Short-term effectiveness of nifedipine in secondary pulmonary hypertension.
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Adult↗
Biomedical subjects
S Rich
Publications and source records attributed to S Rich.
Successful management of labor and delivery in primary pulmonary hypertension.
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Adenosine↗
Abundant expression of transforming growth factor-beta 1 and -beta 2 by Hodgkin's Reed-Sternberg cells and by reactive T lymphocytes in Hodgkin's disease.
The depressed cellular immunity observed in patients with Hodgkin's disease (HD) has been attributed to production of transforming growth factor (TGF)-beta or TGF-beta-like substances by Hodgkin's Reed-Sternberg (H-RS) cells. The TGF-beta produced by L-428 cells (an H-RS cell line) is a 130-kd molecular weight glycoprotein that apparently differs from the TGF-beta (molecular weight, 25 kd) produced by most lymphoid and hematopoietic cells. Among several distinct types of TGF-beta that have been purified, only TGF-beta 1 and TGF-beta 2 have thus far been identified in hematopoietic cells. By using monoclonal antibodies (1D11 and 3C7) and oligonucleotide probes specific for TGF-beta 1 and TGF-beta 2, were confirmed that a cultured H-RS cell line, KM-H2, can produce both TGF-beta types, whereas another line, HDLM-1, produces only TGF-beta 1. Despite the abundance of mRNA in both of these cells, only small amounts of TGF-beta activity were detected, probably because of rapid degradation of TGF-beta 1 mRNA by specific nuclease. No degraded TGF-beta 2 RNA products were observed in KM-H2 cells. The TGF-beta produced by both types of H-RS cells had a molecular weight of approximately 25 kd. In tissues expression of TGF-beta was observed in a small portion (30%) of H-RS cells in 16 of 20 cases examined. A large number of small to medium-sized lymphoid cells (T lymphocytes) in tissues involved by HD also were positive for TGF-beta. These results indicate that there is functional heterogeneity among H-RS cells, and that H-RS cells are not the only source of TGF-beta in tissues involved by HD. Hodgkin's Reed-Sternberg cells are known to secrete several other cytokines, including interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha. These cytokines could be responsible for the increased number of T lymphocytes in tissues involved by HD. Furthermore, T lymphocytes can respond to IL-1 and IL-6 secreted by H-RS cells by increasing their production of TGF-beta. Abundant expression of TGF-beta by T lymphocytes was not observed in lymphoid tissues other than those involved by HD.
Base Sequence↗
Effects of adenosine in combination with calcium channel blockers in patients with primary pulmonary hypertension.
OBJECTIVES: The purpose of this study was to evaluate the effects of vasodilator combination therapy in patients with primary pulmonary hypertension. BACKGROUND: Calcium channel blockers and adenosine have each been shown to be effective in reducing pulmonary artery pressure and pulmonary vascular resistance in patients with primary pulmonary hypertension. However, the effects of combining these vasodilators have not been studied. METHODS: To test the combination, 12 patients were placed on oral nifedipine and 3 on diltiazem therapy, using a dose titrated to maximal effect (mean nifedipine dose 103 +/- 24 mg, mean diltiazem dose 300 +/- 49 mg). Patients were then given maintenance doses of the calcium channel blocker at half the cumulative loading dose at 6-h intervals. One hour after the maintenance dose of calcium blocker, all patients received an infusion of adenosine, starting with 50 micrograms/kg per min and increasing by 50 micrograms/kg per min at 2-min intervals to a maximally tolerated dose (180 +/- 63 micrograms/kg per min). RESULTS: Ten patients responded to calcium channel blockers (defined as a > or = 20% decrease in pulmonary vascular resistance), with a 16% decrease in mean pulmonary artery pressure (p = 0.057), a 39% decrease in pulmonary vascular resistance (p = 0.002) and a 24% increase in stroke volume (p = 0.007). Five patients were nonresponders, with no significant changes in pulmonary artery pressure, pulmonary vascular resistance, cardiac index or stroke volume. In the calcium channel blocker responders, the combination of adenosine and calcium blocker reduced pulmonary vascular resistance by 49%, increased stroke volume by 33% and decreased mean pulmonary artery pressure by 14% compared with drug-free baseline values. In nonresponders, combination therapy resulted in nonsignificant changes in pulmonary artery pressure and pulmonary vascular resistance. CONCLUSIONS: Adenosine has the ability to further decrease pulmonary artery pressure and pulmonary vascular resistance in patients with primary pulmonary hypertension who respond to calcium channel blockers. Those who fail to respond to these agents have little added effect from adenosine.
Adenosine↗
The role of thrombosis in pulmonary hypertension.
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Humans↗
The prevalence and significance of a patent foramen ovale in pulmonary hypertension.
In order to determine the prevalence and significance of a patent foramen ovale (PFO) in pulmonary hypertension, 58 patients were studied with transesophageal echocardiography, right-sided heart catheterization, and exercise testing. In order to examine if a PFO might be associated with a better outcome, survival was estimated, based on a formula derived from the National Institutes of Health Primary Pulmonary Hypertension Registry, for the patients with primary pulmonary hypertension (PPH). A PFO was found in 26 percent (15 of 58) of all patients studied, 25 percent (10 of 40) of those with PPH, and 28 percent (5 of 18) of those with secondary pulmonary hypertension. We found no significant difference in any hemodynamic variable or exercise tolerance between the patients with and without a PFO, or for subsets of patients with primary and secondary pulmonary hypertension. We also found no significant difference in the 1-, 2-, 3-, 4-, or 5-year estimated survival, for the patients with PPH between those with and without a PFO. The prevalence of a PFO in pulmonary hypertension appears similar to the normal population. A PFO provides no detectable influence on resting hemodynamics or exercise tolerance in patients with pulmonary hypertension and is not clearly associated with patients expected to survive longer.
Adolescent↗
pp59fyn mutant mice display differential signaling in thymocytes and peripheral T cells.
We have generated mutant mice that do not express pp59fyn, a nonreceptor protein tyrosine kinase related to pp60src, by homologous recombination in embryonic stem cells. fyn- mice did not display an overt phenotype. Because fyn is associated with the T cell receptor (TCR), thymocyte and T cell signaling was analyzed in the mutant background. Cross-linking of TCR-CD3 in thymocytes led to markedly reduced calcium fluxes and abrogated proliferation, whereas mature splenic T cells retained largely normal proliferation despite depressed calcium movements and IL-2 production. Similarly, proliferation induced by Thy-1 cross-linking was reduced in thymocytes but not in splenic T cells. fyn- thymocytes were impaired at a late stage of maturation and showed limited clonal deletion to the Mls-1a self-super-antigen but not to staphylococcal enterotoxin A. These results implicate fyn as a critical component in TCR signaling in thymocytes and, potentially, in the process that determines T cell repertoire in the adult mouse.
Animals↗
The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension.
BACKGROUND: Primary pulmonary hypertension is a progressive, fatal disease of unknown cause. Vasodilator drugs have been used as a treatment, but their efficacy is uncertain. METHODS: We treated 64 patients with primary pulmonary hypertension with high doses of calcium-channel blockers. Patients who responded to treatment (defined as those whose pulmonary-artery pressure and pulmonary vascular resistance immediately fell by more than 20 percent after challenge) were treated for up to five years. Their survival was compared with that of the patients who did not respond and with patients enrolled in the National Institutes of Health (NIH) Registry on Primary Pulmonary Hypertension. Warfarin was given to 55 percent of the patients as concurrent therapy, on the basis of a lung scan showing nonuniformity of pulmonary blood flow (47 percent of patients who responded and 57 percent of those who did not respond). RESULTS: Seventeen patients (26 percent) responded to treatment, as indicated by a 39 percent fall in pulmonary-artery pressure and a 53 percent fall in the pulmonary-vascular-resistance index (P less than 0.001). Nifedipine (mean [+/- SD] daily dose, 172 +/- 41 mg) was given to 13 patients, and diltiazem (mean daily dose, 720 +/- 208 mg) was given to 4 patients. After five years, 94 percent of the patients who responded (16 of 17) were alive, as compared with 55 percent of the patients who did not respond (26 of 47, P = 0.003). The survival of the patients who responded was also significantly better than that of the NIH registry cohort (P = 0.002) and patients from the NIH registry who were treated at the University of Illinois (P = 0.001). The use of warfarin was associated with improved survival (P = 0.025), particularly in the patients who did not respond. CONCLUSIONS: This study suggests that high doses of calcium-channel blockers in patients with primary pulmonary hypertension who respond with reductions in pulmonary-artery pressure and pulmonary vascular resistance may improve survival over a five-year period.
Adult↗
Autoantibodies in patients with primary pulmonary hypertension: association with anti-Ku.
PURPOSE: Patients with primary pulmonary hypertension (PPH) frequently have Raynaud's phenomenon, serum antinuclear antibodies (ANAs), and/or pulmonary vascular lesions similar to those seen in certain connective tissue diseases, especially scleroderma. A number of relatively disease-specific autoantibodies have been described in connective tissue diseases but have not been studied in patients with PPH. Therefore, sera from PPH patients were studied for a variety of autoantibodies, seeking a possible link between this pulmonary disorder and connective tissue diseases. PATIENTS AND METHODS: Sera from 31 patients with PPH and 24 with secondary pulmonary hypertension (SPH) were studied for the following autoantibodies: anti-centromere (indirect immunofluorescence of Hep-2 cells), anti-CENP-B by immunoblotting and enzyme immunoassay (EIA) using cloned CENP-B fusion protein, anti-topoisomerase I (Scl-70), anti-Ku using immunoblotting of affinity purified antigens, anti-cardiolipin using EIA, and anti-Ro (SS-A), La (SS-B), Sm, nRNP, Jo-1, PM-Scl, and Mi-2 by counter-current immunoelectrophoresis. RESULTS: Anti-Ku antibodies were found in 23% of patients with PPH, 4% with SPH, and none of 24 normal controls (PPH versus SPH, p = 0.06: PPH versus controls, p = 0.01). Antibodies to CENP-B were found in one patient each with PPH and SPH, anti-topoisomerase I in one with SPH, and anti-Ro (SS-A) and La (SS-B) in one with PPH. Overall, 12 patients (39%) with PPH had Raynaud's phenomenon or positive ANA results, with 9 (29%) having more specific autoantibodies associated with connective tissue diseases. CONCLUSIONS: These results further suggest a link between at least a subgroup of patients with PPH and autoimmune connective tissue diseases, with anti-Ku antibodies being a possible new serologic marker.
Adult↗
Doppler echocardiographic demonstration of the differential effects of right ventricular pressure and volume overload on left ventricular geometry and filling.
To compare the effects of isolated right ventricular pressure and volume overload on left ventricular diastolic geometry and filling, 11 patients with primary pulmonary hypertension, 11 patients with severe tricuspid regurgitation due to tricuspid valve resection and 11 normal subjects were studied with use of Doppler echocardiographic techniques. Right ventricular systolic overload in primary pulmonary hypertension resulted in substantial leftward ventricular septal shift that was most marked at end-systole and early diastole and decreased substantially by end-diastole. Right ventricular diastolic overload after tricuspid valve resection resulted in maximal leftward ventricular septal shift at end-diastole sparing end-systole and early diastole. The early diastolic distortion of left ventricular geometry associated with right ventricular pressure overload resulted in prolongation of isovolumetric relaxation of the left ventricle (129 +/- 39 ms) and a reduction in early diastolic filling compared with values in normal subjects. Late diastolic distortion of left ventricular geometry associated with right ventricular volume overload had no influence on the duration of left ventricular isovolumetric relaxation (52 +/- 32 ms) but caused a reduction in the atrial systolic contribution to late diastolic filling of the left ventricle compared with values in normal subjects. In patients with right ventricular pressure overload, 52 +/- 16% of left ventricular filling occurred in early diastole compared with 78 +/- 11% in patients with right ventricular volume overload (p less than 0.001). The differential effects of systolic and diastolic right ventricular overload on the pattern of left ventricular filling appear to be related to the timing of leftward ventricular septal displacement.
Adult↗
Comparison of the effects of adenosine and nifedipine in pulmonary hypertension.
The hemodynamic effects of intravenously administered adenosine, a potent vasodilator, were examined in 15 patients with pulmonary hypertension. All patients were given adenosine, 50 micrograms/kg per min, increased by 50 micrograms/kg per min at 2 min intervals to a maximum of 500 micrograms/kg per min or until the development of untoward side effects. The patients were then given oral nifedipine, 20 mg every hour, until a greater than or equal to 20% decrease in pulmonary vascular resistance or systemic hypotension occurred. The administration of maximal doses of adenosine, 256 +/- 46 micrograms/kg per min, produced a 2.4% reduction in pulmonary artery pressure (p = NS), a 37% decrease in pulmonary vascular resistance (p less than 0.001) and a 57% increase in cardiac index (p less than 0.001). The administration of maximally effective doses of nifedipine (91 +/- 36 mg) produced a 15% reduction in the mean pulmonary artery pressure (p less than 0.05), a 24% decrease in pulmonary vascular resistance (p less than 0.01) and an 8% increase in cardiac index (p = NS). There was a significant correlation (r = 0.714, p = 0.01) between the reduction in pulmonary vascular resistance that resulted from adenosine administration and that achieved with the administration of nifedipine. Six patients had substantial reductions in pulmonary vascular resistance with adenosine but not with nifedipine. Thus, adenosine is an effective vasodilator in patients with pulmonary hypertension and can be used for safe and rapid assessment of vasodilator reserve in these patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Adenosine↗
Analysis of regional pulmonary enhancement in dogs by ultrafast computed tomography.
Measurement of regional pulmonary enhancement was made in five anesthetized dogs with intravenous contrast material-enhanced ultrafast computed tomography (CT). Three or four electrocardiogram-gated flow scans were performed in each dog in the prone and supine positions. Immediately after each flow scan was acquired at four levels (8-mm thick slices), 20 times per level, 0.5 mL/kg (10 mL/second) ionic contrast medium was injected into the inferior vena cavae. Each level of each lung was divided into anterior, middle, and posterior regions for time density curve analysis and regional flow estimation. Images were transferred to an off-line workstation for lung pixel colorization and subjective interpretation. There was a statistically significant gravity-related enhancement gradient in both the supine and prone positions; however, the gradient was much greater in the supine position. This study shows that gravity-related contrast medium enhancement gradients in the lung can be demonstrated by ultrafast CT.
Animals↗
High dose titration of calcium channel blocking agents for primary pulmonary hypertension: guidelines for short-term drug testing.
Forty-seven patients with primary pulmonary hypertension were evaluated with a dose titration protocol utilizing nifedipine (20 mg orally) or diltiazem (60 mg orally) given every hour until maximal effectiveness was achieved. Of the patients tested, 15 (32%) had a greater than 20% reduction in pulmonary artery pressure (mean 36.2 +/- 8%, p less than 0.01) and pulmonary vascular resistance (mean 50.2 +/- 7%, p less than 0.01) (pressure responders). Nineteen (40%) had a greater than 20% reduction in pulmonary vascular resistance (mean 25.2 +/- 12%, p less than 0.01), with less than a 20% decrease in pulmonary artery pressure (resistance responders). Ten had no significant change in pulmonary artery pressure or pulmonary vascular resistance (nonresponders), and three were unable to tolerate the calcium channel blocking agents. No hemodynamic profile allowed prediction of the type of response to these agents. No mortality or serious morbidity was associated with the drug testing. These findings indicate that calcium channel blockers, when titrated to maximally effective doses, may cause substantial reductions in pulmonary artery pressure and pulmonary vascular resistance in patients with primary pulmonary hypertension. Testing with hemodynamic monitoring is necessary to ascertain which patients will respond. Patients with primary pulmonary hypertension are able to tolerate short-term administration of high doses of calcium channel blockers.
Adult↗
Co-stimulation of T cell proliferation by transforming growth factor-beta 1.
Transforming growth factor-beta (TGF-beta) exhibits diverse regulatory roles in the immune system and has been described as a potent inhibitor of lymphocyte and hemopoietic progenitor cell growth. The present studies investigated the effects of TGF-beta 1 on murine T cell proliferation triggered through the T cell receptor/CD3 complex. In contrast to previously reported T cell growth inhibition, TGF-beta 1 costimulated splenic T cell proliferation in the presence of immobilized anti-CD3 antibody 2C11, with maximal effect at anti-CD3 concentration of 50 micrograms/ml. Although TGF-beta 1 induced a modest increase in IL-2R display, TGF-beta 1 co-stimulated proliferation was largely independent of IL-2 and/or IL-4. Anti-IL-2 and/or anti-IL-4 antibody did not significantly block the TGF-beta 1 co-stimulated T cell growth, and no IL-2 or IL-4 bioactivity was detected in TGF-beta 1 co-stimulated cultures. TGF-beta 1 did not enhance IL-2 mRNA expression beyond control levels. However, TGF-beta 1 co-stimulation caused an accelerated evolution of a memory or mature T cell population phenotype. Both CD4+ and CD8+ T cell subsets were significantly enriched for cells of the mature CD45RBloPgp-1hi phenotype, in comparison with T cells stimulated by anti-CD3 alone or with PMA, and CD8+ T cells predominated. These results thus provide initial evidence that TGF-beta 1 is capable of bifunctional T cell growth regulation, which occurs largely via an IL-2- and IL-4-independent pathway.
Animals↗
Reproducibility of left ventricular myocardial volume and mass measurements by ultrafast computed tomography.
Ultrafast computed tomography has been reported to be an accurate method of measuring left ventricular mass in dogs. To assess the interstudy, intraobserver and interobserver variability of left ventricular myocardial mass measurements in humans, left ventricular myocardial volume was measured three times within 24 h in 16 patients with ischemic heart disease. The mean percent difference of the mean of the three studies performed was -0.01 +/- 1.4% (range -2.9% to 3.6%). The regression analysis for the intraobserver variability at baseline was: Y = -4.33 + 1.03X; r = 0.99, SEE = 3.5 ml. The mean percent difference of the mean of the two sets of measurements performed by two independent observers was 0.28 +/- 2.1% (range -4.35% to 4.35%). The interobserver variability excluding papillary muscles at baseline study was: Y = -4.34 + 1.06X; r = 0.99, SEE = 1.5 ml. The regression analysis with versus without papillary muscles showed: Y = -8.72 + 0.97X; r = 0.96, SEE = 2.6 ml. Regression analysis to assess the variability of 24-h studies at end-systole versus end-diastole revealed: Y = 3.07 + 0.94X; r = 0.97, SEE = 1.8 ml. In conclusion, ultrafast computed tomography is a minimally invasive technique, with very low interstudy, intraobserver and interobserver variability for left ventricular myocardial volume and mass determinations in serial studies.
Cardiomegaly↗
Familial pulmonary hypertension in association with an abnormal hemoglobin. Insights into the pathogenesis of primary pulmonary hypertension.
A kindred with a familial hemoglobinopathy and familial primary pulmonary hypertension with autosomal dominant transmission has been identified. Affected family members were obvious from their cyanosis due to a reduced affinity for oxygen by the hemoglobin variant. The mother and one child had clinical pulmonary hypertension, whereas two siblings had cyanosis and preclinical pulmonary vascular disease as evidenced by abnormal perfusion lung scans and elevated levels of fibrinopeptide A in the face of normal pulmonary hemodynamics. In one, pulmonary hypertension could be induced with exercise. The studies on this family support the hypothesis that primary pulmonary hypertension may be initiated by abnormalities of the pulmonary vascular bed that predispose to in situ thrombosis. The possible common genetic transmission of the two diseases offers the speculation that the gene that confers predisposition to pulmonary hypertension may be located near the gene responsible for beta globulin.
Beta-Globulins↗
Genetic linkage studies suggest that Alzheimer's disease is not a single homogeneous disorder.
Alzheimer's disease, a fatal neurodegenerative disorder of unknown aetiology, is usually considered to be a single disorder because of the general uniformity of the disease phenotype. Two recent genetic linkage studies revealed co-segregation of familial Alzheimer disease with the D21S1/S11 and D21S16 loci on chromosome 21. But two other studies, one of predominantly multiplex kindreds with a late age-of-onset, the other of a cadre of kindreds with a unique Volga German ethnic origin, found absence of linkage at least to D21S1/S11. So far it has not been possible to discern whether these conflicting reports reflect aetiological heterogeneity, differences in methods of pedigree selection, effects of confounding variables in the analysis (for example, diagnostic errors, assortative matings), or true non-replication. To resolve this issue, we have now examined the inheritance of five polymorphic DNA markers from the proximal long arm of chromosome 21 in a large unselected series of pedigrees with familial Alzheimer's disease. Our data suggest that Alzheimer's disease is not a single entity, but rather results from genetic defects on chromosome 21 and from other genetic or nongenetic factors.
Alzheimer Disease↗
Fibrinopeptide A levels indicative of pulmonary vascular thrombosis in patients with primary pulmonary hypertension.
Although the mechanisms involved in the pathophysiology of primary pulmonary hypertension have not yet been delineated, thrombosis has been implicated. This study was designed to determine whether thrombin activity as reflected by plasma concentrations of fibrinopeptide A (FPA), a marker of the action of thrombin on fibrinogen, is increased in patients with primary pulmonary hypertension. To evaluate fibrinolytic activity, we measured plasma concentrations of tissue-type plasminogen activator, plasminogen activator inhibitor-1, and cross-linked fibrin degradation products. We studied 31 patients with primary pulmonary hypertension. Plasma FPA concentrations measured by radioimmunoassay, were elevated to 87.4 +/- 36.9 ng/ml (mean +/- SEM). Fifteen minutes after administration of heparin (5,000 U), FPA concentrations decreased to 6.8 +/- 1.4 ng/ml (p less than 0.001 compared with preheparin levels). In 21 of 30 patients (70%), FPA concentrations after heparin administration were less than half the preheparin levels, a response consistent with inhibition of thrombin by heparin and the short half-life of FPA. Despite evidence for marked thrombin activity, plasma concentrations of cross-linked fibrin degradation products were normal in all but four patients. Plasminogen activator inhibitor-1 activity was elevated in 19 of the 27 patients in whom it was measured, potentially limiting the fibrinolytic response. The elevations of FPA indicate that thrombin activity is increased in vivo in patients with primary pulmonary hypertension. Thus, sequential assays of plasma markers of thrombosis and fibrinolysis in vivo may help identify those patients who may benefit from treatment with anticoagulants.
Fibrin Fibrinogen Degradation Products↗