tbuckley/cabot-search huggingface dataset:
Effects of Prandial Versus Fasting Glycemia on Cardiovascular Outcomes in Type 2 Diabetes: The HEART2D trial
Authors: Itamar Raz, Peter W.F. Wilson, Krzysztof Strojek, Irina Kowalska, Velimir Bozikov, Anselm K. Gitt, György Jermendy, Barbara N. Campaigne, Lisa Kerr, Zvonko Milicevic, Scott J. Jacober
Journal: Diabetes Care (2009)

OBJECTIVE—Hyperglycemia and Its Effect After Acute Myocardial Infarction on Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus (HEART2D) is a multinational, randomized, controlled trial designed to compare the effects of prandial versus fasting glycemic control on risk for cardiovascular outcomes in patients with type 2 diabetes after acute myocardial infarction (AMI). RESEARCH DESIGN AND METHODS—Patients (type 2 diabetes, aged 30–75 years) were randomly assigned within 21 days after AMI to the 1) prandial strategy (PRANDIAL) (three premeal doses of insulin lispro targeting 2-h postprandial blood glucose &amp;lt;7.5 mmol/l) or the 2) basal strategy (BASAL) (NPH twice daily or insulin glargine once daily targeting fasting/premeal blood glucose &amp;lt;6.7 mmol/l). RESULTS—A total of 1,115 patients were randomly assigned (PRANDIAL n = 557; BASAL n = 558), and the mean patient participation after randomization was 963 days (range 1–1,687 days). The trial was stopped for lack of efficacy. Risks of first combined adjudicated primary cardiovascular events in the PRANDIAL (n = 174, 31.2%) and BASAL (n = 181, 32.4%) groups were similar (hazard ratio 0.98 [95% CI 0.8–1.21]). Mean A1C did not differ between the PRANDIAL and BASAL groups (7.7 ± 0.1 vs. 7.8 ± 0.1%; P = 0.4) during the study. The PRANDIAL group showed a lower daily mean postprandial blood glucose (7.8 vs. 8.6 mmol/l; P &amp;lt; 0.01) and 2-h postprandial blood glucose excursion (0.1 vs. 1.3 mmol/l; P &amp;lt; 0.001) versus the BASAL group. The BASAL group showed lower mean fasting blood glucose (7.0 vs. 8.1 mmol/l; P &amp;lt; 0.001) and similar daily fasting/premeal blood glucose (7.7 vs. 7.3 mmol/l; P = 0.233) versus the PRANDIAL group. CONCLUSIONS—Treating diabetic survivors of AMI with prandial versus basal strategies achieved differences in fasting blood glucose, less-than-expected differences in postprandial blood glucose, similar levels of A1C, and no difference in risk for future cardiovascular event rates.
EndoU is a novel regulator of AICD during peripheral B cell selection
Authors: Jonathan C. Poe, Evgueni I. Kountikov, Jacquelyn M. Lykken, Abirami Natarajan, Douglas A. Marchuk, Thomas F. Tedder
Journal: The Journal of Experimental Medicine (2013)

Balanced transmembrane signals maintain a competent peripheral B cell pool limited in self-reactive B cells that may produce pathogenic autoantibodies. To identify molecules regulating peripheral B cell survival and tolerance to self-antigens (Ags), a gene modifier screen was performed with B cells from CD22-deficient C57BL/6 (CD22(-/-[B6])) mice that undergo activation-induced cell death (AICD) and fail to up-regulate c-Myc expression after B cell Ag receptor ligation. Likewise, lysozyme auto-Ag-specific B cells in Ig(Tg) hen egg lysozyme (HEL) transgenic mice inhabit the spleen but undergo AICD after auto-Ag encounter. This gene modifier screen identified EndoU, a single-stranded RNA-binding protein of ancient origin, as a major regulator of B cell survival in both models. EndoU gene disruption prevents AICD and normalizes c-Myc expression. These findings reveal that EndoU is a critical regulator of an unexpected and novel RNA-dependent pathway controlling peripheral B cell survival and Ag responsiveness that may contribute to peripheral B cell tolerance.
Expansion of cytokine-producing CD4-CD8- T cells associated with abnormal Fas expression and hypereosinophilia.
Authors: H U Simon, S Yousefi, C C Dommann-Scherrer, D R Zimmermann, S Bauer, J Barandun, K Blaser
Journal: The Journal of Experimental Medicine (1996)

The mechanisms of sustained overproduction of eosinophils in the idiopathic hypereosinophilic syndrome and in some human immunodeficiency virus (HIV)-1-infected individuals are largely unknown. We hypothesized that T cells may release soluble products that regulate eosinophilia in these patients, as has been previously shown in bronchial asthma. We identified one patient with idiopathic hypereosinophilic syndrome and one HIV-1-infected individual with associated hypereosinophilia who demonstrated high numbers of CD4-CD8- T cells in peripheral blood. CD4-CD8- T cells from both patients, although highly activated, did not express functional Fas receptors. In one case, the lack of functional Fas receptors was associated with failure of Fas mRNA and protein expression, and in another, expression of a soluble form of the Fas molecule that may have antagonized normal signaling of Fas ligand. In contrast to the recently described lymphoproliferative/autoimmune syndrome, which is characterized by accumulation of CD4-CD8- T cells and mutations within the Fas gene, this study suggests somatic variations in Fas expression and function quite late in life. Both genetic and somatic abnormalities in regulation of the Fas gene are therefore associated with failures to undergo T cell apoptosis. Furthermore, the expanded population of CD4-CD8- T cells from both patients elaborated cytokines with antiapoptotic properties for eosinophils, indicating a major role of these T cells in the development of eosinophilia. Thus, this study demonstrates a sequential dysregulation of apoptosis in different cell types.
A Crisis of Public Confidence in Vaccines
Authors: Steven Black, Rino Rappuoli
Journal: Science Translational Medicine (2010)

A meeting was held in Siena, Italy, in July 2010 to review the evidence for a decrease in public confidence in vaccines, to discuss possible reasons for this phenomenon, and to develop possible strategies to improve public confidence in vaccines. Prevention of morbidity and mortality by vaccination is one of the major public health accomplishments of the last century. Nevertheless, despite the improved safety and effectiveness of vaccines, public confidence in vaccination is decreasing. Improved methods of vaccine safety assessment have not improved public confidence. In addition, dissemination of false information on the Internet has undermined public confidence globally. Reductions in vaccine uptake or use of available vaccines can and have resulted in increased morbidity and mortality due to infectious diseases. The lack of public confidence in vaccines risks undermining the political will necessary to rapidly respond to a more severe influenza pandemic in the future. To improve the current situation, we must define both the risks and the benefits of individual vaccines so that the public can understand the rationale for vaccine recommendations. Key to regaining public trust in vaccines is a credible, consistent, and unified message developed from the private and public sectors that directly addresses public concerns. Unless an active effort is made to improve public confidence and trust in vaccination, there is a risk that gains made in combating the morbidity and mortality of infectious diseases through the use of vaccines will be lost. Loss of political will resulting from this loss of public confidence may also result in inappropriate decisions regarding the development and use of pandemic influenza vaccines for use in future pandemics, thus compromising public health.
Visceral Adipose Tissue-derived Serine Proteinase Inhibitor Inhibits Apoptosis of Endothelial Cells as a Ligand for the Cell-Surface GRP78/Voltage-dependent Anion Channel Complex
Authors: Atsuko Nakatsuka, Jun Wada, Izumi Iseda, Sanae Teshigawara, Kanji Higashio, Kazutoshi Murakami, Motoko Kanzaki, Kentaro Inoue, Takahiro Terami, Akihiro Katayama, Kazuyuki Hida, Jun Eguchi, Daisuke Ogawa, Yasushi Matsuki, Ryuji Hiramatsu, Hideo Yagita, Shigeru Kakuta, Yoichiro Iwakura, Hirofumi Makino
Journal: Circulation Research (2013)

Visceral adipose tissue-derived serine proteinase inhibitor (vaspin) is an adipokine identified from visceral adipose tissues of genetically obese rats.The role of vaspin in the diabetic vascular complications remains elusive, and we investigated the effects of vaspin on the vascular function under the diabetic milieu.Adenovirus carrying the full length of the vaspin gene (Vaspin-Ad) ameliorated intimal proliferation of balloon-injured carotid arteries in diabetic Wistar rats. The expression of Ccl2, Pdgfb, and Pdgfrb genes was significantly reduced by the treatment of Vaspin-Ad. In cuff-injured femoral arteries, the intimal proliferation was ameliorated in vaspin transgenic (Vaspin Tg) mice. The application of recombinant vaspin and Vaspin-Ad promoted the proliferation and inhibited the apoptosis of human aortic endothelial cells. Adenovirus expressing vaspin with calmodulin and streptavidin-binding peptides was applied to human aortic endothelial cells, subjected to tandem tag purification and liquid chromatography-tandem mass spectrometry, and we identified GRP78 (78-kDa glucose-regulated protein) as an interacting molecule. The complex formation of vaspin, GRP78, and voltage-dependent anion channel on the plasma membrane was confirmed by the immunoprecipitation studies using aortas of Vaspin Tg mice. The binding assay using (125)I-vaspin in human aortic endothelial cells revealed high-affinity binding (dissociation constant = 0.565×10(-9) m) by the treatment of 5 μM thapsigargin, which recruited GRP78 from the endoplasmic reticulum to plasma membrane by inducing endoplasmic reticulum stress. In human aortic endothelial cells, vaspin induced phosphorylation of Akt and inhibited the kringle 5-induced Ca(2+) influx and subsequent apoptosis.Vaspin is a novel ligand for the cell-surface GRP78/voltage-dependent anion channel complex in endothelial cells and promotes proliferation, inhibits apoptosis, and protects vascular injuries in diabetes mellitus.
Automated Ankle-Brachial Pressure Index Measurement by Clinical Staff for Peripheral Arterial Disease Diagnosis in Nondiabetic and Diabetic Patients
Authors: Ricardo Gómez-Huelgas, Julio Martínez-González, Margarita Carrillo de Albornoz, Daniel Peña-Jiménez, Beatriz Sobrino-Díaz, M. Rosa Bernal-López
Journal: Diabetes Care (2010)

Clairotte et al. (1) recently reported in Diabetes Care that the oscillometric measurement of the ankle-brachial index (Osc-ABI) has lower diagnostic performance in diagnosing peripheral arterial disease (PAD) in diabetic patients when compared with the Doppler-measured ankle-brachial pressure index (Dop-ABI).

Our group has validated the use of an automatic oscillometer (Omron M-7) for Osc-ABI calculation. We chose this model because the sleeve adapts better to the truncated cone morphology of the leg. We used the Doppler Hadeco Bidop (Koven Technology, St. Louis, MO) to measure the sonorous and graphical signal. For the Osc-ABI calculation, three measurements were made and the greatest of …
Importance of Blood Pressure Monitoring in Colorectal Cancer Patients Treated with Bevacizumab: the Current Situation
Authors: Satomi Kumazawa, Hiroshi Matsuoka, Yosuke Ando, Maiko Ando, Yukiko Kakumae, Kaori Ito, Hideki Ohta, Shigeki Yamada, Kotaro Maeda
Journal: Annals of Oncology (2014)
Assessment of accuracy and applicability of a new electronic peak flow meter and asthma monitor
Authors: K Richter, F Kanniess, B Mark, RA Jorres, H Magnussen
Journal: European Respiratory Journal (1998)

The aim of this study was to assess the accuracy and applicability of a portable electronic peak flow meter combined with an asthma monitor (AM1, Jaeger, Germany) which measures peak expiratory flow (PEF), forced expiratory volume in one second (FEV1) and forced vital capacity (FVC). The technical accuracy in PEF, FEV1 and FVC measurement was tested according to American Thoracic Society (ATS) criteria for monitoring devices using a flow generator. In addition, the effect of connecting a heated screen pneumotachograph (PT) to the AM1 was determined and the accuracy in FEV1 determinations was evaluated by simultaneous measurements in 49 normal volunteers. The devices tested fulfilled all ATS criteria for monitoring devices with respect to the accuracy of PEF, FEV1, and FVC measurements. The conditions of intra- and interdevice variability were satisfied in all cases. Compared with the PT, the AM1 showed about 4% lower values in FEV1, as measured in the 49 subjects. In conclusion, the electronic peak flow meter and asthma monitor AM1 yielded valid measurements of peak expiratory flow and forced expiratory volume in one second, which matched the accuracy criteria of the American Thoracic Society standards for monitoring devices.
Sentinel Lymph Node Surgery After Neoadjuvant Chemotherapy in Patients With Node-Positive Breast Cancer
Authors: Judy C. Boughey
Journal: JAMA (2013)

Sentinel lymph node (SLN) surgery provides reliable nodal staging information with less morbidity than axillary lymph node dissection (ALND) for patients with clinically node-negative (cN0) breast cancer. The application of SLN surgery for staging the axilla following chemotherapy for women who initially had node-positive cN1 breast cancer is unclear because of high false-negative results reported in previous studies.To determine the false-negative rate (FNR) for SLN surgery following chemotherapy in women initially presenting with biopsy-proven cN1 breast cancer.The American College of Surgeons Oncology Group (ACOSOG) Z1071 trial enrolled women from 136 institutions from July 2009 to June 2011 who had clinical T0 through T4, N1 through N2, M0 breast cancer and received neoadjuvant chemotherapy. Following chemotherapy, patients underwent both SLN surgery and ALND. Sentinel lymph node surgery using both blue dye (isosulfan blue or methylene blue) and a radiolabeled colloid mapping agent was encouraged.The primary end point was the FNR of SLN surgery after chemotherapy in women who presented with cN1 disease. We evaluated the likelihood that the FNR in patients with 2 or more SLNs examined was greater than 10%, the rate expected for women undergoing SLN surgery who present with cN0 disease.Seven hundred fifty-six women were enrolled in the study. Of 663 evaluable patients with cN1 disease, 649 underwent chemotherapy followed by both SLN surgery and ALND. An SLN could not be identified in 46 patients (7.1%). Only 1 SLN was excised in 78 patients (12.0%). Of the remaining 525 patients with 2 or more SLNs removed, no cancer was identified in the axillary lymph nodes of 215 patients, yielding a pathological complete nodal response of 41.0% (95% CI, 36.7%-45.3%). In 39 patients, cancer was not identified in the SLNs but was found in lymph nodes obtained with ALND, resulting in an FNR of 12.6% (90% Bayesian credible interval, 9.85%-16.05%).Among women with cN1 breast cancer receiving neoadjuvant chemotherapy who had 2 or more SLNs examined, the FNR was not found to be 10% or less. Given this FNR threshold, changes in approach and patient selection that result in greater sensitivity would be necessary to support the use of SLN surgery as an alternative to ALND.clinicaltrials.gov Identifier: NCT00881361.
Trastuzumab Emtansine: A Novel Antibody–Drug Conjugate for HER2-Positive Breast Cancer
Authors: Ian Krop, Eric P. Winer
Journal: Clinical Cancer Research (2013)

Trastuzumab emtansine (T-DM1) is a novel HER2-directed antibody-drug conjugate. T-DM1 consists of the potent antimicrotubule agent DM1, linked via a noncleavable linker to the HER2-specific monoclonal antibody trastuzumab. Preclinical studies demonstrate that T-DM1 has dual mechanisms of action: selective delivery of DM1 to the HER2-positive (HER2(+)) tumor cell combined with trastuzumab's activation of antibody-dependent cell-mediated cytotoxicity and inhibition of HER2-mediated signal transduction. In phase II studies, T-DM1 was active in patients with trastuzumab- and lapatinib-refractory metastatic breast cancer and led to improved progression-free survival compared with the combination of trastuzumab and docetaxel in the first-line setting. In a recent phase III trial in patients with metastatic breast cancer who previously received trastuzumab and a taxane, T-DM1 resulted in improved progression-free and overall survival compared with capecitabine and lapatinib. T-DM1 is associated with a favorable toxicity profile; reversible thrombocytopenia and hepatic transaminase elevations are the only grade ≥3 adverse event present in 5% or more of patients. Alopecia, peripheral neuropathy, and neutropenia are distinctly uncommon. On the basis of its improved efficacy and toxicity compared with capecitabine/lapatinib, T-DM1 should be considered the standard for patients with HER2(+) metastatic breast cancer who have previously progressed on trastuzumab and a taxane. Results from additional randomized studies in metastatic breast cancer are pending, and trials in the (neo)adjuvant setting are being initiated.
Urinary C-Peptide Creatinine Ratio Is a Practical Outpatient Tool for Identifying Hepatocyte Nuclear Factor 1-α/Hepatocyte Nuclear Factor 4-α Maturity-Onset Diabetes of the Young From Long-Duration Type 1 Diabetes
Authors: Rachel E.J. Besser, Maggie H. Shepherd, Timothy J. McDonald, Beverley M. Shields, Bridget A. Knight, Sian Ellard, Andrew T. Hattersley
Journal: Diabetes Care (2011)

OBJECTIVE Hepatocyte nuclear factor 1-α (HNF1A)/hepatocyte nuclear factor 4-α (HNF4A) maturity-onset diabetes of the young (MODY) is frequently misdiagnosed as type 1 diabetes, and patients are inappropriately treated with insulin. Blood C-peptide can aid in the diagnosis of MODY, but practical reasons limit its widespread use. Urinary C-peptide creatinine ratio (UCPCR), a stable measure of endogenous insulin secretion, is a noninvasive alternative. We aimed to compare stimulated UCPCR in adults with HNF1A/4A MODY, type 1 diabetes, and type 2 diabetes. RESEARCH DESIGN AND METHODS Adults with diabetes for ≥5years, without renal impairment, were studied (HNF1A MODY [n = 54], HNF4A MODY [n = 23], glucokinase MODY [n = 20], type 1 diabetes [n = 69], and type 2 diabetes [n = 54]). The UCPCR was collected in boric acid 120 min after the largest meal of the day and mailed for analysis. Receiver operating characteristic (ROC) curves were used to identify optimal UCPCR cutoffs to differentiate HNF1A/4A MODY from type 1 and type 2 diabetes. RESULTS UCPCR was lower in type 1 diabetes than HNF1A/4A MODY (median [interquartile range]) (&amp;lt;0.02 nmol/mmol [&amp;lt;0.02 to &amp;lt;0.02] vs. 1.72 nmol/mmol [0.98–2.90]; P &amp;lt; 0.0001). ROC curves showed excellent discrimination (area under curve [AUC] 0.98) and identified a cutoff UCPCR of ≥0.2 nmol/mmol for differentiating HNF1A/4A MODY from type 1 diabetes (97% sensitivity, 96% specificity). UCPCR was lower in HNF1A/4A MODY than in type 2 diabetes (1.72 nmol/mmol [0.98–2.90] vs. 2.47 nmol/mmol [1.4–4.13]); P = 0.007). ROC curves showed a weak distinction between HNF1A/4A MODY and type 2 diabetes (AUC 0.64). CONCLUSIONS UCPCR is a noninvasive outpatient tool that can be used to discriminate HNF1A and HNF4A MODY from long-duration type 1 diabetes. To differentiate MODY from type 1 diabetes of &amp;gt;5 years’ duration, UCPCR could be used to determine whether genetic testing is indicated.
Specific adsorption of H-2-restricted cytotoxi T cells to macrophage monolayers.
Authors: U Kees, A Müllbacher, R V Blanden
Journal: The Journal of Experimental Medicine (1978)

These experiments tested whether Tc cells specific for foreign antigen (X) plus self H-2 adsorbed to macrophage monolayers displaying (a) X with allogeneic H-2; (B) self H-2 alone; (c) X plus self H-2. Specific adsorption occurred only in case (c), a result compatible with altered self and requiring further operational assumptions in dual recognition models.
Vitamin E concentrations in the human stomach and duodenum--correlation with Helicobacter pylori infection.
Authors: P S Phull, A B Price, M S Thorniley, C J Green, M R Jacyna
Journal: Gut (1996)

BACKGROUND: Vitamin E (alpha-tocopherol) is an important endogenous antioxidant and may also act as an anticarcinogen. AIM: To determine the vitamin E status of subjects with, and without, gastroduodenal inflammation and Helicobacter pylori infection. SUBJECTS: 36 patients undergoing routine gastroscopy for investigation of dyspepsia. METHODS: High performance liquid chromatography with fluorometric detection was used to determine alpha-tocopherol values. RESULTS: In H pylori negative subjects with normal gastroduodenal histology (n = 11) median alpha-tocopherol values (ng/mg tissue weight) were significantly higher in the corpus (16.4, interquartile range (IQR) 8.9-22.6) than in the antrum (3.0, IQR 2.6-6.7, p = 0.001) or duodenum (6.7, IQR 2.5-8.4, p = 0.001). H pylori infection (n = 19) was associated with a reduction in the corpus alpha-tocopherol values (median 8.3, IQR 4.9-13.7, p &lt; 0.05) but there was no significant change in the antral concentrations although this was the main site of inflammation and neutrophil activity. Duodenal alpha-tocopherol values were not significantly changed in the presence of duodenitis or gastric H pylori infection. alpha-Tocopherol was not detected in the gastric juice of any of the subjects. Plasma alpha-tocopherol concentrations in the H pylori negative subjects (median 10.4 mg/l, IQR 7.2-11.9) were not significantly different to the values in the H pylori positive subjects (median 11.1 mg/l, IQR 7.6-12.7). CONCLUSIONS: Concentrations of alpha-tocopherol in H pylori negative subjects are higher in the corpus than in the antrum or duodenum. In the presence of predominantly antral H pylori infection and neutrophil activity the major change seen is a reduction in corpus alpha-tocopherol values while antral concentrations are maintained. These findings may reflect a mobilisation of antioxidant defences to the sites of maximal inflammation in the stomach.
Disease-Free Survival Versus Overall Survival As a Primary End Point for Adjuvant Colon Cancer Studies: Individual Patient Data From 20,898 Patients on 18 Randomized Trials
Authors: Daniel J. Sargent, Harry S. Wieand, Daniel G. Haller, Richard Gray, Jacqueline K. Benedetti, Marc Buyse, Roberto Labianca, Jean Francois Seitz, Christopher J. O'Callaghan, Guido Francini, Axel Grothey, Michael O'Connell, Paul J. Catalano, Charles D. Blanke, David Kerr, Erin Green, Norman Wolmark, Thierry Andre, Richard M. Goldberg, Aimery De Gramont
Journal: Journal of Clinical Oncology (2005)

Purpose A traditional end point for colon adjuvant clinical trials is overall survival (OS), with 5 years demonstrating adequate follow-up. A shorter-term end point providing convincing evidence to allow treatment comparisons could significantly speed the translation of advances into practice. Methods Individual patient data were pooled from 18 randomized phase III colon cancer adjuvant clinical trials. Trials included 43 arms, with a pooled sample size of 20,898 patients. The primary hypothesis was that disease-free survival (DFS), with 3 years of follow-up, is an appropriate primary end point to replace OS with 5 years of follow-up. Results The recurrence rates for years 1 through 5 were 12%, 14%, 8%, 5%, and 3%, respectively. Median time from recurrence to death was 12 months. Eighty percent of recurrences were in the first 3 years; 91% of patients with recurrence by 3 years died before 5 years. Correlation between 3-year DFS and 5-year OS was 0.89. Comparing control versus experimental arms within each trial, the correlation between hazard ratios for DFS and OS was 0.92. Within-trial log-rank testing using both DFS and OS provided the same conclusion in 23 (92%) of 25 cases. Formal measures of surrogacy were satisfied. Conclusion In patients treated on phase III adjuvant colon clinical trials, DFS and OS are highly correlated, both within patients and across trials. These results suggest that DFS after 3 years of median follow-up is an appropriate end point for adjuvant colon cancer clinical trials of fluorouracil-based regimens, although marginally significant DFS improvements may not translate into significant OS benefits.