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S Rath

Publications and source records attributed to S Rath.

At least 19 recordsLinked to original sources
PubMed2000

Noninvasive assessment of left ventricular end-diastolic pressure by the response of the transmitral a-wave velocity to a standardized Valsalva maneuver.

Impaired relaxation is frequently masked by elevated filling pressures, resulting in a pseudonormal flow pattern (E/A >1.0). Because the E/A wave ratio increases as filling pressures rise, it is generally assumed that patients with an E/A ratio of <1.0 (impaired relaxation pattern) have relatively low filling pressures. Nevertheless, patients with an E/A ratio of <1.0 can have as profoundly elevated filling pressures as patients with a pseudonormal or restrictive filling pattern. Because left ventricular (LV) pressure during end-diastole essentially determines atrial afterload, the response of the A-wave velocity to a reduction of atrial afterload by a standardized Valsalva maneuver should allow estimation of LV end-diastolic pressure (LVEDP) regardless of the baseline Doppler flow pattern. This was tested in 20 consecutive patients who were studied by pulse-wave Doppler echocardiography during cardiac catheterization. There was a close correlation between LVEDP and the change in A-wave velocity during the Valsalva maneuver (r = 0.85, SEE 6.7 mm Hg) regardless of the baseline E/A ratio. In patients with a LVEDP of <15 mm Hg the A wave decreased by 21 +/- 15 cm/s. In patients with a LVEDP of >25 mm Hg the A wave increased by 18 +/- 13 cm/s. The change in the E/A ratio during Valsalva correlated fairly with LVEDP (r = -0.72, SEE 8.8 mm Hg), the baseline E/A ratio correlated poorly, and scatter was substantial (r = 0.46, SEE 11.2 mm Hg). Just as elevated filling pressures can mask impaired relaxation, the impaired relaxation pattern can mask the presence of elevated filling pressures. This can be revealed by testing the response of the A wave to the Valsalva maneuver, allowing estimation of LVEDP independent of the baseline E/A ratio.

Adolescent↗
PubMed2000

Disruption of T cell tolerance to self-immunoglobulin causes polyclonal B cell stimulation followed by inactivation of responding autoreactive T cells.

Scavenger receptor (SR)-specific delivery by maleylation of a ubiquitous self-protein, Ig, to SR-bearing APCs results in self-limiting induction of autoimmune effects in vivo. Immunization with maleyl-Ig breaks T cell tolerance to self-Ig and causes hypergammaglobulinemia, with increases in spleen weight and cellularity. The majority of splenic B cells show an activated phenotype upon maleyl-Ig immunization, leading to large-scale conversion to a CD138+ phenotype and to significant increases in CD138-expressing splenic plasma cells. The polyclonal B cell activation, hypergammaglobulinemia, and autoreactive Ig-specific T cell responses decline over a 2-mo period postimmunization. Following adoptive transfer, T cells from maleyl-Ig-immune mice taken at 2 wk postimmunization can induce hypergammaglobulinemia in the recipients, but those taken at 10 wk postimmunization cannot. Hypergammaglobulinemia in the adoptive transfer recipients is also transient and is followed by an inability to respond to fresh maleyl-Ig immunization, suggesting that the autoreactive Ig-specific T cells are inactivated peripherally following disruption of tolerance. Thus, although autoreactive T cell responses to a ubiquitous self-Ag, Ig, are induced by SR-mediated delivery to professional APCs in vivo resulting in autoimmune pathophysiological effects, they are effectively and rapidly turned off by inactivation of these activated Ig-specific T cells in vivo.

Animals↗
PubMed2000

Modulation of GABA(A) receptor subunit mRNA levels in olivocerebellar neurons of purkinje cell degeneration and weaver mutant mice.

In olivocerebellar circuits, changes in the subunit composition of GABA(A) receptors occur at a time of extensive synaptic remodeling. In the deep cerebellar nuclei, GABA(A) receptor alpha1, beta2, and gamma2 subunit mRNA expression increases throughout neonatal development, whereas in the inferior olivary complex, the perinatal combination of alpha3, alpha5, beta3, and gamma2 mRNAs switches to the adult combination of alpha2, alpha4, beta3 and gamma1 during postnatal week 2. In situ hybridization was used to examine changes in subunit expression in the olivocerebellar nuclei of Purkinje cell degeneration and weaver mutant mice. In Purkinje cell degeneration, subunit transcripts decreased below control levels in olivary neurons; however, alpha1, beta2, and gamma2 transcript levels were slightly increased in the medial nucleus of the deep cerebellar nuclei. In weaver olivary neurons, although the switch from early- to late-onset subunit mRNAs occurred as in normal mice, transcript levels were differentially modulated by the mutation. Our studies indicate that major alterations in synaptic connectivity do not prevent developmentally programmed switches in GABA(A) receptor gene expression but can modulate the timing and level of transcript expression in afferent and efferent neurons.

Animals↗
PubMed1999

Induction of a germinal center phenotype in B cells in vitro by a Th2 cell line.

We have investigated the contribution of various stimuli for generating in vitro the changes in surface phenotype characteristic of B cells responding to a T-dependent antigen in a germinal center (GC). We show that, unlike many other stimuli such as B cell mitogens, cytokines, and surrogate antigen, alone or in combination, an alloreactive Th2 clonal line induces splenic B cells to become cell surface peanut agglutinin (PNA)(hi), Ig(lo), CD62L(lo), and CD44(hi) to produce mRNA for M17 and to express a GC-specific transgene even without B cell receptor ligation. Neither proliferation nor prior activation of responding B cells is needed, but B cells from CD45-null mice show reduced efficiency of this induction. These findings open up possibilities for separation and dissection of the various components of the GC response.

Animals↗
PubMed1999

Bruton's tyrosine kinase deficiency in macrophages inhibits nitric oxide generation leading to enhancement of IL-12 induction.

We show that macrophages of X-linked immunodeficient mice with a mutant nonfunctional Bruton's tyrosine kinase produce less NO than wild-type macrophages in response to a variety of stimuli. Induction of the inducible NO synthase (iNOS) protein, the transcription factor IFN regulatory factor-1 involved in iNOS expression, and the transcription factor STAT-1 involved in regulating IFN regulatory factor-1 induction are all poorer in X-linked immunodeficient than in wild-type macrophages. On the other hand, induction of IL-12 is higher in X-linked immunodeficient than in wild-type macrophages. Macrophage IL-12 induction is enhanced by iNOS inhibitors such as aminoguanidine and thiocitrulline and is inhibited by NO generation via sodium nitroprusside. There is relative enhancement of IFN-gamma production by immune T cells from mice immunized under aminoguanidine cover. Our data thus suggest that Bruton's tyrosine kinase participates in signaling for iNOS induction via IFN regulatory factor-1 in macrophages and that NO is an inhibitor of IL-12 induction.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed1999

Delayed clearance of filarial infection and enhanced Th1 immunity due to modulation of macrophage APC functions in xid mice.

Bruton's tyrosine kinase (Btk) mutant CBA/N mice show delayed clearance of injected microfilaria (mf) compared with wild-type CBA/J mice. Anti-mf T cells from CBA/N mice make relatively more IFN-gamma than those from CBA/J mice. The anti-mf T cell proliferative responses are also greater in CBA/N mice. This CBA/N immune phenotype is not restricted to filarial Ags, because immunization with pure proteins also yields T cell responses of greater proliferative magnitude skewed away from Th2 cytokines in CBA/N compared with CBA/J mice. The increased magnitude of CBA/N T cell proliferative responses is reflected in increases in both precursor frequencies and clonal burst sizes of responding Ag-specific T cells, and is independent of the source of re-stimulating APCs. Transfer of CBA/J peritoneal resident cells (PRCs) into CBA/N mice before pure protein immunization leads to a wild-type immune phenotype in the recipient CBA/N mice, with a reduction in the proliferative response and a relative decrease in the IFN-gamma produced. When wild-type PRC subpopulations are similarly transferred, the wild-type immune phenotype is transferred by macrophages rather than by B cells. Transfer of wild-type PRCs into CBA/N mice before injection of mf also causes similar changes in the anti-mf T cell responses and enhances the clearance of mf. Thus, Btk is involved in critical macrophage APC functions regulating priming of T cells, and can modulate these responses in pathophysiologically relevant fashion in vivo.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed1999

MHC class I-restricted presentation of maleylated protein binding to scavenger receptors.

Pathways for loading exogenous protein-derived peptides on MHC class I are thought to be present mainly in monocyte-lineage cells and to involve phagocytosis- or macropinocytosis-mediated antigenic leakage into either cytosol or extracellular milieu to give peptide access to MHC class I. We show that maleylation of OVA enhanced its presentation to an OVA-specific MHC class I-restricted T cell line by both macrophages and B cells. This enhanced presentation involved uptake through receptors of scavenger receptor (SR)-like ligand specificity, was TAP-1-independent, and was inhibited by low levels (2 mM) of ammonium chloride. No peptide loading of bystander APCs by maleylated (maleyl) OVA-pulsed macrophages was detected. Demaleylated maleyl-OVA showed enhanced MHC class I-restricted presentation through receptor-mediated uptake and remained highly sensitive to 2 mM ammonium chloride. However, if receptor binding of maleyl-OVA was inhibited by maleylated BSA, the residual presentation was relatively resistant to 2 mM ammonium chloride. Maleyl-OVA directly introduced into the cytosol via osmotic lysis of pinosomes was poorly presented, confirming that receptor-mediated presentation of exogenous maleyl-OVA was unlikely to involve a cytosolic pathway. Demaleylated maleyl-OVA was well presented as a cytosolic Ag, consistent with the dependence of cytosolic processing on protein ubiquitination. Thus, receptor-specific delivery of exogenous protein Ags to APCs can result in enhanced MHC class I-restricted presentation, suggesting that the exogenous pathway of peptide loading for MHC class I may be a constitutive property dependent mainly on the quantity of Ag taken up by APCs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Presence of pentoxifylline during T cell priming increases clonal frequencies in secondary proliferative responses and inhibits apoptosis.

Naive T cells appear to be primed by specific Ag to differentiate into either effectors or memory cells. We have been analyzing the factors involved in this differential commitment in the priming of alloresponsive human T cells in vitro and have shown that the presence of a phosphodiesterase inhibitor, pentoxifylline (POX), during priming results in a decrease in the primary response and enhancement in the secondary proliferative response. We now show that the POX-mediated effect can be mimicked by dibutyryl cAMP. The secondary response enhancement is due to the effects of POX on the T cells rather than the APCs, because even fixed APCs can prime T cells in the presence of POX. POX affects T cells directly by increasing clonal frequency rather than the burst size of the secondary responders. The known inhibition of IL-2 production by POX is not responsible for this effect, because exogenous IL-2 supplementation does not block it. The presence of POX during priming alters the outcome of T cell activation, resulting in a lower frequency of cells expressing IL-2R alpha (CD25) and a decrease in their subsequent apoptosis, and this antiapoptotic effect is consistent with the enhanced commitment of T cells to secondary responsiveness by POX.

Adjuvants, Immunologic↗
PubMed1999

Expression of an immunoglobulin heavy chain transgene in macrophage as well as lymphocyte lineages in vivo.

A rearranged immunoglobulin heavy chain (IgH) transgene-encoded protein is expressed in macrophage lineage cells, in addition to B and T lineages, in transgenic mouse bone marrow. Peripheral macrophages also express transgenic IgH protein. Mature T cells express lower levels than immature thymocytes. Almost all B220+ cells in the bone marrow express transgenic IgH protein, and this early expression in the B lineage is accompanied by a reduction of cell frequency even in the early B220+ CD43+ BP-1- stages, although it is more prominent in BP-1+ pre-B cells. Thus, an IgH transgene can be expressed not only in lymphoid but also in myeloid cells, although its developmental effects are restricted to the B cell lineage.

Animals↗
PubMed1999

Acute myocardial infarction with isolated ST-segment elevation in posterior chest leads V7-9: "hidden" ST-segment elevations revealing acute posterior infarction.

OBJECTIVES: This study was done to determine whether electrocardiographic (ECG) isolated ST-segment elevation (ST) in posterior chest leads can establish the diagnosis of acute posterior infarction in patients with ischemic chest pain and to describe the clinical and echocardiographic characteristics of these patients. BACKGROUND: The absence of ST on the standard 12-lead ECG in many patients with acute posterior infarction hampers the early diagnosis of these infarcts and thus may result in inadequate triage and treatment. Although 4% of all acute myocardial infarction (AMI) patients reveal the presence of isolated ST in posterior chest leads, the significance of this finding has not yet been determined. METHODS: We studied 33 consecutive patients with ischemic chest pain suggestive of AMI without ST in the standard ECG who had isolated ST in posterior chest leads V7 through V9. All patients had echocardiographic imaging within 48 h of admission, and 20 patients underwent coronary angiography. RESULTS: Acute myocardial infarction was confirmed enzymatically in all patients and on discharge ECG pathologic Q-waves appeared in leads V7 through V9 in 75% of the patients. On echocardiography, posterior wall-motion abnormality was visible in 97% of the patients, and 69% had evidence of mitral regurgitation (MR), which was moderate or severe in one-third of the patients. Four patients (12%), all with significant MR, had heart failure, and one died from free-wall rupture. The circumflex coronary artery was the infarct related artery in all catheterized patients. CONCLUSIONS: Isolated ST in leads V7 through V9 identify patients with acute posterior wall myocardial infarction. Early identification of those patients is important for adequate triage and treatment of patients with ischemic chest pain without ST on standard 12-lead ECG.

Adult↗
PubMed1999

Integration of generic indicators for quality management in hospital information systems.

Hospital information systems may contribute in different ways to quality management activities such as monitoring of quality indicators. Most existing quality management activities in hospitals are adjusted to a special medical field or particular disease. These activities often run simultaneously with other procedures and the documentation of patient care. To determine an interdisciplinary integrated quality management procedure, a pilot study was carried out at the Neurosurgery Department and Neonatology Division of the Medical Center of the University of Heidelberg. Predefined generic indicators that may be integrated in an existing information system and used in hospital routine were the basis of this project. The aim of the study was to support the quality management with periodic reports of these indicators. The pilot study showed that there were barriers along the path to an integrated generic quality management. To meet the requirements of routine monitoring, using predefined generic indicators of hospital care, much integration effort, directed at organizational aspects of information processing and information systems architecture, is still needed.

Germany↗
PubMed1999

Th1 dominance in the immune response to live Salmonella typhimurium requires bacterial invasiveness but not persistence.

Factors responsible for the predictable generation of Th1 or Th2 immune responses to microorganisms in vivo are not well characterized, although the ability of antigen presenting cells (APC) to provide co-stimulation, the kinetics of MHC-peptide ligand generation as well as the cytokine environment are all considered important factors for the differential Th1/Th2 priming of T cells. Our earlier findings of an IFN-gamma-dominant, Th1-type response to live Salmonella typhimurium (Stm) and a Th2-type response to killed Stm suggested that persistence of viable bacteria might be an important factor in the generation of IFN-gamma-dominant responses. Using genetically susceptible and resistant strains of mice to limit bacterial replication and persistence in vivo, we show that mice of the lty(r) genotype, capable of a 10-fold better clearance of Stm, mount an IFN-gamma-dominant immune response following immunization with live Stm similar to that in the lty(s) strain. Further, metabolically defective mutants of Stm, aroA and purA, when used in the live form, also elicit IFN-gamma-dominant immune responses similar to the wild-type Stm strain despite their inability to proliferate in vivo. While a laboratory strain of Escherichia coli, which is antigenically cross-reactive but non-invasive, elicits hardly any IFN-gamma in immune responses, an invasive strain of E. coil induces an IFN-gamma-dominant response. These data together indicate that, while entry of bacteria into macrophages is likely to be critical for the generation of IFN-gamma-dominant immune responses, their persistence is not.

Animals↗
PubMed1999

Effect of multiple antigenic exposures in the gut on oral tolerance and induction of antibacterial systemic immunity.

We have analyzed oral tolerance of microbial antigens in an experimental model in which mice are treated orally with a single small dose of soluble antigen and challenged systemically with the antigen in complete Freund's adjuvant. We found that, while oral administration of sonicated extracts of either Leishmania major, Leishmania donovani, or Staphylococcus aureus was tolerogenic, as was administration of the nominal antigen ovalbumin or conalbumin, oral administration of Escherichia coli or Salmonella typhimurium sonicated extract was not. Since E. coli is an enteric commensal that colonizes the intestine soon after birth, these data suggested that lack of demonstrable oral tolerance may be related to the frequency of oral exposure to an antigen. In support of this, we found that multiple oral doses of ovalbumin or S. aureus or L. donovani antigens did not increase systemic hyporesponsiveness beyond that achieved with a single oral dose. We have also tested the ability of mice fed with sonicates of the tolerogenic S. aureus or the nontolerogenic S. typhimurium to clear a subsequent systemic infection with the homologous bacteria and found that, while clearance of S. aureus was unaffected by prior feeding, clearance of S. typhimurium was actually enhanced. The data suggest that frequent oral antigenic exposure may eventually lead to induction of systemic immunity in tolerant mice.

Administration, Oral↗
PubMed1998

Deletion of a recombined Ig heavy chain transgene in B-lineage cells of transgenic mice.

Fully recombined transgenes are stable in their transmission in the germline of transgenic mice, in common with the endogenous genetic complement of most mammalian somatic tissues, including the genes for lymphoid Ag receptors somatically generated from germline minigenes. There have, however, been isolated reports of unusual low frequency transgene losses in various transgenic mice. Here we show, using Southern blots and PCR-based assays, that plasmablast hybridomas and B cells from three independently derived founder lines of transgenic mice bearing a recombined heavy chain Ig transgene we have been studying show a significant net loss of transgene copies. This loss is more marked in the B cells expressing endogenous heavy chains than in those expressing transgenic heavy chains. We have also examined cells of the B lineage in the bone marrow, and a small degree of deletion is also evident in CD19+ CD23- IgM- immature B-lineage cells. As greater deletion is observed in mature B cells, it is possible that the deletion process either continues into B cell maturity and/or provides a selective advantage. We have investigated the relationship between transgene expression and deletion, and we find that while thymocytes in these mice express the transgene well, T cell hybridomas derived from transgenic thymus do not show any loss of the transgene. Thus, a recombined Ig heavy chain transgene prominently undergoes somatic deletion in B-lineage cells independent of its insertion site or expression. This transgenic instability is significant to the analysis of genomic stability as well as to the design of gene therapy strategies.

Animals↗
PubMed1998

Modulation of T cell cytokine profiles and peptide-MHC complex availability in vivo by delivery to scavenger receptors via antigen maleylation.

We have previously shown that conversion of proteins to scavenger receptor (SR) ligands by maleylation increases their immunogenicity. We now show that maleyl-Ag-immune spleen cells make relatively more IFN-gamma and less IL-4 or IL-10 than native Ag-immune cells. This is also reflected in the IgG1:IgG2a ratios in Abs generated in vivo. SR engagement on macrophages does not alter their surface levels of the adhesive/costimulatory molecules CD11a/CD18, CD11b/CD18, CD24, CD54, or CD40, nor does it enhance their ability to support anti-CD3-driven proliferation of naive T cells in vitro. Costimulatory molecules implicated in differential Th1/Th2 commitment--CD80, CD86, and IL-12--are not inducible by SR ligation. In addition to macrophages and dendritic cells, B cells also show receptor-mediated uptake and enhanced presentation of maleyl-Ags. Using a monoclonal T cell line to detect peptide-MHC complexes expressed on spleen cells in Ag-injected mice, we find that higher levels of these complexes are generated in vivo from maleyl-proteins and they persist longer than those generated from the native protein. Together, these data suggest that in certain situations, the levels of cognate ligand available and/or the time course of their availability may play a major role in determining the cytokine profiles of the responding T cells in addition to the costimulatory signals implicated so far.

Animals↗
PubMed1998

Significance of ST segment elevations in posterior chest leads (V7 to V9) in patients with acute inferior myocardial infarction: application for thrombolytic therapy.

OBJECTIVES: This study was designed to examine whether ST segment elevation in posterior chest leads (V7 to V9) during acute inferior myocardial infarction (MI) identifies patients with a concomitant posterior infarction and whether these patients might benefit more from thrombolysis. BACKGROUND: Because the posterior wall is faced by none of the 12 standard electrocardiographic (ECG) leads, the ECG diagnosis of posterior infarction is problematic and has often remained undiagnosed, especially in the acute phase. METHODS: Eighty-seven patients with a first inferior infarction who were treated with recombinant tissue-type plasminogen activator were stratified according to the presence (Group A [46 patients]) or absence (Group B [41 patients]) of concomitant ST segment elevation in posterior chest leads V7 to V9. RESULTS: Patients in Group A had a higher incidence of posterolateral wall motion abnormalities (p < 0.001) on radionuclide ventriculography, a larger infarct area (as evidenced by higher peak creatine kinase levels) (p < 0.02) and a lower left ventricular ejection fraction (LVEF) at hospital discharge (p < 0.008) than those in Group B. ST segment elevation in leads V7 to V9 was associated with a higher incidence of at least one of the following adverse clinical events: reinfarction, heart failure or death (p = 0.05). Although patency of the infarct-related artery (IRA) in Group A resulted in an improved LVEF at discharge (p < 0.012), LVEF was unchanged in Group B, regardless of the patency status of the IRA. CONCLUSIONS: ST segment elevation in leads V7 to V9 identifies patients with a larger inferior MI because of concomitant posterolateral involvement. Such patients might benefit more from thrombolytic therapy.

Adult↗
PubMed1998

Pentoxifylline inhibits Ig kappa gene transcription and rearrangements in pre-B cells.

Pentoxifylline (PF) has been used in a wide variety of clinical situations; however, the molecular consequences of this drug are not well characterized. In this paper we assayed the effects of PF in two models of pre-B differentiation. In 70Z pre-B cells, transcriptional induction of rearranged Ig kappa-chain gene in response to LPS was suppressed by PF, without affecting the induction of Rel family proteins. In contrast, kappa induction by IFN-gamma was not suppressed by PF, indicating that the drug inhibited certain activation pathways. We also found that LPS-induced activation of germline kappa transcription and V kappa to J kappa recombination were inhibited by PF in the pre-B cell line 38B9. These observations suggest that PF may adversely affect B lymphopoiesis during chronic administration.

Animals↗