tbuckley/cabot-search huggingface dataset:
Interactions of flecainide with guinea pig cardiac sodium channels. Importance of activation unblocking to the voltage dependence of recovery.
Authors: T Anno, L M Hondeghem
Journal: Circulation Research (1990)

Effects of flecainide, a potent antiarrhythmic agent, on sodium channel availability was investigated in guinea pig single cardiac cells by the whole-cell voltage-clamp technique. Sodium current (INa) experiments were performed at 17 degrees C, and maximum upstroke velocity (Vmax) experiments were performed at 37 degrees C. Flecainide (3 microM) caused little tonic block, but reduced sodium channel availability in a use-dependent manner. The latter effect was accentuated by depolarization and attenuated by hyperpolarization. Long (200-msec) and short (10-msec) depolarizations yielded similar use-dependent block. These results indicate that flecainide has a low affinity for rested (R) and inactivated (I) channels but a high affinity for activated ones (A). In each of these states, the channels can bind to drug to form the corresponding RD, ID, and AD states. Recovery from flecainide block consisted of two components. An initial fast component was strongly voltage dependent: with increasing hyperpolarization, recovery developed more quickly and to a larger extent. At 17 degrees C, the mean time constant shortened from 132 +/- 81.6 msec at -120 mV to 46.9 +/- 34.1 msec at +/- 160 mV (kinetics were too fast for accurate measurement at 37 degrees C). A later slow component was largely voltage independent: at 37 degrees C, the mean time constant was 9.8 +/- 3.2 seconds at -100 mV and 10.7 +/- 3.8 seconds at -75 mV. The slow component of recovery was similarly independent of voltage at 17 degrees C. In terms of the modulated-receptor theory, our results indicate that the fast recovery depends on availability for unblocking (RD) but occurs during activation (AD----A). Indeed, when the RD state is maximized by strong hyperpolarization, activation unblock was also maximized. However, during depolarization to -100 mV, availability for activation unblock declined with a time constant of 98 +/- 12 msec (RD----ID). Therefore, the voltage-dependent fast unblocking is mostly due to priming of the RD state (RD----ID), and the voltage-independent slow unblock reflects dissociation of flecainide from closed states (RD----R and ID----I). We conclude that flecainide interacts with sodium channels preferentially in the activated state, whereas unblocking occurs via two separate pathways: activated and closed states. Furthermore, drug association with channels shifts the voltage dependence of closed-state transitions (RD in equilibrium ID) and their kinetics toward more negative potentials.
Ovarian feedback, mechanism of action and possible clinical implications
Authors: Ioannis E. Messinis
Journal: Human Reproduction Update (2006)

The secretion of gonadotrophins from the pituitary in women is under ovarian control via negative and positive feedback mechanisms. Steroidal and non-steroidal substances mediate the ovarian effects on the hypothalamic-pituitary system. During the follicular phase of the cycle, estradiol (E2) plays a key role, while circulating progesterone (at low concentrations) and inhibin B contribute to the control of LH and FSH secretion respectively. During the luteal phase, both E2 and progesterone regulate secretion of the two gonadotrophins, while inhibin A plays a role in FSH secretion. The intercycle rise of FSH is related to changes in the levels of the steroidal and non-steroidal substances during the luteal-follicular transition. In terms of the positive feedback mechanism, E2 is the main component sensitizing the pituitary to GnRH. Activity of a non-steroidal ovarian substance, named gonadotrophin surge-attenuating factor (GnSAF), has been detected after ovarian stimulation. It is hypothesized that GnSAF, by antagonizing the sensitizing effect of E2 on the pituitary, regulates the amplitude of the endogenous LH surge at midcycle. Disturbances in the feedback mechanisms can occur in various abnormal conditions or after treatment with pharmaceutical compounds that interfere with the production or the action of endogenous hormones.
Phase I Clinical Trial of Mixed Bacterial Vaccine (Coley's Toxins) in Patients with NY-ESO-1 Expressing Cancers: Immunological Effects and Clinical Activity
Authors: Julia Karbach, Antje Neumann, Kathrin Brand, Claudia Wahle, Ekkehard Siegel, Markus Maeurer, Erika Ritter, Takamasa Tsuji, Sacha Gnjatic, Lloyd J. Old, Gerd Ritter, Elke Jäger
Journal: Clinical Cancer Research (2012)

Mixed bacterial vaccine (MBV, Coley's toxins) is a historical, vaguely defined preparation of heat-inactivated Streptococcus pyogenes and Serratia marcescens used as nonspecific immunotherapy in the treatment of cancer. The mechanism of action is suspected to have an immunologic basis, yet it is poorly defined up to now. We developed a new, biochemically well defined and current good manufacturing practice-compliant MBV preparation, which has been investigated in patients with NY-ESO-1 expressing cancers.Patients received MBV subcutaneously at a starting dose of 250 EU (endotoxin units) twice a week. The MBV dose was escalated in each patient until a body temperature of 38°C to 39.5°C was induced or up to the maximum dose of 547.000 EU. Changes in serum cytokine levels were determined and immune responses to NY-ESO-1 were evaluated. Tumor response was assessed according to RECIST.Twelve patients were enrolled and 11 of them developed fever after the administration of MBV. Ten of 12 patients showed a consistent increase in serum IL-6 levels with the highest levels coinciding with the highest body temperature. A subgroup of patients showed increasing levels of TNF-α, IFN-γ, and IL1-β. A patient with metastatic bladder cancer showed a partial tumor response strongly correlated with MBV-induced fever and highly elevated levels of several cytokines.MBV at fever-inducing dose levels can lead to a massive induction of immunoregulatory cytokines that may be involved in inducing tumor regressions. We propose to further explore the role of MBV as a potent immune modulator at higher dose levels and in conjunction with antigen-specific cancer vaccines.
VARIATIONS IN THE PLASMA CHOLESTEROL AND CHOLESTEROL ESTER CONTENT IN HOG CHOLERA
Authors: Richard E. Shope
Journal: The Journal of Experimental Medicine (1930)

1. The plasma cholesterol and cholesterol ester content of swine, experimentally infected with hog cholera, exhibit a regular succession of changes. During the period of incubation of the disease, for 3 or more days following inoculation with hog cholera virus, hypocholesterolemia prevails. This is followed by a period of hypercholesterolemia which is coincident with the onset of the clinical manifestations of the disease. The hypercholesterolemia after persisting for from 4 to 7 days, gives way to a second period of hypocholesterolemia more marked and more prolonged than that observed immediately after inoculation. In the experiments of the present work this second period lasted 8 and 11 days in the 2 animals surviving long enough for the study of it and was followed by a second period of hypercholesterolemia. In the one animal surviving this period for 8 days a third period of irregular and fluctuating hypocholesterolemia set in. 2. A comparison with the results in other acute infections indicates that hog cholera is unique in showing alternating periods of hypocholesterolemia and hypercholesterolemia. 3. A normal hog inoculated with Bacillus suisepticus rapidly developed the typical marked hypocholesterolemia whereas an animal infected with hog cholera and then inoculated with B. suisepticus failed to show the decrease in plasma cholesterol content.
The C-MYB locus is involved in chromosomal translocation and genomic duplications in human T-cell acute leukemia (T-ALL), the translocation defining a new T-ALL subtype in very young children
Authors: Emmanuelle Clappier, Wendy Cuccuini, Anna Kalota, Antoine Crinquette, Jean-Michel Cayuela, Willem A. Dik, Anton W. Langerak, Bertrand Montpellier, Bertrand Nadel, Pierre Walrafen, Olivier Delattre, Alain Aurias, Thierry Leblanc, Hervé Dombret, Alan M. Gewirtz, André Baruchel, François Sigaux, Jean Soulier
Journal: Blood (2007)
Differential synovial Th1 cell reactivity towards<i>Escherichia coli</i>antigens in patients with ankylosing spondylitis and rheumatoid arthritis
Authors: Uta Syrbe, Rebecca Scheer, Peihua Wu, Joachim Sieper
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objective</h3> Ankylosing spondylitis (AS) is associated with clinical and subclinical mucosal inflammation, suggesting that commensal bacteria contribute to the pathogenesis of the disease. <h3>Methods</h3> The frequency of Th1 cells reacting towards conserved <i>Escherichia coli</i> (<i>E coli</i>) proteins and pathogenicity factors in peripheral blood mononuclear cells (PBMNC) and synovial fluid mononuclear cells (SFMNC) of patients with AS and those with rheumatoid arthritis (RA) was determined. PBMNC from healthy individuals were included as controls. <h3>Results</h3> Higher frequencies of Th1 cells reacting to conserved <i>E coli</i> proteins were observed in SFMNC and, to a lesser extent, in PBMNC of patients with AS compared with patients with RA (SFMNC, p&lt;0.01; PBMNC, p&lt;0.05). In contrast, the frequencies of cytomegalovirus- and staphylococcal enterotoxin B (SEB)-induced Th1 cells did not differ between patients with AS and those with RA in SFMNC, and SEB-induced Th1 cell frequencies in PBMNCs were even higher in patients with RA than in those with AS (p&lt;0.05). <h3>Conclusions</h3> The high frequency and enrichment of <i>E coli</i>-specific CD4 T cells in the inflamed joints of patients with AS but not those with RA suggests that commensal bacteria are relevant antigens in AS that might trigger the disease.
The neuron doctrine in psychiatry
Authors: Christian Perring
Journal: Behavioral and Brain Sciences (1999)

Gold &amp; Stoljar's target article is important because it shows the limitations of neurobiological theories of the mind more powerfully than previous philosophical criticisms, especially those that focus on the subjective nature of experience and those that use considerations from philosophy of language to argue for the holism of the mental. They use less controversial assumptions and clearer arguments, the conclusions of which are applicable to the whole of neuroscience. Their conclusions can be applied to psychiatry to argue that, contrary to many researchers' assumptions, the approaches to both understanding and treating mental disorders must be interdisciplinary.
Peroxisome proliferator-activated receptor ?/?: a new antihypertrophic drug target?
Authors: N PETRASHEVSKAYA, A SCHWARZ
Journal: Cardiovascular Research (2005)

See article by Planavila et al.  [6]  (pages 832–841) in this issue. 

In the normal adult heart, plasticity of ATP production is provided by coordinated changes in the expression of genes involved in cellular fatty acid (FA) utilization and glucose oxidation. The phenotypes of acquired forms of heart failure in human and animal models are associated with energy substrate changes accompanying a reduced mitochondrial FA oxidative capacity and a shift to glucose metabolism, resembling the fetal metabolic program [1]. High glucose conditions, initially serving as a protective response to support contractile function, stimulate the production of angiotensin II (Ang II), a known pathological modulator of cardiac remodeling [2].

Peroxisome proliferator-activated receptors (PPARs) are gene regulatory systems that regulate the transcription of an array of genes involved in cellular fatty acid utilization pathways. PPARs are ligand-dependent transcription factors belonging to the nuclear receptor superfamily. They are designed to rapidly respond to fluctuating substrate and metabolic intermediates. They regulate pathways involved in FA utilization upstream to the transcriptional regulatory network including nuclear respiratory factors 1 and 2 and mitochondrial transcription factor A [3]. PPARs have 3 isoforms, α, β/δ, and γ, that regulate lipid and glucose metabolism, participate in the regulation … 

*Corresponding author. Tel.: +1 513 558 2374; fax: +1 513 558 1778. Email address: petrasnn{at}email.uc.edu
Breast Cancer Among Young U.S. Women in Relation to Oral Contraceptive Use
Authors: Emily White, Kathleen E. Malone, Noel S. Weiss, Janet R. Daling
Journal: JNCI Journal of the National Cancer Institute (1994)

Journal Article Breast Cancer Among Young U.S. Women in Relation to Oral Contraceptive Use Get access Emily White, Emily White Search for other works by this author on: Oxford Academic PubMed Google Scholar Kathleen E. Malone, Kathleen E. Malone Search for other works by this author on: Oxford Academic PubMed Google Scholar Noel S. Weiss, Noel S. Weiss Search for other works by this author on: Oxford Academic PubMed Google Scholar Janet R. Daling Janet R. Daling Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 86, Issue 7, 6 April 1994, Pages 505–514, https://doi.org/10.1093/jnci/86.7.505 Published: 06 April 1994 Article history Revision received: 12 January 1994 Accepted: 13 January 1994 Published: 06 April 1994 Received: 12 October 1994
Harnessing the Power of Integrated Mitochondrial Biology and Physiology
Authors: Peipei Ping, Åsa B. Gustafsson, Don M. Bers, Lothar A. Blatter, Hua Cai, Arshad Jahangir, Daniel Kelly, Deborah Muoio, Brian O’Rourke, Peter Rabinovitch, Natalia Trayanova, Jennifer Van Eyk, James N. Weiss, Renee Wong, Lisa Schwartz Longacre
Journal: Circulation Research (2015)

Mitochondrial biology is the sum of diverse phenomena from molecular profiles to physiological functions. A mechanistic understanding of mitochondria in disease development, and hence the future prospect of clinical translations, relies on a systems-level integration of expertise from multiple fields of investigation. Upon the successful conclusion of a recent National Institutes of Health, National Heart, Lung, and Blood Institute initiative on integrative mitochondrial biology in cardiovascular diseases, we reflect on the accomplishments made possible by this unique interdisciplinary collaboration effort and exciting new fronts on the study of these remarkable organelles.
Consecutive pharmacological activation of PKA and PKC mimics the potent cardioprotection of temperature preconditioning
Authors: Igor Khaliulin, Joanna E. Parker, Andrew P. Halestrap
Journal: Cardiovascular Research (2010)

AimsTemperature preconditioning (TP) provides very powerful protection against ischaemia/reperfusion. Understanding the signalling pathways involved may enable the development of effective pharmacological cardioprotection. We investigated the interrelationship between activation of protein kinase A (PKA) and protein kinase C (PKC) in the signalling mechanisms of TP and developed a potent pharmacological intervention based on this mechanism.
Extracellular Interactions between GluR2 and N-Cadherin in Spine Regulation
Authors: Laura Saglietti, Caroline Dequidt, Kinga Kamieniarz, Marie-Claude Rousset, Pamela Valnegri, Olivier Thoumine, Francesca Beretta, Laurent Fagni, Daniel Choquet, Carlo Sala, Morgan Sheng, Maria Passafaro
Journal: Neuron (2007)
A distinct evolution of the T-cell repertoire categorizes treatment refractory gastrointestinal acute graft-versus-host disease
Authors: Everett H. Meyer, Andro R. Hsu, Joanna Liliental, Andrea Löhr, Mareike Florek, James L. Zehnder, Sam Strober, Philip Lavori, David B. Miklos, David S. Johnson, Robert S. Negrin
Journal: Blood (2013)
Cedar and cypress pollen counts are associated with the prevalence of allergic diseases in <scp>J</scp>apanese schoolchildren
Authors: K. Yoshida, Y. Adachi, M. Akashi, T. Itazawa, Y. Murakami, H. Odajima, Y. Ohya, A. Akasawa
Journal: Allergy (2013)

Abstract Background Patients allergic to pollen have been known to become more symptomatic during pollen season compared with the nonpollen season. However, there are few studies regarding whether higher exposure to pollen might increase the prevalence of allergic diseases. Methods An ecological analysis was conducted to evaluate whether pollen exposure is associated with the prevalence of allergic diseases in schoolchildren. Pollen count data of J apanese cedar ( C ryptomeria japonica ) and J apanese cypress ( C hamaecyparis obtusa ), which are the major pollen allergens in J apan, were obtained from each prefecture. The prevalence of allergic diseases in schoolchildren in each prefecture was based on a nationwide cross‐sectional survey using the International Study of Asthma and Allergies in Childhood questionnaire. Results After omitting three prefectures where pollen data were not available, data of 44 prefectures were analysed. The prevalence of allergic rhinoconjunctivitis in children aged 6–7 years was positively associated with both cedar and cypress pollen counts ( P = 0.01, both), whereas the prevalence of allergic rhinoconjunctivitis in children aged 13–14 years was positively associated with only cypress pollen counts ( P = 0.003). Furthermore, the prevalence of asthma was positively associated with cedar pollen counts in 6‐ to 7‐year‐old children ( P = 0.003) but not cypress pollen counts in either age group. Conclusions There are ecological associations between pollen counts and the prevalence of allergic diseases in J apanese schoolchildren. Further studies are needed to determine whether the difference between the effects of cedar and cypress pollens is attributable to pollen counts or allergenicity.
Identification and characterization of T helper cell epitopes of the major outer membrane protein of Chlamydia trachomatis.
Authors: H Su, R P Morrison, N G Watkins, H D Caldwell
Journal: The Journal of Experimental Medicine (1990)

Chlamydia trachomatis serovars A, B, and C are the causative agents of trachoma, the world's leading cause of preventable blindness. Immunoprophylaxis is a possible approach to control trachoma. The chlamydial major outer membrane protein (MOMP) is thought to play an important role in the development of protective immunity against chlamydial infection, and is therefore considered to be a promising candidate antigen in the development of a trachoma vaccine. Much effort has been focused on the molecular characterization of B cell sites of the MOMP that elicit neutralizing antibodies. Neutralizing sites have been identified as linear epitopes that reside within variable domains (VDs) of the protein whose primary sequences vary among different serovars. No information exists on MOMP T helper (Th) cell antigenic determinants, which are likely critical components for the development of a successful chlamydial vaccine. We used overlapping synthetic peptides (25 mers) representing the entire primary sequence of serovar A MOMP in T cell proliferation assays to identify T cell antigenic determinants of this molecule. Eight synthetic peptides (A-2, A-3, A-7, A-8, A-11, A-22, A-23, and A-24) stimulated proliferative responses of splenic T cells isolated from MOMP-immunized A/J mice. To ascertain if these peptides functioned as Th cell antigens, we determined their ability to prime A/J mice in vivo to produce an anamnestic IgG response specific to the MOMP. Mice primed with synthetic peptides A-8 (106-130) or A-23 (331-355) produced IgG antibodies reactive with the native MOMP and with the synthetic peptides corresponding to surface-accessible serovar-specific epitopes located in VD I and serogroup-specific epitopes located in VD IV of the protein. We synthesized the A-8 and A-23 peptides with the VD I sequence as colinear chimeric peptides. Immunization of mice with the T/B cell peptides produced high titered antibodies against the VD I sequence, and these antibodies reacted with the native MOMP and intact chlamydiae. The MOMP sequences containing these Th cell epitopes are conserved among the MOMP genes of different C. trachomatis serovars, indicating that they are common Th cell antigenic sites. Thus, the Th cell epitopes contained within these peptides, in combination with different trachoma serovar-specific B cell neutralizing determinants, may be useful in the development of a synthetic or recombinant trivalent trachoma vaccine.
Frequent False Detection of Positive Selection by the Likelihood Method with Branch-Site Models
Authors: J. Zhang
Journal: Molecular Biology and Evolution (2004)

Positive Darwinian selection promotes fixations of advantageous mutations during gene evolution and is probably responsible for most adaptations. Detecting positive selection at the DNA sequence level is of substantial interest because such information provides significant insights into possible functional alterations during gene evolution as well as important nucleotide substitutions involved in adaptation. Efficient detection of positive selection, however, has been difficult because selection often operates on only a few sites in a short period of evolutionary time. A likelihood-based method with branch-site models was recently introduced to overcome such difficulties. Here I examine the accuracy of the method using computer simulation. I find that the method detects positive selection in 20%–70% of cases when the DNA sequences are generated by computer simulation under no positive selection. Although the frequency of such false detection varies depending on, among other things, the tree topology, branch length, and selection scheme, the branch-site likelihood method generally gives misleading results. Thus, detection of positive selection by this method alone is unreliable. This unreliability may have resulted from its over-sensitivity to violations of assumptions made in the method, such as certain distributions of selective strength among sites and equal transition/transversion ratios for synonymous and nonsynonymous substitutions.
Tumor Necrosis Factor-α Induces a Biphasic Effect on Myocardial Contractility in Conscious Dogs
Authors: David R. Murray, Gregory L. Freeman
Journal: Circulation Research (1996)

Abstract Tumor necrosis factor-α (TNF-α) likely plays a role in the pathophysiology of myocardial depression observed in septic shock. To evaluate the hemodynamic effects of TNF-α in vivo while eliminating the influence of altered sympathetic tone, eight conscious chronically instrumented dogs were studied after pretreatment with propranolol (2 mg/kg) and atropine (2 mg). Using three sets of piezoelectric crystals to measure left ventricular (LV) volume and LV manometers to measure pressure, we determined load-independent parameters of LV systolic performance before, during, and after infusion of recombinant human TNF-α (rhTNF-α, 40 μg/kg for 1 hour). Plasma was analyzed for epinephrine and norepinephrine. Between 1 and 7 hours of exposure, rhTNF-α induced significant increases in circulating catecholamines. Norepinephrine rose from 268.6±47.2 to 426.2±87.0 pg/mL ( P &lt;.05) at 1 hour and peaked at 921.2±156.8 pg/mL ( P &lt;.001) at 4 hours after initiating rhTNF-α treatment. Similarly, epinephrine increased from 130.2±30.9 to 884.5±210.2 pg/mL ( P &lt;.05) at 1 hour and peaked at 3195.3±476 pg/mL ( P &lt;.001) at 4 hours. Before the surge of circulating catecholamines and despite complete β-adrenergic blockade, rhTNF-α induced a 7% to 40% increase in LV contractile performance during the 60-minute infusion. After this initial positive inotropic effect, rhTNF-α treatment led to precipitous systolic dysfunction between 2 and 7 hours of exposure; this myocardial depressant effect persisted at 25 hours. LV systolic performance declined to 19% to 35% of baseline values, depending on the specific contractile parameter evaluated. We conclude that rhTNF-α affects LV systolic function in a time-dependent biphasic manner. Increases in circulating catecholamines after rhTNF-α infusion cannot account for the early improvement in LV systolic performance.