pinecone/core-2020-05-10-deduplication huggingface dataset:
Determinants and prognostic implications of the negative diastolic pulmonary pressure gradient in patients with pulmonary hypertension due to left heart disease

AIMS: The diastolic pulmonary pressure gradient (DPG) has recently been introduced as a specific marker of combined pre-capillary pulmonary hypertension  (Cpc-PH) in left heart disease (LHD). However, its diagnostic and prognostic superiority compared with traditional haemodynamic indices has been challenged lately. Current recommendations explicitly denote that in the normal heart, DPG values are greater than zero, with DPG >/=7 mmHg indicating Cpc-PH. However, clinicians are perplexed by the frequent observation of DPG <0 mmHg (DPGNEG ), as its physiological explanation and clinical impact are unclear to date. We hypothesized that large V-waves in the pulmonary artery wedge pressure (PAWP) curve yielding asymmetric pressure transmission might account for DPGNEG and undertook this study to clarify the physiological and prognostic implications of  DPGNEG . METHODS AND RESULTS: Right heart catheterization and echocardiography were performed in 316 patients with LHD due to primary myocardial dysfunction or  valvular disease. A total of 256 patients had PH-LHD, of whom 48% demonstrated DPGNEG . The V-wave amplitude inversely correlated with DPG (r = -0.45, P < 0.001) in patients with low pulmonary vascular resistance (PVR), but not in those with elevated PVR (P > 0.05). Patients with large V-waves had negative and lower  DPG than those without augmented V-waves (P < 0.001) despite similar PVR (P >0.05). Positive, but normal DPG (0-6 mmHg) carried a worse 2-year prognosis for  death and/or heart transplantation than DPGNEG (hazard ratio 2.97; P < 0.05). CONCLUSION: Our results advocate against DPGNEG constituting a measurement error. We propose that DPGNEG can partially be ascribed to large V-waves and carries a better prognosis than DPG within the normal positive range
A novel clinical score (InterTAK Diagnostic Score) to differentiate takotsubo syndrome from acute coronary syndrome: results from the International Takotsubo Registry

AIMS: Clinical presentation of takotsubo syndrome (TTS) mimics acute coronary syndrome (ACS) and does not allow differentiation. We aimed to develop a clinical score to estimate the probability of TTS and to distinguish TTS from ACS in the acute stage.\ud
METHODS AND RESULTS: Patients with TTS were recruited from the International Takotsubo Registry ( www.takotsubo-registry.com) and ACS patients from the leading hospital in Zurich. A multiple logistic regression for the presence of TTS was performed in a derivation cohort (TTS, n = 218; ACS, n = 436). The best model was selected and formed a score (InterTAK Diagnostic Score) with seven variables, and each was assigned a score value: female sex 25, emotional trigger 24, physical trigger 13, absence of ST-segment depression (except in lead aVR) 12, psychiatric disorders 11, neurologic disorders 9, and QTc prolongation 6 points. The area under the curve (AUC) for the resulting score was 0.971 [95% confidence interval (CI) 0.96-0.98] and using a cut-off value of 40 score points, sensitivity was 89% and specificity 91%. When patients with a score of ≥50 were diagnosed as TTS, nearly 95% of TTS patients were correctly diagnosed. When patients with a score ≤31 were diagnosed as ACS, ∼95% of ACS patients were diagnosed correctly. The score was subsequently validated in an independent validation cohort (TTS, n = 173; ACS, n = 226), resulting in a score AUC of 0.901 (95% CI 0.87-0.93).\ud
CONCLUSION: The InterTAK Diagnostic Score estimates the probability of the presence of TTS and is able to distinguish TTS from ACS with a high sensitivity and specificity.\ud
TRIAL REGISTRATION: NCT0194762
Effects of ferric carboxymaltose on hospitalisations and mortality rates in iron-deficient heart failure patients: an individual patient data meta-analysis

AIMS Iron deficiency (ID) is a common co-morbidity in patients with heart failure (HF) and has been suggested to be associated with poor prognosis. Recently completed double-blind randomised controlled trials (RCTs) studying HF patients with ID have shown improvements in functional capacity, symptoms and quality of life when treated with i.v. ferric carboxymaltose (FCM). This individual patient data meta-analysis investigates the effect of FCM vs. placebo on recurrent hospitalisations and mortality in HF patients with ID.\ud
METHODS AND RESULTS Individual patient data were extracted from four RCTs comparing FCM with placebo in patients with systolic HF and ID. The main outcome measures were recurrent cardiovascular (CV) hospitalisations and CV mortality. Other outcomes included cause-specific hospitalisations and death. The main analyses of recurrent events were backed up by time-to-first-event analyses. In total, 839 patients, of whom 504 were randomised to FCM, were included. Compared with those taking placebo, patients on FCM had lower rates of recurrent CV hospitalisations and CV mortality [rate ratio 0.59, 95% confidence interval (CI) 0.40-0.88; P = 0.009]. Treatment with FCM also reduced recurrent HF hospitalisations and CV mortality (rate ratio 0.53, 95% CI 0.33-0.86; P = 0.011) and recurrent CV hospitalisations and all-cause mortality (rate ratio 0.60, 95% CI 0.41-0.88; P = 0.009). Time-to-first-event analyses showed similar findings, with somewhat attenuated treatment effects. The administration of i.v. FCM was not associated with an increased risk for adverse events.\ud
CONCLUSIONS Treatment with i.v. FCM was associated with a reduction in recurrent CV hospitalisations in systolic HF patients with ID
Effects of organic and inorganic nitrate on aortic and carotid haemodynamics in heart failure with preserved ejection fraction

Aims To assess the haemodynamic effects of organic vs. inorganic nitrate administration among patients with heart failure with preserved ejection fraction (HFpEF). Methods and results We assessed carotid and aortic pressure-flow relations non-invasively before and after the administration of 0.4 mg of sublingual nitroglycerin (n= 26), and in a separate sub-study, in response to 12.9 mmoL of inorganic nitrate (n= 16). Nitroglycerin did not consistently reduce wave reflections arriving at the proximal aorta (change in real part of reflection coefficient, 1st harmonic: -0.09; P = 0.01; 2nd harmonic: -0.045, P = 0.16; 3rd harmonic: + 0.087; P = 0.05), but produced profound vasodilatation in the carotid territory, with a significant reduction in systolic blood pressure (133.6 vs. 120.5 mmHg; P = 0.011) and a marked reduction in carotid bed vascular resistance (19 580 vs. 13 078 dynes .s/cm(5); P = 0.001) and carotid characteristic impedance (3440 vs. 1923 dynes .s/cm(5); P = 0.002). Inorganic nitrate, in contrast, consistently reduced wave reflections across the first three harmonics (change in real part of reflection coefficient, 1st harmonic: -0.12; P = 0.03; 2nd harmonic: -0.11, P = 0.01; 3rd harmonic: -0.087; P = 0.09) and did not reduce blood pressure, carotid bed vascular resistance, or carotid characteristic impedance (P = NS). Conclusions Nitroglycerin produces marked vasodilatation in the carotid circulation, with a pronounced reduction in blood pressure and inconsistent effects on central wave reflections. Inorganic nitrate, in contrast, produces consistent reductions in wave reflections, and unlike nitroglycerin, it does so without significant hypotension or cerebrovascular dilatation. These haemodynamic differences may underlie the different effects on exercise capacity and side effect profile of inorganic vs. organic nitrate in HFpEF
Target cell-dependent T cell-mediated lysis of vaccinia virus-infected cells

Vaccinia virus specific cytotoxicity against infected target cells was observed in vitro. Spleen lymphocytes from normal and immunized mice of the inbred strains C3H and DBA/2 were incubated with vaccinia virus-infected and non-infected 51Cr-labeled mastocytoma P-815-X2 cells and L-929 fibroblasts, which were used as targets. Cytotoxic lymphocytes could be isolated from the mice as early as 2 days after infection with vaccinia virus. The highest cytotoxic effect was obtained with lymphocytes taken 6 days after infection. The degree of lysi was correlated with the ratio of immune lymphocytes to target cells. Specific blocking of target cell lysis resulted after addition of anti-vaccinia antibody from different sources. The effector cells could be characterized as T cells by elimination of macrophages and B cells. Target cell killing was only possible in a syngeneic system; allogeneic infected target cells were not lysed significantly.
Shared determinants between virus-infected and trinitrophenyl-conjugated H-2-identical target cells detected in cell-mediated lympholysis

Infection of H-2-identical mice with either lymphocytic choriomeningitis (LCM) virus, vaccinia virus, or paramyxo (Sendai) virus resulted in the generation of specifically sensitized cytotoxic T lymphocytes (CTL). CTL generated in vitro against 2,4,6-trinitrophenyl (TNP)-conjugated syngeneic stimulator cells were specifically cytotoxic for TNP-conjugated H-2K(D) region identical targets. Both LCM and vaccinia-induced CTL, however, were found to be strongly cytotoxic towards TNP-conjugated, H-2K(D) region-identical target cells. In contrast, Sendai virus-induced CTL did not lyse TNP-conjugated, syngeneic target cells. Inhibition experiments using cold targets suggested that shared antigenic determinants can be detected on either LCM virus-infected and TNP-conjugated targets, which are not present on the cell surface 6f normal target cells.
Generation of virus-specific cytotoxic T cells in vitro I. Induction conditions of primary and secondary Sendai virus-specific cytotoxic T cells

H-2-restricted cytotoxic T cells specific for Sendai virus were generated in vitro in a primary response from normal mouse lymphocytes cultured in the presence of infective as well as inactivated Sendai virus. Antigen-presenting cells of different origin, including T cells, were found to be effective stimulators. Antibodies to Sendai virus were shown to inhibit the activation of specific precursor killer cells when added to cultures before, but not after, the addition of viral antigen. Data obtained by Lyt phenotyping, revealed that precursor killer cells specific for Sendai virus reside in the Lyt-2,3+ T cell population and that Lyt-l,2,3+ T cells are not required for the generation of cytotoxic lymphocytes. Different activation kinetics were demonstrated for primary and secondary antiviral cytotoxic responses, and the analysis of the proliferation and stimulation requirements suggests qualitative differences.
Generation of virus-specific cytotoxic T cells in vitro II. Induction requirements with functionally inactivated virus preparations

Using noninfectious Sendai virus preparations after selective enzymatic digestion of either of the two viral envelope glycoproteins, it was possible to study the effect of different virion-cell membrane interactions on virus-specific cytotoxic T lymphocyte (CTL) induction in vitro. Three different virus preparations having capacity for virus- cell fusion, for virus-cell adsorption or lacking the ability to bind to cell membranes, were all active in the generation of virus-specific primary and secondary cytotoxic T cells, when added to the culture. Investigations on the responder cell requirements during CTL induction revealed that activation by addition of virions lacking the capacity to bind to cells was sensitive to the depletion of adherent cells. When virions with fusion and binding capacity were presented on tumor stimulator cells, different requirements with respect to adherent cells were obtained in the primary and secondary CTL response to Sendai virus. The data indicate that different viral antigen-cell membrane interactions govern the activation phase and effector phase of antigen- primed T cell populations, while sensitization of unprimed cells is dependent on the presence of adherent, perhaps antigen-presenting cells.
Frequency analysis of cytolytic T cell precursors (CTL-P) generated in vivo during lethal rabies infection of mice. I. Distinction of CTL-P with different interleukin 2 sensitivity

The aim of this study was to determine the number and state of activity of cytolytic T lymphocytes (CTL) and their precursors (CTL-P) present in vivo during the early stages of viral infection. The local response to lethal infection with rabies virus was used as a model system that is not accessible to analysis by secondary activation in vitro. The local response to alloantigen served as a control. Experimental protocols were established that allow frequency estimates of in vivo antigen-triggered CTL-P. Data allow a distinction between CTL-P activated in vivo by alloantigen and viral antigen with respect to their different capacity to utilize T cell growth factors (inter-leukins). In vivo alloantigen-primed CTL-P generate, in vitro, an active effector progeny in the presence of interleukins of xenogeneic origin, whereas the majority of virus-specific CTL-P, in spite of considerable expansion in vivo, fail to generate CTL in vitro unless antigen is added.
The cytolytic T lymphocyte response to the murine cytomegalovirus

Limiting dilution (LD) analysis with two modifications, the expansion and the restimulation LD assay, led to the detection and quantification of two distinct in vivo maturation stages within the lineage of virus- specific self-restricted CTL after infection of mice with the murine cytomegalovirus (MCMV). A low frequency set, representing an average of 15% of the specifically activated CTL-P in a draining lymph node, generated virus-specific lytic activity in the absence of antigen, solely under expansion conditions provided by growth and differentiation interleukins. These cells were considered to be active and were denoted antigen-independent or interleukin-receptive CTL-P (IL- CTL-P). A high frequency set required additional antigen in vitro to generate functionally active clones, and therefore the cells were termed antigen-dependent. Both sets are present in vivo simultaneously at the peak of the acute immune response and represent antigen- activated cells because their existence strictly depends on a preceding priming event. IL-CTL-P disappear quickly after acute infection and are absent during the memory state. It is proposed that the isolation of IL- CTL-P could serve to detect viral antigen expression during persistent and/or recurrent herpes virus infections.
Frequency analysis of cytolytic T lymphocyte precursors (CTL-P) generated in vivo during lethal rabies infection of mice. II. Rabies virus genus specificity of CTL-P

Cytolytic T lymphocyte precursors (CTL-P) were sensitized in vivo by intraplantar infection of C57BL/6 mice with a lethal dose of rabies virus, strain ERA (ERA). As a result of sensitization CTL-P matured to interleukin-receptive CTL-P (IL-CTL-P) that could be expanded in vitro to Thy-1+, Lyt-2+ CTL clones in the presence of IL without subjection to antigen-driven selection. After infection with ERA, IL-CTL-P-derived CTL lysed fibroblasts infected with rabies virus but not those infected with another rhabdovirus, the vesicular stomatitis virus. These CTL, however, did not discriminate between fibroblasts infected with the serologically closely related laboratory strains of classic rabies virus, ERA and HEP-Flury, and the serologically distinct rabies-related African isolate Mokola. This finding implies that in vivo sensitized IL-CTL-P recognize common genus-specific determinants expressed on cells infected with members of the lyssavirus genus.
Discrimination of hepatocyte-stimulating activity from human recombinant tumor necrosis factor alpha

The involvement of tumor necrosis factor alpha (TNF alpha) in the regulation of acute-phase protein synthesis is currently under discussion. In this study the effect of human recombinant TNF alpha on the regulation of the 4 acute-phase proteins alpha 2-macroglobulin, albumin, alpha 1-proteinase inhibitor and alpha 1-acute-phase globulin was investigated in rat hepatocyte primary cultures. No changes in synthesis of any of the 4 proteins were observed. However, an acute-phase response similar to that in vivo could be generated by conditioned media from human monocytes containing natural TNF alpha. This response remained unchanged after neutralizing TNF alpha activity by the addition of a specific antibody to TNF alpha. It is concluded that the hepatocyte-stimulating activity synthesized by human monocytes is different from TNF alpha
Simultaneous expression of CD4 and CD8 antigens by a substantial proportion of resting porcine T lymphocytes

The existence of four subpopulations in resting porcine T lymphocytes is documented. In addition to the two known subpopulations which are typified by a mutually exclusive expression of either the CD8 or the CD4 differentiation antigen, CD4-CD8+ and CD4+CD8- T lymphocytes, respectively, two unusual subpopulations were prominent not only in peripheral blood, but also in lymphoid tissues: CD4-CD8- T lymphocytes expressing neither of these antigens and CD4+CD8+ T lymphocytes coexpressing both antigens. While CD4+CD8+ lymphoblasts have been found also in other species, resting T lymphocytes with that phenotype are without precedent among all species analyzed to date. This unique composition of the porcine T lymphocyte population has to be taken into consideration when the swine is used as a large animal model in experimental medicine.
Redistribution of critical major histocompatibility complex and T cell receptor-binding functions of residues in an antigenic sequence after biterminal substitution

Residues critical for establishing a trimolecular interaction with a major histocompatibility complex (MHC)-encoded receptor and a T cell antigen receptor (TcR) were determined for an antigenic nonapeptide. The N-terminal residue proved to be involved in binding of the peptide to both receptors and the C-terminal residue was essential for MHC binding. While substitution of either of these critical terminal residues by alanine resulted in an almost complete loss of peptide antigenicity, simultaneous substitution of both created a new functional ligand for the same MHC molecule and the same TcR. Notably, in the biterminally substituted peptide, the core residues took on new roles in the trimolecular interaction in that a residue critical in the authentic nonapeptide for TcR binding became critical for MHC binding and former spacer residues became essential to various degrees for the interaction with either receptor or both. Thus, apparently, the loss of the terminal residues' contribution was at least partially compensated by a redistribution of the roles among the remaining residues. These results reflect a cooperative contribution of all residues of an antigenic peptide to its binding to both receptors and thus challenge a static definition of agretope and epitope as MHC and TcR binding sites.
The monoclonal antibody ER-BMDM1 recognizes a macrophage and dendritic cell differentiation antigen with aminopeptidase activity

Abstract  \ud
Here we describe the reactivity of monoclonal antibody (mAb) ER-BMDM1, directed against a 160-kDa cell membrane-associated antigen (Ag) with aminopeptidase activity. The aminopeptidase recognized by ER-BMDM1 is present on various mouse macrophage (MΦ) and dendritic cell (DC) subpopulations as well as on microvillous epithelia. Analysis of ER-BMDM1 Ag expression in in vitro models of MΦ maturation revealed that the Ag is expressed at increasing levels upon maturation of MΦ. In vivo, high level expression of the ER-BMDM1 Ag occurs after thmonocytic stage of maturation, since bone marrow cells and peripheral blood monocytes are essentially ER-BMDM1 negative. Analysis of isolated-resident and elicited MΦ populations showed that ER-BMDM1 recognizes a specific subpopulation of mature MΦ: only some resident peritoneal and alveolar MΦ are ER-BMDM1 positive, whereas virtually all thioglycollate-elicited peritoneal exudate MΦ bind the mAb. In lymphoid organs, a subpopulation of MΦ is recognized as well as interdigitating cells (IDC) located in T cell areas. Phenotypic analysis of isolated DC- the in vitro equivalents of IDC - from spleen and lymph nodes confirmed that the majority of this important antigen-presenting cell population expresses the ER-BMDM1 aminopeptidase. The molecular characteristics of the ER-BMDM1 Ag suggest that it may represent the mouse homolog of human CD13
New simplified molecular design for functional T cell receptor

We have produced a chimeric single-chain T cell receptor (TcR) that combines the specific antibody recognition function and TcR/CD3 signaling properties within the same polypeptide chain. This hybrid molecule consisted of a single-chain antibody combining site that was connected over a short spacer to the transmembrane and cytoplasmic region of CD3. When expressed on TcR- or TcR+ T cell hybridomas it could mediate recognition of relevent target cells and subsequent production of lymphokines; i.e. it could functionally replace the TcR/CD3 complex. Therefore, the single-chain TcR model presented here represents an interesting and useful means for the creation of T cells with new specificities.
An NF-kappa B-like element plays an essential role in interleukin-1-mediated costimulation of the mouse interleukin-2 promoter

Interleukin-1 (IL-1) costimulation is required for efficient IL-2 synthesis and IL-2 receptor (IL-2R) expression of T cells. The molecular events leading to these effects are largely unknown. We utilized an IL-1-responsive and an IL-1-non-responsive subclone of the mouse thymoma cell line EL4 to investigate how IL-1 activates IL-2 gene expression. We correlated IL-2 promoter activity with the activity of the endogenous IL-2 gene, thereby showing the biological significance of our results. Our experiments provide new functional data showing that a major target of IL-1 mediated costimulation is the chi B-like site, T cell element distal TCEd (GGGATTTCAC), of the IL-2 promoter. Thus, deletion or mutation of TCEd within a complete IL-2 promoter abrogated IL-1 costimulation in the IL-1 responsive EL4 subclone. Therefore, the TCEd element is functionally essential for the effect of IL-1. We also identified a nuclear factor (NF), IL-1 NF, that binds to the TCEd site after IL-1 stimulation. This factor was only present in the IL-1-responsive EL4 subclone and not in the IL-1-non-responsive subclone after IL-1 stimulation and did not appear after phytohemagglutinin (PHA)-treatment. Binding of IL-1 NF to the TCEd site was competed by a typical chi B oligonucleotide, suggesting that it is similar to NF-chi B in its DNA-binding properties. However, the TCEd element was only activated by costimulation with PHA and IL-1 whereas a typical chi B element was already activated by IL-1 alone. These data suggest that the biological function of the TCEd element of the IL-2 promoter differs from that of a canonical chi B element. Our data provide new evidence that IL-1 acts on the IL-2 promoter by activating the TCEd element via the transcription factor IL-1 NF. Furthermore, activation of this element requires two signals, delivered by IL-1 and PHA, in this way reflecting the activation requirement for the endogenous IL-2 gene