tbuckley/cabot-search huggingface dataset:
Left Ventricular Dysfunction Induced by Nonsevere Idiopathic Pulmonary Arterial Hypertension
Authors: Mario Kasner, Dirk Westermann, Paul Steendijk, Stephan Dröse, Wolfgang Poller, Heinz-Peter Schultheiss, Carsten Tschöpe
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Severe increase in right ventricular pressure can compromise left ventricular (LV) function because of impaired interventricular interaction and aggravate the symptoms.To elucidate how nonsevere idiopathic pulmonary arterial hypertension (IPAH) influences LV function because of impaired interventricular interaction.Invasive pressure-volume (PV) loop analysis obtained by conductance catheterization was performed at rest and during atrial pacing in patients with mild IPAH (n = 10) compared with patients with isolated LV diastolic dysfunction (DD) (n = 10) and control subjects without heart failure symptoms (n = 9).Patients with nonsevere IPAH (pulmonary artery pressure mean 29 ± 5 mm Hg) and patients with DD showed preserved systolic (ejection fraction 63 ± 12% and 62 ± 9%) and impaired LV diastolic function at rest (LV stiffness 0.027 ± 0.012 ml(-1) and 0.029 ± 0.014 ml(-1)). During pacing at 120 per minute patients with IPAH and DD decreased their stroke volume (-25% and -30%; P < 0.05) and failed to increase cardiac output significantly. Opposite to patients with DD and control subjects, temporary preload reduction during inferior vena cava occlusion initially induced an expansion of LV end-diastolic volume in IPAH (+7%; P < 0.05), whereas end-diastolic pressure continuously dropped. This resulted in an initial downward shift to the right of the PV loop indicating better LV filling, which was associated with a temporary improvement of cardiac output (+11%; P < 0.05) in the patients with IPAH, but not in patients with DD and control subjects.Mild idiopathic pulmonary arterial pressure impairs LV diastolic compliance even in the absence of the intrinsic LV disease and contributes to the reduced cardiac performance at stress.
Genetic and therapeutic targeting of properdin in mice prevents complement-mediated tissue injury
Authors: Yuko Kimura, Lin Zhou, Takashi Miwa, Wen-Chao Song
Journal: Journal of Clinical Investigation (2010)

The alternative pathway (AP) of complement activation is constitutively active and must be regulated by host proteins to prevent autologous tissue injury. Dysfunction of AP regulatory proteins has been linked to several human inflammatory disorders. Properdin is a positive regulator of AP complement activation that has been shown to extend the half-life of cell surface–bound C3 convertase C3bBb; it may also initiate AP complement activation. Here, we demonstrate a critical role for properdin in autologous tissue injury mediated by AP complement activation. We identified myeloid lineage cells as the principal source of plasma properdin by generating mice with global and tissue-specific knockout of Cfp (which encodes properdin) and by generating BM chimeric mice. Properdin deficiency rescued mice from AP complement–mediated embryonic lethality caused by deficiency of the membrane complement regulator Crry and markedly reduced disease severity in the K/BxN model of arthritis. Ab neutralization of properdin in WT mice similarly ameliorated arthritis development, whereas reconstitution of properdin-null mice with exogenous properdin restored arthritis sensitivity. These data implicate systemic properdin as a key contributor to AP complement–mediated injury and support its therapeutic targeting in complement-dependent human diseases.
Randomized Adjuvant Chemotherapy Trial in High-Risk, Lymph Node-Negative Breast Cancer Patients Identified by Urokinase-Type Plasminogen Activator and Plasminogen Activator Inhibitor Type 1
Authors: F Jänicke, A Prechtl, C Thomssen, N Harbeck, C Meisner, M Untch, C G Sweep, H K Selbmann, H Graeff, M Schmitt
Journal: JNCI Journal of the National Cancer Institute (2001)

Background: Most patients with lymph node-negative breast cancer are cured by locoregional treatment; however, about 30% relapse. Because traditional histomorphologic and clinical factors fail to identify the high-risk patients who may benefit from adjuvant chemotherapy, other prognostic factors are needed. In a unicenter study, we have found that levels of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1) in the primary tumor are predictive of disease recurrence. Thus, we designed the Chemo N0 prospective randomized multicenter therapy trial to investigate further whether uPA and PAI-1 are such prognostic factors and whether high-risk patients identified by these factors benefit from adjuvant chemotherapy. After 4.5 years, we present results of the first interim analysis. Methods: We studied 556 patients with lymph node-negative breast cancer. The median follow-up was 32 months. All patients with low tumor levels of uPA (≤3 ng/mg of protein) and of PAI-1 (≤14 ng/mg of protein) were observed. Patients with high tumor levels of uPA (>3 ng/mg of protein) and/or of PAI-1 (>14 ng/mg of protein) were randomly assigned to combination chemotherapy or subjected to observation only. All statistical tests were two-sided. Results: A total of 241 patients had low levels of uPA and PAI-1, and 315 had elevated levels of uPA and/or PAI-1. The estimated 3-year recurrence rate for patients with low tumor levels of uPA and PAI-1 (low-risk group) was 6.7% (95% confidence interval [CI] = 2.5% to 10.8%). This rate for patients with high tumor levels of uPA and/or PAI-1 (high-risk group) was 14.7% (95% CI = 8.5% to 20.9%) (P = .006). First interim analysis suggests that high-risk patients in the chemotherapy group benefit, with a 43.8% lower estimated probability of disease recurrence at 3 years than high-risk patients in the observation group (intention-to-treat analysis: relative risk = 0.56; 95% CI = 0.25 to 1.28), but further follow-up is needed for confirmation. Conclusions: Using uPA and PAI-1, we have been able to classify about half of the patients with lymph node-negative breast cancer as low risk, for whom adjuvant chemotherapy may be avoided, and half as high risk, who appear to benefit from adjuvant chemotherapy.
What role does intersubjectivity play in the facial expression of pain?
Authors: C. Richard Chapman, Yoshio Nakamura
Journal: Behavioral and Brain Sciences (2002)

The facial expression of pain is the end product of a complex process that is, in part, emotional. The evolutionary study of facial expression must account for the social nature of human consciousness and should address the questions of why empathy exists, the adaptive importance of empathy, and whether facial expression is a mechanism of empathy and second-person consciousness.
Antigen Selection Shapes the T-cell Repertoire in Chronic Lymphocytic Leukemia
Authors: Anna Vardi, Andreas Agathangelidis, Evangelia Stalika, Maria Karypidou, Alexandra Siorenta, Achilles Anagnostopoulos, Richard Rosenquist, Anastasia Hadzidimitriou, Paolo Ghia, Lesley-Ann Sutton, Kostas Stamatopoulos
Journal: Clinical Cancer Research (2015)

Abstract Purpose: The role of antigen(s) in shaping the T-cell repertoire in chronic lymphocytic leukemia, although relevant for understanding malignant cell interactions with cognate T cells, is largely unexplored. Experimental Design: Here we profiled the T-cell receptor β chain gene repertoire in 58 chronic lymphocytic leukemia patients, focusing on cases assigned to well-characterized subsets with stereotyped clonotypic B-cell receptor immunoglobulins, therefore those cases most evidently selected by antigen (subsets #1, #2, and #4). Results: Remarkable repertoire skewing and oligoclonality were observed, and differences between subsets were noted regarding both T-cell receptor β chain gene usage and the extent of clonality, with subset #2 being the least oligoclonal. Longitudinal analysis of subset #4 cases revealed that although the repertoire may fluctuate over time, certain clonotypes persist, thus alluding to persistent antigenic stimulation. Shared (“stereotyped”) clonotypes were found between different patients, reflecting selection by common antigenic elements. Cross-comparison of our dataset with public databases showed that some T-cell clonotypes may have expanded secondary to common viral infections; however, the majority of clonotypes proved to be disease-specific. Conclusions: Overall, the T-cell receptor β chain repertoire in chronic lymphocytic leukemia is likely shaped by antigen selection and the implicated antigenic elements may concern epitopes that also select the malignant B-cell progenitors or, more intriguingly, chronic lymphocytic leukemia–derived epitopes. Clin Cancer Res; 22(1); 167–74. ©2015 AACR.
Cause specific mortality, social position, and obesity among women who had never smoked: 28 year cohort study
Authors: C. L. Hart, L. Gruer, G. C. M. Watt
Journal: BMJ (2011)

<b>Objective</b> To investigate the relations between causes of death, social position, and obesity in women who had never smoked. <b>Design</b> Prospective cohort study. <b>Setting</b> Renfrew and Paisley, Scotland. <b>Participants</b> 8353 women and 7049 men aged 45-64 were recruited to the Renfrew and Paisley Study in 1972-6. Of these, 3613 women had never smoked and were the focus of this study. They were categorised by occupational class (I and II, III non-manual, III manual, and IV and V) and body mass index groups (normal weight, overweight, moderately obese, and severely obese). <b>Main outcome measures</b> All cause and cause specific mortality during 28 years of follow-up by occupational class and body mass index, using Cox proportional hazards models adjusted for age and other confounders. <b>Results</b> The women in lower occupational classes who had never smoked were on average shorter and had poorer lung function and higher systolic blood pressure than women in the higher occupational classes. Overall, 43% (n=1555) were overweight, 14% (n=515) moderately obese, and 5% (n=194) severely obese. Obesity rates were higher in lower occupational classes and much higher in all occupational classes than in current smokers in the full cohort. Half the women died, 51% (n=916) from cardiovascular disease and 27% (n=487) from cancer. Relative to occupational class I and II, all cause mortality rates were more than a third higher in occupational classes III manual (relative rate 1.35, 95% confidence interval 1.16 to 1.57) and IV and V (1.34, 1.17 to 1.55) and largely explained by differences in obesity, systolic blood pressure, and lung function. Similar upward gradients were seen for cardiovascular disease and respiratory disease but not for cancer. Mortality rates were highest in severely obese women in the lowest occupational classes. <b>Conclusions</b> Women who had never smoked and were not obese had the lowest mortality rates, regardless of their social position. Where obesity is socially patterned as in this cohort, it may contribute to health inequalities and increase pressure on health and social services serving more disadvantaged populations.
Changes in γ-secretase activity and specificity caused by the introduction of consensus aspartyl protease active motif in Presenilin 1
Authors: Donald B Carter, Edwige Dunn, Adele M Pauley, Denise D McKinley, Timothy J Fleck, Brenda R Ellerbrook, Nancy C Stratman, Xiangdong Zhou, Carol S Himes, Jeffrey S Nye, Alfredo Tomasselli, Riqiang Yan
Journal: Molecular Neurodegeneration (2008)

Presenilin (PS1 or PS2) is an essential component of the active gamma-secretase complex that liberates the Abeta peptides from amyloid precursor protein (APP). PS1 is regarded as an atypical aspartyl protease harboring two essential aspartic acids in the context of the sequence D257LV and D385FI, respectively, rather than the typical DTG...DTG catalytic motif of classical aspartyl proteases. In the present studies, we introduced the sequence DTG in PS1 at and around the catalytic D257 and D385 residues to generate three PS1 mutants: D257TG, D385TG, and the double-mutant D257TG/D385TG. The effects of these changes on the gamma-secretase activity in the presence or absence of gamma-secretase inhibitors and modulators were investigated. The results showed that PS1 mutants having D385TG robustly enhanced Abeta42 production compared to the wild type (wt), and were more sensitive than wt to inhibition by a classical aspartyl protease transition state mimic, and fenchylamine, a sulfonamide derivative. Unlike wt PS1 and some of its clinical mutants, all three PS1 artificial mutants decreased cleavage of Notch S3-site, suggesting that these artificial mutations may trigger conformational changes at the substrate docking and catalytic site that cause alteration of substrate specificity and inhibition pattern. Consistent with this notion, we have found that NSAID enzymatic inhibitors of COX, known modulators of the gamma-secretase activity, cause PS1 mutants containing D385TG to produce higher levels of both Abeta38 and Abeta42, but to reduce levels of Abeta39, showing a pattern of Abeta formation different from that observed with wild type PS1 and its clinical mutants. This study provides an important structural clue for the rational design of drugs to inhibit processing of APP at the gamma-site without interfering with Notch processing.
Influence of decontamination on induction of arthritis in Lewis rats by cell wall fragments of Eubacterium aerofaciens. Arthropathic properties of indigenous anaerobic bacteria.
Authors: J Kool, A J Severijnen, I S Klasen, M Y Gerrits-Boeye, M P Hazenberg
Journal: Annals of the Rheumatic Diseases (1992)

Although the cause (or causes) of rheumatoid arthritis is unknown, many workers have suggested that microorganisms play a part. The intestinal flora in particular has been related to the development of joint inflammation. It has been shown previously that cell wall fragments of several anaerobic Gram positive intestinal bacteria of human origin are arthritogenic after a single intraperitoneal injection in Lewis rats. The part played by indigenous microflora in this model has now been studied by decontaminating Lewis rats before the injection of Eubacterium aerofaciens cell wall fragments. The pattern and severity of arthritis appeared to be comparable in decontaminated and control rats. The second goal of this work was to isolate arthritogenic bacteria from the autochthonous intestinal flora of rats. Only a limited number of bacteria showing a resemblance to arthritogenic strains from human intestinal flora (i.e. E aerofaciens and Bifidobacterium adolescentis) could be isolated. These strains did not induce chronic arthritis after intraperitoneal injection. This may explain why spontaneous arthritis did not develop in Lewis rats.
The Role of the Major Histocompatibility Complex Region in Cognition and Brain Structure: A Schizophrenia GWAS Follow-Up
Authors: James T.R. Walters, Dan Rujescu, Barbara Franke, Ina Giegling, Alejandro Arias Vásquez, April Hargreaves, Giancarlo Russo, Derek W. Morris, Martine Hoogman, Andrea Da Costa, Valentina Moskvina, Guillén Fernández, Michael Gill, Aiden Corvin, Michael C. O’Donovan, Gary Donohoe, Michael J. Owen
Journal: American Journal of Psychiatry (2013)

OBJECTIVE The authors investigated the effects of recently identified genome-wide significant schizophrenia genetic risk variants on cognition and brain structure. METHOD A panel of six single-nucleotide polymorphisms (SNPs) was selected to represent genome-wide significant loci from three recent genome-wide association studies (GWAS) for schizophrenia and was tested for association with cognitive measures in 346 patients with schizophrenia and 2,342 healthy comparison subjects. Nominally significant results were evaluated for replication in an independent case-control sample. For SNPs showing evidence of association with cognition, associations with brain structural volumes were investigated in a large independent healthy comparison sample. RESULTS Five of the six SNPs showed no significant association with any cognitive measure. One marker in the major histocompatibility complex (MHC) region, rs6904071, showed independent, replicated evidence of association with delayed episodic memory and was significant when both samples were combined. In the combined sample of up to 3,100 individuals, this SNP was associated with widespread effects across cognitive domains, although these additional associations were no longer significant after adjusting for delayed episodic memory. In the large independent structural imaging sample, the same SNP was also associated with decreased hippocampal volume. CONCLUSIONS The authors identified a SNP in the MHC region that was associated with cognitive performance in patients with schizophrenia and healthy comparison subjects. This SNP, rs6904071, showed a replicated association with episodic memory and hippocampal volume. These findings implicate the MHC region in hippocampal structure and functioning, consistent with the role of MHC proteins in synaptic development and function. Follow-up of these results has the potential to provide insights into the pathophysiology of schizophrenia and cognition.
Identification of beta-adrenergic receptors in human lymphocytes by (-) (3H) alprenolol binding.
Authors: L T Williams, R Snyderman, R J Lefkowitz
Journal: Journal of Clinical Investigation (1976)

Human lymphocytes are known to posessess a catecholamine-responsive adenylate cyclase which has typical beta-adrenergic specificity. To identify directly and to quantitate these beta-adenergic receptors in human lymphocytes, (-) [3H] alprenolol, a potent beta-adrenergic antagonist, was used to label binding sites in homogenates of human mononuclear leukocytes. Binding of (-) [3H] alprenolol to these sites demonstrated the kinetics, affinity, and stereospecificity expected of binding to adenylate cyclase-coupled beta-adrenergic receptors. Binding was rapid (t1/2 less than 30 s) and rapidly reversible (t1/2 less than 3 min) at 37 degrees C. Binding was a saturable process with 75 +/- 12 fmol (-) [3H] alprenolol bound/mg protein (mean +/- SEM) at saturation, corresponding to about 2,000 sites/cell. Half-maximal saturation occurred at 10 nM (-) [3H] alprenolol, which provides an estimate of the dissociation constant of (-) [3H] alprenolol for the beta-adrenergic receptor. The beta-adrenergic antagonist, (-) propranolol, potently competed for the binding sites, causing half-maximal inhibition of binding at 9 nM. beta-Adrenergic agonists also competed for the binding sites. The order of potency was (-) isoproterenol greater than (-) epinephrine greater than (-)-norepinephrine which agreed with the order of potency of these agents in stimulating leukocyte adenylate cyclase. Dissociation constants computed from binding experiments were virtually identical to those obtained from adenylate cyclase activation studies. Marked stereospecificity was observed for both binding and activation of adenylate cyclase. (-)Stereoisomers of beta-adrenergic agonists and antagonists were 9- to 300-fold more potent than their corresponding (+) stereoisomers. Structurally related compounds devoid of beta-adrenergic activity such as dopamine, dihydroxymandelic acid, normetanephrine, pyrocatechol, and phentolamine did not effectively compete for the binding sites. (-) [3H] alprenolol binding to human mononuclear leukocyte preparations was almost entirely accounted for by binding to small lymphocytes, the predominant cell type in the preparations. No binding was detectable to human erythrocytes. These results demonstrate the feasibility of using direct binding methods to study beta-adrenergic receptors in a human tissue. They also provide an experimental approach to the study of states of altered sensitivity to catecholamines at the receptor level in man.
Role of changes in [Ca2+]i in energy deprivation contracture.
Authors: W H Barry, G A Peeters, C A Rasmussen, M J Cunningham
Journal: Circulation Research (1987)

Mechanisms of energy deprivation contracture were investigated in cultured chick embryo ventricular cells. In the presence of zero-extracellular-Na+, (choline chloride substitution)-nominal-zero-Ca2+ [( Ca2+] approximately 5 microM), exposure of ventricular cells to 1 mM cyanide (CN) and 20 mM 2-deoxyglucose (2-DG)-zero-glucose solution resulted in the development of a contracture (video motion detector) in 5.9 +/- 0.5 minutes. Early after contracture development, the resupply of extracellular Na+, in the continued presence of CN + 2-DG, resulted in a rapid partial relaxation (t1/2 = 1.9 +/- 0.3 seconds), associated with an increase in 45Ca efflux, presumably due to transsarcolemmal Ca2+ extrusion due to Na+-Ca2+ exchange. Resupply of glucose and removal of CN + 2-DG, in the continued absence of Na+, resulted in an initially slower (t1/2 = 11.6 +/- 2.5 seconds), but more complete relaxation of contracture, which was not associated with increased Ca2+ efflux. Pretreatment with 20 mM caffeine delayed the onset of contracture (9.2 +/- 1.1 minutes) and resulted in a contracture that could not be relaxed by resupply of external Na+ only. Studies using the fluorescent Ca2+ probe indo 1 demonstrated that in zero-Na+-zero-Ca2+ solutions, contracture due to CN + 2-DG was associated with an initial rise in [Ca2+]i but that this did not account for all of contracture force development. In cells exposed to CN + 2-DG in the presence of normal extracellular Na+ and Ca2+ concentrations, a small rise in [Ca2+]i was associated with initial contracture development, consistently preceding the development of a larger accelerated contracture presumably due to ATP depletion.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypothermia extends the cardioprotection by ischaemic preconditioning to coronary artery occlusions of longer duration
Authors: M van den Doel
Journal: Cardiovascular Research (1998)

Objective: To test the hypothesis that mild hypothermia potentiates the cardioprotection afforded by ischaemic preconditioning so that infarct size limitation can be obtained after coronary artery occlusion (CAO) durations which exceed the cardioprotective range (>90 min) of either hypothermia or ischaemic preconditioning alone. Methods: Four groups of anaesthetized rats were subjected to different durations of CAO: (i) normothermia (N, 36.5–37.5°C, n = 29), (ii) normothermia+ischaemic preconditioning (N+IP, 15 min CAO followed by 10 min of reperfusion, n = 35), (iii) hypothermia (H, 30–31°C, n = 31) and (iv) hypothermia+ischaemic preconditioning (H+IP, n = 24). Infarct size (IA/AR) was determined after 3 hours of reperfusion using trypan blue to delineate the area at risk (AR) from non-risk region and nitroblue tetrazolium to delineate infarcted area (IA) from viable myocardium. Results: In N the CAO duration versus infarct size relation had a sigmoid shape with virtually no infarction occurring at 15 min CAO and 56±5% of the area at risk being infarcted at 30 min CAO reaching a plateau of 71±2% at 60 min CAO. Hypothermia produced a rightward shift of the relation resulting in an approximately 15 min delay in onset of infarction. Ischaemic preconditioning produced a similar reduction in infarct size (23±4%) at 30 min CAO compared to hypothermia (13±3%) but also limited infarct size at 45 min to 36±3% and at 60 min CAO to 50±3% suggesting a slowing of infarct progression. Neither intervention limited IA/AR produced by 120 min CAO. In H+IP, combined hypothermia and ischaemic preconditioning resulted in synergistic infarct size reduction so that at 45 min and 60 min CAO IA/AR was reduced to 17±3% and 23±3%, respectively, and even at 120 min CAO to 58±5%, which was significantly smaller than during normothermic control conditions (p<0.05 vs. N). Conclusion: Mild hypothermia limited IA/AR modestly but markedly enhanced the cardioprotection afforded by ischaemic preconditioning in the in situ rat heart so that irreversible damage produced by even prolonged coronary artery occlusions was limited.