tbuckley/cabot-search huggingface dataset:
Treating Postprandial Hyperglycemia Does Not Appear to Delay Progression of Early Type 2 Diabetes
Authors: M. Sue Kirkman, R. Ravi Shankar, Sudha Shankar, Changyu Shen, Edward Brizendine, Alain Baron, Janet McGill
Journal: Diabetes Care (2006)

Postprandial hyperglycemia characterizes early type 2 diabetes. We investigated whether ameliorating postprandial hyperglycemia with acarbose would prevent or delay progression of diabetes, defined as progression to frank fasting hyperglycemia, in subjects with early diabetes (fasting plasma glucose [FPG] <140 mg/dl and 2-h plasma glucose > or =200 mg/dl).Two hundred nineteen subjects with early diabetes were randomly assigned to 100 mg acarbose t.i.d. or identical placebo and followed for 5 years or until they reached the primary outcome (two consecutive quarterly FPG measurements of > or =140 mg/dl). Secondary outcomes included measures of glycemia (meal tolerance tests, HbA(1c), annual oral glucose tolerance tests [OGTTs]), measures of insulin resistance (homeostasis model assessment [HOMA] of insulin resistance and insulin sensitivity index from hyperglycemic clamps), and secondary measures of beta-cell function (HOMA-beta, early- and late-phase insulin secretion, and proinsulin-to-insulin ratio).Acarbose significantly reduced postprandial hyperglycemia. However, there was no difference in the cumulative rate of frank fasting hyperglycemia (29% with acarbose and 34% with placebo; P = 0.65 for survival analysis). There were no significant differences between groups in OGTT values, measures of insulin resistance, or secondary measures of beta-cell function. In a post hoc analysis of subjects with initial FPG <126 mg/dl, acarbose reduced the rate of development of FPG > or =126 mg/dl (27 vs. 50%; P = 0.04).Ameliorating postprandial hyperglycemia did not appear to delay progression of early type 2 diabetes. Factors other than postprandial hyperglycemia may be greater determinants of progression of diabetes. Alternatively, once FPG exceeds 126 mg/dl, beta-cell failure may no longer be remediable.
Mutations in the SLC2A10 gene cause arterial abnormalities in mice
Authors: C.-H. Cheng, T. Kikuchi, Y.-H. Chen, N. G. A.-A.-A. Sabbagha, Y.-C. Lee, H.-J. Pan, C. Chang, Y.-T. Chen
Journal: Cardiovascular Research (2008)

Glucose transporter 10 (GLUT10), encoded by the SLC2A10 gene, is a member of the class III facilitative glucose transporter family. Mutations in the SLC2A10 gene cause arterial tortuosity syndrome (ATS) in humans. To further study the pathogenesis of the disease, we generated mice carrying GLUT10 mutations. Using a gene-driven N-ethyl-N-nitrosourea (ENU)-mutagenesis approach, we generated mice carrying GLUT10 mutations c.383G>A and c.449C>T, which resulted in missense mutations of glycine to glutamic acid (p.G128E) and serine to phenylalanine (p.S150F), respectively. Both mutant strains appeared normal at birth, gained weight appropriately and survived to adulthood (>18 months). Blood and urine glucose were normal. Echocardiogram and electrocardiogram were also normal and brain magnetic resonance angiography revealed normal cerebral arteries without tortuosity, stenosis/dilatation, or aneurysm. Histopathology revealed thickening and irregular vessel wall shape of large and medium size arteries characterized by markedly increased elastic fibres, both in number and size. There was also intima endothelial hypertrophy and deranged elastic fibres that resulted in disruption of internal elastic lamina in the aorta of older mice. Abnormal elastogenesis with early elastic fibre proliferation provides a clue to the pathogenesis of arterial tortuosity in human ATS. Availability of this mouse model will allow testing of the relationship between diabetes and its vascular complications, including diabetic retinopathy, nephropathy and peripheral vascular disease.
Social Contexts Influence Ethical Considerations of Research
Authors: Judith B. Gordon, Robert J. Levine, Carolyn M. Mazure, Philip E. Rubin, Barry R. Schaller, John L. Young
Journal: The American Journal of Bioethics (2011)

This article argues that we could improve the design of research protocols by developing an awareness of and a responsiveness to the social contexts of all the actors in the research enterprise, including subjects, investigators, sponsors, and members of the community in which the research will be conducted. "Social context" refers to the settings in which the actors are situated, including, but not limited to, their social, economic, political, cultural, and technological features. The utility of thinking about social contexts is introduced and exemplified by the presentation of a hypothetical case in which one central issue is limitation of the probability of injury to subjects by selection of individuals who are not expected to live long enough for the known risks of the study to become manifest as harms. Benefits of such considerations may include enhanced subject satisfaction and cooperation, community acceptance, and improved data quality, among other desirable consequences.
Tamoxifen Resistance in Breast Tumors Is Driven by Growth Factor Receptor Signaling with Repression of Classic Estrogen Receptor Genomic Function
Authors: Suleiman Massarweh, C. Kent Osborne, Chad J. Creighton, Lanfang Qin, Anna Tsimelzon, Shixia Huang, Heidi Weiss, Mothaffar Rimawi, Rachel Schiff
Journal: Cancer Research (2008)

Abstract Not all breast cancers respond to tamoxifen, and many develop resistance despite initial benefit. We used an in vivo model of estrogen receptor (ER)–positive breast cancer (MCF-7 xenografts) to investigate mechanisms of this resistance and develop strategies to circumvent it. Epidermal growth factor receptor (EGFR) and HER2, which were barely detected in control estrogen-treated tumors, increased slightly with tamoxifen and were markedly increased when tumors became resistant. Gefitinib, which inhibits EGFR/HER2, improved the antitumor effect of tamoxifen and delayed acquired resistance, but had no effect on estrogen-stimulated growth. Phosphorylated levels of p42/44 and p38 mitogen-activated protein kinases (both downstream of EGFR/HER2) were increased in the tamoxifen-resistant tumors and were suppressed by gefitinib. There was no apparent increase in phosphorylated AKT (also downstream of EGFR/HER2) in resistant tumors, but it was nonetheless suppressed by gefitinib. Phosphorylated insulin-like growth factor-IR (IGF-IR), which can interact with both EGFR and membrane ER, was elevated in the tamoxifen-resistant tumors compared with the sensitive group. However, ER-regulated gene products, including total IGF-IR itself and progesterone receptor, remained suppressed even at the time of acquired resistance. Tamoxifen's antagonism of classic ER genomic function was retained in these resistant tumors and even in tumors that overexpress HER2 (MCF-7 HER2/18) and are de novo tamoxifen-resistant. In conclusion, EGFR/HER2 may mediate tamoxifen resistance in ER-positive breast cancer despite continued suppression of ER genomic function by tamoxifen. IGF-IR expression remains dependent on ER but is activated in the tamoxifen-resistant tumors. This study provides a rationale to combine HER inhibitors with tamoxifen in clinical studies, even in tumors that do not initially overexpress EGFR/HER2. [Cancer Res 2008;68(3):826–33]
Factors contributing to severe pneumonia in patients with chronic obstructive pulmonary disease
Authors: Jung Seop Eom, Wonjun Song, Duck Hyun Ryu, Hye Yun Park
Journal: European Respiratory Journal (2014)

Since chronic obstructive pulmonary disease (COPD) is a heterogeneous disorder, factors contributing to severe pneumonia may be diverse or different among each phenotypes. However, little information is available on factors contributing to the severity of pneumonia in COPD population. Thus, we compared the demographic characteristics, CT findings, and COPD-related variables between COPD patients with severe pneumonia and those with non-severe pneumonia to verify the factors contributing to severe pneumonia in COPD population.

Retrospective observational study was conducted with prospectively collected database between January 2008 and December 2012. Over study period, total 1502 immunocompetent patients with pneumonia admitted via the emergency department. Of these patients, 190 patients had the diagnosis of COPD, and 29 patients were excluded due to medical condition or disease which may affect lung function.

Of the 161 study population, 114 (70.8%) and 47 patients (29.2%) were classified as a non-severe and severe pneumonia, respectively. Higher ECOG score (odds ratio 1.459; 95% confidence interval 1.004-2.121; P = 0.048) and the presence of pulmonary emphysema on CT scan (odds ratio 2.688; 95% confidence interval 1.024-7.059; P = 0.045) were independently associated with severe pneumonia in COPD patients. However, there was no difference in pulmonary function test, GOLD grade and COPD medication between non-severe and severe pneumonia.

In conclusion, the presence of pulmonary emphysema on CT scan and poor performance status at the time of hospital admission were associated with severe pneumonia in COPD population.
Homeostatic imbalance of regulatory and effector T cells due to IL-2 deprivation amplifies murine lupus
Authors: J. Humrich, R. Undeutsch, L. Kloke, G.-R. Burmester, G. Riemekasten
Journal: Annals of the Rheumatic Diseases (2010)

The origins and consequences of a regulatory T cell (Treg) disorder in systemic lupus erythematosus (SLE) are poorly understood. In the (NZBxNZW) F1 mouse model of lupus, we found that CD4Foxp3+ Treg failed to maintain a competitive pool size in the peripheral lymphoid organs resulting …
Blood leukocyte microarrays to diagnose systemic onset juvenile idiopathic arthritis and follow the response to IL-1 blockade
Authors: Florence Allantaz, Damien Chaussabel, Dorothee Stichweh, Lynda Bennett, Windy Allman, Asuncion Mejias, Monica Ardura, Wendy Chung, Elisabeth Smith, Carol Wise, Karolina Palucka, Octavio Ramilo, Marilynn Punaro, Jacques Banchereau, Virginia Pascual
Journal: The Journal of Experimental Medicine (2007)

Systemic onset juvenile idiopathic arthritis (SoJIA) represents up to 20% of juvenile idiopathic arthritis. We recently reported that interleukin (IL) 1 is an important mediator of this disease and that IL-1 blockade induces clinical remission. However, lack of specificity of the initial systemic manifestations leads to delays in diagnosis and initiation of therapy. To develop a specific diagnostic test, we analyzed leukocyte gene expression profiles of 44 pediatric SoJIA patients, 94 pediatric patients with acute viral and bacterial infections, 38 pediatric patients with systemic lupus erythematosus (SLE), 6 patients with PAPA syndrome, and 39 healthy children. Statistical group comparison and class prediction identified genes differentially expressed in SoJIA patients compared with healthy children. These genes, however, were also changed in patients with acute infections and SLE. An analysis of significance across all diagnostic groups identified 88 SoJIA-specific genes, 12 of which accurately classified an independent set of SoJIA patients with systemic disease. Transcripts that changed significantly in patients undergoing IL-1 blockade were also identified. Thus, leukocyte transcriptional signatures can be used to distinguish SoJIA from other febrile illnesses and to assess response to therapy. Availability of early diagnostic markers may allow prompt initiation of therapy and prevention of disabilities.
THE RELATION OF THE AURICULAR ACTIVITY FOLLOWING FARADIZATION OF THE DOG'S AURICLE TO ABNORMAL AURICULAR ACTIVITY IN MAN
Authors: G. Canby Robinson
Journal: The Journal of Experimental Medicine (1913)

The tumultuous auricular activity which follows faradization of the auricles of mammals and which has been variously described, could be distinctly seen to consist almost constantly in our experiments on dogs of true fibrillatory movements of the separate muscle fibers coëxisting with a rapid auricular tachycardia. During peripheral stimulation of the right vagus nerve the true fibrillation alone existed, the tachycardia being inhibited. A comparison of the electrocardiograms from dogs with this abnormal auricular activity with those from patients with the type of cardiac arhythmia which has been attributed to auricular fibrillation, and from patients with so called auricular flutter, indicates that the auricular activity in patients with either of these conditions differs somewhat from that usually seen in the faradized auricles of the dog in our experiments. The auricular activity of the cases of cardiac arhythmia is apparently true fibrillation, similar to that seen in the faradized auricles of the dog during right vagus stimulation. The electrocardiograms from cases of so called auricular flutter usually give no evidence of auricular fibrillation, and the auricular activity seems to consist of tachycardia alone. Fibrillation may apparently coëxist with the tachycardia in some cases, when the auricular activity seems to resemble closely that usually seen in the dog after auricular faradization. During peripheral stimulation of the left vagus nerve, the electrocardiograms obtained after auricular faradization show changes which render them more nearly similar to those obtained from patients with auricular flutter. The facts that the auricular activity of the faradized auricles of the dog may apparently pass spontaneously into that closely resembling auricular flutter in man, that it may be changed into true fibrillation by right vagus stimulation, and that the abnormal auricular activity in man passes from a state of flutter to that of fibrillation in a similar manner, may be taken as evidence for the belief that auricular fibrillation and auricular flutter in man are closely allied cardiac disorders.
Re: Ovarian Ablation or Suppression in Premenopausal Early Breast Cancer: Results from the International Adjuvant Breast Cancer Ovarian Ablation or Suppression Randomized Trial
Authors: G. Ferretti, A. Felici, P. Carlini, F. Cognetti
Journal: JNCI Journal of the National Cancer Institute (2007)

According to the Adjuvant Breast Cancer Trials Collaborative Group (ABCTCG) ( 1 ), women were defined as pre-or perimenopausal if their last menstrual period had occurred within the 12 months before breast diagnostic surgery.
Impact of BRCA1/BRCA2 Mutation Testing on Psychologic Distress in a Clinic-Based Sample
Authors: M. D. Schwartz
Journal: Journal of Clinical Oncology (2002)

PURPOSE: Despite the increasingly widespread availability of BRCA1 and BRCA2 genetic testing, little is known about the psychologic impact of such testing in the clinical setting. The objective of this study was to examine the long-term psychologic impact of receiving BRCA1/2 test results within a clinic-based testing program. PATIENTS AND METHODS: The participants were 279 high-risk women who underwent genetic counseling and testing for alterations in the BRCA1/2 genes. At baseline (before genetic testing) and at 6 months after the disclosure of mutation status, we measured perceived risk for breast and ovarian cancer, cancer-specific distress, and general distress. We examined the impact of the test result on each of these outcomes at the 6-month follow-up. Analyses were conducted separately for probands and their relatives who were unaffected with cancer. RESULTS: We found no effect of test result among affected probands. Among unaffected relatives, we found that participants who received definitive negative test results exhibited significant reductions in perceived risk and distress compared with participants who received positive test results. Importantly, relatives who received positive test results did not exhibit increased distress or perceived risk. CONCLUSION: These results suggest that clinic-based BRCA1/2 testing can lead to psychologic benefits for individuals who receive negative test results. At 6 months after disclosure, those who receive positive or uninformative test results do not exhibit increased psychologic distress or perceived risk.
Reply to S. Zucker
Authors: Stefan Hohaus, Giuseppe Leone, Giuseppina Massini, Manuela Giachelia, Barbara Vannata, Luigi Maria Larocca, Maria Teresa Voso, Dorine W. Swinkels
Journal: Journal of Clinical Oncology (2010)

We recently demonstrated that increased interleukin (IL)-6 production in Hodgkin's lymphoma is associated with an induction of hepcidin, which contributes to the iron-restricted anemia of chronic disease often observed at Hodgkin's lymphoma diagnosis. 1Our data also suggested that increased hepcidin levels might not be sufficient for induction of anemia and that other mechanisms, possibly induced by IL-6, might be responsible.On the basis of well-founded reasoning, Zucker proposes in his letter that compensation by increased erythropoietin production may be the missing link to explain the lack of anemia, despite increased hepcidin levels. 2 Inappropriately high erythropoietin levels have been described as a compensation mechanism in hereditary spherocytosis with a reduced erythroid life span and without anemia. 3Zucker points out that IL-6 is a potential stimulator of erythropoietin as shown in a cell line model by Faquin et al. 4 In this model, however, IL-6 -induced erythropoietin stimulation was hypoxia-dependent and was not observed under normoxic conditions.In the tumor tissue, local hypoxia is present in a proportion of patients with Hodgkin's lymphoma, as suggested by necrotic areas resulting in the release of increased levels of circulating cell-free DNA. 5 However, systemic hypoxia from anemia is considered the major stimulus for renal erythropoietin synthesis.Applying the reasoning of Zucker to patients with Hodgkin's lymphoma, one would expect apparently inappropriate high erythropoietin levels in patients without anemia to compensate for the hepcidin-induced iron restriction.There are few data on erythropoietin levels in patients with Hodgkin's lymphoma at diagnosis.Pohl et al 6 reported slightly, although not significant, higher serum erythropoietin levels in patients with nonanemic Hodgkin's lymphoma when compared with control, whereas erythropoietin levels in patients with anemia appeared to be adequate.Zucker mentions the well-documented effect of erythropoietin on downregulation of hepcidin, 7,8 even in the presence of inflammation, 9,10 which indicates that erythropoietin trumps hepcidin as master regulator of erythropoiesis under conditions of inflammation.Continuing with this idea, one would expect that hepcidin levels should be lower than those observed in our patients without anemia.In conclusion, we agree that erythropoietin as a master regulator of erythropoiesis could probably be another player in the complex scenario of Hodgkin's lymphoma anemia, which may be the result of opposing effects between stimulators and inhibitors of erythropoiesis and proteins involved in iron metabolism and iron-sensing pathways.The scenario remains open for other potential pathways to be defined.
Telomerase activity and telomere length in patients with acute promyelocytic leukemia: indicative of proliferative activity, disease progression, and overall survival
Authors: S.H. Ghaffari, N. Shayan-Asl, A.H. Jamialahmadi, K. Alimoghaddam, A. Ghavamzadeh
Journal: Annals of Oncology (2008)

BackgroundThe progressive shortening of telomeres and the activation of telomerase have been considered to be one of the key mechanisms in cellular immortalization and tumor progression.Patients and methodsAbout 300 sequential samples were collected from 40 patients during the course of acute promyelocytic leukemia (APL) disease. Telomerase activity (TA) and terminal restriction fragment (TRF) length were assessed by TRAP and Southern blot analyses, respectively. PML-retinoic acid receptor α (RARa)/glucose-6-phosphate dehydrogenase transcripts were quantified by real-time PCR.ResultsAbout 90% of the patients had a significant reduction in telomere length (TL) relative to the control (median 3.5 versus 11.37 kbp; P < 0.001). A significant positive correlation between TL and PML-RARa expression was found (P = 0.001). Telomerase was activated in all patients; however, TA level was significantly higher in the group of relapsed patients than patient with newly diagnosed. The group of patients with shortened TRF and elevated TA had a significantly poorer overall survival.ConclusionsThe shortened TL and elevated TA in APL patients are mainly indicative of extensive proliferative activity and they correlate with disease progression and relapse; thus, they may serve as prognostic factors for a subset of APL patients with more aggressive disease and poor outcome, those who may not respond favorably to arsenic therapy.
FOLFIRI.3, a new regimen combining 5-fluorouracil, folinic acid and irinotecan, for advanced pancreatic cancer: results of an Association des Gastro-Entérologues Oncologues (Gastroenterologist Oncologist Association) multicenter phase II study
Authors: J. Taïeb, T. Lecomte, T. Aparicio, A. Asnacios, T. Mansourbakht, P. Artru, D. Fallik, J.P. Spano, B. Landi, G. Lledo, J. Desrame
Journal: Annals of Oncology (2006)
Comparisons between geographies of mortality and deprivation from the 1900s and 2001: spatial analysis of census and mortality statistics
Authors: I. N Gregory
Journal: BMJ (2009)

<b>Objectives</b> To examine the geographical relation between mortality and deprivation in England and Wales at the start of the 20th and 21st centuries. To explore the evidence for a strengthening or weakening of this relation over the century and test for relations between the mortality and deprivation patterns of a century ago and modern mortality and causes of death. <b>Design</b> Census and mortality data for 634 districts from the 1900s directly compared with interpolated ward level data from 2001. <b>Setting</b> Census data and national statistics for England and Wales in the 1900s and 2001. <b>Population</b> Entire population in both periods. <b>Main outcome measures</b> Standardised mortality ratios for all districts for both periods with additional cause specific ratios calculated for 2001. Deprivation (Carstairs) scores for each district in 2001, with comparable measure created for the 1900s. Correlations and partial correlations between deprivation scores and standardised mortality ratios in the 1900s and 2001 for the 614 districts for which all data were available. <b>Results</b> The was no evidence of a significant change in the strength of the relation between deprivation and mortality between the start and end of the 20th century. Modern patterns of mortality and deprivation remain closely related to the patterns of a century ago. Even after adjustment for modern deprivation, standardised mortality ratios from the 1900s show a significant correlation with modern mortality and most modern causes of death. Conversely, however, there was no significant relation between deprivation in the 1900s and modern mortality for most causes of death after adjustment for modern deprivation. <b>Conclusions</b> Despite all the medical, public health, social, economic, and political changes over the 20th century, patterns of poverty and mortality and the relations between them remain firmly entrenched. There is a strong relation between the mortality levels of a century ago and those of today. This goes beyond what would have been expected from the continuing relation between deprivation and mortality and holds true for most major modern causes of death.