Search PubMed⌕ Search

Biomedical subjects

P Rudd

Publications and source records attributed to P Rudd.

At least 19 recordsLinked to original sources
PubMed2001

Cross-talk between the p42/p44 MAP kinase and Smad pathways in transforming growth factor beta 1-induced furin gene transactivation.

Furin, a predominant convertase of the cellular constitutive secretory pathway, is known to be involved in the maturation of a number of growth/differentiation factors, but the mechanisms governing its expression remain elusive. We have previously demonstrated that transforming growth factor (TGF) beta 1, through the activation of Smad transducers, regulates its own converting enzyme, furin, creating a unique activation/regulation loop of potential importance in a variety of cell fate and functions. Here we studied the involvement of the p42/p44 MAPK pathway in such regulation. Using HepG2 cells transfected with fur P1 LUC (luciferase) promoter construct, we observed that forced expression of a dominant negative mutant form of the small G protein p21(ras) (RasN17) inhibited TGF beta 1-induced fur gene transcription, suggesting the involvement of the p42/p44 MAPK cascade. In addition, TGF beta induced sustained activation/phosphorylation of endogenous p42/p44 MAPK. Further-more, the role of MAPK cascade in fur gene transcription was highlighted by the use of the MEK1/2 inhibitors, PD98059 or U0126, or co-expression of a p44 antisense construct that repressed the induction of fur promoter transactivation. Conversely, overexpression of a constitutively active form of MEK1 increased unstimulated, TGF beta 1-stimulated, and Smad2-stimulated promoter P1 transactivation, and the universal Smad inhibitor, Smad7, inhibited this effect. Activation of Smad2 by MEK1 or TGF beta 1 resulted in an enhanced nuclear localization of Smad2, which was inhibited upon blocking MEK1 activity. Our findings clearly show that the activation of the p42/p44 MAPK pathway is involved in fur gene expression and led us to propose a co-operative model whereby TGF beta 1-induced receptor activation stimulates not only a Smad pathway but also a parallel p42/p44 MAPK pathway that targets Smad2 for an increased nuclear translocation and enhanced fur gene transactivation. Such an uncovered mechanism may be a key determinant for the regulation of furin in embryogenesis and growth-related physiopathological conditions.

Active Transport, Cell Nucleus↗
PubMed2001

Involvement of Smads in TGFbeta1-induced furin (fur) transcription.

Furin is recognized as being one of the main convertases of the cellular constitutive secretion pathway but the mechanisms regulating its expression are still unknown. We have previously demonstrated that TGFbeta1 up-regulates its own converting enzyme, furin, creating a novel activation/regulation cycle of potential importance in a variety of physiological and pathophysiological conditions. The fur (fes upstream region) gene is regulated via three alternative promoters; P1, P1A, and P1B. To gain insight into the molecular mechanism(s) underlying this up-regulation, we performed transient cell transfections with P1, P1A, and P1B promoter luciferase constructs. Transfection experiments in HepG2 cells revealed that fur P1 promoter is the strongest and the most sensitive to TGFbeta1 stimulation (5 ng/ml) (3.2-fold vs. 2.4-fold for P1A and 2.1-fold for P1B). Cotransfection with either a dominant negative mutant form of Smad2 [Smad2(3SA)] or a known Smad inhibitor [Smad7] inhibit constitutive and TGFbeta1-induced luciferase activity indicating the participation of endogenous Smads. Increased levels of TGFbeta1-induced transcriptional activation of the P1 promoter by overexpression of Smad2 and/or Smad4 is greatly reduced in the presence of Smad2(3SA) and completely inhibited by Smad7, suggesting the participation of endogenous Smad2/Smad4 complexes. Furthermore, the fork-head activin signal transducer (FAST-1), known to interact with Smad2/Smad4 complexes, is a potent stimulator of TGFbeta1-induced transactivation of the fur P1 promoter. Five prime-deletion analysis of this promoter identified the proximal region (between positions -8734 and -7925), as the nucleotide stretch that carries most of the transcriptional activation of fur P1 promoter by Smad2. Overall, the present data demonstrate that Smad2 and Smad4 possibly in complex with FAST-1 or other DNA binding partners participate in the constitutive and inducible transactivation of the fur P1 promoter. This represents the first detailed study of the transcriptional regulation of the fur gene.

Blotting, Northern↗
PubMed1999

Cell-specific glycoforms of sialoadhesin and CD45 are counter-receptors for the cysteine-rich domain of the mannose receptor.

We previously reported that CR-Fc, an Fc chimeric protein containing the cysteine-rich (CR) domain of the mannose receptor, binds to marginal zone metallophilic macrophages (Mo) and B cell areas in the spleen and to subcapsular sinus Mo in lymph nodes of naive mice (CR-Fc(+) cells). Several CR-Fc ligands were found in spleen and lymph node tissue lysates using ligand blots. In this paper we report the identification of two of these ligands as sialoadhesin (Sn), an Mo-specific membrane molecule, and the leukocyte common antigen, CD45. CR-Fc bound selectively to Sn purified from spleen and lymph nodes and to two low molecular weight isoforms of CD45 in a sugar-dependent manner. CR-Fc binding and non-binding forms of Sn, probably derived from CR-Fc(+) and CR-Fc(-) cells respectively, were selected from spleen lysates. Analysis of the glycan pool associated with the CR-Fc-binding form revealed the presence of charged structures resistant to sialidase, absent in the non-binding form, that could correspond to sulfated structures. These results confirm the identification of the CR region of the mannose receptor as a lectin. We also demonstrate that the same glycoprotein expressed in different cells of the same organ can display distinct sugar epitopes that determine its binding properties.

Animals↗
PubMed1998

Compliance with antihypertensive therapy: raising the bar of expectations.

Recent advances in the effectiveness of antihypertensive therapies and the measurement of medication-taking behavior have raised the bar of expectations, both for patients and prescribing clinicians. This article reviews the principal findings and makes recommendations to improve pill taking among patients with hypertension. It summarizes several studies related to hypertension epidemiology, component behaviors contributing to suboptimal compliance with prescribed antihypertensive medications, the direct and indirect costs of nonadherent behaviors, and measures of pill-taking behavior. Based on this analysis, current levels of hypertension detection, treatment, and control remain suboptimal. Heuristics for adjusting antihypertensive regimens may be misleading and too simplistic. More than half of those patients failing to achieve goal blood pressure display suboptimal compliance rather than an inadequate regimen. In conclusion, there is a need for enhanced sophistication about medication-taking behavior, especially for hypertension, so that more patients with this condition can fully benefit from effective treatments.

Ambulatory Care↗
PubMed1995

A multicenter comparison of adverse reaction profiles of isradipine and enalapril at equipotent doses in patients with essential hypertension.

A multicenter, randomized, double-blind trial compared the safety and efficacy of the dihydropyridine isradipine with the angiotensin-converting enzyme (ACE) inhibitor enalapril given twice daily for mild hypertension. 160 patients received either isradipine (starting at 1.25 mg twice daily) or enalapril (starting at 2.5 mg twice daily) for 10 weeks. The dosage was increased if the average sitting diastolic blood pressure was > 90 mm Hg. Significantly greater mean reductions in systolic blood pressure were seen after 2, 6, and 8 weeks of isradipine. However, by the end of the trial, 83% of patients receiving isradipine and 78% receiving enalapril showed a decrease of at least 5 mm Hg in sitting diastolic blood pressure to a level below 96 mm Hg. Possible or probable drug-related adverse effects were reported in 36% of patients showing a good antihypertensive response to isradipine, and in 30% of those who responded to enalapril. There was a trend for a lower frequency of adverse effects in isradipine non-responders (25%) and a higher frequency in enalapril non-responders (43%). Pruritus, dizziness, edema, and fatigue were reported more often with isradipine, and cough and changed bowel habits were more common with enalapril. The relationship between the pattern of adverse effects and the extent of blood pressure reduction may be dependent on the mechanism of action of a drug. In responders, isradipine and enalapril showed differing patterns, but a similar overall incidence of adverse effects.

Adolescent↗
PubMed1995

Clinicians and patients with hypertension: unsettled issues about compliance.

Ambulatory treatment of hypertension depends largely on long-term oral medications to lower blood pressure and delay or prevent cardiovascular morbidity and mortality. Failure to achieve the therapeutic goal may reflect biologic, pharmacologic, or behavioral factors. Ignoring behavioral factors may result in unnecessary or even dangerous regimen escalation. More than half of patients with insufficient reductions in blood pressure display suboptimal medication compliance as assessed by pill count or bioassay. Once-daily dosing may be an important part of enhancing compliance, patient convenience, and regimen simplification; however, drug concentrations may be subtherapeutic when dosing delays or omissions occur. Electronic monitoring data in hypertension, glaucoma, seizure disorders, and other diseases indicate that 50% to 60% of patients adhere well to prescribed regiments, that 5% to 10% adhere poorly, and that the 30% to 45% adhere to an intermediate but markedly variable degree. A growing body of literature offers empirical support for focused and personalized interventions.

Ambulatory Care↗
PubMed1995

Short communication: selective placental transport of maternal IgG to the fetus.

During pregnancy there is a dramatic reduction in the serum levels of agalactosyl IgG (G0IgG) in both normal women and those with rheumatoid arthritis. In order to determine if a similar reduction in G0IgG were apparent in fetal serum, a comparison of the galactose content of IgG from nine paired samples of umbilical vein or fetal blood and peripheral maternal serum, at gestational ages ranging from 16-41 weeks was performed. The full-term maternal IgG samples were highly galactosylated, so confirming previous observations of reduced G0IgG levels during pregnancy. In addition every paired sample of fetal IgG had a higher level of galactosylation than the corresponding maternal IgG. Therefore, during pregnancy there is both a reduced biosynthesis of the G0IgG glycoform by the mother, and a restriction of its transport across the placenta. The ratio of estimated G0IgG in fetal and maternal serum was found to be related to changes in IgG transport, and in particular the active transport of IgG1 across the placenta during gestation. Our data suggest that the placental IgG transport mechanism is either carbohydrate independent by discriminating for IgG1, or is carbohydrate dependent selecting for highly galactosylated IgG glycoforms. This study emphasizes the need for further investigations on the biological function of G0IgG in normal physiological states, in addition to disease states, such as juvenile and adult rheumatoid arthritis, where elevated G0IgG levels correlate with disease activity.

Arthritis, Rheumatoid↗
PubMed1995

Lectin-carbohydrate interactions in disease. T-cell recognition of IgA and IgD; mannose binding protein recognition of IgG0.

Two disease associated lectin-carbohydrate interactions have been studied. (1) A T-cell surface lectin which binds IgA1 and IgD is expressed on CD4+ and CD8+ T-lymphocytes in a number of diseases including systemic lupus erythematosus, rheumatoid arthritis (RA), Behcet's disease and IgA nephropathy. We have demonstrated that calcium independent binding to this receptor is mediated by the O-linked disaccharide Gal beta 3GalNAc which is associated with the hinge regions of both IgA1 and IgD. (2) In rheumatoid arthritis the proportion of IgG0 glycoform populations lacking terminal galactose increases. We have shown that terminal GlcNAc residues on oligosaccharides in the Fc region of IgG0 can bind to the C-type lectin, serum mannose binding protein, and thus activate the classical complement pathway. This provides a mechanism of activation of the complement system not available to the other classes of IgG glycoforms.

Carbohydrate Metabolism↗
PubMed1993

Gaps in cardiovascular medication taking: the tip of the iceberg.

OBJECTIVE: To search for major gaps in medication-taking behavior predisposing patients to cardiovascular morbidity and mortality. DESIGN: Convenience sample; cohort prospectively followed for < or = 5 months. SETTING: General internal medicine and cardiology clinics in a university medical center. PATIENTS: From among 893 patients, the authors identified 132 eligible individuals and entered 33 subjects (25%) with chronic cardiovascular conditions, 1-3 chronic oral medications for these conditions, overall regimen of < or = 6 drugs, regular visits at 1-3-month intervals, literacy in English, willingness to use electronic monitors, and physician permission to participate. OUTCOME MEASURES: Medication compliance rates and patterns by patient self-report, physician estimates, pill count, and electronic monitoring of pill vial opening. RESULTS: Despite moderately complex regimens (5.4 +/- 0.5 pills daily; range 1-11), most subjects took most medications according to the prescription: median intervals between pill vial openings were 1.00, 0.50, and 0.43 days for once, twice, and three times daily dosing, respectively. Medication-taking gaps of > or = 2 times the prescribed interdosing interval occurred for 48% of the patients. Patients' dosing patterns often produced "uncovered" intervals (mean duration 3.7 days, range 0-25) with doubtful pharmacologic effectiveness. These lapses were underestimated by patients and poorly perceived by their treating physicians, despite familiarity with their care. Baseline sociodemographic, psychosocial, medical system, or clinical characteristics did not predict the patterns or degrees of medication noncompliance. CONCLUSIONS: Major treatment gaps occur frequently, even in carefully selected ambulatory populations, and generally escape detection. The compliance patterns and gaps may contribute to reported excesses of cardiovascular morbidity and mortality.

Adult↗
PubMed1993

Antihypertensive medication-taking. Investigation of a simple regimen.

In search of strategies to improve compliance, we assessed medication-taking behavior among 19 ambulatory hypertensives, using both pill counts and electronic monitoring. The regimen consisted of one pill each day for < or = 63 weeks with return visits at 1 to 4 week intervals. The study population was 79% male, 68% white, and 16% black with mean (+/- SEM) age 58.4 +/- 2.5 years. Only 51% of the intervisit intervals displayed > or = 80% of vial openings within the desirable range (24 +/- 6 h). Pill counts detected only 2% of suboptimal interdosing intervals identified by electronic monitoring. Early changes in compliance correlated well with later changes (r = 0.83, P = .002). A few of the subjects exhibited a large deviation from the prescription, uncorrectable with drugs having a long duration of action. We conclude that (a) pill counts tend to overestimate patients' compliance rates; (b) changes in medication-taking behavior early in therapy may predict subsequent compliance rates; and (c) prolonging drug action may compensate for some imperfect medication-taking behavior.

Adult↗
PubMed1993

Partial compliance: implications for clinical practice.

Modern therapeutics unavoidably requires integration of a patient's medication-taking behavior in assessing the clinical response to treatment. Automatic escalation of the drug regimen whenever the treatment goal is not achieved carries major risks and should be discouraged. Medication-taking behavior, when studied carefully by dynamic measures like electronic monitors, displays marked inter- and intra-subject variability over time. Most deviations from the prescription are underdosings and occur randomly, rather than consistently or systematically. Such deviations are frequent, difficult to detect by traditional measures, and hard to predict from common baseline characteristics. Compliance tends to fall as dosing frequency rises above once daily. Better measures of medication-taking behavior permit evaluation of both adverse drug reactions and secondary resistance to therapy as resulting from pill taking itself. Negative consequences of partial compliance among hypertensive patients include marked increases in rates of rehospitalization and rates of coronary events. One alternative strategy to labor-intensive interventions for improving compliance is to develop longer-acting medications, which compensate in part for lapses in dosing frequency. Such a strategy reflects a search for therapeutic sufficiency rather than a rigid concordance between the prescription and medication-taking behavior.

Humans↗
PubMed1993

Characterization of three de novo derivative chromosomes 16 by "reverse chromosome painting" and molecular analysis.

We have analyzed three de novo chromosome 16 rearrangements--two with a 16p+ chromosome and one a 16q+--none of which could be fully characterized by conventional cytogenetics. In each case, flow karyotypes have been produced, and the aberrant chromosome has been isolated by flow sorting. The origin of the additional material has been ascertained by amplifying and labeling the DNA of the abnormal chromosome by degenerate-oligonucleotide-primer-PCR and hybridizing it in situ to normal metaphase spreads (reverse chromosome painting). Both 16p+ chromosomes contain more than 30 Mb of DNA from the short arm of chromosome 9(9p21.2-pter), while the 16q+ contains approximately 9 Mb of DNA from 2q37. The breakpoints on chromosome 16 have been localized in each case; the two breakpoints on the short arm are at different points within the terminal band, 16p13.3. The breakpoint on the long arm of chromosome 16 is very close to (within 230 kb of) the 16q telomere. Determination of the regions of monosomy and trisomy allowed the observed phenotypes to be compared with other reported cases involving aneuploidy for these regions.

Adolescent↗