tbuckley/cabot-search huggingface dataset:
Sinus node response to premature atrial stimulation in the rabbit studied with multiple microelectrode impalements.
Authors: G Steinbeck, M A Allessie, F I Bonke, W J Lammers
Journal: Circulation Research (1978)

In this study we investigated the response of the isolated rabbit sinus node to ectopic atrial premature beats elicited late in the atrial cycle. In three experiments the response of at least 45 different fibers of the sinus node was recorded, whereas, in other experiments, investigation was less extensive. In this way the spread of activation of the total pacemaker area could be mapped accurately both during spontaneous beating and the induction of ectopic atrial beats of different degrees of prematurity. We found that: (1) The conduction of an impulse from the dominant pacemaker area to the atrium during spontaneous rhythm (antegrade conduction) is slower than the conduction of an ectopic atrial impulse towards the center of the sinus node (retrograde conduction). (2) The action potential of the dominant pacemaker fibers in the sinus node is shortened because of premature activation caused by an ectopic impulse from the atrium. Late premature beats had no effect on diastolic depolarization. If the retrograde activation wave did not reach the area of the dominant pacemaker before the spontaneous discharge of these fibers, there was electrotonic influence demonstrable over a distance of about 0.5 mm. (3) Comparison of the true sinoatrial conduction time with the estimated sinoatrial conduction calculated indirectly from the length of the postextrasystolic atrial cycle revealed that, in the isolated rabbit heart, the calculated value is a serious underestimation of the true antegrade sinoatrial conduction time.
AN ANALYSIS OF THE SEQUENCES OF THE VARIABLE REGIONS OF BENCE JONES PROTEINS AND MYELOMA LIGHT CHAINS AND THEIR IMPLICATIONS FOR ANTIBODY COMPLEMENTARITY
Authors: Tai Te Wu, Elvin A. Kabat
Journal: The Journal of Experimental Medicine (1970)

In an attempt to account for antibody specificity and complementarity in terms of structure, human kappa-, human lambda-, and mouse kappa-Bence Jones proteins and light chains are considered as a single population and the variable and constant regions are compared using the sequence data available. Statistical criteria are used in evaluating each position in the sequence as to whether it is essentially invariant or group-specific, subgroup-specific, species-specific, etc. Examination of the invariant residues of the variable and constant regions confirms the existence of a large number of invariant glycines, no invariant valine, lysine, and histidine, and only one invariant leucine and alanine in the variable region, as compared with the absence of invariant glycines and presence of three each of invariant alanine, leucine, and valine and two each of invariant lysine and histidine in the constant region. The unique role of glycine in the variable region is emphasized. Hydrophobicity of the invariant residues of the two regions is also evaluated. A parameter termed variability is defined and plotted against the position for the 107 residues of the variable region. Three stretches of unusually high variability are noted at residues 24-34, 50-56, and 89-97; variations in length have been found in the first and third of these. It is hypothesized that positions 24-34 and 89-97 contain the complementarity-determining residues of the light chain-those which make contact with the antigenic determinant. The heavy chain also has been reported to have a similar region of very high variability which would also participate in forming the antibody-combining site. It is postulated that the information for site complementarity is contained in some extrachromosomal DNA such as an episome and is incorporated by insertion into the DNA of the structural genes for the variable region of short linear sequences of nucleotides. The advantages and disadvantages of this hypothesis are discussed.
Chasing sphingosine-1-phosphate, a lipid mediator for cardiomyocyte survival
Authors: Q YANG
Journal: Cardiovascular Research (2007)

See article by Tao et al.  [5]  (pages 56–63) in this issue. 

Sphingosine-1-phosphate (S1P) is a sphingolipid metabolite that regulates many essential biological processes in various cells and tissues. S1P may act as an extracellular ligand to specific G protein-coupled S1P receptors (S1P1–5) or as an intracellular second messenger. Sphingosine is derived from cleavage of ceramide by ceramidases in the sphingolipid degradative pathway. It can be catalyzed by sphingosine kinases (SphK1 and 2) into S1P, which is then degraded by a S1P lyase and S1P phosphohydrolases. S1P is most abundant in platelets, but it can also be synthesized in various cells such as cardiomyocytes. A “sphingolipid rheostat” hypothesis suggests that the relative levels of these lipids are important determinants of cell fate [1]. In fact, both ceramide and S1P are known to be involved in cardiomyocyte survival and apoptosis. It has been shown that ceramide induces cardiomyocyte apoptosis in the heart [2], and it has been proposed that it is a mediator of cardiomyocyte death in myocardial ischemic–reperfusion injury [3]. On the contrary, S1P exerts an anti-apoptosis effect in rat cultured neonatal cardiomyocytes [4]. … 

*Tel.: +1 404 756 5056; fax: +1 404 742 1042. Email address: qyang{at}msm.edu
Results from a multicentre international registry of familial Mediterranean fever: impact of environment on the expression of a monogenic disease in children
Authors: Seza Ozen, Erkan Demirkaya, Gayane Amaryan, Isabelle Koné-Paut, Adem Polat, Pat Woo, Yosef Uziel, Consuelo Modesto, Martina Finetti, Pierre Quartier, Efimia Papadopoulou-Alataki, Sulaiman M Al-Mayouf, Giovanna Fabio, Romina Gallizzi, Luca Cantarini, Joost Frenkel, Susan Nielsen, Michael Hofer, Antonella Insalaco, C Acikel, Huri Ozdogan, Alberto Martini, Nicolino Ruperto, Marco Gattorno
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background and aim</h3> Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by mutations of the MEFV gene. We analyse the impact of ethnic, environmental and genetic factors on the severity of disease presentation in a large international registry. <h3>Methods</h3> Demographic, genetic and clinical data from validated paediatric FMF patients enrolled in the Eurofever registry were analysed. Three subgroups were considered: (i) patients living in the eastern Mediterranean countries; (ii) patients with an eastern Mediterranean ancestry living in western Europe; (iii) Caucasian patients living in western European countries. A score for disease severity at presentation was elaborated. <h3>Results</h3> Since November 2009, 346 FMF paediatric patients were enrolled in the Eurofever registry. The genetic and demographic features (ethnicity, age of onset, age at diagnosis) were similar among eastern Mediterranean patients whether they lived in their countries or western European countries. European patients had a lower frequency of the high penetrance M694V mutation and a significant delay of diagnosis (p&lt;0.002). Patients living in eastern Mediterranean countries had a higher frequency of fever episodes/year and more frequent arthritis, pericarditis, chest pain, abdominal pain and vomiting compared to the other two groups. Multivariate analysis showed that the variables independently associated with severity of disease presentation were country of residence, presence of M694V mutation and positive family history. <h3>Conclusions</h3> Eastern Mediterranean FMF patients have a milder disease phenotype once they migrate to Europe, reflecting the effect of environment on the expression of a monogenic disease.
Human Leprosy in Normal Mice
Authors: R. J. W. Rees, A. G. M. Weddell, J. M. H. Pearson
Journal: BMJ (1969)

It has now been shown that normal mice can be used as models for studying the early stages in the development of leprosy. Inoculation into the foot pads of mice of as few as 10(4) leprosy bacilli leads to infections which spread to distant sites via the blood stream and after two or more years give rise to granulomata and neural damage at the sites of inoculation. Where the tissue response had fully developed it reproduced exactly the histological features of human leprosy in the borderline range.
Intracellular Acidosis: Can It Delay the Inevitable?
Authors: Richard H. Moseley
Journal: Hepatology (1990)

The relationships between extracellular pH (pH o ), intracellular pH (pH i ), and loss of cell viability were evaluated in cultured rat hepatocytes after ATP depletion by metabolic inhibition with KCN and iodoacetate (chemical hypoxia). pH i was measured in single cells by ratio imaging of 2′, 7′ –biscarboxy–ethyl–5, 6–carboxyfluorescein (BCECF) fluorescence using multiparameter digitized video microscopy. During chemical hypoxia at pH o of 7.4, pH i decreased from 7.36 to 6.33 within 10 min. pH i remained at 6.1-6.5 for 30-40 min. (plateau phase). Thereafter, pH i began to rise and cell death ensued within minutes, as evidenced by nuclear staining with propidium iodide and coincident leakage of BCECF from the cytoplasm. An acidic pH o produced a slightly greater drop in pH f , prolonged the plateau phase of intracellular acidosis, and delayed the onset of cell death. Inhibition of Na + /H + exchange also prolonged the plateau phase and delayed cell death. In contrast, monensin or substitution of gluconate for Cl - in buffer containing HCO 3 - abolished the pH gradient across the plasma membrane and shortened cell survival. The results indicate that intracellular acidosis after ATP depletion delays the onset of cell death, whereas reduction of the degree of acidosis accelerates cell killing. We conclude that intracellular acidosis protects against hepatocellular death from ATP depletion, a phenomenon that may represent a protective adaptation against hypoxic and ischemic stress.
Vasculostatin Inhibits Intracranial Glioma Growth and Negatively Regulates<i>In vivo</i>Angiogenesis through a CD36-Dependent Mechanism
Authors: Balveen Kaur, Sarah M. Cork, Eric M. Sandberg, Narra S. Devi, Zhaobin Zhang, Philip A. Klenotic, Maria Febbraio, Hyunsuk Shim, Hui Mao, Carol Tucker-Burden, Roy L. Silverstein, Daniel J. Brat, Jeffrey J. Olson, Erwin G. Van Meir
Journal: Cancer Research (2009)

Angiogenesis is a critical physiologic process that is appropriated during tumorigenesis. Little is known about how this process is specifically regulated in the brain. Brain angiogenesis inhibitor-1 (BAI1) is a brain-predominant seven-transmembrane protein that contains five antiangiogenic thrombospondin type-1 repeats (TSR). We recently showed that BAI1 is cleaved at a conserved proteolytic cleavage site releasing a soluble, 120 kDa antiangiogenic factor called vasculostatin (Vstat120). Vstat120 has been shown to inhibit in vitro angiogenesis and suppress subcutaneous tumor growth. Here, we examine its effect on the intracranial growth of malignant gliomas and further study its antitumor mechanism. First, we show that expression of Vstat120 strongly suppresses the intracranial growth of malignant gliomas, even in the presence of the strong proangiogenic stimulus mediated by the oncoprotein epidermal growth factor receptor variant III (EGFRvIII). This tumor-suppressive effect is accompanied by a decrease in tumor vascular density, suggesting a potent antiangiogenic effect in the brain. Second, and consistent with this interpretation, we find that treatment with Vstat120 reduces the migration of cultured microvascular endothelial cells in vitro and inhibits corneal angiogenesis in vivo. Third, we show that these antivascular effects critically depend on the presence of the cell surface receptor CD36 on endothelial cells in vitro and in vivo, supporting the role of Vstat120 TSRs in mediating these effects. These results advance the understanding of brain-specific angiogenic regulation, and suggest that Vstat120 has therapeutic potential in the treatment of brain tumors and other intracerebral vasculopathies.
TCT-475 Association of the P53 codon 72 polymorphism with infarct size and left ventricular ejection fraction in patients with ST-segment elevation acute coronary syndrome
Authors: Juan Rama Merchan, Ignacio Cruz-González, Rogelio Gonzalez Sarmiento, Irene Rodriguez Hernandez, Ana Cordero Vaquero, Ana Martin Garcia, Candido Martín Luengo
Journal: Journal of the American College of Cardiology (2012)
Novel differentiation antigens on late erythrocytic progenitor cells detected by alloantisera made between mouse strains congenic at the Fv-2 locus.
Authors: D S Vaithilingam, A A Axelrad
Journal: The Journal of Experimental Medicine (1982)

We have investigated the activities of alloantisera produced in B6 (C57BL/6) and B6.S strain mice reciprocally immunized with unwashed bone marrow and spleen cell suspensions from their respective Fv-2 congenic partner strains, B6.S and B6. These antisera inhibited the formation of colonies by the late erythrocytic progenitors (CFU-E) in plasma cultures seeded with unwashed bone marrow or spleen cells; washed cells were unaffected. Erythropoietic burst formation by the early progenitors (BFU-E) was not significantly inhibited by the antisera, whether the cells were washed or unwashed. We conclude (a) that the congenic antisera are capable of recognizing alloantigens controlled by alleles of Fv-2 or of a closely linked gene locus on chromosome 9; (b) that these alloantigens are situated on the surface of erythrocytic progenitor cells and can be removed by washing; and (c) that the expression of the alloantigens on these cells is influenced by their stage of differentiation.
We know a lot about the cerebellum, but do we know what motor learning is?
Authors: Stephan P. Swinnen, Charles B. Walter, Natalia Dounskaia
Journal: Behavioral and Brain Sciences (1996)

In the behavioral literature on human movement, a distinction is made between the learning of parameters and the learning of new movement forms or topologies. Whereas the target articles by Thach, Smith, and Houk et al. provide evidence for cerebellar involvement in parametrization learning and adaptation, the evidence in favor of its involvement in the generation of new movement patterns is less straightforward. A case is made for focusing more attention on the latter issue in the future. This would directly help to bridge the gap between current neurophysiological approaches to the role of the cerebellum and the behavioral expressions of human motor learning, [HOUK et al.; SMITH; THACH]
Prevalence of self-report photosensitivity in cutaneous lupus erythematosus
Authors: Kristen Foering, Renato Goreshi, Rachel Klein, Joyce Okawa, Mathew Rose, Andrew Cucchiara, Victoria P. Werth
Journal: Journal of the American Academy of Dermatology (2011)

Little is known about the prevalence of self-reported photosensitivity (PS) and its effects on quality of life in a US cutaneous lupus population.We sought to determine the prevalence of self-reported PS among a cutaneous lupus population and to examine its impact on quality of life.A total of 169 patients with lupus were interviewed about PS symptoms and completed the modified Skindex-29+3, a quality-of-life survey. A complete skin examination was conducted and the Cutaneous Lupus Erythematosus Disease Area and Severity Index was completed.In all, 68% of patients reported some symptoms of PS. The PS group (those who reported a history of and current PS) scored worse on PS-related items of the modified Skindex-29+3 and had higher cutaneous disease activity as determined by the Cutaneous Lupus Erythematosus Disease Area and Severity Index. Patients with PS had worse symptoms and emotions and experienced significant functional impairments compared with patients who had cutaneous lupus without PS.This study was done at a single referral center.Self-reported PS is very common among patients with cutaneous lupus and is associated with significant impairments related to symptoms, emotions, and daily functioning.
Enhanced Interleukin-1β in Hypercholesterolemia
Authors: Patrizia Ferroni, Francesca Martini, Cristiano M. Cardarello, Pier Paolo Gazzaniga, Giovanni Davì, Stefania Basili
Journal: Circulation (2003)

This study was aimed at verifying whether activation of platelets might represent a source of interleukin (IL)-1beta levels in hypercholesterolemia. To this purpose, we compared the effects of a short-term treatment with simvastatin or low-dose aspirin on circulating levels of this cytokine.Fifty patients with hypercholesterolemia were randomly allocated to receive an 8-week therapeutic course of simvastatin 20 mg daily (n=25) or aspirin 100 mg daily (n=25). Baseline soluble (s) P-selectin directly correlated with IL-1beta (P<0.0001) and C-reactive protein (CRP) (P<0.05) but not with von Willebrand factor, total cholesterol, or LDL cholesterol levels. Furthermore, sP-selectin (P<0.02) and IL-1beta (P<0.0001) levels were independently related to CRP by multiple regression analysis. Both drugs were associated with comparable, significant reductions in IL-1beta and sP-selectin. Simvastatin, but not aspirin treatment, significantly lowered CRP levels (P<0.05). The change in IL-1beta levels correlated with the change in sP-selectin in patients randomized to either simvastatin (Rho, 0.42; P<0.05) or aspirin (Rho, 0.42; P<0.05). In contrast, the simvastatin-induced change in IL-1beta did not correlate with the change in CRP levels.This study suggests that platelets might contribute to IL-1beta production in hypercholesterolemia, thus providing an additional link between inflammation and the prothrombotic state in this setting.
Involvement of the TGF-β and β-Catenin Pathways in Pelvic Lymph Node Metastasis in Early-Stage Cervical Cancer
Authors: Maartje G. Noordhuis, Rudolf S.N. Fehrmann, G. Bea A. Wisman, Esther R. Nijhuis, Jelmer J. van Zanden, Perry D. Moerland, Emiel Ver Loren van Themaat, Haukeline H. Volders, Mirjam Kok, Klaske A. ten Hoor, Harry Hollema, Elisabeth G.E. de Vries, Geertruida H. de Bock, Ate G.J. van der Zee, Ed Schuuring
Journal: Clinical Cancer Research (2011)

Presence of pelvic lymph node metastases is the main prognostic factor in early-stage cervical cancer patients, primarily treated with surgery. Aim of this study was to identify cellular tumor pathways associated with pelvic lymph node metastasis in early-stage cervical cancer.Gene expression profiles (Affymetrix U133 plus 2.0) of 20 patients with negative (N(0)) and 19 with positive lymph nodes (N(+)), were compared with gene sets that represent all 285 presently available pathway signatures. Validation immunostaining of tumors of 274 consecutive early-stage cervical cancer patients was performed for representatives of the identified pathways.Analysis of 285 pathways resulted in identification of five pathways (TGF-β, NFAT, ALK, BAD, and PAR1) that were dysregulated in the N(0), and two pathways (β-catenin and Glycosphingolipid Biosynthesis Neo Lactoseries) in the N(+) group. Class comparison analysis revealed that five of 149 genes that were most significantly differentially expressed between N(0) and N(+) tumors (P < 0.001) were involved in β-catenin signaling (TCF4, CTNNAL1, CTNND1/p120, DKK3, and WNT5a). Immunohistochemical validation of two well-known cellular tumor pathways (TGF-β and β-catenin) confirmed that the TGF-β pathway (positivity of Smad4) was related to N(0) (OR: 0.20, 95% CI: 0.06-0.66) and the β-catenin pathway (p120 positivity) to N(+) (OR: 1.79, 95%CI: 1.05-3.05).Our study provides new, validated insights in the molecular mechanism of lymph node metastasis in cervical cancer. Pathway analysis of the microarray expression profile suggested that the TGF-β and p120-associated noncanonical β-catenin pathways are important in pelvic lymph node metastasis in early-stage cervical cancer.
Is Nonalbuminuric Renal Insufficiency in Type 2 Diabetes Related to an Increase in Intrarenal Vascular Disease?
Authors: Richard J. MacIsaac, Sianna Panagiotopoulos, Karen J. McNeil, Trudy J. Smith, Con Tsalamandris, Huming Hao, P. Geoffrey Matthews, Merlin C. Thomas, David A. Power, George Jerums
Journal: Diabetes Care (2006)

OBJECTIVE—To investigate the role of intrarenal vascular disease in the pathogenesis of nonalbuminuric renal insufficiency in type 2 diabetes. RESEARCH DESIGN AND METHODS—We studied 325 unselected clinic patients who had sufficient clinical and biochemical information to calculate an estimated glomerular filtration rate (eGFR) using the Modified Diet in Renal Disease six-variable formula, at least two estimations of urinary albumin excretion rates (AER), and a renal duplex scan to estimate the resistance index of the interlobar renal arteries. The resistance index, measured as part of a complications surveillance program, was compared in patients with an eGFR &amp;lt; or ≥60 ml/min per 1.73 m2 who were further stratified into normo- (AER &amp;lt;20), micro- (20–200), or macroalbuminuria (&amp;gt; 200 μg/min) categories. RESULTS—Patients with an eGFR &amp;lt;60 ml/min per 1.73 m2 had a higher resistance index of the renal interlobar arteries compared with patients with an eGFR ≥60 ml/min per 1.73 m2. However, the resistance index was elevated to a similar extent in patients with an eGFR &amp;lt;60 ml/min per 1.73 m2 regardless of albuminuric status (normo- 0.74 ± 0.01, micro- 0.73 ± 0.01, and macroalbuminuria resistance index 0.75 ± 0.11). Multiple regression analysis revealed that increased age (P &amp;lt; 0.0001), elevated BMI (P = 0.0001), decreased eGFR (P &amp;lt; 0.01), and decreased diastolic blood pressure (P &amp;lt; 0.01), but not an increased AER, were independently associated with an elevated resistance index in patients with impaired renal function. CONCLUSIONS—Subjects with type 2 diabetes and reduced glomerular filtration rate had similar degrees of intrarenal vascular disease, as measured by the intrarenal arterial resistance index, regardless of their AER status. The pathological mechanisms that determine the relationship between impaired renal function and AER status in subjects with type 2 diabetes remain to be elucidated.
The Effect of Levarterenol on Polarographic Myocardial Oxygen, the Epicardial Electrocardiogram and Contraction
Authors: J. J. SAYEN, A. H. KATCHER, W. F. SHELDON, C. M. GILBERT
Journal: Circulation Research (1960)

In open-chest dogs it was found that levarterenol produced primary RS-T segment depression in epicardial surface electrocardiograms together with increases of ventricular muscle contractility. These effects occurred in nonischemic, regionally ischemic, and hypoxic myocardium and were accompanied by rises of polarographic myocardial oxygen and a reddening of coronary venous blood in all but the lowest dosages. The findings are discussed in the light of the pertinent experimental literature.