tbuckley/cabot-search huggingface dataset:
An Experimental Study of Propagated Electrical Activity in the Canine Heart
Authors: CONDON R. VANDER ARK, ERNEST W. REYNOLDS
Journal: Circulation Research (1970)

The closest analog to propagated excitation of the heart is an electromotive surface. The width of the cardiac electromotive surface was 0.9 ± 0.1 mm and was remarkably constant. The mean epicardial surface component of voltage across the electromotive surface was 62.4 ± 7.2 mv with the chest closed and 74.1 ± 8.3 mv with the chest open. This 18.7% increase is significant ( P &lt; .001) and suggests a shunting effect of the lungs and thorax. Fortuitous measurement of voltage across the electromotive surface yielded nine values in excess of 80 mv and two above 90 mv, suggesting that the true voltage across the electromotive surface is of about the same magnitude as the transmembrane action potential. Cross-fiber activation resulted in a 29.5% reduction in voltage, a 51.8% reduction in conduction velocity and notched QRS complexes. A closed electromotive surface has no external electrical field, suggesting that its voltage is uniform. The voltage between two electrodes, both in advance or toward the rear of a normally propagated open electromotive surface, is caused by an extracardiac current path, since removal of the lung from the epicardial surface greatly reduces this voltage and augments that across the electromotive surface.
Regulation of cellular functions by extracellular matrix.
Authors: A Teti
Journal: Journal of the American Society of Nephrology (1992)

Multicellular organisms are formed by specialized cells assembled in tissues. Individual cells contact and interact with other cells and with the extracellular matrix--a network of secreted proteins and carbohydrates that fills the intercellular spaces. The extracellular matrix helps cells to bind together and regulates a number of cellular functions, such as adhesion, migration, proliferation, and differentiation. It is formed by macromolecules, locally secreted by resident cells. The two main classes of macromolecules are polysaccharide glycosaminoglycans, usually covalently linked to proteins in the form of proteoglycans, and fibrous proteins of two functional types, structural (collagen, elastin) and adhesive (fibronectin, laminin, vitronectin, etc.). Receptors for extracellular matrix macromolecules are present in virtually all of the cells studied. They belong to the superfamily of integrins, alpha beta heterodimers, which, in most cases, recognize the Arg-Gly-Asp sequence of extracellular matrix proteins. On the exterior side of the cell, integrins link an extracellular matrix macromolecule, whereas in the cytosol, they bind the cytoskeleton, thereby forming a membrane bridge between extracellular and intracellular fibers. This structure enables the cell to adhere to the substratum. Similar to hormone- or growth factor-receptor binding, the interaction of the integrin with its specific ligand induces immediate signal transduction and influences cellular activities.
Esmolol cardioplegia: the cellular mechanism of diastolic arrest
Authors: Hazem B. Fallouh, Sonya C. Bardswell, Linda M. McLatchie, Michael J. Shattock, David J. Chambers, Jonathan C. Kentish
Journal: Cardiovascular Research (2010)

Esmolol, an ultra-short-acting β-blocker, acts as a cardioplegic agent at millimolar concentrations. We investigated the mechanism by which esmolol induces diastolic ventricular arrest. In unpaced Langendorff-perfused rat hearts, esmolol (0.03–3 mmol/L) had a profound negative inotropic effect resulting in diastolic arrest at 1 mmol/L and above. This inhibition of contraction was maintained during ventricular pacing. At 3 mmol/L, esmolol also abolished action potential conduction. To determine the cellular mechanism for the negative inotropism, we measured contraction (sarcomere shortening) and the calcium transient (fura-2 fluorescence ratio; Catr) in electrically-stimulated rat ventricular myocytes at 23 and 34°C. The decrease in contraction (by 72% at 23°C, from 0.16 ± 0.01 to 0.04 ± 0.01 µm, P < 0.001) was similar to that of isolated hearts and was caused by a large decrease in Catr (from 0.13 ± 0.02 to 0.07 ± 0.02, P < 0.001). There was no additional effect on myofilament Ca2+ sensitivity. Esmolol's effects on contraction and Catr were not shared or altered by the β-blocker, atenolol (1 mmol/L). Sarcoplasmic reticulum inhibition with thapsigargin did not alter the inhibitory effects of esmolol. Whole-cell voltage-clamp experiments revealed that esmolol inhibited the L-type calcium current (ICa,L) and the fast sodium current (INa), with IC50 values of 0.45 ± 0.05 and 0.17 ± 0.025 mmol/L, respectively. Esmolol at millimolar concentrations causes diastolic ventricular arrest by two mechanisms: at 1 mmol/L (and below), the pronounced negative inotropic effect is due largely to inhibition of L-type Ca2+ channels; additionally, higher concentrations prevent action potential conduction, probably due to the inhibition of fast Na+ channels.
Evolution of the RNA Polymerase B' Subunit Gene (rpoB') in Halobacteriales: a Complementary Molecular Marker to the SSU rRNA Gene
Authors: D. A. Walsh
Journal: Molecular Biology and Evolution (2004)

Many prokaryotes have multiple ribosomal RNA operons. Generally, sequence differences between small subunit (SSU) rRNA genes are minor (<1%) and cause little concern for phylogenetic inference or environmental diversity studies. For Halobacteriales, an order of extremely halophilic, aerobic Archaea, within-genome SSU rRNA sequence divergence can exceed 5%, rendering phylogenetic assignment problematic. The RNA polymerase B′ subunit gene (rpoB′) is a single-copy conserved gene that may be an appropriate alternative phylogenetic marker for Halobacteriales. We sequenced a fragment of the rpoB′ gene from 21 species, encompassing 15 genera of Halobacteriales. To examine the utility of rpoB′ as a phylogenetic marker in Halobacteriales, we investigated three properties of rpoB′ trees: the variation in resolution between trees inferred from the rpoB′ DNA and RpoB′ protein alignment, the degree of mutational saturation between taxa, and congruence with the SSU rRNA tree. The rpoB′ DNA and protein trees were for the most part congruent and consistently recovered two well-supported monophyletic groups, the clade I and clade II haloarchaea, within a collection of less well resolved Halobacteriales lineages. A comparison of observed versus inferred numbers of substitution revealed mutational saturation in the rpoB′ DNA data set, particularly between more distant species. Thus, the RpoB′ protein sequence may be more reliable than the rpoB′ DNA sequence for inferring Halobacteriales phylogeny. AU tests of tree selection indicated the trees inferred from rpoB′ DNA and protein alignments were significantly incongruent with the SSU rRNA tree. We discuss possible explanations for this incongruence, including tree reconstruction artifact, differential paralog sampling, and lateral gene transfer. This is the first study of Halobacteriales evolution based on a marker other than the SSU rRNA gene. In addition, we present a valuable phylogenetic framework encompassing a broad diversity of Halobacteriales, in which novel sequences can be inserted for evolutionary, ecological, or taxonomic investigations.
Risk of Cancer in Relatives of Prostate Cancer Probands
Authors: S. D. Isaacs, L. A. L. M. Kiemeney, A. Baffoe-Bonnie, T. H. Beaty, P. C. Walsh
Journal: JNCI Journal of the National Cancer Institute (1995)

Background: It is estimated that there will be more than 244 000 new prostate cancer cases diagnosed and that more than 40 000 men will die of this disease during 1995. Evidence exists for a hereditary predisposition to prostate cancer, but the proportion of cases attributable to the inheritance of a specific gene or genes is not large. Some hereditary cancer syndromes involve more than one tumor site, and some studies have reported a familial association between prostate cancer and other cancers. The presence of other cancers in prostate cancer families may indicate a specific type of hereditary predisposition. Purpose: We studied families that were selected because of the presence of prostate cancer to determine whether hereditary prostate cancer is associated with cancers at other sites and possibly with other heritable cancer syndromes. Methods: Data from two distinct study populations were studied retrospectively. The first population consisted of 690 case patients undergoing radical prostatectomy who were not selected for family history of prostate cancer and 640 control subjects who were the spouses or female companions of the case patients. The second population consisted of 75 multiplex families (i.e., families with multiple cases of prostate cancer) referred because they fulfilled the criteria for hereditary prostate cancer. A comparison between case and control populations for the occurrence of 14 aggregated groups of cancer was performed. Data were analyzed using Poisson regression, and relative risks (RRs) and their 95% confidence intervals (CIs) were calculated. Results: Brothers and fathers of prostate cancer probands have a statistically significant higher risk of prostate cancer than the male first-degree relatives of control subjects (RR = 1.76; 95% CI = 1.28–2.43). Therefore, the risk for prostate cancer is 76% higher among first-degree relatives of prostate cancer patients compared with first-degree relatives of control subjects. This higher risk was not modified by an occurrence of breast cancer in the pedigree. Also, a statistically significant higher risk was found for tumors of the central nervous system in hereditary families (RR = 3.02; 95= CI = 1.08–8.41). Statistically significant higher risks of cancer at other major sites, such as breast, ovary, or endometrium were not observed in these families. Conclusion: Even among families that were specifically selected because of the presence of prostate cancer, risks for cancer at other sites appeared not to be increased. Therefore, hereditary prostate cancer appears to be a relatively site-specific disease, and it does not seem to be a part of other hereditary cancer syndromes. [J Natl Cancer Inst 87:991–996,1995]
Intensive Care of Human Immunodeficiency Virus–infected Patients during the Era of Highly Active Antiretroviral Therapy
Authors: Alison Morris, Jennifer Creasman, Joan Turner, John M. Luce, Robert M. Wachter, Laurence Huang
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

Highly active antiretroviral therapy for human immunodeficiency virus (HIV) infection has produced significant declines in morbidity and mortality from acquired immunodeficiency syndrome (AIDS). Whether this therapy has resulted in changes in epidemiology and outcomes of intensive care among HIV-infected patients is unknown. We performed chart review of all intensive care unit admissions for HIV-infected patients at San Francisco General Hospital from 1996 through 1999. There were an average of 88.5 admissions per year with 71% survival to hospital discharge. Univariate analysis demonstrated that prior highly active antiretroviral therapy (odds ratio [OR] = 1.8, p = 0.04), a non-AIDS-associated admission diagnosis (OR = 3.7, p = 0.001), a lower Acute Physiology and Chronic Health Evaluation II score (OR = 5.4, p = 0.001), and higher serum albumin (OR = 4.4, p = 0.001) predicted improved survival. Pneumocystis carinii pneumonia (OR = 0.24, p = 0.001), mechanical ventilation (OR = 0.19, p = 0.001), or a pneumothorax (OR = 0.08, p = 0.001) were associated with worse survival. In multivariate logistic regression, all variables except prior use of highly active antiretroviral therapy and pneumothorax were significant independent predictors of outcome. At our institution, overall survival for HIV-infected intensive care unit patients has improved, especially among patients receiving highly active antiretroviral therapy. These patients may have an improved survival because of effects of therapy on variables such as likelihood of non-AIDS-associated admission diagnoses and serum albumin levels.
Low socioeconomic status and lung function
Authors: David C. Taylor-Robinson, Karsten Thielen, Tania Pressler, Hanne V. Olesen, Peter J. Diggle
Journal: European Respiratory Journal (2015)

We thank P.H. Quanjer for his comments regarding our paper, in which we apply a novel modelling approach to lung function data from the unique Danish cystic fibrosis registry and show that low socioeconomic status (SES), as measured by parental education level, is associated with an increased rate of decline of % predicted forced expiratory volume in 1 s in the Danish cystic fibrosis population [1]. We agree that it is important to develop a better understanding of the pathways to social inequalities in cystic fibrosis outcomes. Studies should use the Diderichsen approach to unpick the causal chains that link social inequalities and health <http://ow.ly/H406C>
Flexible sigmoidoscopy and the changing distribution of colorectal cancer: implications for screening
Authors: K McCallion
Journal: Gut (2001)

<h3>BACKGROUND AND AIMS</h3> There has been a significant proximal shift in the distribution of colorectal cancer (CRC) in Northern Ireland over recent decades. The aim of this study was to investigate the potential implications of this proximal shift in CRC distribution on the efficacy of flexible sigmoidoscopy (FS) as a screening tool. <h3>PATIENTS AND METHODS</h3> The site distribution of 5153 CRCs was available from the Northern Ireland Colorectal Cancer Register for the period 1990–1997. Similar data on 1241 CRCs between 1976 and 1978 were available from a previous study. Data on the site reached by FS were obtained from a prospectively collected endoscopy database at one of Northern Ireland9s main teaching hospitals for the period 1993–1998. <h3>RESULTS</h3> There was a significant proximal shift in CRC distribution between the two periods (23.5% proximal to the splenic flexure between 1976 and 1978<i>v</i> 36.7% between 1990 and 1997; p&lt;0.001). The descending colon was visualised during 74.4% of FS examinations. By combining the observed extent of FS examination with CRC site distribution, it was calculated that FS could have visualised 68.8% of CRCs between 1976 and 1978 but only 56.0% between 1990 and 1997. Extrapolating these data to a Northern Ireland screening programme involving FS and faecal occult blood testing suggests that significantly more CRCs could have been detected between 1976 and 1978 than between 1990 and 1997 (51.7% <i>v</i> 48.2%, respectively; p=0.03). <h3>CONCLUSIONS</h3> This study confirms the previously documented left to right shift in CRC distribution in Northern Ireland and demonstrates that if this shift continues, FS will become less successful as a screening tool than is currently predicted.
Relationships between gene trees and species trees.
Authors: P Pamilo, M Nei
Journal: Molecular Biology and Evolution (1988)

It is well known that a phylogenetic tree (gene tree) constructed from DNA sequences for a genetic locus does not necessarily agree with the tree that represents the actual evolutionary pathway of the species involved (species tree). One of the important factors that cause this difference is genetic polymorphism in the ancestral species. Under the assumption of neutral mutations, this problem can be studied by evaluating the probability (P) that a gene tree has the same topology as that of the species tree. When one gene (allele) is used from each of the species involved, the probability can be expressed as a simple function of Ti = ti/(2N), where ti is the evolutionary time measured in generations for the ith internodal branch of the species tree and N is the effective population size. When any of the Ti's is less than 1, the probability P becomes considerably less than 1.0. This probability cannot be substantially increased by increasing the number of alleles sampled from a locus. To increase the probability, one has to use DNA sequences from many different loci that have evolved independently of each other.
IMMUNOCOMPETENCE OF SPLEEN CELLS FROM NEONATALLY THYMECTOMIZED MICE CONFERRED IN VITRO BY A SYNGENEIC THYMUS EXTRACT
Authors: Nathan Trainin, Myra Small, Amiela Globerson
Journal: The Journal of Experimental Medicine (1969)

Impaired immunological competence of spleen cells from neonatally thymectomized C57B1/6 young adult mice was apparent when these cells were tested in an in vitro graft-versus-host assay. Spleen cell inocula prepared from thymectomized mice did not induce enlargement of (C3H/eb x C57BI/6)F1 newborn spleen explants, whereas the same number of cells from intact donors consistently initiated splenomegaly. Spleen enlargement was observed, however, when the explants were challenged by cells from thymectomized donors in the presence of syngeneic thymus extract, indicating that the spleen cells in suspension attained immunological competence under the influence of a non-cellular component of the thymus. Immunocompetence was also evident when the cells from thymectomized donors were first incubated with thymus extract for 1 hr and subsequently tested for reactivity. Cells from the same thymectomized donor mice exposed in parallel to extracts from syngeneic spleen or mesenteric lymph node at an equivalent protein concentration did not initiate a graft-versus-host response. These experiments demonstrate that immune reactivity in the graft-versus-host response involves activation of lymphoid cells by a humoral factor of the thymus acting directly upon these cells.
Is isolated idiopathic pancreatitis associated with CFTR mutations?
Authors: N PALLARES-RUIZ
Journal: Gut (2000)

Editor,—In one of two recently published studies which looked at a link between mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene and idiopathic pancreatitis,1 2 Cohn et al estimated that 37% of a cohort of 27 patients with idiopathic pancreatitis had at least one abnormal CFTR gene, which is 11 times the expected frequency.1 Furthermore, the authors concluded that additional CFTR mutations might be detected by more comprehensive DNA testing, because they had tested DNA samples for only 16 of the more than 800 mutations associated with cystic fibrosis.

In order to document …
Role of adenosine in dialysis-induced hypotension.
Authors: T Shinzato, M Miwa, S Nakai, H Morita, H Odani, I Inoue, K Maeda
Journal: Journal of the American Society of Nephrology (1994)

First, this investigation showed that plasma levels of inosine, hypoxanthine, and xanthine, which are metabolites of adenosine, rose sharply when blood pressure dropped suddenly along with symptoms during a hemodialysis session (sudden hypotension), but not when it decreased gradually with eventual symptoms (gradual hypotension). Because adenosine has an action to dilate vessels, this result indicates the possibility that the increased release of adenosine would be a cause of sudden hypotension. Second, it was found that the frequency of sudden hypotension decreases with the administration of caffeine, which is an adenosine-receptor antagonist, whereas the frequency of gradual hypotension did not change. This result supports the above-mentioned hypothesis that adenosine may well be a mediator of sudden hypotension, but not of gradual hypotension. Third, our investigation demonstrated no significant differences in plasma norepinephrine level, in plasma renin activity, or in mean blood pressure between the hemodialysis session in which caffeine was administered and the session in which a placebo was given. These findings suggest that the effect of caffeine administration to prevent sudden hypotension is not mediated by the stimulation of the sympathetic nervous system or activation of the renin-angiotensin system, but by the adenosine-receptor antagonism.
Phase II Trial of Postoperative Adjuvant Paclitaxel/Carboplatin and Thoracic Radiotherapy in Resected Stage II and IIIA Non–Small-Cell Lung Cancer: Promising Long-Term Results of the Radiation Therapy Oncology Group—RTOG 9705
Authors: Jeffrey D. Bradley, Rebecca Paulus, Mary V. Graham, David S. Ettinger, David W. Johnstone, Miljenko V. Pilepich, Mitchell Machtay, Ritsuko Komaki, James Atkins, Walter J. Curran
Journal: Journal of Clinical Oncology (2005)

Purpose To determine the overall survival, progression-free survival, and toxicity associated with concurrent paclitaxel/carboplatin and thoracic radiotherapy for completely resected patients with stage II and IIIA non–small-cell lung cancer (NSCLC). Patients and Methods Eighty-eight eligible patients had surgical resection for pathologic stage II or IIIA disease and received postoperative paclitaxel and carboplatin. Concurrent thoracic radiotherapy at 50.4 Gy in 28 fractions for 6 weeks (1.8 Gy/d, 5 days/wk) was given during cycles 1 and 2. A boost of 10.8 Gy in six fractions was given for extracapsular nodal extension or T3 lesions. Results Treatment compliance was acceptable, with 93% compliance for radiation therapy and 86% for chemotherapy completion. The median duration of follow-up was 56.7 months (range, 17 to 61 months). The median overall survival time was 56.3 months, with 1-, 2-, and 3-year survival rates of 86%, 70%, and 61%, respectively. The 1-, 2-, and 3- year progression-free survival rates were 70%, 57%, and 50%, respectively. Brain metastasis occurred as the sole site of first failure in 11%, and 9% failed in other metastatic sites as first failure. Of the 43 patients who died, the cause of death was the treated cancer in 31 (35%). Local failure was a component of first failure in 15% of patients. Toxicities were acceptable. An overall survival comparison to Eastern Cooperative Oncology Group 3590 is favorable. Conclusion The mature results of this trial suggest an improved overall and progression-free survival in this group of resected NSCLC patients, compared with previously reported trials. A phase III trial comparing this treatment regimen with standard therapy seems warranted.
Reducing CD73 Expression by IL1β-Programmed Th17 Cells Improves Immunotherapeutic Control of Tumors
Authors: Shilpak Chatterjee, Krishnamurthy Thyagarajan, Pravin Kesarwani, Jin H. Song, Myroslawa Soloshchenko, Jianing Fu, Stefanie R. Bailey, Chenthamarkshan Vasu, Andrew S. Kraft, Chrystal M. Paulos, Xue-Zhong Yu, Shikhar Mehrotra
Journal: Cancer Research (2014)

T cells of the T helper (Th)17 subset offer promise in adoptive T-cell therapy for cancer. However, current protocols for ex vivo programming of Th17 cells, which include TGFβ exposure, increase the expression of CD39 and CD73, two cell surface ATP ectonucleotidases that reduce T-cell effector functions and promote immunosuppression. Here, we report that ATP-mediated suppression of IFNγ production by Th17 cells can be overcome by genetic ablation of CD73 or by using IL1β instead of TGFβ to program Th17 cells ex vivo. Th17 cells cultured in IL1β were also highly polyfunctional, expressing high levels of effector molecules and exhibiting superior short-term control of melanoma in mice, despite reduced stem cell-like properties. TGFβ addition at low doses that did not upregulate CD73 expression but induced stemness properties drastically improved the antitumor effects of IL1β-cultured Th17 cells. Effector properties of IL1β-dependent Th17 cells were likely related to their high glycolytic capacity, since ex vivo programming in pyruvate impaired glycolysis and antitumor effects. Overall, we show that including TGFβ in ex vivo cultures used to program Th17 cells blunts their immunotherapeutic potential and demonstrate how this potential can be more fully realized for adoptive T-cell therapy.