Optimization of Calcineurin Inhibitor Treatment after Solid Organ Transplantation

On December 23, 1954, Ronald Herrick donated a kidney to his identical twin brother Richard who was dying of renal failure. The kidney transplant produced urine immediately and in February 1955, Richard Herrick was discharged from hospital. He survived for another nine years (at which time his kidney allograft failed from recurrent glomerulonephritis), married the nurse who attended him, became father of two children and returned to work as a radio and television engineer. His brother Ronald lived on for more than 50 years after donating his kidney.1-3 In the years following this first successful human kidney transplantation, several more kidney transplants were performed between identical twins. Most of these patients had a return of normal kidney function and survived for a considerable period of time.4 However, it was clear from previous experience that if kidney transplantation was to be extended successfully to genetically non-identical individuals, suppressing the recipient’s immune system was necessary in order to prevent acute rejection. Early after World War II, a small number of human kidney transplantations had been performed in Europe and the United States. The recipients had received no immunosuppression except for a few cases in which short courses of ACTH or cortisone had been given. Although some of these kidney allografts did function for a limited period of time -most likely as a result of profound uremia5- most of the transplanted kidneys were acutely rejected or destroyed as a result of thrombosis or infection, and none of the recipients survived for a long period of time

The State of Self-Organized Criticality of the Sun During the Last 3 Solar Cycles. I. Observations

We analyze the occurrence frequency distributions of peak fluxes $P$, total fluxes $E$, and durations $T$ of solar flares over the last three solar cycles (during 1980--2010) from hard X-ray data of HXRBS/SMM, BATSE/CGRO, and RHESSI. From the synthesized data we find powerlaw slopes with mean values of $\alpha_P=1.72\pm0.08$ for the peak flux, $\alpha_E=1.60\pm0.14$ for the total flux, and $\alpha_T=1.98\pm0.35$ for flare durations. We find a systematic anti-correlation of the powerlaw slope of peak fluxes as a function of the solar cycle, varying with an approximate sinusoidal variation $\alpha_P(t)=\alpha_0+\Delta \alpha \cos{[2\pi (t-t_0)/T_{cycle}]}$, with a mean of $\alpha_0=1.73$, a variation of $\Delta \alpha =0.14$, a solar cycle period $T_{cycle}=12.6$ yrs, and a cycle minimum time $t_0=1984.1$. The powerlaw slope is flattest during the maximum of a solar cycle, which indicates a higher magnetic complexity of the solar corona that leads to an overproportional rate of powerful flares.Comment: subm. to Solar Physic

Personalized immunosuppression in elderly renal transplant recipients

The number of elderly people has increased considerably over the last decades, due to a rising life expectancy and ageing populations. As a result, an increased number of elderly with end-stage-renal-disease are diagnosed, for which the preferred treatment is renal transplantation. Over the past years the awareness of the elderly as a specific patient population has grown, which increases the importance of research in this group.Elderly patients often receive kidneys from elderly donors while younger donor kidneys are preferentially reserved for younger recipients. Although the rate of acute rejection after transplantation is lower in the elderly, these rejections may lead to graft loss more frequently, as kidneys from elderly donors have marginal reserve capacity. To prevent acute rejection, immunosuppressive therapy is needed. On the other hand, elderly patients have a higher risk to die from infectious complications, and thus less immunosuppression would be preferable.Immunosuppressive treatm

Numerical simulations of a swimmer’s head and cap wearing different types of goggles

The aim of this study was to analyse the effect of swimming goggles on swimming hydrodynamics by numerical simulations. An elite swimmer volunteered for this research. The swimmer's head was scanned both without goggles, and while wearing 3 different types of goggles (Nikko, Ankor and Swedish). Numerical simulations were conducted at 2 m/s with the Fluent code. The condition without goggles showed the highest viscous drag (1.65 N), followed by the Ankor (1.64 N), Swedish (1.63 N) and Nikko (1.62 N) goggles, respectively. The highest pressure drag was found in the situation without goggles (11.34 N), followed by the Ankor (10.87 N), Nikko (10.78 N) and Swedish (10.20 N) goggles. The condition without goggles presented the highest total drag (12.99 N), followed by the Ankor (12.52 N), Nikko (12.40 N) and Swedish (11.83 N) goggles. Thus, Swedish goggles yields the best hydrodynamics, followed by the Nikko and Ankor goggles and lastly without goggles. Thus, goggles minimise the swimmer's drag comparing to not wearing any. The design of the goggles may impose varying drag forces and therefore it is advised to use goggles at least in competition.This work was supported by the Portuguese Foundation for Science and Technology, I.P. [UIDB04045/2020].info:eu-repo/semantics/publishedVersio

Down-regulation of surface CD28 under belatacept treatment: An escape mechanism for antigen-reactive T-cells

Background The co-stimulatory inhibitor of the CD28-CD80/86-pathway, belatacept, allows calcineurininhibitor-free immunosuppression in kidney transplantation. However, aggressive T-cell mediated allogeneic responses have been observed in belatacept-treated patients, which could be explained by effector-memory T-cells that lack membrane expression of CD28, i.e. CD28-negative (CD28NULL) T-cells. CD28-positive (CD28POS) T-cells that down regulate their surface CD28 after allogeneic stimulation could also pose a threat against the renal graft. The aim of this study was to investigate this potential escape mechanism for CD28POS T-cells under belatacept treatment. Materials & Methods PBMCs, isolated T-cell memory subsets and isolated CD28POS T-cells were obtained from end-stage renal disease (ESRD) patients and co-cultured with allo-antigen in the presence of belatacept to mimic allogeneic reactions in kidney-transplant patients under belatacept treatment. As a control, IgG was used in the absence of belatacept. Results Despite high in vitro belatacept concentrations, a residual T-cell growth of ±30% was observed compared to the IgG control after allogeneic stimulation. Of the alloreactive Tcells, the majority expressed an effector-memory phenotype. This predominance for effector-memory T-cells within the proliferated cells was even larger when a higher dose of belatacept was added. Contrary to isolated naïve and central-memory T cells, isolated effectormemory T cells could not be inhibited by belatacept in differentiation or allogeneic IFNγ production. The proportion of CD28-positive T cells was lower within the proliferated T cell population, but was still substantial. A fair number of the isolated initially CD28POS T-cells differentiated into CD28NULL T-cells, which made them not targetable by belatacept. These induced CD28NULL T-cells were not anergic as they produced high amounts of IFNγ upon allogeneic stimulat

The Fragility of Quantum Information?

We address the question whether there is a fundamental reason why quantum information is more fragile than classical information. We show that some answers can be found by considering the existence of quantum memories and their dimensional dependence.Comment: Essay on quantum information: no new results. Ten pages, published in Lec. Notes in Comp. Science, Vol. 7505, pp. 47-56 (2012. One reference adde

Usage of Tacrolimus and Mycophenolic Acid During Conception, Pregnancy, and Lactation, and Its Implications for Therapeutic Drug Monitoring: A Systematic Critical Review

BACKGROUND: Conception, pregnancy, and lactation following solid organ transplantation require appropriate management. The most frequently used immunosu

Pharmacogenetic aspects of the use of tacrolimus in renal transplantation: Recent developments and ethnic considerations

Introduction: Tacrolimus (Tac) is effective in preventing acute rejection but has considerable toxicity and inter-individual variability in pharmacokinetics and pharmacodynamics. Part of this is explained by polymorphisms in genes encoding Tac-metabolizing enzymes and transporters. A better understanding of Tac pharmacokinetics and pharmacodynamics may help to minimize different outcomes amongst transplant recipients by personalizing immunosuppression.Areas covered: The pharmacogenetic contribution of Tac metabolism will be examined, with a focus on recent discoveries, new developments and ethnic considerations.Expert opinion: The strongest and most consistent association in pharmacogenetics is between the CYP3A5 genotype and Tac dose requirement, with CYP3A5 expressers having a ∼ 40-50% higher dose requirement compared to non-expressers. Two recent randomized-controlled clinical trials using CYP3A5 genotype, however, did not show a decrease in acute rejections nor reduced toxicity. CYP3A4∗22, CYP3A4∗26, and POR∗28 are also associated with Tac dose requirements and may be included to provide the expected improvement of Tac therapy. Studies focusing on the intracellular drug concentrations and on calcineurin inhibitor-induced nephrotoxicity also seem promising. For all studies, however, the ethnic prevalence of genotypes should be taken into account, as this may significantly impact the effect of pre-emptive genotyping