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Biomedical subjects

R Fagard

Publications and source records attributed to R Fagard.

At least 181 records · Page 10Linked to original sources
PubMed1993

The older hypertensive. Assessment and treatment.

A meta-analysis is presented of 8 therapeutic trials in elderly hypertensive patients. In an intention-to-treat analysis, cardiovascular mortality was decreased on average by 22% (95% confidence interval ranging from -32% to -10%). This decrease was explained by both a reduction in coronary mortality by 26% (-40% to -9%) and in cerebrovascular mortality by 33% (-50% to -9%). The effectiveness of therapy in terms of reducing cardiovascular mortality is not established with confidence in those trials where the diastolic blood pressure at randomization is below 95 mmHg or in the patients above 75 years of age. A goal blood pressure is not definitively established, but a reduction of the systolic blood pressure to about 150 mmHg may be optimal. Extrapolation of the trial results to the elderly population with systolo-diastolic hypertension at large seems acceptable for the western population, but may be premature for the Asian and African elderly. Beta-blockers and especially diuretics are recommended as first-line drugs in elderly patients with symptomless, uncomplicated hypertension, since the effectiveness of other drugs in reducing morbidity and mortality is not yet established. Recommendation for treatment of symptomless patients with isolated systolic hypertension may be premature. The ongoing Syst-Eur and Syst-Chin trials may provide further information.

Aged↗
PubMed1993

Nitrendipine in older patients with isolated systolic hypertension: second progress report on the SYST-EUR trial.

This report from the double-blind placebo-controlled SYST-EUR trial investigated whether modern antihypertensive drugs are suitable for maintaining long-term BP control in older (> or = 60 years of age) subjects with isolated systolic hypertension (SBP 160-219 mmHg and DBP < 95 mmHg). Active treatment consisted of nitredipine (10-40 mg/day) with the possible addition of enalapril (5-20 mg/day) and hydrochlorothiazide (12.5-25 mg/day), if necessary to reduce SBP to < 150 mmHg and by > or = 20 mmHg. Matching placebos were used in the control group. This analysis was restricted to 18 months of follow-up. The placebo (n = 456) and active treatment (n = 485) groups had similar characteristics at randomisation (sitting pressure 176/85 mmHg; age 73 years). SBP fell (P < 0.001) on average 10 mmHg more on active treatment than on placebo and DBP 4 mmHg more. Fewer patients remained on monotherapy in the placebo than in the active treatment group (P < 0.001); on placebo the second and third line medications were started earlier (P < 0.001). Nitrendipine tablets were discontinued in nine patients on placebo and in 29 patients assigned to active treatment (P < 0.001). In conclusion, a significant BP reduction can be achieved and maintained in older patients with isolated systolic hypertension treated with a calcium antagonist (associated with a converting-enzyme inhibitor and a thiazide, where necessary). Whether this BP reduction results in a clinically meaningful decrease of cardiovascular complications is under investigation.

Aged↗
PubMed1993

Cardiac variables and blood pressure as determinants of left ventricular inflow velocities.

The determinants of the left ventricular diastolic transmitral flow pattern, measured by use of Doppler velocimetry, were assessed in 40 patients referred for hypertension. The ratio of the atrial to early filling peak velocity (A/E ratio) averaged 0.82 +/- 0.23, BP 156 +/- 19/100 +/- 13 mmHg and left ventricular mass 220 +/- 57. In multiple regression analysis the A/E ratio was independently and positively related to age (P < 0.001) and BP (P < 0.001) and inversely to the fractional shortening of the left ventricular internal diameter (P < 0.01) and left atrial size at end-systole (P < 0.05); these variables accounted for 71% of the variance of the A/E ratio. The peak flow velocity during atrial contraction was positively and independently related to age (P < 0.001), BP (P < 0.05) and heart rate (P < 0.05); early filling velocity decreased with age (P < 0.001) and was positively related to heart rate (P < 0.01), left atrial diameter (P < 0.01) and fractional shortening (P < 0.001). The weak positive associations of the A/E ratio with left ventricular mass (r = 0.32; P < 0.05) and wall thickness (r = 0.38; P < 0.05) did not persist in multiple regression analysis. In conclusion, the left ventricular diastolic filling indexes are related to age, BP, left atrial size and to systolic left ventricular function but left ventricular structural variables, as measured by echocardiography, are not significantly involved.

Adult↗
PubMed1992

Spleen protein tyrosine kinases TPK-IIB and CSK display different immunoreactivity and opposite specificities toward c-src-derived peptides.

Polyclonal antibodies have been raised against two synthetic peptides reproducing the 48-64 and 353-369 sequences of CSK, a protein tyrosine kinase implicated in the down-regulation of src-related protein kinases. Both antibodies specifically recognize recombinant CSK and a CSK-related 49 kDa protein tyrosine kinase present in spleen but they do not cross-react with purified TPK-IIB, a spleen protein tyrosine kinase sharing with CSK catalytic activity toward src kinases and incapability to autophosphorylate. CSK and TPK-IIB once resolved from each other by heparin-Sepharose affinity chromatography, display opposite specificities toward synthetic peptides reproducing the sequences around the main phosphoacceptor residues of pp60c-src, namely Tyr-416 and Tyr-527. These data support the view that TPK-IIB and CSK may exert opposite effects on the activity of src-related protein tyrosine kinases.

Amino Acid Sequence↗
PubMed1992

The increase in blood pressure with age and body mass index is overestimated by conventional sphygmomanometry.

This cross-sectional study investigated whether the technique of blood pressure measurement used (conventional sphygmomanometry vs. ambulatory monitoring) affects the relation between blood pressure and both age and body mass index. Two independent data sets were analyzed. The first comprised 328 subjects (48% men) drawn from the population of a small Belgian town, and the second comprised 776 Irish bank employees (51% men). Age ranged from 17 years to 81 years, and body mass index (weight (kg)/height (m)2) ranged from 16.6 to 40.2. Twenty-four-hour ambulatory blood pressure was lower than blood pressure measured by a nurse in both the Belgian population sample (118/71 mmHg vs. 122/73 mmHg) and the Irish employees (118/72 mmHg vs. 119/76 mmHg). When blood pressure was measured by an observer, the well-established relations between systolic and diastolic blood pressure and both age and body mass index were evident. When the analyses were repeated using 24-hour measurements, the increment (cross-sectionally assessed) in blood pressure with age was weaker, especially in young and middle-aged subjects (20-60 years), while the increase in blood pressure with body mass index was also reduced. The within-subject differences between the conventional and ambulatory blood pressure measurements increased with older age and greater body mass index. Several other relations with blood pressure as the response variable may require revision in light of the present findings.

Adult↗
PubMed1992

The lymphocyte-specific tyrosine protein kinase p56lck is endocytosed in Jurkat cells stimulated via CD2.

Incubation of the human T cells, Jurkat, with two sets of activating anti-CD2 mAb (T11(2) + T11(3), D66 + T11(1)) induced delocalization of p56lck and CD2 receptors from the plasma membrane and increased the tyrosine kinase activity of p56lck. The anti-CD2 mAb combination (T11(2) + T11(3)) that produced the most rapid increase in p56lck kinase activity also induced the most rapid delocalization of the kinase. In stimulated cells, both p56lck and CD2 receptors are detected in cytoplasmic vesicles. The internalization of p56lck in endocytic vesicles was established by confocal microscopy. By double staining it was shown that only part of the p56lck colocalized with the internalized CD2 receptor suggesting distinct sorting processes. Internalization of p56lck appeared to be specific of CD2 stimulation as: 1) in Jurkat cells triggered with an anti-CD3 mAb, p56lck was not internalized whereas CD3 receptors were completely endocytosed; 2) when cells were stimulated via CD4, the kinase and CD4 receptors remained associated with the plasma membrane. In addition, internalization of p56lck upon stimulation of CD2 receptors was not modified in CD2+/CD3-Jurkat cells indicating that CD3 is not involved in this process. The identification of different subcellular localizations of p56lck in resting and stimulated T cells should represent an important step in the definition of its functional activity.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1992

Both T cell receptor (TcR)-CD3 complex and CD2 increase the tyrosine kinase activity of p56lck. CD2 can mediate TcR-CD3-independent and CD45-dependent activation of p56lck.

T cell activation by triggering the T cell receptor (TcR)-CD3 complex leads to a dramatic increase in tyrosine phosphorylation of multiple cellular proteins. To date, there has been no direct evidence on the identity of the tyrosine kinase activity implicated in this signaling pathway. In this study, we demonstrate that activation of human T cells with anti-CD3 monoclonal antibody increases tyrosine kinase activity of p56lck. This extends our previous findings which demonstrated the involvement of p56lck kinase activity in the CD2 signal transduction pathway. The results from peripheral blood lymphocytes and Jurkat cell line showed in both cases an early and transient change in the specific activity of p56lck, followed by a shift to a higher apparent molecular mass. Therefore, to test directly the role of TcR-CD3 in CD2-induced activation of p56lck, we utilized mutant variants of the Jurkat cell line lacking in cell surface TcR-CD3. We found that cell surface expression of TcR-CD3 is not required for the activation of p56lck via CD2 but is necessary for the appearance of the reduced-electrophoretic-mobility form of p56lck observed after CD2 triggering. By isolating CD45- mutants from Jurkat cells, we observed that surface expression of the tyrosine phosphatase CD45 is required in order to increase p56lck activity following CD2 stimulation, while CD4-induced activation of the kinase remained unchanged. These data provide evidence for a specific functional linkage between CD2 and p56lck, in which CD45 may play an essential role.

Antibodies, Monoclonal↗
PubMed1992

Treatment of the older hypertensive: paradigms, practices, and proofs.

Recent outcome trials in patients above age 60 with systolo-diastolic hypertension are reviewed. The meta-analysis suggests that antihypertensive drug therapy can decrease cardiovascular and coronary mortality in selected patients. Based on these studies it is suggested that antihypertensive drug therapy is indicated in patients between age 60 and 75 when the diastolic pressure remains above 95 mmHg after repeated measurements. A target for systolic b.p. is not definitely established but a pressure of 150 mmHg may serve as a temporary proposal. Whether uncomplicated isolated systolic hypertension in symptomless patients should be treated is still under investigation.

Aged↗
PubMed1992

Effects of baroceptor and cardiopulmonary reflexes on neural control of heart rate in normal man, as assessed by power spectral analysis.

This study was designed to establish the neurally-mediated effects of baroceptor and cardiopulmonary reflexes on heart rate in normal subjects. We therefore studied the effects of various interventions, able to modify the activity of arterial baroreceptors and cardiopulmonary receptors, on the power spectrum of the R-R interval in nine healthy men. To confirm the efficacy of these interventions left ventricular volume was monitored using a portable radionuclide probe. Isosorbide dinitrate (5 mgm sublingually) while sitting unloads both baroreceptors and the cardiopulmonary receptors; it decreased left ventricular end-diastolic volume (p < 0.01) and the mean R-R interval (p < 0.005), increased the power of the low-frequency (LF) component of the R-R interval (p < 0.01), decreased the power of the high-frequency (HF) component (p < 0.005) and increased the LF/HF ratio (p < 0.05). The application of cuffs around the thighs in the supine position, which unloads only cardiopulmonary receptors, decreased left ventricular end-diastolic volume (p < 0.05) but did not affect mean R-R interval, LF component, HF component and LF/HF ratio (p > or = 0.10). Leg raising, which loads only cardiopulmonary receptors, increased left ventricular end-diastolic volume (p < 0.05) and did not affect the mean R-R interval, LF component, HF component and LF/HF ratio (p > or = 0.10). In conclusion, our data suggest that, in normal man, baroreceptor unloading increased sympathetic and decreased parasympathetic neural control of heart rate; cardiopulmonary reflexes do not appear to have a direct neurally mediated effect on heart rate.

Adult↗
PubMed1992

Twenty-four hour blood pressure monitoring in the Syst-Eur trial.

This article describes the objectives and protocol of a study on ambulatory blood pressure in elderly patients with isolated systolic hypertension. This study constitutes an optional side-project to the Syst-Eur trial. The multicentre Syst-Eur trial investigates whether antihypertensive treatment of elderly patients with isolated systolic hypertension will influence the incidence of stroke. Secondary endpoints include cardiovascular events, such as myocardial infarction. The main objective of the side-project is to investigate whether ambulatory blood pressure monitoring will improve the prediction of cardiovascular complications based on blood pressure measurement in the clinic. The side-project also provides the opportunity to evaluate the diurnal profile of blood pressure in elderly patients with isolated systolic hypertension randomized to placebo or active antihypertensive treatment.

Aged↗
PubMed1992

Interleukin 4 inhibits IL-2-induced proliferation of a human T-leukemia cell line without interfering with p56-LCK kinase activation.

Recently we described the establishment in culture and the immunophenotypic and functional characteristics of a human T-leukemia line TALL-103/2 derived from the T-cell receptor (TCR)-gamma/delta subset of T-lymphocytes. TALL-103/2 cells are absolutely dependent on interleukin 2 (IL-2) for their growth and survival in culture and thus provide a model cell line for studies of IL-2 signal transduction in a TCR-gamma/delta T-cell. In this report, we focus on the regulation of SRC-family protein tyrosine kinases (PTKs) by IL-2. TALL-103/2 cells were found to contain p56-LCK, p59-FYN, p62-YES and p53/56-LYN. Stimulation of growth factor-deprived TALL-103/2 cells with IL-2, however, induced increases in the relative activity only of the p56-LCK kinase. This IL-2-mediated increase in LCK kinase activity was manifested both by increased kinase autophosphorylation and by increased phosphorylation of the exogenous substrate enolase during in vitro kinase assays. Furthermore, immunoblot assays determined that the levels of p56-LCK protein were unaltered by IL-2-treatment, indicating that the measured elevations in LCK kinase activity reflected an increase in the specific activity of this PTK. In TALL-103/2 cells, IL-2 stimulated concentration-dependent increases in p56-LCK activity that displayed rapid and transient kinetics: detectable increases occurred within 1 minute after IL-2 stimulation, peaked at 10 minutes, and declined to baseline levels by 30 minutes. Treatment of TALL-103/2 cells with IL-4 abrogated IL-2-initiated proliferation, but did not inhibit IL-2-mediated activation of p56-LCK.(ABSTRACT TRUNCATED AT 250 WORDS)

Dose-Response Relationship, Drug↗
PubMed1992

Effect of physical training on systemic and brachial artery haemodynamics in normal men.

The effect of endurance training on resting systemic and brachial haemodynamics was studied in 27 normal sedentary volunteers using a randomized cross-over design. After four months of physical training, peak oxygen uptake and physical working capacity at a heart rate of 130 beats/min (PW130) were increased by 16% (p less than 0.01) and 29% (p less than 0.001), respectively. At end-diastole left ventricular wall thickness was increased (p less than 0.01), whereas internal diameter was not changed. However, the change in internal diameter was positively related (r = 0.44, p less than 0.036) to the change in PWC130, indicating that the internal diameter increased, particularly in those subjects with the greatest increase in exercise capacity. The systemic haemodynamic adaptation to training was characterized by an increased stroke volume and concomitant reduction in heart rate so that cardiac output was not changed. On the other hand, brachial blood flow decreased by 36% on average. The change in blood flow was negatively related (r = -0.43, p = 0.03) to the change in PWC130 after training. Half the number of subjects were restudied after a four-month detraining period. The echocardiographic and Doppler variables tended to return to the pretraining level.

Adult↗
PubMed1992

The protein tyrosine kinase p56lck inhibits CD4 endocytosis by preventing entry of CD4 into coated pits.

The lymphocyte glycoprotein CD4 is constitutively internalized and recycled in nonlymphoid cells, but is excluded from the endocytic pathway in lymphocytic cells (Pelchen-Matthews, A., J. E. Armes, G. Griffiths, and M. Marsh. 1991. J. Exp. Med. 173: 575-587). Inhibition of CD4 endocytosis is dependent on CD4 expressing an intact cytoplasmic domain and is only observed in cells where CD4 can interact with the protein tyrosine kinase p56lck, a member of the src gene family. We have expressed p56lck, p60c-src, or chimeras of the two proteins in CD4-transfected NIH-3T3 or HeLa cells. Immunoprecipitation of CD4 and in vitro kinase assays showed that p56lck and the lck/src chimera, which contains the NH2 terminus of p56lck, can associate with CD4. In contrast, p60c-src and the src/lck chimera, which has the NH2 terminus of p60c-src, do not associate with CD4. Endocytosis assays using radioiodinated anti-CD4 monoclonal antibodies demonstrated that coexpression of CD4 with p56lck, but not with p60c-src, inhibited CD4 endocytosis, and that the extent of the inhibition depended directly on the relative levels of CD4 and p56lck expressed. The uptake of mutant CD4 molecules which cannot interact with p56lck was not affected. Measurement of the fluid-phase endocytosis of HRP or the internalization of transferrin indicated that the effect of p56lck was specific for CD4, and did not extend to other receptor-mediated or fluid-phase endocytic processes. Immunogold labeling of CD4 at the cell surface and observation by electron microscopy demonstrated directly that p56lck inhibits CD4 endocytosis by preventing its entry into coated pits.

3T3 Cells↗
PubMed1992

The diurnal blood pressure profile. A population study.

This population study included 399 subjects, of whom 370 (93%) showed a significant diurnal blood pressure (BP) rhythm. The nocturnal BP fall was normally distributed and averaged 16 +/- 9 mm Hg systolic and 14 +/- 7 mm Hg diastolic (mean +/- SD). The amplitude of the diurnal BP curve followed a positively skewed distribution, with a mean of 16 +/- 5 mm Hg for systolic BP and 14 +/- 4 mm Hg for diastolic BP. The daily BP maximum occurred at 15:54 +/- 4:47 for systolic BP and at 15:11 +/- 4:20 for diastolic BP. Thirty-four subjects were reexamined after a median interval of 350 days. The test for the presence of a significant diurnal rhythm was discordant in only two subjects. Repeatability (twice the standard deviation of the differences between paired recordings expressed as a percentage of the mean) varied from 11 to 25% for the 24 h, daytime, and overnight BP, and from 76 to 138% for the parameters describing the diurnal BP rhythm. In nine subjects with an initial night/day ratio of mean BP less than 0.78, the nighttime BP was significantly increased at the repeat examination, whereas the opposite tendency was observed in nine subjects with an initial ratio greater than 0.87. In conclusion, the distribution of the nocturnal BP fall is unimodal. The reproducibility of the ambulatory BP is satisfactory for the level of BP and for the presence of a diurnal BP rhythm, but not for the parameters of the diurnal BP curve. Thus, one 24 h recording is insufficient to fully characterize an individual's diurnal BP profile.

Adult↗
PubMed1992

Interaction of human immunodeficiency virus glycoprotein 160 with CD4 in Jurkat cells increases p56lck autophosphorylation and kinase activity.

The tyrosine protein kinase p56lck, specifically expressed in lymphoid cells, undergoes modifications of its autophosphorylation and kinase activity when these cells are triggered by mAbs to the T cell determinants. The kinase activity and the autophosphorylation of p56lck were analysed following triggering Jurkat cells with the human immunodeficiency virus (HIV) glycoprotein gp160 which interacts with CD4: both the autophosphorylation and the kinase activity are increased within 1-5 min following addition of gp160, this increase is maximum at 5 min and is followed by a gradual return to the basal level within 2 h. Similar to observations made with anti-CD4 mAbs the increase in kinase activity of p56lck is not associated with changes in the gel mobility nor is it associated with T cell activation. Triggering of T cells with a combination of anti-CD3 mAbs which activate T cells but not p56lck and gp160 greatly potentiated the increase of p56lck autophosphorylation and kinase activity.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1992

Automated versus observer blood pressure as determinants of left ventricular structure.

We studied the contribution of automated blood pressure measurements to the variation in left ventricular structural characteristics, independent of pressure measured by an observer. Thirty eight patients referred for hypertension underwent 24 h blood pressure monitoring. Echocardiography and repeated blood pressure measurements were taken on 2 different days by an observer and by the use of the Dinamap 845 device. Blood pressure by the observer averaged 157/101 mmHg, Dinamap pressure 152/94 mmHg, 24 h pressure 137/92 mmHg, left ventricular mass 218 g and mean wall thickness 12.7 mm. Left ventricular mass and wall thickness were related (P < 0.05) to systolic observer (r = +0.46; r = +0.47), Dinamap (r = +0.42; r = +0.41) and 24 h blood pressure (r = +0.46; r = +0.53); the correlation coefficients were lower (r = +0.35 to +0.51; P < 0.05) for diastolic pressure. These relations were independent of age, gender, height, weight and heart rate. The Dinamap pressure did not contribute to the difference in the left ventricular structural characteristics, independent of the observer pressure. The 24 h ambulatory pressure explained a small but significant (P < 0.05) fraction of the variation in mean wall thickness in addition to the observer pressure. Left ventricular mass and mean wall thickness were not related to the day-night difference in blood pressure (P > 0.25). In conclusion, observer, Dinamap and ambulatory pressures are significantly related to cardiac structural variables. Ambulatory pressure, but not Dinamap pressure, explains a small part of wall thickness variance in addition to well-standardized pressure measured by an observer.

Adult↗