tbuckley/cabot-search huggingface dataset:
Enhancement of GABAergic Activity: Neuropharmacological Effects of Benzodiazepines and Therapeutic Use in Anesthesiology
Authors: Teijo I. Saari, Mikko Uusi-Oukari, Jouni Ahonen, Klaus T. Olkkola
Journal: Pharmacological Reviews (2011)

GABA is the major inhibitory neurotransmitter in the central nervous system (CNS). The type A GABA receptor (GABA<sub>A</sub>R) system is the primary pharmacological target for many drugs used in clinical anesthesia. The α1, β2, and γ2 subunit-containing GABA<sub>A</sub>Rs located in the various parts of CNS are thought to be involved in versatile effects caused by inhaled anesthetics and classic benzodiazepines (BZD), both of which are widely used in clinical anesthesiology. During the past decade, the emergence of tonic inhibitory conductance in extrasynaptic GABA<sub>A</sub>Rs has coincided with evidence showing that these receptors are highly sensitive to the sedatives and hypnotics used in anesthesia. Anesthetic enhancement of tonic GABAergic inhibition seems to be preferentially increased in regions shown to be important in controlling memory, awareness, and sleep. This review focuses on the physiology of the GABA<sub>A</sub>Rs and the pharmacological properties of clinically used BZDs. Although classic BZDs are widely used in anesthesiological practice, there is a constant need for new drugs with more favorable pharmacokinetic and pharmacodynamic effects and fewer side effects. New hypnotics are currently developed, and promising results for one of these, the GABA<sub>A</sub>R agonist remimazolam, have recently been published.
A comparative analysis of DNA methylation across human embryonic stem cell lines
Authors: Pao-Yang Chen, Suhua Feng, Jong Joo, Steve E Jacobsen, Matteo Pellegrini
Journal: Genome biology (2011)

We performed a comparative analysis of the genome-wide DNA methylation profiles from three human embryonic stem cell (HESC) lines. It had previously been shown that HESC lines had significantly higher non-CG methylation than differentiated cells, and we therefore asked whether these sites were conserved across cell lines. We find that heavily methylated non-CG sites are strongly conserved, especially when found within the motif TACAG. They are enriched in splice sites and are more methylated than other non-CG sites in genes. We next studied the relationship between allele-specific expression and allele-specific methylation. By combining bisulfite sequencing and whole transcriptome shotgun sequencing (RNA-seq) data we identified 1,020 genes that show allele-specific expression, and 14% of CG sites genome-wide have allele-specific methylation. Finally, we asked whether the methylation state of transcription factor binding sites affects the binding of transcription factors. We identified variations in methylation levels at binding sites and found that for several transcription factors the correlation between the methylation at binding sites and gene expression is generally stronger than in the neighboring sequences. These results suggest a possible but as yet unknown functional role for the highly methylated conserved non-CG sites in the regulation of HESCs. We also identified a novel set of genes that are likely transcriptionally regulated by methylation in an allele-specific manner. The analysis of transcription factor binding sites suggests that the methylation state of cis-regulatory elements impacts the ability of factors to bind and regulate transcription.
Admission Glucose and Mortality in Elderly Patients Hospitalized With Acute Myocardial Infarction
Authors: Mikhail Kosiborod, Saif S. Rathore, Silvio E. Inzucchi, Frederick A. Masoudi, Yongfei Wang, Edward P. Havranek, Harlan M. Krumholz
Journal: Circulation (2005)

Background— The relationship between admission glucose levels and outcomes in older diabetic and nondiabetic patients with acute myocardial infarction is not well defined. Methods and Results— We evaluated a national sample of elderly patients (n=141 680) hospitalized with acute myocardial infarction from 1994 to 1996. Admission glucose was analyzed as a categorical (≤110, &gt;110 to 140, &gt;140 to 170, &gt;170 to 240, &gt;240 mg/dL) and continuous variable for its association with mortality in patients with and without recognized diabetes. A substantial proportion of hyperglycemic patients (eg, 26% of those with glucose &gt;240 mg/dL) did not have recognized diabetes. Fewer hyperglycemic patients without known diabetes received insulin during hospitalization than diabetics with similar glucose levels (eg, glucose &gt;240 mg/dL, 22% versus 73%; P &lt;0.001). Higher glucose levels were associated with greater risk of 30-day mortality in patients without known diabetes (for glucose range from ≤110 to &gt;240 mg/dL, 10% to 39%) compared with diabetics (range, 16% to 24%; P for interaction &lt;0.001). After multivariable adjustment, higher glucose levels continued to be associated with a graded increase in 30-day mortality in patients without known diabetes (referent, glucose ≤110 mg/dL; range from glucose &gt;110 to 140 mg/dL: hazard ratio [HR], 1.17; 95% CI, 1.11 to 1.24; to glucose &gt;240 mg/dL: HR, 1.87; 95% CI, 1.75 to 2.00). In contrast, among diabetic patients, greater mortality risk was observed only in those with glucose &gt;240 mg/dL (HR, 1.32; 95% CI, 1.17 to 1.50 versus glucose ≤110 mg/dL; P for interaction &lt;0.001). One-year mortality results were similar. Conclusions— Elevated glucose is common, rarely treated, and associated with increased mortality risk in elderly acute myocardial infarction patients, particularly those without recognized diabetes.
A reassessment of the role of B7-1 expression in tumor rejection.
Authors: T C Wu, A Y Huang, E M Jaffee, H I Levitsky, D M Pardoll
Journal: The Journal of Experimental Medicine (1995)

Introduction of the B7-1 gene into murine tumor cells can result in rejection of the B7-1 transductants and, in some cases, systemic immunity to subsequent challenge with the nontransduced tumor cells. These effects have been largely attributed to the function of B7-1 as a costimulator in directly activating tumor specific, major histocompatibility class I-restricted CD8+ T cells. We examined the role of B7-1 expression in the direct rejection as well as in the induction of systemic immunity to a nonimmunogenic murine tumor. B-16 melanoma cells with high levels of B7-1 expression did not grow in C57BL/6 recipient mice, while wild-type B-16 cells and cells with low B7-1 expression grew progressively within 21 d. In mixing experiments with B7-1hi and wild-type B-16 cells, tumors grew out in vivo even when a minority of cells were B7-1-. Furthermore, the occasional tumors that grew out after injection of 100% B-16 B7-1hi cells showed markedly decreased B7-1 expression. In vivo antibody depletions showed that NK1.1 and CD8+ T cells, but not CD4+ T cells, were essential for the in vivo rejection of tumors. Animals that rejected B-16 B7-1hi tumors did not develop enhanced systemic immunity against challenge with wild-type B-16 cells. These results suggest that a major role of B7-1 expression by tumors is to mediate direct recognition and killing by natural killer cells. With an intrinsically nonimmunogenic tumor, this direct killing does not lead to enhanced systemic immunity.
Direct Inhibition of Cardiac Hyperpolarization-Activated Cyclic Nucleotide–Gated Pacemaker Channels by Clonidine
Authors: Anne Knaus, Xiangang Zong, Nadine Beetz, Roland Jahns, Martin J. Lohse, Martin Biel, Lutz Hein
Journal: Circulation (2007)

Background— Inhibition of cardiac sympathetic tone represents an important strategy for treatment of cardiovascular disease, including arrhythmia, coronary heart disease, and chronic heart failure. Activation of presynaptic α 2 -adrenoceptors is the most widely accepted mechanism of action of the antisympathetic drug clonidine; however, other target proteins have been postulated to contribute to the in vivo actions of clonidine. Methods and Results— To test whether clonidine elicits pharmacological effects independent of α 2 -adrenoceptors, we have generated mice with a targeted deletion of all 3 α 2 -adrenoceptor subtypes (α 2ABC −/− ). α 2ABC −/− mice were completely unresponsive to the analgesic and hypnotic effects of clonidine; however, clonidine significantly lowered heart rate in α 2ABC −/− mice by up to 150 bpm. Clonidine-induced bradycardia in conscious α 2ABC −/− mice was 32.3% (10 μg/kg) and 26.6% (100 μg/kg) of the effect in wild-type mice. A similar bradycardic effect of clonidine was observed in isolated spontaneously beating right atria from α 2ABC -knockout and wild-type mice. Clonidine inhibited the native pacemaker current ( I f ) in isolated sinoatrial node pacemaker cells and the I f -generating hyperpolarization-activated cyclic nucleotide–gated (HCN) 2 and HCN4 channels in transfected HEK293 cells. As a consequence of blocking I f , clonidine reduced the slope of the diastolic depolarization and the frequency of pacemaker potentials in sinoatrial node cells from wild-type and α 2ABC -knockout mice. Conclusions— Direct inhibition of cardiac HCN pacemaker channels contributes to the bradycardic effects of clonidine gene-targeted mice in vivo, and thus, clonidine-like drugs represent novel structures for future HCN channel inhibitors.
Multiplexed immunoglobulin <scp>E</scp> sensitization in relation to exhaled nitric oxide in a population sample of children
Authors: T.‐C. Yao, H.‐J. Tsai, Y.‐L. Tu, S.‐W. Chang, M.‐C. Hua, S.‐L. Liao, M.‐H. Tsai, C.‐Y. Chiu, S.‐H. Lai, K.‐W. Yeh, J.‐L. Huang
Journal: Allergy (2014)

This study investigated the relationship between the specific immunoglobulin E (IgE) profile for 40 allergens using a novel microarray technique (BioIC) and fraction of exhaled nitric oxide (FeNO) in a population sample of 1321 children. Significant positive associations were found between FeNO and sensitization to mites (P < 0.001), animals (P = 0.001), cockroaches (P < 0.001), and foods (P = 0.042), and furthermore, between FeNO and the number of sensitizations (all P < 0.05) or the sum of specific IgE (all P ≤ 0.01) against the aforementioned allergen categories. Specifically, sensitization to the following allergens was significantly related to higher FeNO: Dermatophagoides pteronyssinus, Dermatophagoides farina, Blomia tropicalis, cat, German cockroach, Oriental cockroach, codfish, crab, shrimp, and cheese (all P ≤ 0.01). In conclusion, IgE sensitization to mites, pets, cockroaches, seafood, and cheese, respectively, is significantly associated with elevated FeNO levels in a dose-dependent fashion in children. Our results provide new evidence that sensitization to certain food allergens may contribute to prompt inflammation in the airways.
Crucial Role of Jak3 in Negative Selection of Self-reactive T Cells
Authors: Kaoru Saijo, Seung Yong Park, Yasuo Ishida, Hisashi Arase, Takashi Saito
Journal: The Journal of Experimental Medicine (1997)

Jak3 mediates growth signals through cytokine receptors such as interleukin-2 (IL-2), IL-4, and IL-7, and its deficiency results in autosomal recessive SCID in mice and humans. In spite of the severely reduced number of lymphocytes in Jak3-deficient mice, the differentiation profile of thymocytes was normal and mature T cells accumulated in the periphery with age. However, we found that self-reactive T cells were not deleted in the thymus and the peripheral tissues in Jak3-deficient mice. All peripheral T cells were in the activation state and thus were unable to be activated further, as demonstrated by the failure of eliciting Ca2+ response upon T cell receptor (TCR) stimulation. From the analysis of TCR-transgenic Jak3-deficient mice, only self-reactive T cells appeared to be in the activated state and anergic. These findings demonstrate a crucial function of Jak3 in the negative selection of autoreactive T cells and the maintenance of functional peripheral T cells.
Plesiomonas Gastroenteritis in Texas
Authors: Deborah L. Martin
Journal: JAMA (1985)

<h3>To the Editor.—</h3> <i>Plesiomanas shigelloides</i>is a straight, motile gramnegative bacillus of the family Vibrionaceae. It is widespread in tropical and subtropical environments and has been isolated from ponds and rivers, as well as fish and oysters. Although the pathogenicity of<i>P shigelloides</i>has been questioned, the organism has been isolated in the absence of other pathogens from stools of more than 100 persons with gastroenteritis. Recent laboratory studies have indicated that this organism can produce an enterotoxin.<sup>1,2</sup>Thus, the emerging consensus is that it can cause gastroenteritis in immunocompetent patients. Although accummulated evidence suggests that<i>P shigelloides</i>is an intestinal pathogen, the source(s) of illness has only been hypothesized. Rutala et al<sup>3</sup>reported an outbreak of gastrointestinal tract illness associated with a North Carolina oyster roast. In that outbreak,<i>P shigelloides</i>was isolated from a single stool specimen as well as an oyster harvested from the same
A Systematic Review of Molecular and Biological Tumor Markers in Neuroblastoma
Authors: Richard D. Riley, David Heney, David R. Jones, Alex J. Sutton, Paul C. Lambert, Keith R. Abrams, Bridget Young, Alan J. Wailoo, Susan A. Burchill
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The aim of this study was to conduct a systematic review, and where possible meta-analyses, of molecular and biological tumor markers described in neuroblastoma, and to establish an evidence-based perspective on their clinical value for the screening, diagnosis, prognosis, and monitoring of patients. Experimental Design: A well-defined, reproducible search strategy was used to identify the relevant literature from 1966 to February 2000. Results: A total of 428 papers studying the use of 195 different tumor markers in neuroblastoma were identified. Small sample sizes, poor statistical reporting, large heterogeneity across studies (e.g., in cutoff levels), and publication bias limited meta-analysis to the area of prognosis only; MYCN, chromosome 1p, DNA index, vanillylmandelic acid:homovanillic acid ratio, CD44, Trk-A, neuron-specific enolase, lactate dehydrogenase, ferritin, and multidrug resistance were all identified as potentially important prognostic tools. Conclusions: This systematic review forms a knowledge base of the tumor markers studied thus far in neuroblastoma, and has identified some of the most important prognostic markers, which should be considered in future research and treatment strategies. Importantly, the review has also highlighted some general problems across primary tumor marker studies, in particular poor and heterogeneous reporting. These need to be addressed to allow better clinical interpretation and enable more appropriate evidence-based reviews in the future. In particular, collaboration of cancer research groups is needed to enable bigger sample sizes, standardize methods of analysis and reporting, and facilitate the pooling of individual patient data.
Wegener's granulomatosis: isolated involvement of the trachea and larynx.
Authors: D Hellmann, T Laing, M Petri, D Jacobs, R Crumley, M Stulbarg
Journal: Annals of the Rheumatic Diseases (1987)

A 26 year old man with subacute hoarseness and stridor was shown to have Wegener's granulomatosis isolated to the trachea and larynx. Although isolated laryngeal Wegener's is unusual, a review of the literature suggests that early treatment with cyclophosphamide is warranted.
Molecular Detection of Lymph Node Metastases in Breast Cancer Patients: Results of a Multicenter Trial Using the One-Step Nucleic Acid Amplification Assay
Authors: Yasuhiro Tamaki, Futoshi Akiyama, Takuji Iwase, Tomoyo Kaneko, Hitoshi Tsuda, Kazuhiko Sato, Shigeto Ueda, Masayuki Mano, Norikazu Masuda, Masashi Takeda, Masahiko Tsujimoto, Katsuhide Yoshidome, Hideo Inaji, Hiromu Nakajima, Yoshifumi Komoike, Tatsuki R. Kataoka, Seigo Nakamura, Koyu Suzuki, Koichiro Tsugawa, Kenichi Wakasa, Tsuyoshi Okino, Yo Kato, Shinzaburo Noguchi, Nariaki Matsuura
Journal: Clinical Cancer Research (2009)

Accurate assessment of metastasis in sentinel lymph nodes (SLN) of breast cancer is important but involves a heavy workload for the pathologist. We conducted a multicenter clinical trial in Japan to evaluate a new automated assay system for cytokeratin 19 mRNA, the one-step nucleic acid amplification (OSNA) assay (Sysmex), to detect lymph node metastasis of breast cancer.Surgically obtained axillary lymph nodes were sectioned into four pieces, two of which were examined with the OSNA assay. The other two adjacent pieces were examined with H&E and immunohistochemical staining for cytokeratin 19. Serial sections at 0.2-mm intervals were used in trial 1 to determine the specificity of the OSNA assay, and three pairs of sections cut from the sliced surfaces of the pieces were used in trial 2 to compare the accuracy of the OSNA assay with that of a routine pathologic examination for SLNs in Japan.In trial 1, the sensitivity and specificity were 95.0% [95% confidence interval (95% CI), 75.1-99.9%] and 97.1% (95% CI, 91.8-99.4%), respectively, for 124 axillary lymph nodes obtained from 34 patients. In trial 2, the agreement between findings of the assay and of the pathologic examination was 92.9% (95% CI, 90.1-95.1%) for 450 axillary lymph nodes obtained from 164 patients.The OSNA assay can detect lymph node metastasis as accurately as can conventional pathology and thus can be an effective addition to or alternative for rapid intraoperative examination of SLNs.
Serum Insulin, Glucose, Indices of Insulin Resistance, and Risk of Prostate Cancer
Authors: Demetrius Albanes, Stephanie J. Weinstein, Margaret E. Wright, Satu Männistö, Paul J. Limburg, Kirk Snyder, Jarmo Virtamo
Journal: JNCI Journal of the National Cancer Institute (2009)

The mitogenic and growth-stimulatory effects of insulin-like growth factors appear to play a role in prostate carcinogenesis, yet any direct association of circulating insulin levels and risk of prostate cancer remains unclear.We investigated the relationship of the level of serum insulin, glucose, and surrogate indices of insulin resistance (ie, the molar ratio of insulin to glucose and the homeostasis model assessment of insulin resistance [HOMA-IR]) to the development of prostate cancer in a case-cohort study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort of Finnish men. We studied 100 case subjects with incident prostate cancer and 400 noncase subjects without prostate cancer from the larger cohort. Fasting serum was collected 5-12 years before diagnosis. We determined insulin concentrations with a double-antibody immunochemiluminometric assay and glucose concentrations with a hexokinase assay. Multivariable logistic regression models estimated relative risks as odds ratios (ORs), and all statistical tests were two-sided.Insulin concentrations in fasting serum that was collected on average 9.2 years before diagnosis among case subjects were 8% higher than among noncase subjects, and the molar ratio of insulin to glucose and HOMA-IR were 10% and 6% higher, respectively, but these differences were not statistically significant. Among subjects in the second through fourth insulin quartiles, compared with those in the first quartile, increased insulin levels were associated with statistically significantly increased risks of prostate cancer (OR = 1.50, 95% confidence interval [CI] = 0.75 to 3.03; OR = 1.75, 95% CI = 0.86 to 3.56; and OR = 2.55, 95% CI = 1.18 to 5.51; for the second through fourth insulin quartiles, respectively; P(trend) = .02). A similar pattern was observed with the HOMA-IR (OR = 2.10, 95% CI = 1.03 to 4.26; P(trend) = .02) for the highest vs lowest quartiles. Risk varied inconsistently with glucose concentration (P(trend) = .38). A stronger association between insulin level and prostate cancer risk was observed among leaner men and among men who were less physically active at work. Crude prostate cancer incidence was 154 prostate cancers per 100 000 person-years in the lowest quartile of fasting serum insulin vs 394 prostate cancers per 100 000 person-years in the highest quartile.Elevated fasting levels of serum insulin (but not glucose) within the normal range appear to be associated with a higher risk of prostate cancer.
Antigen-specific T lymphocyte clones. III. Papain splits purified T suppressor molecules into two functional domains.
Authors: M Fresno, L McVay-Boudreau, H Cantor
Journal: The Journal of Experimental Medicine (1982)

Purified molecules (70,000 mol wt) from a T-suppressor (Ts) clone bind to sheep erythrocyte glycophorin and specifically suppress the response to this antigen. Papain splits purified 70,000-mol wt Ts molecules into two peptides: mol wt 45,000 and 24,000. The 45,000-mol wt peptide nonspecifically suppresses antibody response to several antigens and lacks antigen-binding activity. The 24,000-mol wt peptide does not suppress but retains antigen-binding activity. The results indicate that papain splits the Ts molecule into a "constant" region responsible for function and a "variable" region responsible for antigen-binding. Since binding of the 70,000-mol wt molecule to antigen also results in release of the 45,000 mol wt subunit, this cleavage may allow Ts molecules specific for one determinant to suppress immunity to complex foreign proteins.
Prostate Cancer Cell Adhesion to Bone Marrow Endothelium
Authors: Victor I. Romanov, Terry Whyard, Howard L. Adler, Wayne C. Waltzer, Stanley Zucker
Journal: Cancer Research (2004)

Abstract Bone metastasis is the most frequent complication of prostate cancer (PC). Elucidation of the biological basis of this specificity is required for the development of approaches for metastatic inhibition. We investigated the possibility that the preferential attachment of PC cells to bone marrow endothelium (as opposed to endothelium from other organs) affects this specificity. We selected, from peptide phage-displayed libraries, peptide ligands to surfaces of PC cells (C4-2B) attenuated (30–40%) binding of C4-2B cells to bone marrow endothelial cells (BMECs). We then determined the molecules on the surface of C4-2B cells interacted with the selected peptides using column affinity chromatography and a cDNA expression phage-displayed library generated from C4-2B cells in T7 phage. We identified a phage from the cDNA library that specifically bound to one of the selected peptides-L11. This phage displayed the amino acid sequence homologous for the COOH-terminal portion of prostate-specific antigen (PSA). To examine the possible direct involvement of PSA in the interactions between PC and BMECs, we performed a cell–cell adhesion assay. Antibodies to PSA attenuated PC cells adhesion to BMECs. In addition, exogenous proteolytically active PSA modulated this adhesion. Finally, inactivation of mRNA coding PSA by a small interfering RNA (siRNA) diminished C4-2B cell adhesion to BMECs. These results indicate that PSA expressed as secreted and surface-associated molecules in C4-2B cells is involved in cell–cell interactions and/or digests components of bone marrow endothelium for preferential adhesion and penetration of PC cells. The suggested experimental approach is a promising strategy for identification of cell surface molecules involved in intercellular interactions.