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PubMed1995

Interplay between design and analysis for behavioral intervention trials with community as the unit of randomization.

This paper outlines an approach for the design and analysis of randomized controlled trials investigating community-based interventions for behavioral change aimed at health promotion. The approach is illustrated using the Community Intervention Trial for Smoking Cessation (COMMIT), conducted from 1988 to 1993, involving 11 pairs of communities in North America, matched on geographic location, size, and sociodemographic factors. The situation discussed is when assignment to intervention is done at the community level; for COMMIT, the very nature of the intervention required this. The number of communities as a key determinant of the statistical power of the trial. The use of matched pairs of communities can achieve a gain in statistical efficiency. Randomization is used to obtain an unbiased assessment of the intervention effect; randomization also provides the basis for statistical analysis. Permutation tests (and corresponding test-based confidence intervals), using community as the unit of analysis, follow directly from the randomization distribution. Within this framework, individual-level covariates can be used for imputation of missing values and for adjusting analyses of intervention effect.

Health Behavior↗
PubMed1991

Regulation of c-fos expression in Swiss 3T3 cells: an interplay of multiple signal transduction pathways.

The mitogenic response of Swiss 3T3 cells is regulated by synergistic interactions between multiple signal transduction pathways. Among the earliest nuclear signals in quiescent cells stimulated to divide is a dramatic increase in the expression of the c-fos proto-oncogene. The regulation of c-fos expression itself is a complex process involving several upstream enhancer elements which dictate the transcriptional response to specific intracellular signals. Here, we review our studies concerning the effects of defined molecular signals, alone or in combination, on c-fos mRNA levels in Swiss 3T3 cells. We propose that cell proliferation requires the cooperative interaction of distinct signalling pathways and that in this context c-fos induction plays a regulatory role in mitogenesis.

Animals↗
PubMed1999

Interplay of maturation-promoting factor and mitogen-activated protein kinase inactivation during metaphase-to-interphase transition of activated bovine oocytes.

The objective of the present study was to examine the activity changes in histone H1 kinase (also known as maturation-promoting factor [MPF]) and mitogen-activated protein kinase (MAPK) and their constituent proteins in in vitro-matured bovine oocytes after in vitro fertilization (IVF) or after parthenogenetic activation induced by calcium ionophore A23187 alone or by the ionophore followed by either 6-dimethylaminopurine (6-DMAP) or cycloheximide (CHX). Inactivation of both H1 kinase and MAPK occurred after both A23187+6-DMAP treatment and IVF; inactivation of H1 kinase preceded inactivation of MAPK. However, MAPK was inactivated much earlier in 6-DMAP-treated oocytes. Further analysis of constituent cell cycle proteins of these kinases by Western blot showed that A23187 alone could not induce changes in cdc2, cdc25, or ERK2 but induced reduction of cyclin B1. IVF and A23187+CHX induced similar changes: cyclin B1 was destroyed shortly after activation followed by accumulation of cyclin B1, phosphorylation of cdc2, and dephosphorylation of ERK2 at pronuclear formation 15 h after activation. No change in cdc25 was observed at this time. In contrast, A23187+6-DMAP treatment resulted in earlier phosphorylation of cdc2 and dephosphorylation of ERK2 at 4 h after treatment when the pronucleus formed. Moreover, accumulation of both cdc25 and cyclin B1 was detected at 15 h. Microinjection of ERK2 antibody into A23187-treated oocytes resulted in pronuclear formation. In conclusion, activation of bovine oocytes with 6-DMAP led to earlier inactivation of MAPK, while CHX induced inactivation of MAPK parallel to that following sperm-induced oocyte activation. Destruction of cyclin B is responsible for inactivation of MPF, while phosphorylation of cdc2 is likely responsible for maintaining its low activity. Inactivation of MAPK is closely associated with pronuclear development regardless of the activation protocol used.

Adenine↗
PubMed1995

Regulation of cellular calcium through signaling cross-talk involves an intricate interplay between the actions of receptors, G-proteins, and second messengers.

Various external stimuli regulate cellular Ca2+ fluxes. Information from these stimuli is transmitted to the cell interior by signal transducing systems that involve interactions between receptors, G-proteins, and enzymes that generate second messengers. The possible mechanisms by which "cross-talk" within and between these second messenger-generating systems provides an intricate molecular avenue for fine modulation of intracellular Ca2+ are reviewed.

Alternative Splicing↗
PubMed2003

Hypothalamic vasopressin release and hepatocyte Ca2+ signaling during liver regeneration: an interplay stimulating liver growth and bile flow.

Liver regeneration after partial hepatectomy is a plastic process during which the mechanisms that coordinate liver mass restoration compensate one another through a complex regulatory network of cytokines, growth factors, and hormones. Vasopressin, an agonist that triggers highly organized Ca2+ signals in the liver, may be one of these factors, although little in vivo evidence is available in support of this hypothesis. We provide evidence that hypothalamic vasopressin secretion is stimulated early after partial hepatectomy. Although hepatocytes were fully responsive to vasopressin during the first hours of regeneration, they became desensitized and exhibited slow oscillating Ca2+ responses to vasopressin on the following days. On the first day, hepatocyte V1a receptor density decreased and its lobular gradient increased in hepatectomized rats. By antagonizing the V1a receptor in vivo, we demonstrated that vasopressin contributes to NF-kappaB and cyclin (D1 and A) activation, to hepatocyte progression in the cell cycle, and to liver mass restoration. Finally, vasopressin exerted a choleretic effect shortly after hepatectomy, both in the isolated perfused liver and in the intact rat. In conclusion, we provide compelling in vivo evidence that vasopressin contributes significantly to growth initiation and bile flow stimulation in the early stages of liver regeneration.

Animals↗
PubMed1993

Interplay of T lymphocytes and HLA-DR molecules in rheumatoid arthritis.

One of the genetic components of seropositive rheumatoid arthritis has been mapped to a short sequence stretch in the third hypervariable region of the HLA-DRB1 gene. A new concept has emerged, proposing that the shared-sequence motif is functional in determining the clinical patterns of rheumatoid arthritis and the severity of the disease in a codominant mode. Patients with a double dose of the shared sequence tend to have more serious disease manifestations, suggesting a model in which the genetic element is involved in perpetuating the disease. The pathogenetic model in which the shared epitope selectively binds and presents an arthritogenic peptide appears too simplistic to account for these findings. Our understanding of how the shared epitope may contribute to forming the molecular complex of the T-cell receptor, peptide, and HLA-DR molecule is advancing. Molecular analyses of the synovial T-cell infiltrate continue to define the various components involved in recruiting T cells to the site of synovial inflammation. Adhesion molecules, predominantly the endothelial cell ligands vascular adhesion molecule 1 and endothelial leukocyte adhesion molecule 1, attract phenotypically selected T cells with a wide spectrum of specificities. The rheumatoid factor-positive B cells may be important antigen-presenting cells in the joint and may activate T cells with many different specificities. Rheumatoid factor immunoglobulin genes show clear evidence of somatic mutation, indicating a T cell-dependent, antigen-driven process. Thus, multiple factors contribute to the composition of the inflammatory infiltrate and may well modulate the repertoire of T cells recruited to the tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Arthritis, Rheumatoid↗
PubMed2000

Interplay between the gamma isoform of PKC and calcineurin in regulation of vulnerability to focal cerebral ischemia.

Protein phosphorylation and dephosphorylation mediated by protein kinases and protein phosphatases, respectively, represent essential steps in a variety of vital neuronal processes that could affect susceptibility to ischemic stroke. In this study, the role of the neuron-specific gamma isoform of protein kinase C (gammaPKC) in reversible focal ischemia was examined using mutant mice in which the gene for gammaPKC was knocked-out (gammaPKC-KO). A period of 150 minutes of unilateral middle cerebral artery and common carotid artery (MCA/CCA) occlusion followed by 21.5 hours of reperfusion resulted in significantly larger (P < 0.005) infarct volumes (n = 10; 31.1+/-4.2 mm3) in gammaPKC-KO than in wild-type (WT) animals (n = 12; 22.6+/-7.4 mm3). To control for possible differences related to genetic background, the authors analyzed Balb/cJ, C57BL/6J, and 129SVJ WT in the MCA/CCA model of focal ischemia. No significant differences in stroke volume were detected between these WT strains. Impaired substrate phosphorylation as a consequence of gammaPKC-KO might be corrected by inhibition of protein dephosphorylation. To test this possibility, gammaPKC-KO mice were treated with the protein phosphatase 2B (calcineurin) inhibitor, FK-506, before ischemia. FK-506 reduced (P < 0.008) the infarct volume in gammaPKC-KO mice (n = 7; 24.6+/-4.6 mm3), but at this dose in this model, had no effect on the infarct volume in WT mice (n = 7; 20.5+/-10.7 mm3). These results indicate that gammaPKC plays some neuroprotective role in reversible focal ischemia.

Animals↗
PubMed2000

Echo-dipyridamole stress test evaluation of isosorbide-5-mononitrate efficacy and tolerance in patients with coronary heart disease: interplay with sympathetic activity.

In 22 patients with stable myocardial ischemia, we prospectively studied the short- and long-term effects of isosorbide-5-mononitrate (5-ISMN) on dipyridamole-induced myocardial ischemia, the ability of dipyridamole-stress echocardiography to evaluate nitrate tolerance, and the role of activation of the neurohumoral system in nitrate tolerance development, assessed by modifications of catecholamines plasma levels and heart rate variability. After brief treatment with 5-ISMN, dipyridamole-stress echocardiography was negative in 19 of 22 patients (p < 0.001 vs. placebo). During the sustained phase, dipyridamole-stress echocardiography was positive after both placebo and active drug (p = NS vs. placebo). Heart rate variability showed significantly higher values in power of the low frequency (LF) band and low- to high-frequency ratio (L/H), as well as significantly lower values of the power of the high-frequency (HF) band (all p < 0.001) during brief but not during sustained administration of 5-ISMN. Norepinephrine plasma levels were significantly higher (p < 0.001) during short-term 5-ISMN administration but not during the sustained phase. Our results indicate that short-term administration of 5-ISMN antagonizes dipyridamole-induced myocardial ischemia and show the loss of antiischemic efficacy in 95% of patients during sustained treatment, demonstrating that dipyridamole-stress echocardiography is a useful tool to assess the presence of nitrate tolerance. Spectral analysis of heart rate variability and norepinephrine values confirm that brief nitrate administration increases sympathetic activity, a possible crucial trigger event in the development of nitrate tolerance, whereas prolonged nitrate treatment is not associated with prolonged neurohumoral activation.

Aged↗
PubMed2001

Interplay between inhibition of adenosine uptake and phosphodiesterase type 3 on cardiac function by cilostazol, an agent to treat intermittent claudication.

The authors have recently shown that cilostazol, a type 3 cyclic nucleotide phosphodiesterase (PDE3) inhibitor, has a much weaker positive inotropic effect than milrinone, a PDE3 inhibitor of similar potency. They have also shown that cilostazol inhibits adenosine uptake, whereas milrinone has no such effect. This study investigated the possible cardiac functional significance of cilostazol on adenosine uptake inhibition. In isolated rabbit hearts, 10 microM of cilostazol elevated adenosine concentration in interstitial dialysate (0.16 +/- 0.01 microM, or approximately 0.81 microM in the interstitial space when adjusted for recovery rate of microdialysis) and coronary effluent (0.69 +/- 0.03 microM ). The values are significantly higher than those for 10 microM of milrinone (0.11 +/- 0.1 microM in interstitial dialysate and 0.2 +/- 0.04 microM in coronary effluent). Although cilostazol increased contractility, heart rate, and coronary flow in isolated rabbit hearts, the effect on contractility and heart rate was significantly augmented in the presence of an adenosine A 1 receptor antagonist. Conversely, an adenosine A 1 receptor agonist or an adenosine uptake inhibitor attenuated the positive inotropic effect of milrinone. These results indicate that adenosine uptake inhibition by cilostazol increases interstitial and circulatory adenosine concentration, and antagonizes PDE3 inhibition-induced contractility and heart rate increases through an adenosine A 1 receptor-mediated mechanism.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2002

New mechanism of action for cilostazol: interplay between adenosine and cilostazol in inhibiting platelet activation.

Cilostazol, a potent phosphodiesterase 3 inhibitor and anti-thrombotic agent, was recently shown to inhibit adenosine uptake into cardiac myocytes and vascular cells. In the present studies, cilostazol inhibited [ H]-adenosine uptake in both platelets and erythrocytes with a median inhibitory concentration (IC ) of 7 micro M. Next collagen-induced platelet aggregation was studied and it was found that adenosine (1 micro M ), having no effect by itself, shifted the IC of cilostazol from 2.66 micro M to 0.38 micro M (p < 0.01). This shifting was due to an enhanced accumulation of cAMP in platelets and was significantly larger than that by the combination of adenosine and milrinone, which has no effect on adenosine uptake. Similarly, cilostazol, by blocking adenosine uptake, enhanced the adenosine-mediated cAMP increase in Chinese hamster ovary cells that overexpress human A receptor. Furthermore, the inhibitory effect of cilostazol on platelet aggregation in whole blood was significantly reversed by ZM241385 (100 n ), an A adenosine receptor antagonist, and by adenosine deaminase (2 U/ml). These data suggest that the inhibitory effects of cilostazol on adenosine uptake and phosphodiesterase 3 together elevate intracellular cAMP, resulting in greater inhibition of agonist-induced platelet activation.

Adenosine↗
PubMed1996

Posttransplant lymphoproliferative disease in pediatric liver transplantation. Interplay between primary Epstein-Barr virus infection and immunosuppression.

The incidence, risk factors, and outcome of posttransplant lymphoproliferative disease (PTLD) were examined for 298 children undergoing liver transplantation. The overall incidence of PTLD was 8.4% (25 of 298). Intensity of immunosuppression was found to be a major risk factor for the development of PTLD. Cyclosporine and tacrolimus when used as primary immunosuppression were associated with the development of PTLD in 4.3% and 6.6% of cases (P=NS). OKT3 and tacrolimus, when used as rescue therapy for steroid-resistant rejection, were associated with a comparable increase in the risk of developing PTLD (10.9% and 11.1%, P=NS). Patients requiring both OKT3 and tacrolimus to treat refractory rejection were at significantly increased risk for PTLD (28.1% vs. 4.3% or 6.6%, P<0.0001). PTLD was more common in patients who received transplants for Langerhans cell histiocytosis relative to other indications for transplantation (66% vs. 8.4%, P=0.0005). The data also support an association between primary Epstein-Barr virus (EBV) infections following transplantation and the development of PTLD. While only three patients were EBV seropositive before transplantation (14%), 19 patients were EBV seropositive at the time of diagnosis of PTLD (90%), confirming a high incidence of primary EBV infections in patients with PTLD (21 patients had both pre- and posttransplant EBV serologies). In this series, PTLD was associated with a mortality rate of 60%, and 12 of the 15 patients who died had persistent tumor at the time of death. Five of the 13 patients rendered disease-free developed ductopenic rejection. Of the four with severe liver dysfunction, two have undergone successful retransplantation and are alive without evidence of PTLD. In conclusion, intense immunosuppression using OKT3 and tacrolimus as rescue agents was associated with a significant increase in the incidence of PTLD. Primary EBV infection after transplantation further accentuated this risk. Independent of these risk factors, patients with Langerhans cell histiocytosis were at significantly increased risk for PTLD. The identification of high-risk patients should allow the development of protocols to screen patients for primary EBV infections and early indications of PTLD, as well as the institution of preemptive antiviral and antitumor therapies.

Adolescent↗