Endothelial function in migraine: a cross-sectional study

ABSTRACT: BACKGROUND: Migraine has been associated with cardiovascular disorders. Endothelial dysfunction may be a mechanism underlying this association. The present study tested the hypothesis that endothelium-dependent vasodilation, basal endothelial nitric oxide release and endothelial fibrinolytic capacity are impaired in migraine patients. METHODS: Graded doses of sodium nitroprusside (SNP, 0.2 to 0.8 microg.min 1.dL-1 forearm), substance P (0.2 to 0.8 pmol.min-1.dL-1 forearm) and NG monomethyl-L-arginine (L-NMMA, 0.1 to 0.4 micromol.min-1.dL-1 forearm) were infused into the brachial artery of 16 migraine patients with or without aura during a headache-free interval and 16 age- and sex-matched subjects without a history of migraine. Forearm blood flow (FBF) was measured by strain-gauge venous occlusion plethysmography. Local forearm release of tissue plasminogen activator (t-PA) in response to substance P infusion was assessed using the arteriovenous plasma concentration gradient. Responses to infused drugs were compared between patients and matched controls by analysis of variance. RESULTS: In both migraine patients and control subjects, SNP and substance P caused a dose-dependent increase, and L NMMA a dose-dependent decrease in FBF (P < 0.001 for all responses). In both groups, substance P caused an increase in t-PA release (P < 0.001). FBF responses and t-PA release were comparable between migraine patients and control subjects. CONCLUSIONS: The absence of differences in endothelium-dependent vasodilation, basal endothelial nitric oxide production and stimulated t-PA release between migraine patients and healthy control subjects argues against the presence of endothelial dysfunction in forearm resistance vessels of migraine patients.status: publishe

The Impact of Caesarean Delivery on Paracetamol and Ketorolac Pharmacokinetics: A Paired Analysis

Pharmacokinetics is a first, but essential step to improve population-tailored postoperative analgesia, also after Caesarean delivery. We therefore aimed to quantify the impact of caesarean delivery on the pharmacokinetics of intravenous (iv) paracetamol (2 g, single dose) and iv ketorolac tromethamine (30 mg, single dose) in 2 cohorts eachof 8 women at caesarean delivery and to compare these findings with postpartum to quantify intrapatient changes. We documented a higher median paracetamol clearance at delivery when compared to 10–15 weeks postpartum (11.7 to 6.4 L/h·m2, P < 0.01), even after correction for weight-related changes. Similar conclusions were drawn for ketorolac: median clearance was higher at delivery with a subsequent decrease (2.03 to 1.43 L/h·m2, P < 0.05) in postpartum (17–23 weeks). These differences likely reflect pregnancy- and caesarean-delivery-related changes in drug disposition. Moreover, postpartum paracetamol clearance was significantly lower when compared to estimates published in healthy young volunteers (6.4  versus  9.6 L/h·m2), while this was not the case for ketorolac (1.43  versus  1.48 L/h·m2). This suggests that postpartum is another specific status in young women that merits focused, compound-specific pharmacokinetic evaluation

The New First-in-Human EMA Guideline: Disruptive or Constructive? Outcomes From the First EUFEMED Discussion Forum

The European Federation for Exploratory Medicines Development (EUFEMED) organized a meeting in Leuven, Belgium entitled ‘The new FIH EMA guideline: Disruptive or constructive?’ to provide a forum for stakeholders to discuss the guideline’s operational impact. The revised EMA Guideline on strategies to identify and mitigate risks for first-in-human (FIH) and early clinical trials with investigational products was published on 20 July 2017. The revision gave guidance on sentinel dosing/staggering of subjects within a multiple-ascending dose (MAD) clinical trial, permissible maximum exposure/investigation of supra-therapeutic doses and dose escalations above the no-observed adverse effect level. As the guidelines came into operation on 1 February, 2018 it was assumed that by the date of the meeting many early phase stakeholders had gathered sufficient first-hand experience of working within the guideline to discuss their thoughts on its impact. The concluding part of the meeting focused on the possible differences between European countries in handling the revised FIH guideline and ways of achieving harmonization. Information on current industry practice was gathered by online polling during the meeting, where perception of the revised guideline as either ‘disruptive’ or ‘constructive’ was explored at the start and at the end of the Forum along with recommendations on reducing future regulatory discordance. It was generally agreed that the necessary changes encompassed by new guidelines included both constructive and disruptive aspects. The final vote on whether the new FIH guideline is disruptive or constructive was taken by 69 delegates: 51% stated that it was both constructive and disruptive, 48% decided on constructive, none on disruptive and 1% were still undecided. It was generally accepted that stakeholders need to continue in a process of stakeholder engagement and discussion, particularly on critical safety issues. Such an approach allows partners to adopt a proactive approach to sharing best practice. For example, attendees agreed that a ‘Question and Answer’ document harmonized between the European agencies is required for the sentinel approach and for the selection of supratherapeutic doses

Silencing CAFFEOYL SHIKIMATE ESTERASE affects lignification and improves saccharification in poplar

Caffeoyl shikimate esterase (CSE) was recently shown to play an essential role in lignin biosynthesis in Arabidopsis (Arabidopsis thaliana) and later in Medicago truncatula. However, the general function of this enzyme was recently questioned by the apparent lack of CSE activity in lignifying tissues of different plant species. Here, we show that down-regulation of CSE in hybrid poplar (Populus tremula x Populus alba) resulted in up to 25% reduced lignin deposition, increased levels of p-hydroxyphenyl units in the lignin polymer, and a relatively higher cellulose content. The transgenic trees were morphologically indistinguishable from the wild type. Ultra-high-performance liquid chromatography-mass spectrometry-based phenolic profiling revealed a reduced abundance of several oligolignols containing guaiacyl and syringyl units and their corresponding hydroxycinnamaldehyde units, in agreement with the reduced flux toward coniferyl and sinapyl alcohol. These trees accumulated the CSE substrate caffeoyl shikimate along with other compounds belonging to the metabolic classes of benzenoids and hydroxycinnamates. Furthermore, the reduced lignin amount combined with the relative increase in cellulose content in the CSE down-regulated lines resulted in up to 62% more glucose released per plant upon limited saccharification when no pretreatment was applied and by up to 86% and 91% when acid and alkaline pretreatments were used. Our results show that CSE is not only important for the lignification process in poplar but is also a promising target for the development of improved lignocellulosic biomass crops for sugar platform biorefineries

The X-ray luminous galaxy cluster XMMU J1007.4+1237 at z=1.56 - The dawn of starburst activity in cluster cores

Observational galaxy cluster studies at z>1.5 probe the formation of the first massive M>10^14 Msun dark matter halos, the early thermal history of the hot ICM, and the emergence of the red-sequence population of quenched early-type galaxies. We present first results for the newly discovered X-ray luminous galaxy cluster XMMU J1007.4+1237 at z=1.555, detected and confirmed by the XMM-Newton Distant Cluster Project (XDCP) survey. We selected the system as a serendipitous weak extended X-ray source in XMM-Newton archival data and followed it up with two-band near-infrared imaging and deep optical spectroscopy. We can establish XMMU J1007.4+1237 as a spectroscopically confirmed, massive, bona fide galaxy cluster with a bolometric X-ray luminosity of Lx=(2.1+-0.4)\times 10^44 erg/s, a red galaxy population centered on the X-ray emission, and a central radio-loud brightest cluster galaxy. However, we see evidence for the first time that the massive end of the galaxy population and the cluster red-sequence are not yet fully in place. In particular, we find ongoing starburst activity for the third ranked galaxy close to the center and another slightly fainter object. At a lookback time of 9.4Gyr, the cluster galaxy population appears to be caught in an important evolutionary phase, prior to full star-formation quenching and mass assembly in the core region. X-ray selection techniques are an efficient means of identifying and probing the most distant clusters without any prior assumptions about their galaxy content.Comment: 6 pages, 3 color figures, accepted for publication in A&

Stable X chromosome reactivation in female human induced pluripotent stem cells

In placental mammals, balanced expression of X-linked genes is accomplished by X chromosome inactivation (XCI) in female cells. In humans, random XCI is initiated early during embryonic development. To investigate whether reprogramming of female human fibroblasts into induced pluripotent stem cells (iPSCs) leads to reactivation of the inactive X chromosome (Xi), we have generated iPSC lines from fibroblasts heterozygous for large X-chromosomal deletions. These fibroblasts show completely skewed XCI of the mutated X chromosome, enabling monitoring of X chromosome reactivation (XCR) and XCI using allele-specific single-cell expression analysis. This approach revealed that XCR is robust under standard culture conditions, but does not prevent reinitiation of XCI, resulting in a mixed population of cells with either two active X chromosomes (Xas) or one Xa and one Xi. This mixed population of XaXa and XaXi cells is stabilized in naive human stem cell medium, allowing expansion of clones with two Xas

Operation of a high-Tc_{c} SQUID gradiometer with a two-stage Joule-Thomson micro-cooler

Practical applications of high-T$_{c}$ SQUIDs require cheap, simple in operation, and cryogen-free cooling. Mechanical cryo-coolers are generally not suitable for operation with SQUIDs due to their inherent magnetic and vibrational noise. In this work, we utilized a Joule-Thomson microfluidic cooling system to operate our high-T$_{c}$ SQUIDs [1]. The micro-cooler system is based on a commercial desktop CryoLab unit from DEMCON kryoz [2]. It contains a two-stage MEMS micro-cooler with a base temperature of 75 K, gross cooling power of 75 mW@80 K, and temperature stability ± 50 mK. Our high-TC dc SQUID gradiometers were fabricated from YBa$_{2}$Cu$_{3}$O$_{7-x}$ thin films grown by pulsed laser deposition on 10 mm × 10 mm SrTiO$_{3}$ bicrystal substrates with 24° misorientation angle. The SQUID chip was glued onto a 0.3 mm thick silicon wafer chip carrier that was attached to the second stage of the cold head. The vacuum housing of the cold stage was made from non-magnetic material (polyethylene terephthalate, PET) and evacuated to a base pressure below 2x10$^{-3}$ mbar. The vacuum chamber features a 0.3 mm thick sapphire window that is placed above the sensor/cold stage. We demonstrated that the equivalent magnetic flux noise of the high-T$_{c}$ SQUID gradiometer is largely unaffected by the micro-cooler setup. The cut-off frequency of the 1/f noise in our SQUID measured on the micro-cooler was around 10 Hz. This indicates that the micro-cooler does not introduce significant magnetic fields in the vicinity of the cold stage. We thus demonstrate that such a microfluidic cooling system is a promising technology for cooling of high-T$_{c}$ SQUIDs in practical applications. We also used the micro-cooler system to build a prototype a magnetic ac susceptibility (ACS) system for detection of specific binding reactions between DNA target molecules and functionalized magnetic nanoparticles (fMNP) in liquid solution. The detection principle relies on changes in Brownian rotation dynamics of fMNPs. We present the results of experiments with various concentrations of magnetic nanoparticles and discuss further development of the portable magnetic bioassay system for detection of influenza virus using oligonucleotide-tagged magnetic nanoparticles with sub-picomolar sensitivity. [1] A. Kalabukhov et al., Supercond. Sci. Technol. 29 095014 (2016). [2] http://kryoz.nl/portfolio-item/cryolab-msg

Translation-competent 48S complex formation on HCV IRES requires the RNA-binding protein NSAP1

Translation of many cellular and viral mRNAs is directed by internal ribosomal entry sites (IRESs). Several proteins that enhance IRES activity through interactions with IRES elements have been discovered. However, the molecular basis for the IRES-activating function of the IRES-binding proteins remains unknown. Here, we report that NS1-associated protein 1 (NSAP1), which augments several cellular and viral IRES activities, enhances hepatitis C viral (HCV) IRES function by facilitating the formation of translation-competent 48S ribosome–mRNA complex. NSAP1, which is associated with the solvent side of the 40S ribosomal subunit, enhances 80S complex formation through correct positioning of HCV mRNA on the 40S ribosomal subunit. NSAP1 seems to accomplish this positioning function by directly binding to both a specific site in the mRNA downstream of the initiation codon and a 40S ribosomal protein (or proteins)