In search of hypertensive mechanisms : use of pharmacological probes

Over the past decade, a great deal of clinical research of our group has been directed toward two major areas of the pathophysiology of hypertension: (1) the significance of the renin-angiotensin system; and (2) the role of serotonin. Serotonin was identified by Irvin Page as, in his words, a "nuisance factor" interfering with his attempt to isolate and identify angiotensin II,in which he fortunately succeeded. The first part of this thesis deals with clinical aspects of Page's second moiety, angiotensin II, and the enzymatic cascade involved in its formation. The second part of the thesis entertains the idea that the "nuisance factor" serotonin deserves more clinical attention than it had enjoyed in the pas

Effect of a single oral dose of milrinone on left ventricular diastolic performance in the failing human heart

In 14 patients with severe congestive heart failure, left ventricular pressure (measured by tip manometer) and derived variables were measured before and every 10 minutes after administration of oral milrinone (10 mg) for 50 minutes along with measurements of coronary sinus blood flow and drug plasma levels. Arterial and coronary sinus catecholamines were measured only before and 50 minutes after milrinone. Left ventricular pressure, volume (as determined by angiography) and derived indexes were simultaneously assessed at matched atrial paced heart rate before and 60 minutes after milrinone. Three patients who did not achieve a therapeutic plasma level (less than 150 ng/ml) were excluded. Peak negative first derivative of left ventricular pressure (-dP/dt) progressively and significantly increased (10%) together with a decrease in the two exponential time constants of relaxation, namely, Tau 1 (19%) and Tau 2 (22

Increased interleukin (IL)-7Rα expression in salivary glands of patients with primary Sjögren's syndrome is restricted to T cells and correlates with IL-7 expression, lymphocyte numbers and activity

Objective: To identify interleukin (IL)-7Rα expression in the labial salivary gland (LSG) of patients with primary Sjögren's syndrome (pSS) and non-Sjögren's syndrome sicca (nSS-sicca) and to study its correlation with glandular infl ammation and IL-7 expression. Methods: The presence of infi ltrating immune cells and IL-7Rα cells in infl amed LSG of patients with pSS (n=12) and nSS-sicca controls (n=7) was studied by immunohistochemistry and fl uorescence activated cell sorting analysis upon tissue digestion (n=15 and n=13, respectively). Additionally, the correlations of IL-7Rαcells with hallmark disease parameters of pSS, major infi ltrating infl ammatory cells and IL-7 were assessed. Results: In the LSG of patients with pSS increased numbers of IL-7Rα cells were found as compared with nSS-sicca patients. IL7Rα cells strongly correlated with the lymphocytic focus score, IL-7 expression, the decrease in percentage of IgA plasma cells and numbers of CD3 T cells, CD20 B cells, and CD1a and CD208 myeloid dendritic cells. Analysis of isolated cells from the LSG demonstrated strongly increased percentages of IL-7Rα CD3 T cells in pSS as compared with nSS, showing abundant IL-7Rα expression on both CD4 and CD8 T cells. Other CD45 leucocytes and CD45- tissue cells scarcely expressed IL-7Rα. Percentages of IL-7RαT cells also signifi cantly correlated with glandular infl ammation. Conclusions: This study shows the presence of increased IL-7Rα T cells in the LSG of patients with pSS and their association with the severity of sialadenitis, disease parameters and IL-7 expression. Considering the immunostimulatory ability of IL-7Rα T cells and IL-7, this suggests that IL-7(R)-dependent T cell-driven immune activation plays an important role in infl ammation in pSS

Treatment with cyclosporin and risks of graft rejection in male kidney and heart transplant recipients with non-O blood

In a consecutive series of 146 kidney transplant recipients treated with cyclosporin A a strong correlation between matching for the HLA-A, HLA-B, and HLA-DR loci specificities and outcome of the grafts was observed in male recipients with non-O blood groups. Such a beneficial effect of matching was not found in female patients or male patients with blood group O. In these patients survival of the grafts at one year was good irrespective of the number of HLA-A, B, and DR mismatches. Also in 47 male heart transplant recipients immune responsiveness against mismatched HLA antigens was related to blood group. A significantly higher incidence of rejection episodes was observed in male patients with non-O blood groups (n = 32) than in those with blood group O (n = 15). Matching for HLA-DR reduced the number of acute rejection episodes in male patients with non-O blood. These findings may help explain the controversial repor