Mycophenolate pharmacokinetics and pharmacodynamics in belatacept treated renal allograft recipients – a pilot study

<p>Abstract</p> <p>Background</p> <p>Mycophenolic acid (MPA) is widely used as part of immunosuppressive regimens following allograft transplantation. The large pharmacokinetic (PK) and pharmacodynamic (PD) variability and narrow therapeutic range of MPA provide a potential for therapeutic drug monitoring. The objective of this pilot study was to investigate the MPA PK and PD relation in combination with belatacept (2^ndgeneration CTLA4-Ig) or cyclosporine (CsA).</p> <p>Methods</p> <p>Seven renal allograft recipients were randomized to either belatacept (n = 4) or cyclosporine (n = 3) based immunosuppression. Samples for MPA PK and PD evaluations were collected predose and at 1, 2 and 13 weeks posttransplant. Plasma concentrations of MPA were determined by HPLC-UV. Activity of inosine monophosphate dehydrogenase (IMPDH) and the expressions of two <it>IMPDH </it>isoforms were measured in CD4+ cells by HPLC-UV and real-time reverse-transcription PCR, respectively. Subsets of T cells were characterized by flow cytometry.</p> <p>Results</p> <p>The MPA exposure tended to be higher among belatacept patients than in CsA patients at week 1 (P = 0.057). Further, MPA concentrations (AUC_{0–9 h}and C₀) increased with time in both groups and were higher at week 13 than at week 2 (P = 0.031, n = 6). In contrast to the postdose reductions of IMPDH activity observed early posttransplant, IMPDH activity within both treatment groups was elevated throughout the dosing interval at week 13. Transient postdose increments were also observed for <it>IMPDH1 </it>expression, starting at week 1. Higher MPA exposure was associated with larger elevations of <it>IMPDH1 </it>(r = 0.81, P = 0.023, n = 7 for MPA and <it>IMPDH1 </it>AUC_{0–9 h}at week 1). The maximum <it>IMPDH1 </it>expression was 52 (13–177)% higher at week 13 compared to week 1 (P = 0.031, n = 6). One patient showed lower MPA exposure with time and did neither display elevations of IMPDH activity nor <it>IMPDH1 </it>expression. No difference was observed in T cell subsets between treatment groups.</p> <p>Conclusion</p> <p>The significant influence of MPA on <it>IMPDH1 </it>expression, possibly mediated through reduced guanine nucleotide levels, could explain the elevations of IMPDH activity within dosing intervals at week 13. The present regulation of IMPDH in CD4+ cells should be considered when interpreting measurements of IMPDH inhibition.</p

Conical square function estimates in UMD Banach spaces and applications to H-infinity functional calculi

We study conical square function estimates for Banach-valued functions, and introduce a vector-valued analogue of the Coifman-Meyer-Stein tent spaces. Following recent work of Auscher-McIntosh-Russ, the tent spaces in turn are used to construct a scale of vector-valued Hardy spaces associated with a given bisectorial operator (A) with certain off-diagonal bounds, such that (A) always has a bounded (H^{\infty})-functional calculus on these spaces. This provides a new way of proving functional calculus of (A) on the Bochner spaces (L^p(\R^n;X)) by checking appropriate conical square function estimates, and also a conical analogue of Bourgain's extension of the Littlewood-Paley theory to the UMD-valued context. Even when (X=\C), our approach gives refined (p)-dependent versions of known results.Comment: 28 pages; submitted for publicatio

Biosynthesis of Macrolactam BE-14106 Involves Two Distinct PKS Systems and Amino Acid Processing Enzymes for Generation of the Aminoacyl Starter Unit

SummaryBE-14106 is a macrocyclic lactam with an acyl side chain previously identified in a marine-derived Streptomyces sp. The gene cluster for BE-14106 biosynthesis was cloned from a Streptomyces strain newly isolated from marine sediments collected in the Trondheimsfjord (Norway). Bioinformatics and experimental analyses of the genes in the cluster suggested an unusual mechanism for assembly of the molecule. Biosynthesis of the aminoacyl starter apparently involves the concerted action of a distinct polyketide synthase (PKS) system and several enzymes that activate and process an amino acid. The resulting starter unit is loaded onto a second PKS complex, which completes the synthesis of the macrolactam ring. Gene inactivation experiments, enzyme assays with heterologously expressed proteins, and feeding studies supported the proposed model for the biosynthesis and provided new insights into the assembly of macrolactams with acyl side chain

The Norwegian PraksisNett: a nationwide practice-based research network with a novel IT infrastructure

Clinical research in primary care is relatively scarce. Practice-based research networks (PBRNs) are research infrastructures to overcome hurdles associated with conducting studies in primary care. In Norway, almost all 5.4 million inhabitants have access to a general practitioner (GP) through a patient-list system. This gives opportunity for a PBRN with reliable information about the general population. The aim of the current paper is to describe the establishment, organization and function of PraksisNett (the Norwegian Primary Care Research Network). Materials and Methods We describe the development, funding and logistics of PraksisNett as a nationwide PBRN. Results PraksisNett received funding from the Research Council of Norway for an establishment period of five years (2018–2022). It is comprised of two parts; a human infrastructure (employees, including academic GPs) organized as four regional nodes and a coordinating node and an IT infrastructure comprised by the Snow system in conjunction with the Medrave M4 system. The core of the infrastructure is the 92 general practices that are contractually linked to PraksisNett. These include 492 GPs, serving almost 520,000 patients. Practices were recruited during 2019–2020 and comprise a representative mix of rural and urban settings spread throughout all regions of Norway. Conclusion Norway has established a nationwide PBRN to reduce hurdles for conducting clinical studies in primary care. Improved infrastructure for clinical studies in primary care is expected to increase the attractiveness for studies on the management of disorders and diseases in primary care and facilitate international research collaboration. This will benefit both patients, GPs and society in terms of improved quality of care.publishedVersio

Subsea Compression Applications - Panel Session

TutorialThe use of Subsea gas compression technology for subsea re-injection and/or gas transport boosting represents a new and exciting application for rotating equipment, which will allow new gas/condensate field production opportunities, enhanced recovery of existing gas/condensate fields and cost effective production from marginal gas fields. This panel session includes short presentations on the benefits of subsea compression, an overview of currently ongoing projects, and recent advances and technologies that are available and/or under development for subsea gas compression. The panel session includes presentations from Shell Global Solutions, Aker Solutions, MAN DIESEL & TURBO, GE OIL & GAS and DRESSER-RAND. The respective presentation titles are: Subsea Processing - Multiphase Boosting and Compression – Shell Global Solutions; Subsea Compression; Present Status and Experience – Aker Solutions; HOFIMTM Type Compressors for Subsea Applications; MAN Diesel & Turbo; GE Oil & Gas Experience in Subsea Gas Compression Technology Development – GE Oil & Gas; DATUM I Compressor for Subsea Applications: Update on Qualification Efforts- Dresser-Rand

"Drop in" gastroscopy outpatient clinic - experience after 9 months

<p>Abstract</p> <p>Background</p> <p>Logistics handling referrals for gastroscopy may be more time consuming than the examination itself. For the patient, "drop in" gastroscopy may reduce uncertainty, inadequate therapy and time off work.</p> <p>Methods</p> <p>After an 8-9 month run-in period we asked patients, hospital staff and GPs to fill in a questionnaire to evaluate their experience with "drop in" gastroscopy and gastroscopy by appointment, respectively. The diagnostic gain was evaluated.</p> <p>Results</p> <p>112 patients had "drop in" gastroscopy and 101 gastroscopy by appointment. The number of "drop in" patients varied between 3 and 12 per day (mean 6.5). Mean time from first GP consultation to gastroscopy was 3.6 weeks in the "drop in" group and 14 weeks in the appointment group. The half-yearly number of outpatient gastroscopies increased from 696 before introducing "drop in" to 1022 after (47% increase) and the proportion of examinations with pathological findings increased from 42% to 58%. Patients and GPs expressed great satisfaction with "drop in". Hospital staff also acclaimed although it caused more unpredictable working days with no additional staff.</p> <p>Conclusions</p> <p>"Drop in" gastroscopy was introduced without increase in staff. The observed increase in gastroscopies was paralleled by a similar increase in pathological findings without any apparent disadvantages for other groups of patients. This should legitimise "drop in" outpatient gastroscopies, but it requires meticulous observation of possible unwanted effects when implemented.</p

The ESO Nearby Abell Cluster Survey. XI. Segregation of cluster galaxies and subclustering

We study luminosity and morphology segregation of over 3000 cluster galaxies in an ensemble cluster of 59 rich, nearby galaxy clusters observed in the ESO Nearby Cluster Survey (ENACS). Within this sample we identify those galaxies that are in substructures. We compare the distribution of projected clustercentric distance, R, and 'normalized' relative line-of-sight velocity, v, of several subsamples, using the 2D Kolmogorov-Smirnov test. We find evidence of luminosity segregation only for the ellipticals outside substructure and brighter than M_R = -22.0 +/- 0.1 (h0=100 km/s/Mpc). We confirm the well-known segregation of early- and late-type galaxies. The early and late spirals (Sa--Sb and Sbc--Ir respectively) outside substructure also appear to have different (R,v)-distributions. In each morphological class, the galaxies within substructure have different (R,v)-distributions from the galaxies that are not in substructure. Among the samples of galaxies that are not in substructure, at least 3 ensembles can and must be distinguished: [E+S0], S_early, and [S_late+ELG]. The [E+S0] ensemble is most centrally concentrated and has a fairly low velocity dispersion that hardly varies with radius. The [S_late+ELG] ensemble is least concentrated and has the highest velocity dispersion, which increases significantly towards the centre. The (R,v)-distribution of S_early galaxies is intermediate between those of the two other ensembles. Among the galaxies within substructure the S0 and [S_late+ELG] galaxies have different (R,v) distributions. We discuss briefly the implications of our results for processes of galaxy destruction and transformation within clusters. [ABRIDGED]Comment: 18 pages. Accepted for publication in A

Radiative transfer with scattering for domain-decomposed 3D MHD simulations of cool stellar atmospheres

We present the implementation of a radiative transfer solver with coherent scattering in the new BIFROST code for radiative magneto-hydrodynamical (MHD) simulations of stellar surface convection. The code is fully parallelized using MPI domain decomposition, which allows for large grid sizes and improved resolution of hydrodynamical structures. We apply the code to simulate the surface granulation in a solar-type star, ignoring magnetic fields, and investigate the importance of coherent scattering for the atmospheric structure. A scattering term is added to the radiative transfer equation, requiring an iterative computation of the radiation field. We use a short-characteristics-based Gauss-Seidel acceleration scheme to compute radiative flux divergences for the energy equation. The effects of coherent scattering are tested by comparing the temperature stratification of three 3D time-dependent hydrodynamical atmosphere models of a solar-type star: without scattering, with continuum scattering only, and with both continuum and line scattering. We show that continuum scattering does not have a significant impact on the photospheric temperature structure for a star like the Sun. Including scattering in line-blanketing, however, leads to a decrease of temperatures by about 350\,K below log tau < -4. The effect is opposite to that of 1D hydrostatic models in radiative equilibrium, where scattering reduces the cooling effect of strong LTE lines in the higher layers of the photosphere. Coherent line scattering also changes the temperature distribution in the high atmosphere, where we observe stronger fluctuations compared to a treatment of lines as true absorbers.Comment: A&A, in pres

The Linearity of the Cosmic Expansion Field from 300 to 30,000 km/s and the Bulk Motion of the Local Supercluster with Respect to the CMB

The meaning of "linear expansion" is explained. Particularly accurate relative distances are compiled and homogenized a) for 246 SNe Ia and 35 clusters with v<30,000 km/s, and b) for relatively nearby galaxies with 176 TRGB and 30 Cepheid distances. The 487 objects define a tight Hubble diagram from 300-30,000 km/s implying individual distance errors of <7.5%. Here the velocities are corrected for Virgocentric steaming (locally 220 km/s) and - if v_220>3500 km/s - for a 495 km/s motion of the Local Supercluster towards the warm CMB pole at l=275, b=12; local peculiar motions are averaged out by large numbers. A test for linear expansion shows that the corrected velocities increase with distance as predicted by a standard model with q_0=-0.55 [corresponding to (Omega_M, Omega_Lambda)=(0.3,0.7)], but the same holds - due to the distance limitation of the present sample - for a range of models with q_0 between ~0.00 and -1.00. For these models H_0 does not vary systematically by more than +/-2.3% over the entire range. Local, distance-dependent variations are equally limited to 2.3% on average. In particular the proposed Hubble Bubble of Zehavi et al. and Jha et al. is rejected at the 4sigma level. - Velocity residuals in function of the angle from the CMB pole yield a satisfactory apex velocity of 448+/-73 km/s and a coherence radius of the Local Supercluster of ~3500 km/s (~56 Mpc), beyond which galaxies are seen on average at rest in co-moving coordinates with respect to the CMB. Since no obvious single accelerator of the Local Supercluster exists in the direction of the CMB dipole its motion must be due to the integral gravitational force of all surrounding structures. Most of the gravitational dipole comes probably from within 5000 km/s.Comment: 52 pages, 12 figures, 6 tables; accepted for publication in The Astrophysical Journal. v2: minor changes in both text and figure