Evidence for involvement of both IKCa and SKCa channels in hyperpolarizing responses of the rat middle cerebral artery

Endothelium-derived hyperpolarizing factor responses in the rat middle cerebral artery are blocked by inhibiting IKCa channels alone, contrasting with peripheral vessels where block of both IKCa and SKCa is required. As the contribution of IKCa and SKCa to endothelium-dependent hyperpolarization differs in peripheral arteries, depending on the level of arterial constriction, we investigated the possibility that SKCa might contribute to equivalent hyperpolarization in cerebral arteries under certain conditions. METHODS: Rat middle cerebral arteries (approximately 175 microm) were mounted in a wire myograph. The effect of KCa channel blockers on endothelium-dependent responses to the protease-activated receptor 2 agonist, SLIGRL (20 micromol/L), were then assessed as simultaneous changes in tension and membrane potential. These data were correlated with the distribution of arterial KCa channels revealed with immunohistochemistry. RESULTS: SLIGRL hyperpolarized and relaxed cerebral arteries undergoing variable levels of stretch-induced tone. The relaxation was unaffected by specific inhibitors of IKCa (TRAM-34, 1 micromol/L) or SKCa (apamin, 50 nmol/L) alone or in combination. In contrast, the associated smooth-muscle hyperpolarization was inhibited, but only with these blockers in combination. Blocking nitric oxide synthase (NOS) or guanylyl cyclase evoked smooth-muscle depolarization and constriction, with both hyperpolarization and relaxation to SLIGRL being abolished by TRAM-34 alone, whereas apamin had no effect. Immunolabeling showed SKCa and IKCa within the endothelium. CONCLUSIONS: In the absence of NO, IKCa underpins endothelium-dependent hyperpolarization and relaxation in cerebral arteries. However, when NOS is active SKCa contributes to hyperpolarization, whatever the extent of background contraction. These changes may have relevance in vascular disease states where NO release is compromised and when the levels of SKCa expression may be altered

The VLT-FLAMES Tarantula Survey

A spectroscopic analysis has been undertaken for the B-type multiple systems (excluding those with supergiant primaries) in the VLT-FLAMES Tarantula Survey (VFTS). Projected rotational velocities, vesini, for the primaries have been estimated using a Fourier Transform technique and confirmed by fitting rotationally broadened profiles. A subset of 33 systems with vesini ≤ 80 km s-1 have been analysed using a TLUSTY grid of model atmospheres to estimate stellar parameters and surface abundances for the primaries. The effects of a potential flux contribution from an unseen secondary have also been considered. For 20 targets it was possible to reliably estimate their effective temperatures (Teff) but for the other 13 objects it was only possible to provide a constraint of 20 000 ≤ Teff ≤ 26 000 K – the other parameters estimated for these targets will be consequently less reliable. The estimated stellar properties are compared with evolutionary models and are generally consistent with their membership of 30 Doradus, while the nature of the secondaries of 3 SB2 system is discussed. A comparison with a sample of single stars with vesini ≤ 80 km s-1 obtained from the VFTS and analysed with the same techniques implies that the atmospheric parameters and nitrogen abundances of the two samples are similar. However, the binary sample may have a lack of primaries with significant nitrogen enhancements, which would be consistent with them having low rotational velocities and having effectively evolved as single stars without significant rotational mixing. This result, which may be actually a consequence of the limitations of the pathfinder investigation presented in this paper, should be considered as a motivation for spectroscopic abundance analysis of large samples of binary stars, with high quality observational data

Evidence both L-type and non-L-type voltage-dependent calcium channels contribute to cerebral artery vasospasm following loss of NO in the rat

We recently found block of NO synthase in rat middle cerebral artery caused spasm, associated with depolarizing oscillations in membrane potential (Em) similar in form but faster in frequency (circa 1 Hz) to vasomotion. T-type voltage-gated Ca2+ channels contribute to cerebral myogenic tone and vasomotion, so we investigated the significance of T-type and other ion channels for membrane potential oscillations underlying arterial spasm. Smooth muscle cell membrane potential (Em) and tension were measured simultaneously in rat middle cerebral artery. NO synthase blockade caused temporally coupled depolarizing oscillations in cerebrovascular Em with associated vasoconstriction. Both events were accentuated by block of smooth muscle BKCa. Block of T-type channels or inhibition of Na+/K+-ATPase abolished the oscillations in Em and reduced vasoconstriction. Oscillations in Em were either attenuated or accentuated by reducing [Ca2+]o or block of KV, respectively. TRAM-34 attenuated oscillations in both Em and tone, apparently independent of effects against KCa3.1. Thus, rapid depolarizing oscillations in Em and tone observed after endothelial function has been disrupted reflect input from T-type calcium channels in addition to L-type channels, while other depolarizing currents appear to be unimportant. These data suggest that combined block of T and L-type channels may represent an effective approach to reverse cerebral vasospasm

The VLT-FLAMES Tarantula Survey XXVIII. Nitrogen abundances for apparently single dwarf and giant B-type stars with small projected rotational velocities

Previous analyses of the spectra of OB-type stars in the Magellanic Clouds have identified targets with low projected rotational velocities and relatively high nitrogen abundances; the evolutionary status of these objects remains unclear. The VLT-FLAMES Tarantula Survey obtained spectroscopy for over 800 early-type stars in 30 Doradus of which 434 stars were classified as B-type. We have estimated atmospheric parameters and nitrogen abundances using tlusty model atmospheres for 54 B-type targets that appear to be single, have projected rotational velocities, ve sin i ≤ 80 km s−1 and were not classified as supergiants. In addition, nitrogen abundances for 34 similar stars observed in a previous FLAMES survey of the Large Magellanic Cloud have been re-evaluated. For both samples, approximately 75-80% of the targets have nitrogen enhancements of less than 0.3 dex, consistent with them having experienced only small amounts of mixing. However, stars with low projected rotational velocities, ve sin i ≤ 40 km s−1 and significant nitrogen enrichments are found in both our samples and simulations imply that these cannot all be rapidly rotating objects observed near pole-on. For example, adopting an enhancement threshold of 0.6 dex, we observed five and four stars in our VFTS and previous FLAMES survey samples, yet stellar evolution models with rotation predict only 1.25±1.11 and 0.26±0.51 based on our sample sizes and random stellar viewing inclinations. The excess of such objects is estimated to be 20-30% of all stars with current rotational velocities of less than 40 km s−1 . This would correspond to ∼2-4% of the total non-supergiant single B-type sample. Given the relatively large nitrogen enhancement adopted, these estimates constitute lower limits for stars that appear inconsistent with current grids of stellar evolutionary models. Including targets with smaller nitrogen enhancements of greater than 0.2 dex implies larger percentages of targets that are inconsistent with current evolutionary models, viz. ∼70% of the stars with rotational velocities less than 40 km s−1 and ∼6-8% of the total single stellar population. We consider possible explanations of which the most promising would appear to be breaking due to magnetic fields or stellar mergers with subsequent magnetic braking

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Felsic lavas or rheomorphic ignimbrites: is there a chemical distinction?

In the environment of felsic magma generation associated with continental flood basalt (CFB) provinces there is a close association between magma composition, phenocryst assemblage, temperature and eruption mechanism. In this paper we propose that by examining the chemical composition and, in particular the high field strength element (Zr and Nb) contents of the high silica rocks, we can identify those that contained halogen-rich volatiles and which degassed at different levels (deep versus shallow). The degassing depth has a direct influence on the type of eruption, with shallow degassing promoting explosive rather than effusive behaviour and consequentially the former is more likely to give rise to ignimbrites. Thus, we can infer likely eruption mechanisms, as high concentrations of F and Cl dramatically decrease magma viscosities and should favour deep degassing and hence promote lava effusion rather than explosive pyroclastic eruption. This hypothesis is tested by constraining the other possible variables which have an effect on the mode of eruption, and by examining the nature and composition of melt and fluid inclusions in quartz from CFB-associated felsic volcanic rocks.</p

Elucidation of the temporal relationship between endothelial-derived NO and EDHF in mesenteric vessels

MEDLINE® is the source for the MeSH terms of this document.Although the endothelium co-generates both nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF), the relative contribution from each vasodilator is not clear. In studies where the endothelium is stimulated acutely, EDHF responses predominate in small arteries. However, the temporal relationship between endothelial-derived NO and EDHF over more prolonged periods is unclear but of major physiological importance. Here we have used a classical pharmacological approach to show that EDHF is released transiently compared with NO. Acetylcholine (3 × 10 mol/l) dilated second- and/or third-order mesenteric arteries for prolonged periods of up to 1 h, an effect that was reversed fully and immediately by the subsequent addition of L-NAME (10 mol/l) but not TRAM-34 (10 mol/l) plus apamin (5 × 10 mol/l). When vessels were pretreated with L-NAME, acetylcholine induced relatively transient dilator responses (declining over ∼5 min), and vessels were sensitive to TRAM-34 plus apamin. When measured in parallel, the dilator effects of acetylcholine outlasted the smooth muscle hyperpolarization. However, in the presence of L-NAME, vasodilatation and hyperpolarization followed an identical time course. In vessels from NOSIII mice, acetylcholine induced small but detectable dilator responses that were transient in duration and blocked by TRAM-34 plus apamin. EDHF responses in these mouse arteries were inhibited by an intracellular calcium blocker, TMB-8, and the phospholipase A inhibitor AACOCF, suggesting a role for lipid metabolites. These data show for the first time that EDHF is released transiently, whereas endothelial-derived NO is released in a sustained manner.Peer reviewe