Blood pressure responses to hypertension treatment and trends in cognitive function in patients with initially difficult-to-treat hypertension: a retrospective subgroup analysis of the Observational Study on Cognitive Function and SBP Reduction (OSCAR) study

J Clin Hypertens (Greenwich). 2012;14:78–84. ©2012 Wiley Periodicals, Inc.The Observational Study on Cognitive Function and SBP Reduction (OSCAR) provided opportunities to examine the influence of eprosartan on trends in cognitive performance in a large population of patients with difficult‐to‐treat hypertension (DTTH). A total of 4649 patients diagnosed retrospectively with DTTH, defined as systolic/diastolic blood pressure (SBP/DBP) ≥140/90 mm Hg despite use of at least 3 antihypertensive drugs during the month preceding the baseline visit comprised the intention‐to‐treat (ITT) cohort. The patients were given eprosartan‐based antihypertension therapy (EBT; 600 mg/d). Blood pressure and cognitive function parameters included significant (P<.001) differences for DTTH vs non‐DTTH patients such as older age, body mass index, SBP and pulse pressure (PP), and lower Mini‐Mental State Examination (MMSE) score. After EBT for 6 months, SBP/DBP in DTTH was 138.8±12.2/81.9±7.4 (ΔSBP−26±15.7; ΔDBP−11.4±9.8); PP was 57.0±10.8 (ΔPP−14.5±13.8) (all P<.001 vs baseline and non‐DTTH group). A total of 2576 patients (87.4%) responded to EBT (ie, SBP <140 mm Hg and/or ΔSBP ≥15 mm Hg, or DBP <90 mm Hg and/or ΔDBP ≥10 mm Hg); 1426 DTTH patients (48.4%) achieved normalized SBP/DBP (ie, SBP <140 mm Hg and DBP <90 mm Hg). ΔPP in DTTH‐isolated systolic hypertension (ISH) was −18.0±13.3 mm Hg (P=.003 vs DTTH‐systolic‐diastolic hypertension). End‐of‐EBT mean MMSE was 27.5±3.0 (P<.001 vs baseline). Blood pressure responses after EBT coincided with stabilization/improvement of MMSE in this retrospective investigation in DTTH patients. The average improvement in MMSE in DTTH patients was similar to that in non‐DTTH patients. EBT effects on PP may be relevant to the evolution of MMSE in DTTH‐ISH patients.

The Observational Study on Cognitive Function and SBP Reduction (OSCAR) was designed to examine the safety and tolerability of once‐daily therapy with eprosartan in a very large community‐dwelling population of patients with arterial hypertension recruited in 28 countries and managed in routine primary care. This study provided opportunities to examine the influence of the angiotensin receptor blocker (ARB) eprosartan on trends in cognitive performance in a large population of patients with high blood pressure (BP).The principal findings of OSCAR have been reported previously. ¹ A 6‐month period of antihypertensive therapy based on eprosartan was associated with a significant reduction in mean systolic BP (SBP) and a significant improvement in mean Mini‐Mental State Examination (MMSE) score (P<.0001 for both outcomes). In multiple linear regression, cognitive decline was demonstrated to be independently and inversely correlated with SBP reduction (odds ratio, 0.77; 95% confidence interval [CI], 0.73–0.82).The intention‐to‐treat (ITT) cohort of OSCAR comprised 25,745 adult patients with hypertension. This large number of patients enabled us to identify several large subgroups for further investigation, with the intention of adding to what are still sometimes limited epidemiologic data on specific types of patients.Recent revisions to extant European hypertension guidelines and first reports of new treatment options for this condition ² , ³ , ⁴ are indications that resistant hypertension is a pressing clinical priority. Poorly controlled high BP may be a factor in cognitive decline in older patients. Observations from several thousand patients in a real‐world survey may be instructive for the better management of this condition. Accordingly, we report here our findings in a retrospectively identified cohort of almost 3000 patients from the OSCAR population classified as having difficult‐to‐treat hypertension (DTTH) at baseline.     

Internalisation of the protease-activated receptor 1: role of the third intracellular loop and of the cytoplasmic tail

To analyse the mechanisms of PAR-1 internalisation, we constructed several PAR-1 mutants and stably expressed them in CHO cells. Our study shows that the Ser(306)-->Ala mutation (S306A), which eliminates a potential site of phosphorylation by PKC in the third intracellular loop of PAR-1, did not change the rate of phosphorylation but reduced the rate of thrombin-induced internalisation of the PAR-1 mutant (58 versus 78% of membrane PAR-1 in 15 min, p<0.005). Deletion of the last 43 amino acid residues of the PAR-1 cytoplasmic tail completely suppressed the thrombin phosphorylation of the mutated receptor and significantly reduced its internalisation upon activation. This deletion also inhibited the PMA-induced and the agonist-independent internalisation of the receptor. The Tyr(371)--> Ala mutation (Y371A), in a NPXXY motif of the seventh transmembrane domain of the receptor had no effect on the receptor behaviour. Our results indicate that both the C-tail and the third intracellular loop are involved in PAR-1 internalisation induced by thrombin while only the C-tail plays a role in the PMA-induced and in the agonist-independent PAR-1 internalisation.     

ECLA grading: a system of acne classification for every day dermatological practice]

BACKGROUND: Different acne gradings have been proposed: global grading, semi-global grading, quantitative grading and photographic grading. They are mainly used in clinical studies for the evaluation of acne treatment. However, it would be important for physicians to have an acne grade which would be useful for assessing acne lesions prior to treatment and following treatment efficacy. METHODS: Six French dermatologists developed an acne grading scaled called "ECLA" which only takes 2 minutes to fill out and specifically designed for use by dermatologist practitioners. In addition, the intra- and inter-observer reliability of the grading scale was assessed. RESULTS: This analysis demonstrated the excellent reliability of the ECLA grading scale both in terms of intra- and inter-observer variability except for the retentional factor. The cross physician reliability decreased with time specificity for the retention factor, indicating that previous training prior to a multicentric clinical study would be necessary. CONCLUSION: ECLA grading appears to be an interesting and useful tool in dermatology for the follow-up of acne patients.     

Increased proliferation of bone marrow-derived fibroblasts in primitive hypertrophic osteoarthropathy with severe myelofibrosis

Pachydermoperiostosis or primary hypertrophic osteoarthropathy (HOA) is a rare congenital growth disorder of connective tissue. We report a case of severe myelofibrosis in a patient with HOA. When cultured in vitro, patient bone marrow-derived fibroblasts displayed a high proliferative potential with a shortened doubling time (24 hours v 36 to 48 hours for normal fibroblasts). The role of platelet-derived growth factor (PDGF), previously implicated in the pathogenesis of secondary acquired myelofibrosis, was studied. HOA fibroblasts expressed an increased number of PDGF-BB binding sites (300,000 sites/cell v 200,000 sites/cell for normal fibroblasts) without any modification of affinity. The increased expression of PDGF-R beta appeared to result from an accelerated rate of PDGF-R beta resynthesis with normal kinetics of endocytosis. As a consequence, a several-fold increase of PDGF-R beta tyrosine kinase activity was observed. No autocrine mechanism of growth was suspected as neither spontaneous PDGF- R beta autophosphorylation nor mitogenic activity in HOA fibroblast- conditioned medium was detected. Patient serum and platelet lysate were less potent than controls in inducing [3H]thymidine incorporation into HOA fibroblasts. This was inconsistent with a paracrine mechanism of growth. In vitro, human serum or PDGF-BB were not more mitogenic for HOA than normal fibroblasts. High levels of cyclin D1, a putative oncogene, were detected in serum-deprived HOA fibroblasts. Cyclin D1 overexpression could be implicated in the accelerated growth of these cells. Our results suggest that the mechanism of fibroblastic proliferation observed in this case of myelofibrosis might differ from those reported in other acquired myeloproliferative syndromes and could be associated with an intrinsic abnormality of HOA fibroblast growth.     

Tissue-type plasminogen activator activity in HIV-associated HUS

Background: In children, haemolytic uraemic syndrome (HUS) is associated with high plasma plasminogen activator inhibitor type 1 (PAI-1), which may contribute to the persistence of renal glomerular and arteriolar thrombi. HUS has been described in HIV-infected patients, but the pathophysiology of HUS in these patients is poorly understood. The aim of the study was to investigate plasma fibrinolytic activity in 18 patients with HIV-associated HUS. Methods: We measured tissue type plasminogen activator (t-PA) and PAI-1 activities in the plasma of 18 HIV-infected patients with biopsy-proven HUS (HIV+/HUS+0 and 48 HIV-infected patients without HUS (HIV+/HUS-). Results: Patients with HUS had a significantly higher serum creatinine, a lower platelet count and an increased incidence of cytomegalovirus (CMV) infection (72% of patients HIV+/HUS+, vs 25% of patients HIV+/HUS-). Unexpectedly, plasma PAI-1 activity was similar in both groups. However, t-PA activity was significantly higher in HUS cases (11.5 vs 4.5 U/ml, P=0.001). Patients with CMV infection, with or without HUS, had significantly increased t-PA level (P=0.01). Multivariate analysis identified high t-PA (RR=9.21) and CMV infection (RR=3.36) as risk factors for HUS. Conclusion: This study provides evidence that HIV-infected patients with HUS have high plasma t-PA activity. PAI-1 plasma activity is not significantly increased, as opposed to non-HIV-associated HUS. Thus, in the setting of HIV infection, HUS cannot be attributed to decreased fibrinolytic activity.     

Perceptions regarding antimicrobial use and resistance among adult hospital patients in Saudi Arabian Ministry of Health (MOH) hospitals

BackgroundEducation, a key strategy within antimicrobial stewardship programmes (ASPs), has been mainly directed towards healthcare professionals and prescribers more than hospitalised patients.AimTo examine patients’ knowledge and perceptions of antibiotic use and resistance, while evaluating the institutional role of patient education on antibiotic use in two Saudi Arabian hospitals, one with an implemented ASP and one without an ASP.MethodA cross-sectional self-administered survey was developed and piloted. A total of 400 surveys were distributed, 200 within the hospital with an ASP and another 200 within the hospital without an ASP. Data were coded and analysed. Ethical approval was obtained before the start of the study.Findings176 patients responded to the survey with 150 surveys completed and analysed. 78% of patients agreed that they should only take an antibiotic when prescribed by the doctor, however they still tended to keep left over antibiotics for future use. 84% of patients were unaware ‘antibiotic resistance’, with 48% believing that antibiotics help them get better quicker when they had a ‘cold’. Information on antibiotic use and resistance were provided to patients in the hospital with an ASP in contrast to the hospital without an ASP.ConclusionOverall there are poor perceptions regarding antibiotic use and resistance among hospital patients in Saudi Arabia. Patients in the hospital with ASP demonstrated greater knowledge during their hospitalisation. ASPs should not only focus on educating healthcare professionals but should involve the patients and seize the opportunity to educate them while hospitalised.     

Role of the third intracellular loop and of the cytoplasmic tail in the mitogenic signaling of the protease-activated receptor 1

The activation of the protease-activated receptor 1 (PAR-1) by thrombin has been shown to induce an activation of the MAP kinase cascade and to stimulate cell proliferation. To examine the mechanisms of signal transduction by PAR-1, we constructed several PAR-1 mutants which were stably expressed in CHO cells. When compared to wild-type PAR-1, mutation of Ser306-->Ala (S306A) in the third intracellular loop of PAR-1 inhibited MAP kinase activation and cell proliferation stimulated by thrombin. The thrombin activation of MAP kinase was inhibited by pertussis toxin, suggesting a role for a Gi-like protein. As shown by calcium signaling and inosotol trisphosphate generation, the Ser306-mutated PAR-1 induced a strong activation of phospholipase C after thrombin addition. Deletion of the cytoplasmic tail of PAR-1 also inhibited thrombin-induced DNA synthesis but the MAP kinase pathway was activated as with wild-type PAR-1. In contrast, the deletion of the C-tail of PAR-1 prevented almost completely the activation of the phospholipase C pathway. Taken together these results suggest that the C-tail of PAR-1 is a critical site for PAR-1 coupling to phospholipase C activation, while the third intracellular loop of PAR-1 is implicated in PAR-1 coupling to Gi and MAP kinase activation. In addition, these results also show that MAP kinase activation is necessary but not sufficient for thrombin to induce cell proliferation.