Role of soluble guanylyl cyclase in renal afferent and efferent arterioles.

Renal arteriolar tone depends considerably on the dilatory action of nitric oxide (NO) via activation of soluble guanylyl cyclase (sGC) and cGMP action. NO deficiency and hypoxia/reoxygenation are important pathophysiological factors in the development of acute kidney injury. It was hypothesized that the NO-sGC-cGMP system functions differently in renal afferent arterioles (AA) compared with efferent arterioles (EA) and that the sGC activator cinaciguat differentially dilates these arterioles. Experiments were performed in isolated, perfused mouse glomerular arterioles. Hypoxia (0.1% oxygen) was achieved by using a hypoxia chamber. Phosphodiesterase 5 (PDE5) and sGC subunits were considerably expressed on the mRNA level in AA. PDE5 inhibition with sildenafil, which blocks cGMP degradation, diminished the responses to ANG II bolus application in AA, but not significantly in EA. Vasodilation induced by sildenafil in ANG II-preconstricted vessels was stronger in EA than AA. Cinaciguat, an NO- and heme-independent sGC activator, dilated EA more strongly than AA after NG-nitro-l-arginine methyl ester (l-NAME; NO synthase inhibitor) treatment and preconstriction with ANG II. Cinaciguat-induced dilatation of l-NAME-pretreated and ANG II-preconstricted arterioles was similar to controls without l-NAME treatment. Cinaciguat also induced dilatation in iodinated contrast medium treated AA. Furthermore, it dilated EA, but not AA, after hypoxia/reoxygenation. The results reveal an important role of the NO-sGC-cGMP system for renal dilatation and that EA have a more potent sGC activated dilatory system. Furthermore, AA seem to be more sensitive to hypoxia/reoxygenation than EA under these experimental conditions.

[Contrast medium-induced acute kidney injury-Consensus paper of the working group "Heart and Kidney" of the German Cardiac Society and the German Society of Nephrology]. / Kontrastmittelinduzierte akute Nierenschädigung ­ Konsensuspapier der Arbeitsgemeinschaft "Herz ­ Niere" der Deutschen Gesellschaft für Kardiologie ­ Herz- und Kreislaufforschung e. V. und der Deutschen Gesellschaft für Nephrologie e. V.

This consensus paper summarizes the expert consensus and recommendations of the working group "Heart and Kidney" of the German Cardiac Society (DGK) and the German Society of Nephrology (DGfN) on contrast medium-induced acute kidney injury. Potentially nephrotoxic contrast agents containing iodine are frequently used in interventional medicine and for computer tomography diagnostics. Acute kidney injury occurs in approximately 8-17% of patients exposed to contrast media. The risk factors and underlying pathophysiology are discussed and recommendations for the prophylaxis and treatment of contrast medium-induced acute nephropathy are presented.

Evaluation of lung and chest wall mechanics during anaesthesia using the PEEP-step method.

BACKGROUND: Postoperative pulmonary complications are common. Between patients there are differences in lung and chest wall mechanics. Individualised mechanical ventilation based on measurement of transpulmonary pressures would be a step forward. A previously described method evaluates lung and chest wall mechanics from a change of ΔPEEP and calculation of change in end-expiratory lung volume (ΔEELV). The aim of the present study was to validate this PEEP-step method (PSM) during general anaesthesia by comparing it with the conventional method using oesophageal pressure (PES) measurements. METHODS: In 24 lung healthy subjects (BMI 18.5-32), three different sizes of PEEP steps were performed during general anaesthesia and ΔEELVs were calculated. Transpulmonary driving pressure (ΔPL) for a tidal volume equal to each ΔEELV was measured using PES measurements and compared to ΔPEEP with limits of agreement and intraclass correlation coefficients (ICC). ΔPL calculated with both methods was compared with a Bland-Altman plot. RESULTS: Mean differences between ΔPEEP and ΔPL were <0.15 cm H2O, 95% limits of agreements -2.1 to 2.0 cm H2O, ICC 0.6-0.83. Mean differences between ΔPL calculated by both methods were <0.2 cm H2O. Ratio of lung elastance and respiratory system elastance was 0.5-0.95. CONCLUSIONS: The large variation in mechanical properties among the lung healthy patients stresses the need for individualised ventilator settings based on measurements of lung and chest wall mechanics. The agreement between ΔPLs measured by the two methods during general anaesthesia suggests the use of the non-invasive PSM in this patient population. CLINICAL TRIAL REGISTRATION: NCT 02830516.

Myoglobin facilitates angiotensin II-induced constriction of renal afferent arterioles.

Vasoconstriction plays an important role in the development of acute kidney injury in rhabdomyolysis. We hypothesized that myoglobin enhances the angiotensin II (ANG II) response in afferent arterioles by increasing superoxide and reducing nitric oxide (NO) bioavailability. Afferent arterioles of C57Bl6 mice were isolated perfused, and vasoreactivity was analyzed using video microscopy. NO bioavailability, superoxide concentration in the vessel wall, and changes in cytosolic calcium were measured using fluorescence techniques. Myoglobin treatment (10-5 M) did not change the basal arteriolar diameter during a 20-min period compared with control conditions. NG-nitro-l-arginine methyl ester (l-NAME, 10-4 M) and l-NAME + myoglobin reduced diameters to 94.7 and 97.9% of the initial diameter, respectively. Myoglobin or l-NAME enhanced the ANG II-induced constriction of arterioles compared with control (36.6 and 34.2%, respectively, vs. 65.9%). Norepinephrine responses were not influenced by myoglobin. Combined application of myoglobin and l-NAME further facilitated the ANG II response (7.0%). Myoglobin or l-NAME decreased the NO-related fluorescence in arterioles similarly. Myoglobin enhanced the superoxide-related fluorescence, and tempol prevented this enhancement. Tempol also partly prevented the myoglobin effect on the ANG II response. Myoglobin increased the fura 2 fluorescence ratio (cytosolic calcium) during ANG II application (10-12 to 10-6 M). The results suggest that the enhanced afferent arteriolar reactivity to ANG II is mainly due to a myoglobin-induced increase in superoxide and associated reduction in the NO bioavailability. Signaling pathways for the augmented ANG II response include enhanced cytosolic calcium transients. In conclusion, myoglobin may contribute to the afferent arteriolar vasoconstriction in this rhabdomyolysis model.

Measuring FVIII activity of glycopegylated recombinant factor VIII, N8-GP, with commercially available one-stage clotting and chromogenic assay kits: a two-centre study.

INTRODUCTION: Factor VIII activity (FVIII:C) assays of samples containing glycoPEGylated recombinant FVIII such as turoctocog alfa pegol (N8-GP) can be associated with differences in FVIII recovery in vitro between various one-stage activated partial thromboplastin time (APTT)-based clotting assays and some chromogenic assays. Careful validation and qualification of specific assays and conditions is therefore necessary for the assessment of FVIII:C in samples containing modified FVIII molecules. AIM: To assess the ability of various one-stage clotting and chromogenic FVIII:C assays to measure samples containing N8-GP compared to unmodified recombinant FVIII (rFVIII) across two laboratory sites. METHODS: Factor VIII activity in severe haemophilia A (HA) plasma spiked with a range of concentrations (from low, 0.20 IU mL-1 , to high, 0.90 IU mL-1 ) of N8-GP and rFVIII, was determined at two laboratory sites using 12 commercially available one-stage clotting and chromogenic FVIII:C assays. Assays were performed using a plasma calibrator and different analysers. RESULTS: Acceptable N8-GP recovery was observed in the low to high concentration samples tested using the majority of the tested APTT reagents with only one reagent causing a significant underestimation as compared to rFVIII. For the chromogenic assays, a slight overestimation was observed with some of the kits. Variability between the two laboratory sites are likely attributable to the use of different analysers with the respective APTT reagents. CONCLUSIONS: These results highlight the need to investigate the performance of modified factor products using standard assays. The performance of different one-stage clotting assays, APTT reagents, reference calibrators and instrumentation should also be evaluated.

Pharmacokinetics of a novel extended half-life glycoPEGylated factor IX, nonacog beta pegol (N9-GP) in previously treated patients with haemophilia B: results from two phase 3 clinical trials.

INTRODUCTION: Nonacog beta pegol (N9-GP) is a glycoPEGylated recombinant factor IX (FIX) with an extended half-life developed for routine prophylaxis and the prevention and treatment of bleeding episodes in patients with haemophilia B. AIM: The aim of this study was to evaluate the pharmacokinetics (PK) of N9-GP. METHODS: Data from 41 previously treated haemophilia B patients, enrolled globally (16 adolescents/adults and 25 children; FIX activity ≤0.02 IU mL-1 ) with no history of FIX inhibitors, were included. N9-GP was administered once-weekly as 10 IU kg-1 or 40 IU kg-1 in adolescents/adults and 40 IU kg-1 in children. Blood was sampled up to 168 h (1 week) post dose. Standard PK was estimated on the basis of plasma FIX activity vs. time (PK profiles) using non-compartmental methods. Furthermore, a population PK analysis and FIX activity predictions were performed. RESULTS: Incremental recoveries were 0.02 (IU mL-1 )/(IU kg-1 ) in both adolescents/adults and children. The extended half-life resulted in mean trough levels of 0.27 IU mL-1 for adolescents/adults and 0.17 IU mL-1 for children at steady-state after weekly dosing at 40 IU kg-1 . The population PK analysis confirmed a mono-exponential decay in FIX activity and allowed for predictions of FIX activity for adolescents/adults above 0.15 IU mL-1 at all times and 6.4 days week-1 in children. CONCLUSION: N9-GP has the potential to shift previously treated haemophilia B patients from a severe/moderate disease state into a mild- or non-haemophilic range for most of the dosing interval, which is expected to reduce the number of bleeding episodes.

Core-shell formation in self-induced InAlN nanorods.

We have examined the early stages of self-induced InAlN core-shell nanorod (NR) formation processes on amorphous carbon substrates in plan-view geometry by means of transmission electron microscopy methods. The results show that the grown structure phase separates during the initial moments of deposition into a majority of Al-rich InAlN and a minority of In-enriched InAlN islands. The islands possess polygonal shapes and are mainly oriented along a crystallographic c-axis. The growth proceeds with densification and coalescence of the In-enriched islands, resulting in a base for the In-enriched NR cores with shape transformation to hexagonal. The Al-rich shell formation around such early cores is observed at this stage. The matured core-shell structure grows axially and radially, eventually reaching a steady growth state which is dominated by the axial NR growth. We discuss the NR formation mechanism by considering the adatom surface kinetics, island surface energy, phase separation of InAlN alloys, and incoming flux directions during dual magnetron sputter epitaxy.

Excitons and biexcitons in InGaN quantum dot like localization centers.

Indium segregation in a narrow InGaN single quantum well creates quantum dot (QD) like exciton localization centers. Cross-section transmission electron microscopy reveals varying shapes and lateral sizes in the range ∼1-5 nm of the QD-like features, while scanning near field optical microscopy demonstrates a highly inhomogeneous spatial distribution of optically active individual localization centers. Microphotoluminescence spectroscopy confirms the spectrally inhomogeneous distribution of localization centers, in which the exciton and the biexciton related emissions from single centers of varying geometry could be identified by means of excitation power dependencies. Interestingly, the biexciton binding energy (E(b)xx) was found to vary from center to center, between 3 to -22 meV, in correlation with the exciton emission energy. Negative binding energies are only justified by a three-dimensional quantum confinement, which confirms QD-like properties of the localization centers. The observed energy correlation is proposed to be understood as variations of the lateral extension of the confinement potential, which would yield smaller values of E(b)xx for reduced lateral extension and higher exciton emission energy. The proposed relation between lateral extension and E(b)xx is further supported by the exciton and the biexciton recombination lifetimes of a single QD, which suggest a lateral extension of merely ∼3 nm for a QD with strongly negative E(b)xx = -15.5 meV.

Magnetic self-organized atomic laminate from first principles and thin film synthesis.

The first experimental realization of a magnetic M(n+1)AX(n) (MAX) phase, (Cr(0.75)Mn(0.25))(2)GeC, is presented, synthesized as a heteroepitaxial single crystal thin film, exhibiting excellent structural quality. This self-organized atomic laminate is based on the well-known Cr(2)GeC, with Mn, a new element in MAX phase research, substituting Cr. The compound was predicted using first-principles calculations, from which a variety of magnetic behavior is envisaged, depending on the Mn concentration and Cr/Mn atomic configuration within the sublattice. The analyzed thin films display a magnetic signal at room temperature.

Pelvic organ prolapse after subtotal and total hysterectomy: a long-term follow-up of an open randomised controlled multicentre study.

OBJECTIVE: To analyse the development of pelvic organ prolapse (POP) after subtotal (SH) and total hysterectomy (TH) in the long-term, and to assess patient-reported symptoms regarding pelvic floor dysfunction (PFD). DESIGN: Long-term follow-up study of a randomised controlled multicentre study. SETTING: Seven hospitals and one private clinic in the south-east of Sweden. POPULATION: Of the 184 women who were eligible from the original trial, 151 (82%) responded to a postal questionnaire and 128 (70%) were clinically examined. METHODS: Postal questionnaire using the short-form version of the Pelvic Floor Distress Inventory (PFDI-20) and clinical examination using the POP-Q system. Multivariate analyses were used. MAIN OUTCOME MEASURES: POP-Q measurements and symptoms of PFD. RESULTS: Follow-up time was a median of 11.3 years. Less than 3% had stage-3 prolapse. No significant difference was found in the presence of stage-2 or higher stage prolapse between the two hysterectomy groups (39% in SH versus 37% in TH; OR 1.28, 95% CI 0.59-2.80). Nor was there any significant difference in the quality-of-life measurement between the SH and TH groups [summary score PFDI-20: median 93 (range 60-201) versus 87 (range 60-186); Fisher's protected least significant difference post hoc test, P = 0.78 ). None of the symptoms of PFD revealed statistically significant differences between the hysterectomy groups. CONCLUSIONS: This long-term follow-up study of PFD showed basically no significant differences in subjective or objective measurements of POP, or in specific pelvic floor quality-of-life aspects after SH and TH. However, because of the low statistical power the results are inconclusive. Larger trials, and probably also a longer follow-up period, are necessary.

Continuous observations of the surface energy budget and meteorology over the Arctic sea ice during MOSAiC.

The Multidisciplinary drifting Observatory for the Study of Arctic Climate (MOSAiC) was a yearlong expedition supported by the icebreaker R/V Polarstern, following the Transpolar Drift from October 2019 to October 2020. The campaign documented an annual cycle of physical, biological, and chemical processes impacting the atmosphere-ice-ocean system. Of central importance were measurements of the thermodynamic and dynamic evolution of the sea ice. A multi-agency international team led by the University of Colorado/CIRES and NOAA-PSL observed meteorology and surface-atmosphere energy exchanges, including radiation; turbulent momentum flux; turbulent latent and sensible heat flux; and snow conductive flux. There were four stations on the ice, a 10 m micrometeorological tower paired with a 23/30 m mast and radiation station and three autonomous Atmospheric Surface Flux Stations. Collectively, the four stations acquired ~928 days of data. This manuscript documents the acquisition and post-processing of those measurements and provides a guide for researchers to access and use the data products.

InGaN quantum dot formation mechanism on hexagonal GaN/InGaN/GaN pyramids.

Growing InGaN quantum dots (QDs) at the apex of hexagonal GaN pyramids is an elegant approach to achieve a deterministic positioning of QDs. Despite similar synthesis procedures by metal organic chemical vapor deposition, the optical properties of the QDs reported in the literature vary drastically. The QDs tend to exhibit either narrow or broad emission lines in the micro-photoluminescence spectra. By coupled microstructural and optical investigations, the QDs giving rise to narrow emission lines were concluded to nucleate in association with a (0001) facet at the apex of the GaN pyramid.

Crucial role of the interleukin 1 receptor family member T1/ST2 in T helper cell type 2-mediated lung mucosal immune responses.

T1/ST2 is an orphan receptor of unknown function that is expressed on the surface of murine T helper cell type 2 (Th2), but not Th1 effector cells. In vitro blockade of T1/ST2 signaling with an immunoglobulin (Ig) fusion protein suppresses both differentiation to and activation of Th2, but not Th1 effector populations. In a nascent Th2-dominated response, anti-T1/ST2 monoclonal antibody (mAb) inhibited eosinophil infiltration, interleukin 5 secretion, and IgE production. To determine if these effects were mediated by a direct effect on Th2 cells, we next used a murine adoptive transfer model of Th1- and Th2-mediated lung mucosal immune responses. Administration of either T1/ST2 mAb or T1/ST2-Ig abrogated Th2 cytokine production in vivo and the induction of an eosinophilic inflammatory response, but failed to modify Th1-mediated inflammation. Taken together, our data demonstrate an important role of T1/ST2 in Th2-mediated inflammatory responses and suggest that T1/ST2 may prove to be a novel target for the selective suppression of Th2 immune responses.

Short-term recovery after subtotal and total abdominal hysterectomy--a randomised clinical trial.

OBJECTIVE: To determine whether the day-by-day postoperative recovery differs between women undergoing subtotal and total abdominal hysterectomy, and to analyse factors associated with postoperative recovery and sick leave. DESIGN: A prospective, open, randomised multicentre trial. SETTING: Seven hospitals and one private clinic in the south-east of Sweden. POPULATION: Two-hundred women scheduled for hysterectomy for benign conditions were enrolled in the study, and 178 women completed the study. Ninety-four women were randomised to subtotal abdominal hysterectomy; 84 women were randomised to total abdominal hysterectomy. METHODS: The day-by-day recovery of general wellbeing was measured on a visual analogue scale in a diary 7 days preoperatively and 35 days postoperatively. Psychometric measurements included depression, anxiety and general psychological wellbeing. MAIN OUTCOME MEASURES: Effects of operating method and preoperative wellbeing on the day-by-day recovery and duration of sick leave. RESULTS: No significant difference was found in the day-by-day recovery between operating methods. The day-by-day recovery of general wellbeing and duration of sick leave was strongly associated with the occurrence of minor complications, but not with major complications. The level of psychological wellbeing preoperatively was strongly associated with the day-by-day recovery of general wellbeing and duration of sick leave. CONCLUSIONS: Day-by-day recovery of general wellbeing is no faster in subtotal versus total abdominal hysterectomy. Independent of operation method there is an interaction between preoperative psychological wellbeing, postoperative recovery of general wellbeing and the duration of sick leave. Postoperative complications and preoperative psychological wellbeing are strong determinants for the duration of sick leave. There is a need for intervention studies with a focus on complications and preoperative wellbeing.

A 1-year follow up of psychological wellbeing after subtotal and total hysterectomy--a randomised study.

OBJECTIVE: To compare subtotal abdominal hysterectomy (SH) and total abdominal hysterectomy (TH) regarding influence on postoperative psychological wellbeing and surgical outcome measurements. DESIGN: A prospective, open, randomised multicentre trial. SETTING: Seven hospitals and one private clinic in the south-east of Sweden. POPULATION: Two-hundred women scheduled for abdominal hysterectomy for benign conditions were enrolled in the study; 179 women completed the study (94 SH and 85 TH). METHODS: Four different psychometric tests were used to measure general wellbeing, depression and anxiety preoperatively, and at 6 and 12 months postoperatively. Statistical analysis of variance and covariance were used. MAIN OUTCOME MEASURES: Effects of operating method on psychological wellbeing postoperatively. Analysis of demographic, clinical and surgical data, including peri- and postoperative complications and complaints at follow up. RESULTS: No significant differences were observed between the two groups in any of the psychometric tests. Both surgical methods were associated with a significantly higher degree of psychological wellbeing at 6 and 12 months postoperatively, compared with preoperatively. No significant differences were found in the clinical measures including complications. A substantial number of women experienced persistent cyclic vaginal bleedings after SH. Neither minor or major postoperative complications, nor serum concentration of sex hormones, were associated with general psychological wellbeing 12 months after the operation. CONCLUSIONS: General psychological wellbeing is equally improved after both SH and TH within 12 months of the operation, and does not seem to be associated with the occurrence of peroperative complications or serum concentration of sex hormones.

The effects of microstructure, Nb content and secondary Ruddlesden-Popper phase on thermoelectric properties in perovskite CaMn1-x Nb x O3 (x = 0-0.10) thin films.

CaMn1-x Nb x O3 (x = 0, 0.5, 0.6, 0.7 and 0.10) thin films have been grown by a two-step sputtering/annealing method. First, rock-salt-structured (Ca,Mn1-x ,Nb x )O thin films were deposited on 11̄00 sapphire using reactive RF magnetron co-sputtering from elemental targets of Ca, Mn and Nb. The CaMn1-x Nb x O3 films were then obtained by thermally induced phase transformation from rock-salt-structured (Ca,Mn1-x Nb x )O to orthorhombic during post-deposition annealing at 700 °C for 3 h in oxygen flow. The X-ray diffraction patterns of pure CaMnO3 showed mixed orientation, while Nb-containing films were epitaxially grown in [101] out of-plane-direction. Scanning transmission electron microscopy showed a Ruddlesden-Popper (R-P) secondary phase in the films, which results in reduction of the electrical and thermal conductivity of CaMn1-x Nb x O3. The electrical resistivity and Seebeck coefficient of the pure CaMnO3 film were measured to 2.7 Ω cm and -270 µV K-1 at room temperature, respectively. The electrical resistivity and Seebeck coefficient were reduced by alloying with Nb and was measured to 0.09 Ω cm and -145 µV K-1 for x = 0.05. Yielding a power factor of 21.5 µW K-2 m-1 near room temperature, nearly eight times higher than for pure CaMnO3 (2.8 µW K-2 m-1). The power factors for alloyed samples are low compared to other studies on phase-pure material. This is due to high electrical resistivity originating from the secondary R-P phase. The thermal conductivity of the CaMn1-x Nb x O3 films is low for all samples and is the lowest for x = 0.07 and 0.10, determined to 1.6 W m-1 K-1. The low thermal conductivity is attributed to grain boundary scattering and the secondary R-P phase.

Aligned AlN nanowires by self-organized vapor-solid growth.

Highly oriented AlN single crystal nanowires with aspect ratio up to 600, diameter in the range of 40-500 nm, and 100 microm lengths, have been synthesized via a vapor-solid growth mechanism. The results were obtained at 1750 degrees C and 850 mbar nitrogen pressure on vicinal SiC substrates pretreated by SiC sublimation epitaxy in order to attain distinguishable terraces. It was found that the nanowires change in thickness after they have reached a critical length, and this fact contributes to an understanding of the growth mechanism of AlN nanowires. The nanowires are hexagonally shaped and perfectly aligned along the [0001] direction with a small tilt given by the substrate vicinality. Under nitrogen excess a preferential growth along the c-axis of the wurtzite structure takes place while below some critical value of nitrogen pressure the growth mode switches to lateral. The AlN nanowires are shown to have a dislocation free wurtzite crystal structure. Some possible applications are discussed.

Ti n+1C n MXenes with fully saturated and thermally stable Cl terminations.

MXenes are a rapidly growing family of 2D materials that exhibit a highly versatile structure and composition, allowing for significant tuning of the materials properties. These properties are, however, ultimately limited by the surface terminations, which are typically a mixture of species, including F and O that are inherent to the MXene processing. Other and robust terminations are lacking. Here, we apply high-resolution scanning transmission electron microscopy (STEM), corresponding image simulations and first-principles calculations to investigate the surface terminations on MXenes synthesized from MAX phases through Lewis acidic melts. The results show that atomic Cl terminates the synthesized MXenes, with mere residual presence of other termination species. Furthermore, in situ STEM-electron energy loss spectroscopy (EELS) heating experiments show that the Cl terminations are stable up to 750 °C. Thus, we present an attractive new termination that widely expands the MXenes' functionalization space and enables new applications.