Mycophenolate mofetil attenuates DOCA-salt hypertension: Effects on vascular tone

Inflammation is increasingly recognized as a driver of hypertension. Both genetic and pharmacological inhibition of B and T cells attenuates most forms of experimental hypertension. Accordingly, the immunosuppressive drug mycophenolate mofetil (MMF) reduces blood pressure in the deoxycorticosterone acetate (DOCA-) salt model. However, the mechanisms by which MMF prevent hypertension in the DOCA-salt model remain unclear. Recent studies indicate that immunosuppression can inhibit sodium transporter activity in the kidney, but its effect on vascular tone is not well characterized. Therefore, the aim of the present study was to analyze the vascular and renal tubular effects of MMF in the DOCA-salt model in rats (4 weeks without uninephrectomy). Co-treatment with MMF attenuated the rise in blood pressure from day 11 onward resulting in a significantly lower telemetric mean arterial pressure after 4 weeks of treatment (108 ± 7 vs. 130 ± 9 mmHg, P < 0.001 by two-way analysis of variance). MMF significantly reduced the number of CD3+ cells in kidney cortex and inner medulla, but not in outer medulla. In addition, MMF significantly reduced urinary interferon-γ excretion. Vascular tone was studied ex vivo using wire myographs. An angiotensin II type 2 (AT2) receptor antagonist blocked the effects of angiotensin II (Ang II) only in the vehicle group. Conversely, L-NAME significantly increased the Ang II response only in the MMF group. An endothelin A receptor blocker prevented vasoconstriction by endothelin-1 in the MMF but not in the vehicle group. MMF did not reduce the abundances of the kidney sodium transporters NHE3, NKCC2, NCC, or ENaC. Together, our ex vivo results suggest that DOCA-salt induces AT2 receptor-mediated vasoconstriction. MMF prevents this response and increases nitric oxide availability. These data provide insight in the antihypertensive mechanism of MMF and the role of inflammation in dysregulating vascular tone

Development of a low-aspect ratio fin for flight research experiments

A second-generation flight test fixture, developed at NASA Dryden Flight Research Center, offers a generic testbed for aerodynamic and fluid mechanics research. The new fixture, a low-aspect ratio vertical fin shape mounted on the centerline of an F-15B aircraft lower fuselage, is designed for flight research at Mach numbers up to 2.0. The new fixture is a composite structure with a modular configuration and removable components for functional flexibility. This report describes the multidisciplinary design and analysis approach used to develop the fixture. The approach integrates conservative assumptions with simple analysis techniques to minimize the time and cost associated with its development. Presented are the principal disciplines required for this effort, which include aerodynamics, structures, stability, and operational considerations. In addition, preliminary results from the first phase of flight testing are presented. Acceptable directional stability and flow quality are documented and show agreement with predictions. Future envelope expansion activities will minimize current limitations so that the fixture can be used for a wide variety of high-speed aerodynamic and fluid mechanics research experiments

Liquid Galaxy POIs Controller

Per tal de contextualitzar la proposta del TFG, al llarg d'aquesta memòria, presentarem el programa Google Summer of Code (durant la memòria també referenciat com a “GSoC”). Així doncs, introduirem els conceptes de GSoC, algunes dades històricament significatives, l’estructura que el composa, la seva organització, el procediment per a escollir els membres que en formaran part i la meva relació amb el programa. També explicarem breument què és el projecte Open Source Liquid Galaxy (d’aquí en endavant anomenat també com “LG”), en què consisteix, la relació amb els dos projectes que vam presentar al GSoC 2015 (Liquid Galaxy POIs Controller, el qual va ser finalment escollit, i Wikipedia Liquid Galaxy Mashup) i algunes de les seves característiques. Posteriorment, essent el nucli d’informació més rellevant d’aquesta memòria, expliquem les tasques realitzades prèviament a l’inici del projecte com són l’aprenentatge de tecnologies i llenguatges nous, la presa de requeriments i riscs, l’establiment dels objectius del projecte i el càlcul de la línia de temps que guia aquest. Definim l’estructura de la base de dades de l’aplicació i exposem exemples del seu funcionament, expliquem el disseny i l’estructura de l’aplicació, tant en aspectes a nivell d’usuari com a nivell d’implementació, detallem l’evolució de l’aplicació juntament amb els problemes sorgits i les corresponents solucions i finalment determinem les tasques que s’han de realitzar per finalitzar la implementació de l’aplicació juntament amb una avaluació del treball realitzat

Identification of a Sudden Cardiac Death Susceptibility Locus at 2q24.2 through Genome-Wide Association in European Ancestry Individuals

Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000–300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10−10). The risk allele, while ancestral, has a frequency of ∼1.4%, suggesting strong negative selection and increases risk for SCD by 1.92–fold per allele (95% CI 1.57–2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006)

Mycophenolate Mofetil Attenuates DOCA-Salt Hypertension: Effects on Vascular Tone

Inflammation is increasingly recognized as a driver of hypertension. Both genetic and pharmacological inhibition of B and T cells attenuates most forms of experimental hypertension. Accordingly, the immunosuppressive drug mycophenolate mofetil (MMF) reduces blood pressure in the deoxycorticosterone acetate (DOCA-) salt model. However, the mechanisms by which MMF prevent hypertension in the DOCA-salt model remain unclear. Recent studies indicate that immunosuppression can inhibit sodium transporter activity in the kidney, but its effect on vascular tone is not well characterized. Therefore, the aim of the present study was to analyze the vascular and renal tubular effects of MMF in the DOCA-salt model in rats (4 weeks without uninephrectomy). Co-treatment with MMF attenuated the rise in blood pressure from day 11 onward resulting in a significantly lower telemetric mean arterial pressure after 4 weeks of treatment (108 ± 7 vs. 130 ± 9 mmHg, P &lt; 0.001 by two-way analysis of variance). MMF significantly reduced the number of CD3+ cells in kidney cortex and inner medulla, but not in outer medulla. In addition, MMF significantly reduced urinary interferon-γ excretion. Vascular tone was studied ex vivo using wire myographs. An angiotensin II type 2 (AT2) receptor antagonist blocked the effects of angiotensin II (Ang II) only in the vehicle group. Conversely, L-NAME significantly increased the Ang II response only in the MMF group. An endothelin A receptor blocker prevented vasoconstriction by endothelin-1 in the MMF but not in the vehicle group. MMF did not reduce the abundances of the kidney sodium transporters NHE3, NKCC2, NCC, or ENaC. Together, our ex vivo results suggest that DOCA-salt induces AT2 receptor-mediated vasoconstriction. MMF prevents this response and increases nitric oxide availability. These data provide insight in the antihypertensive mechanism of MMF and the role of inflammation in dysregulating vascular tone

Nontraumatic Myelopathy in Malawi: A Prospective Study in an Area with High HIV Prevalence

Nontraumatic myelopathy causes severe morbidity and is not uncommon in Africa. Clinically, patients often present with paraplegia, and extrinsic cord compression and transverse myelitis are most common causes. Data on exact pathogenesis are scanty because of limitations in diagnostic methods. In Queen Elizabeth Central Hospital, Blantyre, Malawi, we recorded consecutive patients presenting with nontraumatic paraplegia for maximally 6 months between January and July 2010 and from March to December 2011. The diagnostic workup included imaging and examining blood, stool, urine, sputum, and cerebrospinal fluid (CSF) samples for infection. After discharge, additional diagnostic tests, including screening for virus infections, borreliosis, syphilis, and schistosomiasis, were carried out in the Netherlands. The clinical diagnosis was, thus, revised in retrospect with a more accurate final differential diagnosis. Of 58 patients included, the mean age was 41 years (range, 12-83 years) and the median time between onset and presentation was 18 days (range, 0-121 days), and of 55 patients tested, 23 (42%) were HIV positive. Spinal tuberculosis (n = 24, 41%), tumors (n = 16, 28%), and transverse myelitis (n = 6, 10%) were most common; in six cases (10%), no diagnosis could be made. The additional tests yielded evidence for CSF infection with Schistosoma, Treponema pallidum, Epstein-Barr virus (EBV), HHV-6, HIV, as well as a novel cyclovirus. The diagnosis of the cause of paraplegia is complex and requires access to an magnetic resonance imaging (MRI) scan and other diagnostic (molecular) tools to demonstrate infection. The major challenge is to confirm the role of detected pathogens in the pathophysiology and to design an effective and affordable diagnostic approach

NaCl cotransporter abundance in urinary vesicles is increased by calcineurin inhibitors and predicts thiazide sensitivity

<div><p>Animal studies have shown that the calcineurin inhibitors (CNIs) cyclosporine and tacrolimus can activate the thiazide-sensitive NaCl cotransporter (NCC). A common side effect of CNIs is hypertension. Renal salt transporters such as NCC are excreted in urinary extracellular vesicles (uEVs) after internalization into multivesicular bodies. Human studies indicate that CNIs also increase NCC abundance in uEVs, but results are conflicting and no relationship with NCC function has been shown. Therefore, we investigated the effects of CsA and Tac on the abundance of both total NCC (tNCC) and phosphorylated NCC at Thr60 phosphorylation site (pNCC) in uEVs, and assessed whether NCC abundance in uEVs predicts the blood pressure response to thiazide diuretics. Our results show that in kidney transplant recipients treated with cyclosporine (n = 9) or tacrolimus (n = 23), the abundance of both tNCC and pNCC in uEVs is 4–5 fold higher than in CNI-free kidney transplant recipients (n = 13) or healthy volunteers (n = 6). In hypertensive kidney transplant recipients, higher abundances of tNCC and pNCC prior to treatment with thiazides predicted the blood pressure response to thiazides. During thiazide treatment, the abundance of pNCC in uEVs increased in responders (n = 10), but markedly decreased in non-responders (n = 8). Thus, our results show that CNIs increase the abundance of both tNCC and pNCC in uEVs, and these increases correlate with the blood pressure response to thiazides. This implies that assessment of NCC in uEVs could represent an alternate method to guide anti-hypertensive therapy in kidney transplant recipients.</p></div

Densitometry of tNCC and pNCC immunoreactive bands in uEVs of all kidney transplant recipients treated with CsA (n = 9), Tac (n = 23) or CNI-free immunosuppressive regimens (n = 13) and healthy volunteers (n = 6).

<p>Both tNCC (A) and pNCC (C) abundance in both CsA- and Tac-treated kidney transplant recipients was significantly higher in comparison to kidney transplant recipients treated with CNI-free immunosuppressive regimens and healthy volunteers. Densitometry analysis of CD9 expression of the immunoblots for tNCC (B) and pNCC (D) showed no significant differences between the four groups. The ratio of pNCC to tNCC abundance in uEVs of CsA- and Tac-treated group was not significantly higher in comparison to kidney transplant recipients treated with CNI-free immunosuppressive regimens and healthy volunteers (E). The original immunoblots are shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0176220#pone.0176220.g001" target="_blank">Fig 1</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0176220#pone.0176220.s008" target="_blank">S3</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0176220#pone.0176220.s009" target="_blank">S4</a> Figs. Values are mean ± SEM normalized to kidney transplant recipients treated with CNI-free immunosuppressive regimens (one-way ANOVA, *<i>P</i><0.05, n = 51).</p