Decision making under uncertainty in a quasi realistic binary decision task - An fMRI study.

Approaching real life decision making through Quasi Realistic Decision Making may increase the ecological validity of decision making experiments. This could help narrow the gap between laboratory settings and observations in real world contexts and thus allow for generalization of laboratory results to everyday life. A binary decision task with quasi realistic context and stimuli was created to investigate neural processing of certain and uncertain decision making, using functional Magnetic Resonance Imaging. On the basis of behavioral data (consistency of decisions in identical contexts), trials with uncertain and certain decision making were identified. This allowed for comparing uncertain and certain conditions, and contrasting each condition with a low level baseline (i.e., between trial fixation dot). A Conjunction analysis between contrasts of uncertainty versus baseline and certainty versus baseline indicated a large overlap of neural network recruitment distributed in bilateral middle frontal, medial frontal, inferior parietal, occipito-temporal, and medio-temporal areas, and the cingulate cortex. While basic neural processing principles in uncertain and certain contexts were comparable, the direct contrast revealed activation foci in middle cingulate and in frontal and parietal areas. The quasi realistic approach revealed a common network for decision making which is modulated by uncertainty.

MEF2C transcription factor is associated with the genetic and epigenetic risk architecture of schizophrenia and improves cognition in mice.

Large-scale consortia mapping the genomic risk architectures of schizophrenia provide vast amounts of molecular information, with largely unexplored therapeutic potential. We harnessed publically available information from the Psychiatric Genomics Consortium, and report myocyte enhancer factor 2C (MEF2C) motif enrichment in sequences surrounding the top scoring single-nucleotide polymorphisms within risk loci contributing by individual small effect to disease heritability. Chromatin profiling at base-pair resolution in neuronal nucleosomes extracted from prefrontal cortex of 34 subjects, including 17 cases diagnosed with schizophrenia, revealed MEF2C motif enrichment within cis-regulatory sequences, including neuron-specific promoters and superenhancers, affected by histone H3K4 hypermethylation in disease cases. Vector-induced short- and long-term Mef2c upregulation in mouse prefrontal projection neurons consistently resulted in enhanced cognitive performance in working memory and object recognition paradigms at baseline and after psychotogenic drug challenge, in conjunction with remodeling of local connectivity. Neuronal genome tagging in vivo by Mef2c-Dam adenine methyltransferase fusion protein confirmed the link between cognitive enhancement and MEF2C occupancy at promoters harboring canonical and variant MEF2C motifs. The multilayered integrative approaches presented here provide a roadmap to uncover the therapeutic potential of transcriptional regulators for schizophrenia and related disorders.

Sensitization and desensitization of burn patients as potential candidates for vascularized composite allotransplantation.

Sensitization describes the acquired ability of the immune system to react to foreign human leukocyte antigens (HLA) by producing antibodies and developing memory cells. In the field of transplantation, recipient preformed HLA antibodies due to previous sensitization have been identified - beneath ABO incompatibility - as a major factor for acute graft rejection. Several reasons for sensitization have largely been studied, such as previous blood transfusions, pregnancies or former transplants. Recent studies indicate that the use of assist devices (e.g. ECMO) or cadaveric skin allotransplantation providing temporary coverage in burn patients may lead to additional sensitization. As vascularized composite allotransplantation (VCA) has become a rapidly advancing therapeutic option for reconstruction of complex tissue defects in burns, it seems even more important to become familiar with immunological principles and to be cautiously aware of both sources of sensitization and therapeutic concepts in burns avoiding sensitization. This may also include emergency VCAs in burn patients as potential strategy for early definitive reconstruction avoiding procedures triggering HLA antibody formation. We hereby provide an overview on current evidence in the field of pre- and peritransplant sensitization, followed by posttransplant strategies of desensitization and their potential impact on future treatments of burn patients.

Effect of Twice-Yearly Denosumab on Prevention of Bone Mineral Density Loss in De Novo Kidney Transplant Recipients: A Randomized Controlled Trial.

We conducted an open-label, prospective, randomized trial to assess the efficacy and safety of RANKL inhibition with denosumab to prevent the loss of bone mineral density (BMD) in the first year after kidney transplantation. Ninety kidney transplant recipients were randomized 1:1 2 weeks after surgery to receive denosumab (60 mg at baseline and 6 months) or no treatment. After 12 months, total lumbar spine areal BMD (aBMD) increased by 4.6% (95% confidence interval [CI] 3.3-5.9%) in 46 patients in the denosumab group and decreased by -0.5% (95% CI -1.8% to 0.9%) in 44 patients in the control group (between-group difference 5.1% [95% CI 3.1-7.0%], p < 0.0001). Denosumab also increased aBMD at the total hip by 1.9% (95% CI, 0.1-3.7%; p = 0.035) over that in the control group at 12 months. High-resolution peripheral quantitative computed tomography in a subgroup of 24 patients showed that denosumab increased volumetric BMD at the distal tibia and radius (all p < 0.05). Biomarkers of bone turnover (C-terminal telopeptide of type I collagen, procollagen type I N-terminal propeptide) markedly decreased with denosumab (all p < 0.0001). Episodes of cystitis and asymptomatic hypocalcemia occurred more often with denosumab, whereas graft function, rate of rejections, and incidence of opportunistic infections were similar. In conclusion, denosumab increased BMD in the first year after kidney transplantation but was associated with more frequent episodes of urinary tract infection.

Stringent adherence to a cytomegalovirus-prevention protocol is associated with reduced overall costs in the first 6 months after kidney transplantation.

BACKGROUND: We previously documented that a stringent implementation of a preemptive cytomegalovirus (CMV) prevention protocol reduced the number of CMV disease episodes after kidney transplantation, when compared with a routine preemptive protocol. The impact on overall costs was assessed. METHODS: Cost comparisons were made for inpatient and outpatient costs and overall costs, using costs provided by the financial department. Variables were analyzed using the Wilcoxon rank-sum test. A multivariable global linear model evaluated the effect of all co-variables on cost differences. In Cohort 1 (n = 84), 74% were followed with a standard CMV preemptive protocol, and 26% received prophylaxis. In Cohort 2 (n = 74), an intensified CMV surveillance protocol was applied in 74% of patients, and 26% were given prophylaxis. RESULTS: Overall, Cohort 1 had significantly higher treatment costs as compared with Cohort 2 (mean Swiss francs [CHF] 104,548 and CHF 76,983, respectively, P = 0.0005). Excluding patients who received prophylaxis reduced these costs to CHF 89,318 in Cohort 1 and CHF 73,652 in Cohort 2. Outcome between Cohort 1 and 2 was comparable. CONCLUSION: A stringent adherence to the CMV prevention protocol was associated with a significant reduction in overall costs. Whether this benefit is because of the demonstrated reduction in the rate of CMV disease needs to be assessed in a randomized trial.

Variability in color-choice Stroop performance within and across EEG and MRI laboratory contexts.

To examine the reproducibility of the Stroop effect, behavioral data from 22 healthy female individuals were repeatedly (three-month interval between two separate measurement sessions) obtained while performing a color-choice Stroop task under realistic magnetic resonance imaging (MRI) and electroencephalography (EEG) laboratory conditions. At the group statistical level, the Stroop effect, indicated by longer response times for incongruent than for congruent stimulus conditions, was consistently present for almost all examined measurement levels. However, differential effects of laboratory contexts on retest reproducibility were observed across repeated measurement levels, both within and between sessions. These results challenge existing theories about the underlying nature of Stroop interference processing. It appears necessary to apply a multitheoretical approach, because intraindividual variability within and across measurement sessions suggests potential fluctuations in the individual mental strategies applied, recruitment of varying memory resources, the influence of mediator variables such as working memory capacity and/or attention, and many more possible variations. Single-observation studies run the risk of favoring a single theoretical concept and therefore underestimating the individual factor. We further conclude that dependent analysis-of-variance statistics are a more fit test for reproducibility than are correlative reliability estimations.

Neural correlates of the empathic perceptual processing of realistic social interaction scenarios displayed from a first-order perspective.

The neural processing of impulsive behavior is a central topic in various clinical and non-clinical contexts. To investigate neural and behavioral correlates of the empathic processing of complex social scenarios, especially considering ecological validity of the experimental procedure, we developed and investigated a video stimulus inventory. It includes realistic neutral, social-positive, and reactive-aggressive action scenarios. Short video-clips showing these social scenarios from a first-person perspective triggering different emotional states were presented to a non-clinical sample of 20 young adult male participants during fMRI measurements. Both affective interaction conditions (social-positive and reactive-aggressive) were contrasted against a neutral baseline condition and against each other. Behavioral evaluation data largely confirmed the validity of the emotion-inducing stimulus material. Reactive-aggressive and social-positive interaction scenarios produced widely overlapping fMRI activation patterns in hetero-modal association cortices, but also in subcortical regions, such as the peri-aqueductal gray. Reactive-aggressive compared to social-positive scenarios yielded a more anterior distribution of activations in pre-motor and inferior frontal brain regions associated to motor-preparation and inhibitory control processing as well as in the insula associated to pain- and/or aversion-processing. We argue that there are both principally common neural networks recruited for the processing of reactive-aggressive and social-positive scenarios, but also exclusive network parts in particular involved depending on individual socialization.

Bcl-2 inhibition to overcome memory cell barriers in transplantation.

Memory T cells (Tm) represent a major barrier for immunosuppression and tolerance induction after solid organ transplantation. Taking into consideration the critical role of the intrinsic apoptosis pathway in the generation and maintenance of Tm, we developed a new concept to deplete alloreactive Tm by targeting Bcl-2 proteins. The small-molecule Bcl-2/Bcl-XL inhibitor ABT-737 efficiently induced apoptosis in alloreactive Tm in vitro and in vivo and prolonged skin graft survival in sensitized recipients. A short course of ABT-737 induction therapy prevented Tm-mediated resistance in a donor-specific transfusion model and allowed mixed chimerism induction across Tm barriers. Since Bcl-2 inhibitors yielded encouraging safety results in cancer trials, this novel approach might represent a substantial advance to prevent allograft rejection and induce tolerance in sensitized recipients.

Association of BK viremia with human leukocyte antigen mismatches and acute rejection, but not with type of calcineurin inhibitor.

INTRODUCTION: BK viremia and polyomavirus-associated nephropathy (PVN) represent a significant problem after kidney transplantation. Both are associated with intensified immunosuppression, but other risk factors and the impact of a screening program on outcome are incompletely understood. METHODS: Here, we report on the short- and long-term outcome of a cohort of patients, who were transplanted in 2006/2007 and included in a newly introduced systematic 3-monthly screening for BK viremia at the University Hospital Zurich. In patients testing positive for BK viremia, screening frequency was intensified and immunosuppression reduced. Patients with suspected PVN underwent transplant biopsy. RESULTS: Among 152 included patients, 49 (32%) tested positive for BK viremia, but only 8 developed biopsy-proven PVN. BK viremia had a significant impact on estimated glomerular filtration rate and proteinuria in the first 2 years. Acute rejection episodes and the number of human leukocyte antigen (HLA) mismatches were the strongest independent predictors of BK viremia in a multiple logistic model. In contrast, no particular immunosuppressive agent or regimen was associated with enhanced risk. CONCLUSION: Taken together, systematic BK viremia screening led to detection of a high percentage of viremic patients. With adjustment of immunosuppression, an excellent outcome was achieved. The independent association of HLA mismatches with BK viremia suggests impaired polyomavirus immunosurveillance in highly mismatched allografts.

Allospecific rejection of MHC class I-deficient bone marrow by CD8 T cells.

Avoidance of long-term immunosuppression is a desired goal in organ transplantation. Mixed chimerism offers a promising approach to tolerance induction, and we have aimed to develop low-toxicity, nonimmunodepleting approaches to achieve this outcome. In a mouse model achieving fully MHC-mismatched allogeneic bone marrow engraftment with minimal conditioning (3 Gy total body irradiation followed by anti-CD154 and T cell-depleted allogeneic bone marrow cells), CD4 T cells in the recipient are required to promote tolerance of preexisting alloreactive recipient CD8 T cells and thereby permit chimerism induction. We now demonstrate that mice devoid of CD4 T cells and NK cells reject MHC Class I-deficient and Class I/Class II-deficient marrow in a CD8 T cell-dependent manner. This rejection is specific for donor alloantigens, since recipient hematopoiesis is not affected by donor marrow rejection and MHC Class I-deficient bone marrow that is syngeneic to the recipient is not rejected. Recipient CD8 T cells are activated and develop cytotoxicity against MHC Class I-deficient donor cells in association with rejection. These data implicate a novel CD8 T cell-dependent bone marrow rejection pathway, wherein recipient CD8 T cells indirectly activated by donor alloantigens promote direct killing, in a T cell receptor-independent manner, of Class I-deficient donor cells.

A stringent preemptive protocol reduces cytomegalovirus disease in the first 6 months after kidney transplantation.

BACKGROUND: The optimal strategy to prevent cytomegalovirus (CMV) disease after kidney transplantation continues to be open to debate. The preemptive approach requires regular determination of CMV viremia and prompt initiation of therapy. METHODS: We retrospectively compared the incidence of CMV disease during two periods at our center: A first phase (P1, n = 84 kidney recipients), during which time the intensity of surveillance was determined by the responsible physician, was compared to a second phase (P2, n = 74), when a stringent protocol of CMV surveillance was required for all patients. The preemptive approach was applied for all CMV risk groups; prophylaxis was optional in the case of treatment for rejection or delayed graft function in the intermediate- and high-risk group. Follow-up was truncated at 6 months after transplant surgery. CMV syndrome was differentiated from asymptomatic replication by the presence of at least one systemic symptom, while diagnosis of CMV end-organ disease required histological confirmation. RESULTS: Immunosuppression was similar in the two periods. CMV prophylaxis was used equally (26 %) in both periods. The probability for asymptomatic viremia episodes was not different for patients in P1 and P2 regardless of the prevention strategy. For patients following the preemptive strategy, the probability for CMV disease was increased during P1 (p = 0.016), despite fewer PCR assays being performed in phase 2. Protocol violations were only observed during P1. CONCLUSIONS: The probability of CMV disease episodes (CMV syndrome and CMV end-organ disease) was substantially reduced using a very stringent protocol. This study highlights the crucial importance of a stringent protocol with optimal adherence by all caregivers if the preemptive strategy is to be successful.

Resistance to ABT-737 in activated T lymphocytes: molecular mechanisms and reversibility by inhibition of the calcineurin-NFAT pathway.

Dynamic regulation of the intrinsic apoptosis pathway controls central and peripheral lymphocyte deletion, and may interfere with the pro-apoptotic potency of B-cell lymphoma 2 inhibitors such as ABT-737. By following a T-cell receptor (TCR) transgenic population of alloantigen-specific T cells, we found that sensitivity to ABT-737 radically changed during the course of allo-specific immune responses. Particularly, activated T cells were fully resistant to ABT-737 during the first days after antigen recognition. This phenomenon was caused by a TCR-calcineurin-nuclear factor of activated T cells-dependent upregulation of A1, and was therefore prevented by cyclosporine A (CsA). As a result, exposure to ABT-737 after alloantigen recognition induced selection of alloreactive T cells in vivo, whereas in combination with low-dose CsA, ABT-737 efficiently depleted alloreactive T cells in murine host-versus-graft and graft-versus-host models. Thus, ABT-737 resistance is not a prerogative of neoplastic cells, but it physiologically occurs in T cells after antigen recognition. Reversibility of this process by calcineurin inhibitors opens new pharmacological opportunities to modulate this process in the context of cancer, autoimmunity and transplantation.

Hemophagocytic syndrome caused by primary herpes simplex virus 1 infection: report of a first case.

INTRODUCTION: Hemophagocytic syndrome represents a severe hyperinflammatory condition by activated macrophages. Leading viral triggering agents are Epstein-Barr virus (EBV), cytomegalovirus (CMV), and adenovirus. MATERIALS AND METHODS: We present a patient with Wegener's granulomatosis on azathioprine and prednisone medication, who developed a life-threatening hemophagocytic syndrome. Positive plasma polymerase chain reaction (PCR) with negative serology revealed a primary, disseminated infection with herpes simplex virus-1 as the triggering pathogen. After treatment with acyclovir, high-dose steroids, immunoglobulins, and etoposide, the patient recovered. CONCLUSION: Early diagnosis of potentially underlying infections of hemophagocytic syndrome influences the therapeutic approach. It is important to consider a variety of infectious agents, particularly in immunosuppressed individuals. The reported case emphasizes the importance of screening for herpes simplex virus 1.

Donor-derived aspergillosis from use of a solid organ recipient as a multiorgan donor.

The growing need for organs and the scarcity of donors has resulted in an increased use of extended criteria donors. We report a case where a recipient of a cardiac graft was used as an organ donor. Death of the recipient occurred 9 days after transplantation and was attributed to presumed cerebral hemorrhage, which post mortem was diagnosed as invasive aspergillosis of the brain. One recipient of a kidney transplant lost the graft due to infection with Aspergillus fumigatus, whereas prompt initiation of therapy successfully prevented disseminated aspergillosis in the other recipients. Despite the pressure to extend the use of organs by lowering the acceptance criteria, organs should only be accepted if the cause of death of the donors is unequivocally explained.

Molecular evidence of interhuman transmission in an outbreak of Pneumocystis jirovecii pneumonia among renal transplant recipients.

Pneumocystis jirovecii pneumonia (PCP) remains an important cause of morbidity and mortality in immunocompromised individuals. The epidemiology and pathogenesis of this infection are poorly understood, and the exact mode of transmission remains unclear. Recent studies reported clusters of PCP among immunocompromised patients, raising the suspicion of interhuman transmission. An unexpected increase of the incidence of PCP cases in our nephrology outpatient clinic prompted us to conduct a detailed analysis. Genotyping of 7 available specimens obtained from renal transplant recipients was performed using multi-locus DNA sequence typing (MLST). Fragments of 4 variable regions of the P. jirovecii genome (ITS1, 26S, mt26S, beta-tubulin) were sequenced and compared with those of 4 independent control patients. MLST analysis revealed identical sequences of the 4 regions among all 7 renal allograft recipients with available samples, indicating an infection with the same P. jirovecii genotype. We observed that all but 1 of the 19 PCP-infected transplant recipients had at least 1 concomitant visit with another PCP-infected patient within a common waiting area. This study provides evidence that nosocomial transmission among immunocompromised patients may have occurred in our nephrology outpatient clinic. Our findings have epidemiological implications and suggest that prolonged chemoprophylaxis for PCP may be warranted in an era of more intense immunosuppression.

[Chronic kidney disease in the general practitioner's office]. / Chronische Niereninsuffizienz in der Hausarztpraxis.

People suffer increasingly from arterial hypertension and/or diabetes mellitus. These two diseases represent the most frequent causes leading to chronic kidney disease. The assessment of renal function by means of formulas serves as a basis for further decision making regarding the management of patients with chronic kidney disease. On one hand, the therapy focuses on the treatment of the underlying illness as well as possible, acute and reversible causes of renal dysfunction. On the other hand, the therapy includes measures to decelerate the progression of chronic kidney disease (nephroprotection) and to correct its associated complications (renal hypertension, renal anemia, secondary hyperparathyroidism). If these therapeutic measures are applied timely (ideally as of CKD stage 3 with glomerular filtration rate <60 ml/min) and in close collaboration with a nephrologist, end stage renal disease can be delayed by several years.

Changes of circulating antibody levels induced by ABO antibody adsorption for ABO-incompatible kidney transplantation.

ABO-incompatible kidney transplantation using immunoadsorption to remove anti-A/B antibodies has become a successful clinical practice. Since the data on the specificity of the ABO columns are controversial, the present study assessed the efficiency and specificity of the ABO immunoadsorption, the effect on total immunoglobulins and antibodies previously induced by vaccination. Anti-A/B antibodies were measured by agglutination and ABO flow cytometry, total IgG/IgM, carbohydrate- and protein-specific antibodies by nephelometry and ELISA. The first immunoadsorption not only efficiently reduced donor-specific anti-A/B IgM (81%) and IgG (56%) but also reduced compatible anti-A/B IgM (59%) and IgG (34%). The measurements of antidonor A/B antibodies by direct agglutination (IgM) or flow cytometry better represented the effective antibody levels than the indirect agglutination test (IgG). The median reduction of total IgM and total IgG levels after a single immunoadsorption was 34% and 18%, respectively. Antibodies against pneumococcus and haemophilus polysaccharide antigens were significantly reduced, whereas antitetanus and antidiphtheria protein antibodies were not affected. Intravenous immunoglobulin administration restored the protective anticarbohydrate antibody levels. In summary, immunoadsorption efficiently removed antidonor A/B antibodies, but was not specific for A/B antigens. Anti-A/B antibody levels as determined by ABO flow cytometry are useful to establish the minimal number of immunoadsorptions needed for successful ABO-incompatible transplantation.

Safety and tolerability of ferric carboxymaltose (FCM) for treatment of iron deficiency in patients with chronic kidney disease and in kidney transplant recipients.

BACKGROUND: Iron deficiency is common in patients with chronic kidney disease and in kidney transplant recipients. PATIENTS AND METHODS: We analyzed the safety and tolerability of the new intravenous iron preparation ferric carboxymaltose (FCM) in these two patient groups. Adverse events after administration of the drug were assessed by using a questionnaire. Vital signs and laboratory data were collected before and after the application of FCM. A total of 46 FCM doses were applied to 44 patients (17 with chronic kidney disease and 27 kidney transplant recipients) either as single injection of 100 or 200 mg (n = 42) or as short infusion with up to 500 mg (n = 4). RESULTS: Mild and transient adverse events (metallic taste, headache, dizziness) occurred in six patients. The estimated glomerular filtration rate remained unchanged by the FCM administration. CONCLUSION: We conclude that safety and tolerability of FCM were excellent. Compared with other intravenous iron preparations the considerably shorter administration time of FCM allows to save time and to reduce costs.

Myeloma responses and tolerance following combined kidney and nonmyeloablative marrow transplantation: in vivo and in vitro analyses.

Six patients with renal failure due to multiple myeloma (MM) received simultaneous kidney and bone marrow transplantation (BMT) from HLA-identical sibling donors following nonmyeloablative conditioning, including cyclophosphamide (CP), peritransplant antithymocyte globulin and thymic irradiation. Cyclosporine (CyA) was given for approximately 2 months posttransplant, followed by donor leukocyte infusions. All six patients accepted their kidney grafts long-term. Three patients lost detectable chimerism but accepted their kidney grafts off immunosuppression for 1.3 to >7 years. One such patient had strong antidonor cytotoxic T lymphocyte (CTL) responses in association with marrow rejection. Two patients achieved full donor chimerism, but resumed immunosuppression to treat graft-versus-host disease. Only one patient experienced rejection following CyA withdrawal. He responded to immunosuppression, which was later successfully withdrawn. The rejection episode was associated with antidonor Th reactivity. Patients showed CTL unresponsiveness to cultured donor renal tubular epithelial cells. Initially recovering T cells were memory cells and were enriched for CD4+CD25+ cells. Three patients are in sustained complete remissions of MM, despite loss of chimerism in two. Combined kidney/BMT with nonmyeloablative conditioning can achieve renal allograft tolerance and excellent myeloma responses, even in the presence of donor marrow rejection and antidonor alloresponses in vitro.