Reynolds stresses and mean fields generated by pure waves: applications to shear flows and convection in a rotating shell

A general reformulation of the Reynolds stresses created by two-dimensional waves breaking a translational or a rotational invariance is described. This reformulation emphasizes the importance of a geometrical factor: the slope of the separatrices of the wave flow. Its physical relevance is illustrated by two model systems: waves destabilizing open shear flows; and thermal Rossby waves in spherical shell convection with rotation. In the case of shear-flow waves, a new expression of the Reynolds–Orr amplification mechanism is obtained, and a good understanding of the form of the mean pressure and velocity fields created by weakly nonlinear waves is gained. In the case of thermal Rossby waves, results of a three-dimensional code using no-slip boundary conditions are presented in the nonlinear regime, and compared with those of a two-dimensional quasi-geostrophic model. A semi-quantitative agreement is obtained on the flow amplitudes, but discrepancies are observed concerning the nonlinear frequency shifts. With the quasi-geostrophic model we also revisit a geometrical formula proposed by Zhang to interpret the form of the zonal flow created by the waves, and explore the very low Ekman-number regime. A change in the nature of the wave bifurcation, from supercritical to subcritical, is found

Étude théorique d'ondes De Rossby thermiques non linéaires en géométrie sphérique: influence du mode de chauffage

Thermal Rossby waves appear by thermoconvective instabilities in the liquid core of rotating planets. Our study, which uses 2D quasigeostrophic models and 3D models, the latters being used to validate the formers, shows that the heating mode, internal or external, can modify the nature of the bifurcation towards these waves

TLR9 activation induces normal neutrophil responses in a child with IRAK-4 deficiency: involvement of the direct PI3K pathway.

International audiencePolymorphonuclear neutrophils (PMN) play a key role in innate immunity. Their activation and survival are tightly regulated by microbial products via pattern recognition receptors such as TLRs, which mediate recruitment of the IL-1R-associated kinase (IRAK) complex. We describe a new inherited IRAK-4 deficiency in a child with recurrent pyogenic bacterial infections. Analysis of the IRAK4 gene showed compound heterozygosity with two mutations: a missense mutation in the death domain of the protein (pArg12Cys) associated in cis-with a predicted benign variant (pArg391His); and a splice site mutation in intron 7 that led to the skipping of exon 7. A nontruncated IRAK-4 protein was detected by Western blotting. The patient's functional deficiency of IRAK-4 protein was confirmed by the absence of IRAK-1 phosphorylation after stimulation with all TLR agonists tested. The patient's PMNs showed strongly impaired responses (L-selectin and CD11b expression, oxidative burst, cytokine production, cell survival) to TLR agonists which engage TLR1/2, TLR2/6, TLR4, and TLR7/8; in contrast, the patient's PMN responses to CpG-DNA (TLR9) were normal, except for cytokine production. The surprisingly normal effect of CpG-DNA on PMN functions and apoptosis disappeared after pretreatment with PI3K inhibitors. Together, these results suggest the existence of an IRAK-4-independent TLR9-induced transduction pathway leading to PI3K activation. This alternative pathway may play a key role in PMN control of infections by microorganisms other than pyogenic bacteria in inherited IRAK-4 deficiency

Pretransplant identification of acute rejection risk following kidney transplantation

Lack of an accepted definition for 'high immunological risk' hampers individualization of immunosuppressive therapy after kidney transplantation. For recipient-related risk factors for acute rejection, the most compelling evidence points to younger age and African American ethnicity. Recipient gender, body mass, previous transplantation, and concomitant infection or disease do not appear to be influential. Deceased donation now has only a minor effect on rejection risk, but older donor age remains a significant predictor. Conventional immunological markers (human leukocyte antigen [HLA] mismatching, pretransplant anti-HLA alloantibodies, and panel reactive antibodies) are being reassessed in light of growing understanding about the role of donor-specific antibodies (DSA). At the time of transplant, delayed graft function is one of the most clear-cut risk factors for acute rejection. Extended cold ischemia time (≥24 h) may also play a contributory role. While it is not yet possible to establish conclusively the relative contribution of different risk factors for acute rejection after kidney transplantation, the available data point to variables that should be taken into account at the time of transplant. Together, these offer a realistic basis for planning an appropriate immunosuppression regimen in individual patients

Influence of FK 506 (tacrolimus) on circulating CD4 ⁺ t cells expressing cd25 and cd45ra antigens in 19 patients with chronic progressive multiple sclerosis participating in an open label drug safety trial

We have taken the opportunity of a clinical trial of the potential efficacy and safety of FK 506 (tacrolimus) in chronic progressive multiple sclerosis (MS) to examine the influence of this potent new immunosuppressant on circulating T-lymphocytes in an otherwise healthy non-transplant population. Peripheral blood levels of subsets of CD4+ T lymphocytes expressing the activation molecule interleukin-2 receptor (p55 α chain; CD25) or the CD45RA isoform were determined sequentially in 19 patients that were treated continuously with oral FK 506 (starting dose 0.15 mg/kg/day) for 12 months. No significant change in the proportion of circulating CD25 + CD4+ cells was observed over the study period in which the mean trough plasma FK 506 level rose from 0.3 ±0.2 to 0.5 ±0.4 ng/ml. There was also no significant effect of FK 506 on the percentage of CD45RA + CD4 + cells in the peripheral blood at 12 months compared with pretreatment values. Analysis of a subgroup of 7 patients, who showed a sustained reduction in CD25 + CD4+ cells and a reciprocal increase in CD45RA* CD4 * cells for at least 6 months after start of treatment, did not reveal any difference in disability at one year compared with the treatment group as a whole. The side effects of FK 506 were mild and the overall degree of disability estimated by the mean Kurtzke expanded disability status scale (EDSS) score or the ambulation index did not deteriorate significantly in the 19 patients studied over the 12 months of FK 506 administration. © 1994 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted

A comparative performance evaluation framework for power based wind turbine fault detection methods

International audienc

ADHERE: randomized controlled trial comparing renal function in de novo kidney transplant recipients receiving prolonged-release tacrolimus plus mycophenolate mofetil or sirolimus

ADHERE was a randomized, open-label, Phase IV study comparing renal function at Week 52 postkidney transplant, in patients who received prolongedrelease tacrolimus-based immunosuppressive regimens. On Days 0?27, patients received prolonged-release tacrolimus (initially 0.2 mg/kg/day), corticosteroids, and mycophenolate mofetil (MMF). Patients were randomized on Day 28 to receive either prolonged-release tacrolimus plus MMF (Arm 1) or prolongedrelease tacrolimus (?25% dose reduction on Day 42) plus sirolimus (Arm 2). The primary endpoint was glomerular filtration rate by iohexol clearance (mGFR) at Week 52. Secondary endpoints included eGFR, creatinine clearance (CrCl), efficacy failure (patient withdrawal or graft loss), and patient/graft survival. Tolerability was analyzed. The full-analysis set comprised 569 patients (Arm 1: 287; Arm 2: 282). Week 52 mean mGFR was similar in Arm 1 versus Arm 2 (40.73 vs. 41.75 ml/min/1.73 m2; P = 0.405), as were the secondary endpoints, except composite efficacy failure, which was higher in Arm 2 versus 1 (18.2% vs. 11.5%; P = 0.002) owing to a higher postrandomization withdrawal rate due to adverse events (AEs) (14.4% vs. 5.2%). Results from this study show comparable renal function between arms at Week 52, with fewer AEs leading to study discontinuation with prolonged-release tacrolimus plus MMF (Arm 1) versus lower dose prolonged-release tacrolimus plus sirolimus (Arm 2)

New Directions for Rabbit Antithymocyte Globulin (Thymoglobulin®) in Solid Organ Transplants, Stem Cell Transplants and Autoimmunity

In the 30 years since the rabbit antithymocyte globulin (rATG) Thymoglobulin(®) was first licensed, its use in solid organ transplantation and hematology has expanded progressively. Although the evidence base is incomplete, specific roles for rATG in organ transplant recipients using contemporary dosing strategies are now relatively well-identified. The addition of rATG induction to a standard triple or dual regimen reduces acute cellular rejection, and possibly humoral rejection. It is an appropriate first choice in patients with moderate or high immunological risk, and may be used in low-risk patients receiving a calcineurin inhibitor (CNI)-sparing regimen from time of transplant, or if early steroid withdrawal is planned. Kidney transplant patients at risk of delayed graft function may also benefit from the use of rATG to facilitate delayed CNI introduction. In hematopoietic stem cell transplantation, rATG has become an important component of conventional myeloablative conditioning regimens, following demonstration of reduced acute and chronic graft-versus-host disease. More recently, a role for rATG has also been established in reduced-intensity conditioning regimens. In autoimmunity, rATG contributes to the treatment of severe aplastic anemia, and has been incorporated in autograft projects for the management of conditions such as multiple sclerosis, Crohn’s disease, and systemic sclerosis. Finally, research is underway for the induction of tolerance exploiting the ability of rATG to induce immunosuppresive cells such as regulatory T-cells. Despite its long history, rATG remains a key component of the immunosuppressive armamentarium, and its complex immunological properties indicate that its use will expand to a wider range of disease conditions in the future

Choice of induction regimens on the risk of cytomegalovirus infection in donor-positive and recipient-negative kidney transplant recipients

F.L. Luan, M. Samaniego, M. Kommareddi, J.M. Park, A.O. Ojo. Choice of induction regimens on the risk of cytomegalovirus infection in donor-positive and recipient-negative kidney transplant recipients. Transpl Infect Dis 2010: 12: 473–479. All rights reservedLate occurrence of cytomegalovirus (CMV) infection remains a concern in CMV-seronegative kidney and/or pancreas transplant recipients of CMV-seropositive organs (donor positive/recipient negative, D+/R−) despite the use of prophylaxis. We investigated the impact of various antibody induction regimens on CMV infection in this group of patients.A total of 254 consecutive D+/R− kidney and/or pancreas transplant patients were studied. The induction agents rabbit anti-thymocyte globulin (rATG) or basiliximab were used according to the center practice. All patients received prophylaxis with valganciclovir (VGCV) for either 3 or 6 months. The occurrence of CMV infection was confirmed by positive DNA viremia. Multivariate Cox regression analyses were performed to determine risk factors for CMV infection.The cumulative incidence of CMV infection was 58, 112, and 59 cases per 1000 patient-years for patients who received no antibody induction, induction with rATG, or basiliximab induction, respectively ( P =0.02). The use of rATG but not basiliximab was associated with an increased risk for CMV infection (adjusted hazard ratio [AHR] 2.13, 95% confidence interval [CI] 1.24–3.54, P =0.006). Acute rejection and its treatment with rATG were not associated with an increased risk for CMV infection when an additional course of VGCV was given following the treatment. Longer duration of prophylaxis was associated with a reduced risk for CMV infection (AHR 0.54, 95% CI 0.33–0.87, P =0.011).Induction with rATG is associated with increased risk of CMV infection. Longer duration of prophylaxis is beneficial.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79309/1/j.1399-3062.2010.00532.x.pd

Safety and efficacy of eculizumab for the prevention of antibody-mediated rejection after deceased-donor kidney transplantation in patients with preformed donor-specific antibodies

Abstract View references (47) The presence of preformed donor-specific antibodies in transplant recipients increases the risk of acute antibody-mediated rejection (AMR). Results of an open-label single-arm trial to evaluate the safety and efficacy of eculizumab in preventing acute AMR in recipients of deceased-donor kidney transplants with preformed donor-specific antibodies are reported. Participants received eculizumab as follows: 1200 mg immediately before reperfusion; 900 mg on posttransplant days 1, 7, 14, 21, and 28; and 1200 mg at weeks 5, 7, and 9. All patients received thymoglobulin induction therapy and standard maintenance immunosuppression including steroids. The primary end point was treatment failure rate, a composite of biopsy-proved grade II/III AMR (Banff 2007 criteria), graft loss, death, or loss to follow-up, within 9 weeks posttransplant. Eighty patients received transplants (48 women); the median age was 52 years (range 24-70 years). Observed treatment failure rate (8.8%) was significantly lower than expected for standard care (40%; P <.001). By 9 weeks, 3 of 80 patients had experienced AMR, and 4 of 80 had experienced graft loss. At 36 months, graft and patient survival rates were 83.4% and 91.5%, respectively. Eculizumab was well tolerated and no new safety concerns were identified. Eculizumab has the potential to provide prophylaxis against injury caused by acute AMR in such patients (EudraCT 2010-019631-35). \ua9 2019 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of The American Society of Transplantation and the American Society of Transplant Surgeon