Changes in Aortic Pulse Wave Velocity in Hypertensive Postmenopausal Women: Comparison Between a Calcium Channel Blocker vs Angiotensin Receptor Blocker Regimen.

J Clin Hypertens (Greenwich). 2012;14:773-778. ©2012 Wiley Periodicals, Inc. Postmenopausal women are at greater risk for hypertension-related cardiovascular disease. Antihypertensive therapy may help alleviate arterial stiffness that represents a potential modifiable risk factor of hypertension. This randomized controlled study investigated the difference between an angiotensin receptor blocker and a calcium channel blocker in reducing arterial stiffness. Overall, 125 postmenopausal hypertensive women (age, 61.4±6 years; systolic blood pressure/diastolic blood pressure [SBP/DBP], 158±11/92±9 mm Hg) were randomized to valsartan 320 mg±hydrochlorothiazide (HCTZ) (n=63) or amlodipine 10 mg±HCTZ (n=62). The primary outcome was carotid-to-femoral pulse wave velocity (PWV) changes after 38 weeks of treatment. Both treatments lowered peripheral blood pressure (BP) (-22.9/-10.9 mm Hg for valsartan and -25.2/-11.7 mm Hg for amlodipine, P=not significant) and central BP (-15.7/-7.6 mm Hg for valsartan and -19.2/-10.3 mm Hg for amlodipine, P<.05 for central DBP). Both treatments similarly reduced the carotid-femoral PWV (-1.9 vs -1.7 m/s; P=not significant). Amlodipine was associated with a higher incidence of peripheral edema compared with the valsartan group (77% vs 14%, P<.001). BP lowering in postmenopausal women led to a reduction in arterial stiffness as assessed by PWV measurement. Both regimens reduced PWV to a similar degree after 38 weeks of treatment despite differences in central BP lowering, suggesting that the effect of valsartan on PWV is mediated through nonhemodynamic effects.

BRF1 mutations alter RNA polymerase III-dependent transcription and cause neurodevelopmental anomalies.

RNA polymerase III (Pol III) synthesizes tRNAs and other small noncoding RNAs to regulate protein synthesis. Dysregulation of Pol III transcription has been linked to cancer, and germline mutations in genes encoding Pol III subunits or tRNA processing factors cause neurogenetic disorders in humans, such as hypomyelinating leukodystrophies and pontocerebellar hypoplasia. Here we describe an autosomal recessive disorder characterized by cerebellar hypoplasia and intellectual disability, as well as facial dysmorphic features, short stature, microcephaly, and dental anomalies. Whole-exome sequencing revealed biallelic missense alterations of BRF1 in three families. In support of the pathogenic potential of the discovered alleles, suppression or CRISPR-mediated deletion of brf1 in zebrafish embryos recapitulated key neurodevelopmental phenotypes; in vivo complementation showed all four candidate mutations to be pathogenic in an apparent isoform-specific context. BRF1 associates with BDP1 and TBP to form the transcription factor IIIB (TFIIIB), which recruits Pol III to target genes. We show that disease-causing mutations reduce Brf1 occupancy at tRNA target genes in Saccharomyces cerevisiae and impair cell growth. Moreover, BRF1 mutations reduce Pol III-related transcription activity in vitro. Taken together, our data show that BRF1 mutations that reduce protein activity cause neurodevelopmental anomalies, suggesting that BRF1-mediated Pol III transcription is required for normal cerebellar and cognitive development.

Inhibition of the renin-angiotensin system does not reduce platelet activity at rest or during stress in hypertension.

OBJECTIVES: We investigated the influence of angiotensin receptor blockade and angiotensin-converting enzyme inhibition on stress-induced platelet activation in hypertensive patients. Secondary aims were effects on inflammation, coagulation, and endothelial function. METHODS: Following a 4-week placebo period, 25 hypertensive patients entered a double-blind, crossover study comparing enalapril (20 mg once daily) and losartan (100 mg once daily) treatment (each for 8 weeks). Patients were studied at rest and after a standardized exercise test. RESULTS: Mean arterial pressure was reduced from 119 ± 2 to 104 ± 2 (enalapril) and 106 ± 2 (losartan) mmHg (both P <0.001). Plasma angiotensin II decreased from 2.4 ± 0.4 to 0.5 ± 0.1 pmol/l with enalapril, and increased to 7.2 ± 1.3 pmol/l with losartan (both P <0.001). Exercise-evoked platelet activation, as evidenced by increased numbers of P-selectin-positive platelets (P <0.01), elevated circulating platelet-platelet aggregates (P <0.01) and soluble P-selectin levels (P <0.001), and increased platelet responsiveness to adenosine diphosphate and thrombin (both P <0.05). Neither drug influenced these markers of platelet activation at rest or following exercise. Markers of inflammation (high-sensitivity C reactive protein, interleukin-6, tissue necrosis factor-α), coagulation (tissue plasminogen activator antigen, prothrombin fragment F1+2), and endothelial function (von Willebrand factor, soluble vascular cellular adhesion molecule-1, and intercellular adhesion molecule-1) were also uninfluenced by treatment. CONCLUSION: Enalapril and losartan failed to reduce platelet activity both at rest and during exercise in hypertensive patients. Markers of inflammation, coagulation, and endothelial function were similarly unaffected. Inhibition of the renin-angiotensin system promotes its beneficial effects in hypertension through mechanisms other than platelet inhibition.

Load Ratings for Standard Bridges, HR-239 Phase III, 1998

In this report, 25 secondary bridge standards for three types of bridges are rated for the AASHTO HS20-44 vehicle configuration and five typical Iowa legal vehicles. The ratings apply only to those bridges which: (1) are built according to the applicable bridge standard plans, (2) have no structural deterioration or damage, and (3) have no added wearing surface in excess of 0.5-in. (1.27-cm) integral wearing surface. Appendix A contains the results of the original October 1982 report on load ratings for standard bridges.

Desempenho de novos clones de seringueira: III. seleções promissoras para a região de Votuporanga, Estado de São Paulo

É apresentado o resultado da primeira seleção de 25 clones de seringueira (Hevea brasiliensis (Willd. ex Adr. de Juss.) Müell. Arg.), a maior parte constituída de introduções de diferentes origens. Após multiplicados, foram avaliados em experimentos do tipo pequena escala, obedecendo ao delineamento de blocos ao acaso, instalado na Estação Experimental de Votuporanga, SP. Os caracteres avaliados foram: produção de borracha seca, vigor expresso pelo perímetro do caule, espessura de casca e número de anéis de vasos laticíferos. Com relação à produção de borracha seca, destacaram-se os clones IAN 3156, IAC 40, 7/6, 3/5 e 3/1, produzindo 124%, 105%, 27%, 26% e 19% superiores em relação ao RRIM 600, recomendando-se seu plantio em pequena escala na região de Jaú. Caracteres secundários tais como o vigor, espessura de casca e número de anéis de vasos laticíferos dos clones testados são também discutidos. Sugere-se sua avaliação em experimentos do tipo grande escala com o objetivo de avaliar, além da produção, outros caracteres secundários para futuras recomendações no Estado de São Paulo.

Innovative Solutions for Slope Stability Reinforcement and Characterization: Vol. III, TR-489, 2005

Soil slope instability concerning highway infrastructure is an ongoing problem in Iowa, as slope failures endanger public safety and continue to result in costly repair work. Volume I of this current study summarizes research methods and findings, while Volume II provides procedural details for incorporating into practice an infrequently-used testing technique–borehole shear tests. Volume III of this study of field investigation of fifteen slopes in Iowa demonstrates through further experimental testing how lateral forces develop along stabilizing piles to resist slope movements. Results establish the feasibility of an alternative stabilization approach utilizing small-diameter pile elements. Also, a step-by-step procedure that can be used by both state and county transportation agencies to design slope reinforcement using slender piles is documented. Initial evidence of the efficiency and cost-effectiveness of stabilizing nuisance slope failures with grouted micropiles is presented. Employment of the remediation alternative is deemed more appropriate for stabilizing shallow slope failures. Overall, work accomplished in this research study included completing a comprehensive literature review on the state of the knowledge of slope stability and slope stabilization, the preparation and performance of fourteen full-scale pile load tests, the analysis of load test results, and the documentation of a design methodology for implementing the technology into current practices of slope stabilization. Recommendations for further research include monitoring pilot studies of slope reinforcement with grouted micropiles, supplementary experimental studies, and advanced numerical studies.

Design, conduct, and analyses of Breast International Group (BIG) 1-98: a randomized, double-blind, phase-III study comparing letrozole and tamoxifen as adjuvant endocrine therapy for postmenopausal women with receptor-positive, early breast cancer.

BACKGROUND: Aromatase inhibitors provide superior disease control when compared with tamoxifen as adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer. PURPOSE: To present the design, history, and analytic challenges of the Breast International Group (BIG) 1-98 trial: an international, multicenter, randomized, double-blind, phase-III study comparing the aromatase inhibitor letrozole with tamoxifen in this clinical setting. METHODS: From 1998-2003, BIG 1-98 enrolled 8028 women to receive monotherapy with either tamoxifen or letrozole for 5 years, or sequential therapy of 2 years of one agent followed by 3 years of the other. Randomization to one of four treatment groups permitted two complementary analyses to be conducted several years apart. The first, reported in 2005, provided a head-to-head comparison of letrozole versus tamoxifen. Statistical power was increased by an enriched design, which included patients who were assigned sequential treatments until the time of the treatment switch. The second, reported in late 2008, used a conditional landmark approach to test the hypothesis that switching endocrine agents at approximately 2 years from randomization for patients who are disease-free is superior to continuing with the original agent. RESULTS: The 2005 analysis showed the superiority of letrozole compared with tamoxifen. The patients who were assigned tamoxifen alone were unblinded and offered the opportunity to switch to letrozole. Results from other trials increased the clinical relevance about whether or not to start treatment with letrozole or tamoxifen, and analysis plans were expanded to evaluate sequential versus single-agent strategies from randomization. LIMITATIONS: Due to the unblinding of patients assigned tamoxifen alone, analysis of updated data will require ascertainment of the influence of selective crossover from tamoxifen to letrozole. CONCLUSIONS: BIG 1-98 is an example of an enriched design, involving complementary analyses addressing different questions several years apart, and subject to evolving analytic plans influenced by new data that emerge over time.

Complementary effects of adenosine and angiotensin II in hypoxemia-induced renal dysfunction in the rabbit.

The acute renal effects of hypoxemia and the ability of the co-administration of an angiotensin converting enzyme inhibitor (perindoprilat) and an adenosine receptor antagonist (theophylline) to prevent these effects were assessed in anesthetized and mechanically-ventilated rabbits. Renal blood flow (RBF) and glomerular filtration rate (GFR) were determined by the clearances of para-aminohippuric acid and inulin, respectively. Each animal acted as its own control. In 8 untreated rabbits, hypoxemia induced a significant drop in mean blood pressure (-12 +/- 2%), GFR (-16 +/- 3%) and RBF (-12 +/- 3%) with a concomitant increase in renal vascular resistance (RVR) (+ 18 +/- 5%), without changes in filtration fraction (FF) (-4 +/- 2%). These results suggest the occurrence of both pre- and postglomerular vasoconstriction during the hypoxemic stress. In 7 rabbits pretreated with intravenous perindoprilat (20 microg/kg), the hypoxemia-induced changes in RBF and RVR were prevented. FF decreased significantly (-18 +/- 2%), while the drop in GFR was partially blunted. These results could be explained by the inhibition of the angiotensin-mediated efferent vasoconstriction by perindoprilat. In 7 additional rabbits, co-administration of perindoprilat and theophylline (1 mg/kg) completely prevented the hypoxemia-induced changes in RBF (+ 11 +/- 3%) and GFR (+ 2 +/- 3%), while RVR decreased significantly (-14 +/- 3%). Since adenosine and angiotensin II were both shown to participate, at least in part, in the renal changes induced by hypoxemia, the beneficial effects of perindoprilat and theophylline in this model could be mediated by complementary actions of angiotensin II and adenosine on the renal vasculature.

Le principe de transparence dans le canton de Vaud : évaluation des chapitres I, III, IV et VI de la Loi du 24 septembre 2002 sur l'information

La Loi vaudoise sur l'information (LInfo), en vigueur depuis le 1er septembre 2003, contient les bases légales relatives à l'information communiquée par l'Etat aux médias et au public. A l'image de plus en plus de législations en la matière, elle consacre le principe de l'information sur demande, selon lequel tout individu a désormais le droit de consulter des documents officiels et d'obtenir de l'information de la part des autorités sans devoir motiver sa demande. La présente évaluation s'intéresse à comprendre comment ce principe de transparence est défini dans cette loi, quelle est son application par l'administration, dans quelle mesure il est utilisé par les citoyens et enfin quels sont ses effets six ans après son entrée en vigueur. Das waadtländische Informationsgesetz (LInfo), in Kraft seit dem 1. September 2003, liefert die rechtliche Grundlage betreffend Informationen die durch den Kanton an die Medien und die Öffentlichkeit kommuniziert werden. Als Grundlage dient dazu das Prinzip um Erhalt von Informationen, nach welchem jede Person das Recht hat offizielle Dokumente einzusehen und Informationen von den Behörden zu erhalten ohne die Anfrage begründen zu müssen. Der vorliegende Beitrag hinterfragt wie dieses Transparenzprinzip im Gesetz definiert ist und wie es durch die Verwaltung angewendet wird. Weiter wird untersucht in welchem Ausmass es durch die Bürger und Bürgerinnen angewendet wird und was das Gesetz sechs Jahre nach seinem Inkrafttreten bewirkt hat.

An angiotensin II- and NF-kappaB-dependent mechanism increases connexin 43 in murine arteries targeted by renin-dependent hypertension.

AIMS: Connexins (Cxs) play a role in the contractility of the aorta wall. We investigated how connexins of the endothelial cells (ECs; Cx37, Cx40) and smooth muscle cells (SMCs; Cx43, Cx45) of the aorta change during renin-dependent and -independent hypertension. METHODS AND RESULTS: We subjected both wild-type (WT) mice and mice lacking Cx40 (Cx40(-/-)), to either a two-kidney, one-clip procedure or to N-nitro-l-arginine-methyl-ester treatment, which induce renin-dependent and -independent hypertension, respectively. All hypertensive mice featured a thickened aortic wall, increased levels of Cx37 and Cx45 in SMC, and of Cx40 in EC (except in Cx40(-/-) mice). Cx43 was up-regulated, with no effect on its S368 phosphorylation, only in the SMCs of renin-dependent models of hypertension. Blockade of the renin-angiotensin system of Cx40(-/-) mice normalized blood pressure and prevented both aortic thickening and Cx alterations. Ex vivo exposure of WT aortas, carotids, and mesenteric arteries to physiologically relevant levels of angiotensin II (AngII) increased the levels of Cx43, but not of other Cx. In the aortic SMC line of A7r5 cells, AngII activated kinase-dependent pathways and induced binding of the nuclear factor-kappa B (NF-kappaB) to the Cx43 gene promoter, increasing Cx43 expression. CONCLUSION: In both large and small arteries, hypertension differently regulates Cx expression in SMC and EC layers. Cx43 is selectively increased in renin-dependent hypertension via an AngII activation of the extracellular signal-regulated kinase and NF-kappaB pathways.

Metric Training for the Transportation Industry Module III - Road and Bridge Design, HR-376

"Metric Training For The Highway Industry", HR-376 was designed to produce training materials for the various divisions of the Iowa DOT, local government and the highway construction industry. The project materials were to be used to introduce the highway industry in Iowa to metric measurements in their daily activities. Five modules were developed and used in training over 1,000 DOT, county, city, consultant and contractor staff in the use of metric measurements. The training modules developed deal with the planning through operation areas of highway transportation. The materials and selection of modules were developed with the aid of an advisory personnel from the highway industry. Each module is design as a four hour block of instruction and a stand along module for specific types of personnel. Each module is subdivided into four chapters with chapter one and four covering general topics common to all subjects. Chapters two and three are aimed at hands on experience for a specific group and subject. This module includes: Module 3 - Road and Bridge Design. This module provides hands on examples of how to use metric measurements in the design of roads and structures.