Acute effects of hypouricemia on endothelium, oxidative stress, and arterial stiffness: A randomized, double-blind, crossover study.

We hypothesized acute moderate and drastic reductions in uric acid concentration exert different effects on arterial function in healthy normotensive and hypertensive adults. Thirty-six adults (aged 58 [55;63] years) with or without primary hypertension participated in a three-way, randomized, double-blind, crossover study in which [placebo] and [febuxostat] and [febuxostat and rasburicase] were administered. Febuxostat and rasburicase reduce the uric acid concentration by xanthine oxidoreductase inhibition and uric acid degradation into allantoin, respectively. Endothelial function was assessed in response to acetylcholine, sodium nitroprusside, heating (with and without nitric oxide synthase inhibition) using a laser Doppler imager. Arterial stiffness was determined by applanation tonometry, together with blood pressure, renin-angiotensin system activity, oxidative stress, and inflammation. Uric acid concentration was 5.1 [4.1;5.9], 1.9 [1.2;2.2] and 0.2 [0.2;0.3] mg/dL with [placebo], [febuxostat] and [febuxostat-rasburicase] treatments, respectively (p < 0.0001). Febuxostat improved endothelial response to heat particularly when nitric oxide synthase was inhibited (p < 0.05) and reduced diastolic and mean arterial pressure (p = 0.008 and 0.02, respectively). The augmentation index decreased with febuxostat (ANOVA p < 0.04). Myeloperoxidase activity profoundly decreased with febuxostat combined with rasburicase (p < 0.0001). When uric acid dropped, plasmatic antioxidant capacity markedly decreased, while superoxide dismutase activity increased (p < 0.0001). Other inflammatory and oxidant markers did not differ. Acute moderate hypouricemia encompasses minor improvements in endothelial function, blood pressure, and arterial stiffness. Clinical Trial Registration: NCT03395977, https://clinicaltrials.gov/ct2/show/NCT03395977.

Severe Hypouricemia Impairs Endothelium-Dependent Vasodilatation and Reduces Blood Pressure in Healthy Young Men: A Randomized, Placebo-Controlled, and Crossover Study.

Background Uric acid (UA) is a plasmatic antioxidant that has possible effects on blood pressure. The effects of UA on endothelial function are unclear. We hypothesize that endothelial function is not impaired unless significant UA depletion is achieved through selective xanthine oxidase inhibition with febuxostat and recombinant uricase (rasburicase). Methods and Results Microvascular hyperemia, induced by iontophoresis of acetylcholine and sodium nitroprusside, and heating-induced local hyperemia after iontophoresis of saline and a specific nitric oxide synthase inhibitor were assessed by laser Doppler imaging. Blood pressure and renin-angiotensin system markers were measured, and arterial stiffness was assessed. CRP (C-reactive protein), allantoin, chlorotyrosine/tyrosine ratio, homocitrulline/lysine ratio, myeloperoxidase activity, malondialdehyde, and interleukin-8 were used to characterize inflammation and oxidative stress. Seventeen young healthy men were enrolled in a randomized, double-blind, placebo-controlled, 3-way crossover study. The 3 compared conditions were placebo, febuxostat alone, and febuxostat together with rasburicase. The allantoin (µmol/L)/UA (µmol/L) ratio differed between sessions (P<0.0001). During the febuxostat-rasburicase session, heating-induced hyperemia became altered in the presence of nitric oxide synthase inhibition; and systolic blood pressure, angiotensin II, and myeloperoxidase activity decreased (P≤0.03 versus febuxostat). The aldosterone concentration decreased in the febuxostat-rasburicase group (P=0.01). Malondialdehyde increased when UA concentration decreased (both P<0.01 for febuxostat and febuxostat-rasburicase versus placebo). Other parameters remained unchanged. Conclusions A large and short-term decrease in UA in humans alters heat-induced endothelium-dependent microvascular vasodilation, slightly reduces systolic blood pressure through renin-angiotensin system activity reduction, and markedly reduces myeloperoxidase activity when compared with moderate UA reduction. A moderate or severe hypouricemia leads to an increase in lipid peroxidation through loss of antioxidant capacity of plasma. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT03395977.

Pilot study of risk factors associated with cardiovascular disease in northern and southern Cameroonians.

AIM: The aim of the study was to evaluate whether the risk factors for cardiovascular disease (CVD) are similar in the northern and southern regions of Cameroon. METHODS: The participants answered a questionnaire concerning their lifestyle. Anthropometric and blood pressure measurements were evaluated in 192 individuals and biochemical parameters in 50 randomly selected volunteers. RESULTS: Northerners displayed low alcohol and tobacco consumption, little practice of sport but physically demanding professions, and consumption of soybean, refined palm and other polyunsaturated oils. Southerners consumed alcohol, practiced sport, had intellectually based professions, and consumed crude and refined palm oils. Waist circumference and body mass index were higher in the southerners compared to the northerners. Blood glucose levels, and systolic and diastolic blood pressures were higher among the northerners than the southerners. Among the southerners, there were positive correlations between total cholesterol levels and systolic or diastolic blood pressure, low-density lipoprotein cholesterol and blood glucose levels or diastolic blood pressure, triglyceride levels and systolic blood pressure. CONCLUSION: Providing region-adapted, health-related advice for northern and southern Cameroonians would contribute to reducing risk factors for CVD.

ENDOGLIN/CD105 is expressed in KIT positive cells in the gut and in gastrointestinal stromal tumours.

ENDOGLIN/CD105 (ENG) is a transmembrane glycoprotein and an auxiliary unit of the transforming growth factor-ß (TGF-ß); receptor, expressed predominantly in vascular endothelium. Noteworthy, Eng mRNA expression has been reported also in Kit(+) interstitial cells of Cajal (ICC) in the mouse intestine. Gastrointestinal stromal tumours (GIST) are thought to derive from ICC. Here we have investigated Eng expression in the Kit(K641E) mouse GIST model, in human GIST and in the Ba/F3 cell model. In wild type (WT) mouse antrum, Eng immunoreactivity (-ir) was detected in CD34(+) /CD31(+) endothelium and in Kit(+) ICC. In Kit(K641E) mice, hyperplasia of Kit(+) cells made Eng-ir even more evident. Quantitative PCR confirmed the increased expression of Eng transcript in Kit(K641E) mice. On human GIST TMA, 26/49 cases stained positive for ENG. Strong ENG staining was associated with malignant and high-risk tumours. ENG negative cases were predominantly of the epithelioid type or harboured PDGFRA mutation. In vitro, Eng mRNA was up-regulated in Ba/F3 cell lines stably expressing various oncogenic Kit mutations (K641E, del559, del814). This effect appeared to be independent of Kit activation, as neither the stimulation of WT Kit by its ligand SCF, nor the inhibition of Kit autophosphorylation by imatinib mesylate in oncogenic mutants, altered Eng expression. Elevated Eng expression in Kit oncogenic mutants appeared rather to be indirectly mediated by DNA hypomethylation, because treatment with the demethylating agent 5-Aza/dC increased Eng mRNA expression in Kit(WT) cells. ENG expression in ICC and in GIST deserves further consideration as ENG is emerging as a potential target for cancer therapy.

MDCT for suspected acute appendicitis in adults: impact of oral and IV contrast media at standard-dose and simulated low-dose techniques.

OBJECTIVE: The objective of this study was to prospectively investigate the influence of oral, IV, and oral and IV contrast media on the information provided by MDCT at standard and simulated low radiation doses in adults suspected of having acute appendicitis. SUBJECTS AND METHODS: One hundred thirty-one consecutive patients (80 women, 51 men; age range, 18-87 years; mean age, 37 years) suspected of having appendicitis were randomly assigned to either ingest or not ingest iodinated contrast material. Thereafter, all patients underwent IV unenhanced and enhanced abdominopelvic MDCT with a 4 x 2.5 mm collimation at 120 kVp and 100 mAs(eff). Dose reduction corresponding to 30 mAs(eff) was simulated. Two radiologists independently read scans during separate sessions, assessed appendix visualization, and proposed a diagnosis (i.e., appendicitis or an alternative diagnosis). The final diagnosis was based on either surgical findings or clinical follow-up. Data were analyzed by factorial analysis of multiple correspondences followed by an ascending hierarchic classification method. RESULTS: Factorial analysis and ascending hierarchic classification revealed that, in terms of diagnostic correctness, reader influence predominated over the influence of IV and oral contrast media use and radiation dose but that correctness was also influenced by the patient's sex (p = 0.048) and was lower in cases of alternative diseases (p < 0.001). Visualization of the appendix depended predominantly on the reader rather than on the use of IV, oral, or oral and IV contrast agents or on radiation dose. CONCLUSION: Diagnostic correctness is much more influenced by the reader than by the use of contrast medium (oral, IV, or both) or of simulated low-radiation-dose technique.