResultsThe effect of treatment on death or metastasis did not vary with time. The risk of local recurrence was lower during the first 5 years for the breast-conserving surgery group as compared with the mastectomy group, but higher after 5 years (P = 10–4 for a different treatment effect over time). Similar results were found in a database including 1847 patients with small breast tumours at diagnosis. In this analysis, late breast recurrences were also more frequent in the breast-conserving surgery group and this treatment effect was greater among younger patients (≤40 years at the time of diagnosis).ConclusionsLate breast recurrences were more frequently observed in younger patients treated with breast-conserving treatment compared with those submitted to mastectomy. These results require confirmation in other randomised studies so that younger patients with early breast cancer can receive adequate counselling and so that a more stringent long-term follow-up policy can be adopted when breast-conserving treatment is planned.
Michelangelo's divine goitre
Authors: L. Bondeson, A.-G. Bondeson
Journal: Journal of the Royal Society of Medicine (2003)

When all things began, goitre already was—at least if we are to believe in Michelangelo's idea of the 'big bang' painted on the ceiling of the Sistine Chapel. In his image of the Separation of Light from Darkness (Figure 1), the Creator shows a clear-cut goitre (Figure 2), a remarkable trait that has passed unnoticed for almost five hundred years.



Figure 1

The Creator separating light from darkness. Fresco painted in 1512 on the ceiling of the Sistine Chapel by Michelangelo Buonarroti. (Photograph courtesy of the Vatican Museums)





Figure 2

The Creator exhibits a multinodular goitre. (Photograph courtesy of the Vatican Museums)
Developmental Change in Amygdala Reactivity During Adolescence: Effects of Family History of Depression and Stressful Life Events
Authors: Johnna R. Swartz, Douglas E. Williamson, Ahmad R. Hariri
Journal: American Journal of Psychiatry (2014)

Objective: Although heightened amygdala reactivity is observed in patients with major depression, two critical gaps in our knowledge remain. First, it is unclear whether heightened amygdala reactivity is a premorbid vulnerability or a consequence of the disorder. Second, it is unknown how and when this neural phenotype develops. The authors sought to address these gaps by evaluating developmental change in threat-related amygdala reactivity in adolescents at high or low risk for depression based on family history, before onset of disorder. Method: At baseline and again 2 years later, adolescents (initially 11–15 years of age) participated in a functional MRI paradigm that elicited threat-related amygdala reactivity. After quality control, data were available for 232 adolescents at wave 1 and 197 adolescents at wave 2; longitudinal data meeting quality control at both waves were available for 157 of these participants. Change in amygdala reactivity was assessed as a function of family history of depression and severity of stressful life events. Results: Threat-related amygdala reactivity increased with age in participants with a positive family history regardless of the severity of life stress reported, and it increased in adolescents with a negative family history who reported relatively severe life stress. These changes in amygdala reactivity with age occurred in the absence of clinical disorder or increases in depressive symptoms. Conclusions: These results suggest that heightened amygdala reactivity emerges during adolescence, prior to the development of depression, as a function of familial risk or, in the absence of familial risk, stressful life events.
<i>Klinische Studien und Erfahrungen betreffs der Familiaren Myoklonie und damit Verwandten Krankheiten.</i>Von Herman Lundborg. (<i>Clinical Studies and Deductions concerning Family Myoclonia and Related Diseases.</i>) Stockholm: A. B. Nordiska Bokhandeln, 1901
Authors: L. Pierce Clark
Journal: American Journal of Psychiatry (1903)
The Use and Interpretation of Commercial<i>APC</i>Gene Testing for Familial Adenomatous Polyposis
Authors: Francis M. Giardiello, Jill D. Brensinger, Gloria M. Petersen, Michael C. Luce, Linda M. Hylind, Judith A. Bacon, Susan V. Booker, Rodger D. Parker, Stanley R. Hamilton
Journal: New England Journal of Medicine (1997)

The use of commercially available tests for genes linked to familial cancer has aroused concern about the impact of these tests on patients. Familial adenomatous polyposis is an autosomal dominant disease caused by a germ-line mutation of the adenomatous polyposis coli (APC) gene that causes colorectal cancer if prophylactic colectomy is not performed. We evaluated the clinical use of commercial APC gene testing.We assessed indications for APC gene testing, whether informed consent was obtained and genetic counseling was offered before testing, and the interpretation of the results through telephone interviews with physicians and genetic counselors in a nationwide sample of 177 patients from 125 families who underwent testing during 1995.Of the 177 patients tested, 83.0 percent had clinical features of familial adenomatous polyposis or were at risk for the disease-both valid indications for being tested. The appropriate strategy for presymptomatic testing was used in 79.4 percent (50 of 63 patients). Only 18.6 percent (33 of 177) received genetic counseling before the test, and only 16.9 percent (28 of 166) provided written informed consent. In 31.6 percent of the cases the physicians misinterpreted the test results. Among the patients with unconventional indications for testing, the rate of positive results was only 2.3 percent (1 of 44).Patients who underwent genetic tests for familial adenomatous polyposis often received inadequate counseling and would have been given incorrectly interpreted results. Physicians should be prepared to offer genetic counseling if they order genetic tests.
Neurofibromatosis of the Stomach
Authors: Victor D. Perea
Journal: JAMA (1962)

A case of neurofibroma of the stomach and mesentery associated with von Recklinghausen's disease and chronic ulcerative colitis in a 44-year-old female is reported. Severe upper abdominal pain, vomiting, and anemia were the most prominent symptoms and all disappeared following subtotal gastrectomy. Review of the English medical literature showed 29 cases of gastric neurofibroma, either single or multiple, 5 of which were also accompanied by generalized cutaneous neurofibromatosis. All patients were 30 years of age or more; there were 18 females and 11 males. Abdominal pain, anemia, and gastrointestinal bleeding were the most frequent presenting symptoms. Ulceration was rather frequent and a gross lesion was noted in 16 patients.
Long-Term Prognosis of Acute Myeloid Leukemia According to the New Genetic Risk Classification of the European LeukemiaNet Recommendations: Evaluation of the Proposed Reporting System
Authors: Christoph Röllig, Martin Bornhäuser, Christian Thiede, Franziska Taube, Michael Kramer, Brigitte Mohr, Walter Aulitzky, Heinrich Bodenstein, Hans-Joachim Tischler, Reingard Stuhlmann, Ulrich Schuler, Friedrich Stölzel, Malte von Bonin, Hannes Wandt, Kerstin Schäfer-Eckart, Markus Schaich, Gerhard Ehninger
Journal: Journal of Clinical Oncology (2011)

The current European LeukemiaNet (ELN) recommendations for acute myeloid leukemia (AML) propose a new risk reporting system, integrating molecular and cytogenetic factors and subdividing the large heterogenous group of intermediate-risk patients into intermediate-I (IR-I) and intermediate-II (IR-II). We assessed the prognostic value of the new risk classification in a large cohort of patients.Complete data for classification were available for 1,557 of 1,862 patients treated in the AML96 trial. Patients were assigned to the proposed genetic groups from the ELN recommendations, and survival analyses were performed using the Kaplan-Meier method and log-rank test for significance testing.The median age of all patients was 67 years. With a median follow-up of 8.3 years, significant differences between all risk categories were observed in patients age ≤ 60 years regarding the time to relapse, relapse-free survival, and overall survival (OS). Patients in the IR-II group had a better prognosis than patients in the IR-I group. The median OS times in young patients with favorable risk (FR), IR-I, IR-II, and adverse risk (AR) were 5.3, 1.1, 1.6, and 0.5 years, respectively. Separate analyses in the age group older than 60 years revealed significant differences between FR, AR, and IR as a whole, but not between IR-I and IR-II.In younger patients with AML, the ELN classification seems to be the best available framework for prognostic estimations to date. Caution is advised concerning its use for prospective treatment allocation before it has been prospectively validated. In elderly patients, alternative prognostic factors are desirable for further risk stratification of IR.
Abstract 13308: The Transcriptome of Kawasaki Disease Arteritis Reveals Activation of T Lymphocyte and Natural Killer Cell Function, Antigen Presentation, Immunoglobulin Production, and Interferon Response
Authors: Anne H Rowley, Kristine Wylie, Adam Pink, Rebecca Reindel, Susan Baker, Stanford Shulman, Jan Orenstein, Elizabeth Perlman, Mark Lingen, George Weinstock, Todd Wylie
Journal: Circulation (2014)

Introduction: We recently published the new information that necrotizing arteritis, subacute/chronic vasculitis and luminal myofibroblastic proliferation are the three linked pathologic processes of Kawasaki Disease (KD) vasculopathy, which critically affects the coronary arteries (CA). The specific dysregulated immune pathways in KD CA have been unknown, and controversy exists as to whether immune dysregulation is primarily macrophage or T and B lymphocyte-driven. Hypothesis: We hypothesized that the immune transcriptome of KD arteritis was primarily one of T and B lymphocyte rather than macrophage activation. Methods: RNA was isolated from paraffin-embedded CA tissues. RNA samples passing quality control assays were subjected to ribosomal RNA subtraction, and Illumina HiSeq 2000 RNA sequencing (101 nt paired-end reads, 40-100million reads/sample) was performed. Reads were aligned to the human genome, and Cuffdiff used to test for differential gene expression in CA tissues from 8 KD children (median age=7 mo, median 4 wks from onset) compared to 7 controls who had normal CA pathology (median age=5 mo). Pathways analysis was performed using Ingenuity iReport™. Results: 1057 differentially expressed transcripts were identified with &gt;1.5-fold change and q-value &lt;0.05. The most significantly upregulated pathways included T lymphocyte, dendritic cell and natural killer cell signaling, antigen presentation, and toll-like receptor (TLR) signaling (p values 1e-18 to 5e-05). Immunoglobulin A, G, and M genes and at least 50 type I interferon-stimulated genes were significantly upregulated. Tumor necrosis factor α (TNFα) receptor and transforming growth factor β signaling pathways were not significantly altered (p-value &gt;0.1). 50 immune response genes encoding secreted proteins were upregulated and are candidate biomarkers of KD arteritis. Conclusions: The host transcriptional response in target CA tissues in KD demonstrates a prominent innate and acquired immune response to antigen. Genes related to T and B lymphocyte activation were upregulated but macrophage responses were not prominent. This first report of the CA transcriptome of KD could lead to identification of new therapeutic targets and biomarkers for KD arteriopathy.
A Large Permissive Regulatory Domain Exclusively Controls <i>Tbx3</i> Expression in the Cardiac Conduction System
Authors: Jan Hendrik van Weerd, Ileana Badi, Malou van den Boogaard, Sonia Stefanovic, Harmen J.G. van de Werken, Melisa Gomez-Velazquez, Claudio Badia-Careaga, Miguel Manzanares, Wouter de Laat, Phil Barnett, Vincent M. Christoffels
Journal: Circulation Research (2014)

The evolutionary conserved Tbx3/Tbx5 gene cluster encodes T-box transcription factors that play crucial roles in the development and homeostasis of the cardiac conduction system in human and mouse. Both genes are expressed in overlapping patterns and function in strictly tissue-specific and dose-dependent manners, yet, their regulation is poorly understood.To analyze the mechanism underlying the complex regulation of the Tbx3/Tbx5 cluster.By probing the 3-dimensional architecture of the Tbx3/Tbx5 cluster using high-resolution circular chromosome conformation capture sequencing in vivo, we found that its regulatory landscape is in a preformed conformation similar in embryonic heart, limbs, and brain. Tbx3 and its flanking gene desert form a 1 Mbp loop between CCCTC-binding factor (CTCF)-binding sites that is separated from the neighboring Tbx5 loop. However, Ctcf inactivation did not result in transcriptional regulatory interaction between Tbx3 and Tbx5. Multiple sites within the Tbx3 locus contact the promoter, including sites corresponding to regions known to contain variations in the human genome influencing conduction. We identified an atrioventricular-specific enhancer and a pan-cardiac enhancer that contact the promoter and each other and synergize to activate transcription in the atrioventricular conduction system.We provide a high-resolution model of the 3-dimensional structure and function of the Tbx3/Tbx5 locus and show that the locus is organized in a preformed, permissive structure. The Tbx3 locus forms a CTCF-independent autonomous regulatory domain with multiple combinatorial regulatory elements that control the precise pattern of Tbx3 in the cardiac conduction system.
Coronary Heart Disease Risk Equivalence in Diabetes Depends on Concomitant Risk Factors
Authors: Barbara V. Howard, Lyle G. Best, James M. Galloway, William James Howard, Kristina Jones, Elisa T. Lee, Robert E. Ratner, Helaine E. Resnick, Richard B. Devereux
Journal: Diabetes Care (2006)

OBJECTIVE—Diabetes has been defined as a coronary heart disease (CHD) risk equivalent, and more aggressive treatment goals have been proposed for diabetic patients. RESEARCH DESIGN AND METHODS—We studied the influence of single and multiple risk factors on the 10-year cumulative incidence of fatal and nonfatal CHD and cardiovascular disease (CVD) in diabetic and nondiabetic men and women, with and without baseline CHD or CVD, in a population (n = 4,549) with a high prevalence of diabetes. RESULTS—In both sexes, diabetes increased the risk for CHD (hazard ratio 1.99 and 2.93 for men and women, respectively). Diabetic men and women had a 10-year cumulative incidence of CHD of 25.9 and 19.1%, respectively, compared with 57.4 and 58.4% for nondiabetic men and women with previous CHD. The pattern was similar when only fatal events were considered. Diabetic individuals with one or two risk factors had a 10-year cumulative incidence of CHD that was only 1.4 times higher than that of nondiabetic individuals (14%). However, the 10-year incidence of CHD in diabetic subjects with multiple risk factors was &amp;gt;40%, and the incidence of fatal CHD was higher in these subjects than in nondiabetic subjects with previous CHD. Data for CVD showed similar patterns, as did separate analyses by sex. CONCLUSIONS—Our results and comparisons with other available data show wide variation in the rate of CHD in diabetes, depending on the population and existing risk factors. Most individuals had a 10-year cumulative incidence &amp;gt;20%, but only those with multiple risk factors had a 10-year cumulative incidence that was equivalent to that of patients with CHD. Until more data are available, it may be prudent to consider targets based on the entire risk factor profile rather than just the presence of diabetes.
Clinical experience with thalidomide in the management of severe oral and genital ulceration in conditions such as Behcet's disease: use of neurophysiological studies to detect thalidomide neuropathy.
Authors: J M Gardner-Medwin, N J Smith, R J Powell
Journal: Annals of the Rheumatic Diseases (1994)

OBJECTIVE--To examine the efficacy, dose, and safety profile, including neurophysiological testing of thalidomide used in 59 patients (including 23 with Behçet9s disease) to treat severe oral or genital ulceration (OGU). METHODS--We identified prospectively subjects (including women of childbearing potential) who had persistent OGU over periods lasting one to 40 years and whose active ulceration was not controlled by other therapies. They were treated with thalidomide. Retrospectively, we identified the number of subjects with complete resolution of the ulcers at one and two months of thalidomide therapy, and the dose required to maintain that improvement in those individuals who relapsed after stopping thalidomide. The decrease from the baseline sensory nerve action potential (baseline SNAP) amplitude value (derived from median, radial and sural nerve SNAPs) at which the development of paraesthesiae was likely to occur was also determined. RESULTS--Complete resolution of the ulcers occurred in 81% of patients within one month of thalidomide therapy at doses of 200 mg/day. No further thalidomide was required by 20% of patients responding and in the remainder improvement was maintained with smaller doses (7-200 mg/day). Using an approximate 50% decrease from baseline SNAP as an indication to discontinue thalidomide, the incidence of symptomatic neuropathy was 13.5%. No patients with a decrease of less than 42% developed neuropathy, and a further 13.5% were asymptomatic with a decrease in SNAP between 42 and 69%. Other side effects were seen in 44% of patients. There were no pregnancies and no requirement for urgent pregnancy testing. CONCLUSIONS--Thalidomide provided a useful therapeutic option in severe oral and genital ulceration which had not responded to other therapies. The physician must remain vigilant to the continuing danger of axonal neuropathy and teratogenesis at all times during thalidomide therapy.
Effect of Intrauterine Diabetes Exposure on the Incidence of End-Stage Renal Disease in Young Adults With Type 2 Diabetes
Authors: Meda E. Pavkov, Robert L. Hanson, William C. Knowler, Maurice L. Sievers, Peter H. Bennett, Robert G. Nelson
Journal: Diabetes Care (2010)

OBJECTIVE We examined the effect of intrauterine diabetes exposure (IDE) on the incidence of diabetic end-stage renal disease (ESRD) in Pima Indians with type 2 diabetes. RESEARCH DESIGN AND METHODS Individuals were followed from their first diabetic examination until December 2006, death, ESRD, or age of 45 years. RESULTS Among the 1,850 diabetic participants, 102 had IDE. ESRD developed in 57, 5 of whom had IDE. Cumulative incidence of ESRD by age 45 was 19.3% in participants with IDE and 5.1% in those without; the age- and sex-adjusted incidence rate ratio was 4.12 (95% CI 1.54–11.02). After additional adjustment for age at diabetes onset, ESRD incidence was similar in the two groups (incidence rate ratio 1.38, 95% CI 0.45–4.24). CONCLUSIONS IDE increases the age- and sex-adjusted incidence of ESRD fourfold in young adults with type 2 diabetes, mediated primarily by the earlier onset of type 2 diabetes in those with IDE.
Rapamycin Disrupts Cyclin/Cyclin-Dependent Kinase/p21/Proliferating Cell Nuclear Antigen Complexes and Cyclin D1 Reverses Rapamycin Action by Stabilizing These Complexes
Authors: Mary Law, Elizabeth Forrester, Anna Chytil, Patrick Corsino, Gail Green, Bradley Davis, Thomas Rowe, Brian Law
Journal: Cancer Research (2006)

Abstract Rapamycin and its derivatives are promising anticancer agents, but the exact mechanisms by which these drugs induce cell cycle arrest and inhibit tumor growth are unknown. A biochemical analysis of human mammary tumor cell lines indicated that rapamycin-induced antiproliferative effects correlated with down-regulation of cellular p21 levels and the levels of p21 in cyclin-dependent kinase (Cdk) 2 and 4 complexes. Cyclin D1 overexpression reversed rapamycin action and this reversal correlated with increased levels of cellular p21, higher levels of p21 associated with Cdk2, and stabilization of cyclin D1/Cdk2/p21/proliferating cell nuclear antigen (PCNA) complexes. Experiments using a novel cyclin D1-Cdk2 fusion protein or a kinase-dead mutant of the fusion protein indicated that reversal of rapamycin action required not only the formation of complexes with p21 and PCNA but also complex-associated kinase activity. Similar results were observed in vivo. The rapamycin derivative RAD001 (everolimus) inhibited the growth of mouse mammary tumors, which correlated with the disruption of cyclin D1/Cdk2 complexes. The potential implications of these results with respect to the use of rapamycin derivatives in breast cancer therapy are discussed. (Cancer Res 2006; 66(2): 1070-80)
Richard Doll at 80.
Authors: T Smith
Journal: BMJ (1993)

group and does not necessitate an expensive mass screening programme.More sensitive conventional cultures should be used when possible.We suggest the following: when an additional risk factor (preterm labour, prolonged rupture of membranes, or fever) is present conventional culture and a rapid test should be performed, and if either gives a positive result antibiotics should be given during labour.In some cases-for example, maternal pyrexia and prolonged rupture of membranes-the rapid test is unnecessary and antibiotics should be given regardless of carriage.Rectal and vaginal cultures should be taken during a multiple pregnancy and if these yield group B streptococcus, prophylaxis should be started during labour.If results are negative a rapid test should be performed during labour.As there are no reliable data on mothers who have already had an infected child, they should receive chemoprophylaxis regardless of culture.It can be argued that such mothers may not develop protective IgG antibodies and may continue to carry the same strain of group B streptococcus.Ampicillin or amoxycillin remain the drugs of choice,9 although a first generation cephalosporin may be used in the case of ampicillin allergy.'