Prolongation of small bowel allograft survival with a sequential therapy consisting of a synthetic MHC class II peptide and temporarily low-dose cyclosporine A

It has been extensively documented the role of the indirect pathway of allorecognition in allograft rejection. However, recent data demonstrate that the manipulation of this pathway could be also sufficient to promote prolongation of allograft survival. In the present study we evaluated the effect of preoperative immunization with the WF-specific MHC class II peptides RT1.D2 and RT1.B2 in combination with low-dose CsA from days 0 to 7 (5 mg/kg/day) and from days 8 to 30 (1 mg/kg/day) after WF small bowel transplantation. Seven days before and on the day of transplantation, LEW recipients were immunized with the two WF MHC class II peptides RT1.B2 and RT1.D2. The CsA monotherapy induced an allograft survival of 49.3 +/- 6.1 days. MHC class II peptide immunization had a limited effect on allograft survival for RT1.D2 (47.1 +/- 3.8 days) and induced prolongation of allograft survival for RT1.B2 (73.6 +/- 34.6 days). This effect seems to be based on the absence or silence of RT1.B2-reactive T cells and rejection seems to be correlated with the presence of RT1.B2-specific T cells in the late phase. Therefore, the combination of RT1.B2 with low-dose CsA shifts the immunological response and protects small bowel allograft rejection.     

Enolase 1 of Candida albicans binds human CD4+ T cells and modulates naïve and memory responses

To obtain a better understanding of the biology behind life-threatening fungal infections caused by Candida albicans, we recently conducted an in silico screening for fungal and host protein interaction partners. We report here that the extracellular domain of human CD4 binds to the moonlighting protein enolase 1 (Eno1) of C. albicans as predicted bioinformatically. By using different anti-CD4 monoclonal antibodies, we determined that C. albicans Eno1 (CaEno1) primarily binds to the extracellular domain 3 of CD4. Functionally, we observed that CaEno1 binding to CD4 activated lymphocyte-specific protein tyrosine kinase (LCK), which was also the case for anti-CD4 monoclonal antibodies tested in parallel. CaEno1 binding to naïve human CD4⁺ T cells skewed cytokine secretion toward a Th2 profile indicative of poor fungal control. Moreover, CaEno1 inhibited human memory CD4⁺ T-cell recall responses. Therapeutically, CD4⁺ T cells transduced with a p41/Crf1-specific T-cell receptor developed for adoptive T-cell therapy were not inhibited by CaEno1 in vitro. Together, the interaction of human CD4⁺ T cells with CaEno1 modulated host CD4⁺ T-cell responses in favor of the fungus. Thus, CaEno1 mediates not only immune evasion through its interference with complement regulators but also through the direct modulation of CD4⁺ T-cell responses.     

Midregional pro-A-type natriuretic peptide for diagnosis and prognosis in patients with suspected acute myocardial infarction

We hypothesized that midregional pro-A-type natriuretic peptide (MR-proANP), the stable midregional epitope of proANP, might be useful in the early diagnosis and risk stratification of patients with suspected acute myocardial infarction (AMI). In this multicenter study we measured MR-proANP, cardiac troponin T (cTnT), and high-sensitive cTnT (hs-cTnT) at presentation in 675 consecutive patients presenting to the emergency department with suspected AMI. The final diagnosis was adjudicated by 2 independent cardiologists. Patients were followed 360 days for mortality and AMI. AMI was the final diagnosis in 119 patients (18%). Median MR-proANP levels at presentation were significantly higher in patients with AMI (189 pmol/L, interquartile range 97 to 341) versus patients with another final diagnosis (83 pmol/L, 49 to 144, p <0.001). However, neither the combination of MR-proANP with cTnT nor its combination with hs-cTnT significantly improved diagnostic accuracy as quantified by area under the receiver operating characteristic curve (0.91 vs 0.89 for cTnT alone, p = 0.086; 0.95 vs 0.96 for hs-cTnT, respectively, p = 0.02). Cumulative 360-day mortality/AMI rates were 2.4% in the first, 3.6% in the second, 9.5% in the third, and 18.8% in the fourth quartiles of MR-proANP (p <0.001). MR-proANP (area under the curve 0.76) predicted mortality/AMI independently of and more accurately than cTnT (area under the curve 0.62), hs-cTnT (area under the curve 0.71), and Thrombolysis In Myocardial Infarction risk score (area under the curve 0.72). Net reclassification improvements offered by the additional use of MR-proANP were 0.388 (p <0.001), 0.425 (p <0.001), and 0.217 (p = 0.007), respectively. In conclusion, MR-proANP improves risk prediction for 360-day mortality/AMI but does not seem to help in the early diagnosis of AMI.     

S100A8/A9 aggravates post-ischemic heart failure through activation of RAGE-dependent NF-κB signaling

The extracellular heterodimeric protein S100A8/A9 activates the innate immune system through activation of the receptor of advanced glycation end products (RAGE) and Toll-like receptors. As activation of RAGE has recently been associated with sustained myocardial inflammation and heart failure (HF) we studied the role of S100A8/A9 in the development of post-ischemic HF. Hypoxia led to sustained induction of S100A8/A9 accompanied by increased nuclear factor (NF-)κB binding activity and increased expression of pro-inflammatory cytokines in cardiac fibroblasts and macrophages. Knockdown of either S100A8/A9 or RAGE rescued the induction of pro-inflammatory cytokines and NF-κB activation after hypoxia. In a murine model of post-ischemic HF both cardiac RNA and protein levels of S100A8/A9 were elevated as soon as 30 min after hypoxia with sustained activation up to 28 days after ischemic injury. Treatment with recombinant S100A8/A9 resulted in reduced cardiac performance following ischemia/reperfusion. Chimera experiments after bone marrow transplantation demonstrated the importance of RAGE expression on immune cells for their recruitment to the injured myocardium aggravating post-ischemic heart failure. Signaling studies in isolated ventricles indicated that MAP kinases JNK, ERK1/2 as well as NF-κB mediate signals downstream of S100A8/A9-RAGE in post-ischemic heart failure. Interestingly, cardiac performance was not affected by administration of S100A8/A9 in RAGE^?/?-mice, which demonstrated significantly improved cardiac recovery compared to WT-mice. Our study provides evidence that sustained activation of S100A8/A9 critically contributes to the development of post-ischemic HF driving the progressive course of HF through activation of RAGE.     

Bimanual Recoupling by Visual Cueing in Callosal Disconnection

Abstract

The cerebral control of bimanual movements is not completely understood. We investigated a 59-year-old, right-handed man who presented with an acute bimanual coordination deficit. Magnetic resonance imaging showed a lesion involving the entire corpus callosum, which was found on stereotactic biopsy to be an ischemic infarct. Paired-pulse transcranial magnetic stimulation indicated that the patient had a lack of interhemispheric inhibition, while intracortical inhibition in motor cortex of either side was normal. Functional magnetic resonance imaging showed activation of the left SMA, the bilateral motor cortex and anterior cerebellum during spontaneous bimanual thumb-index oppositions, which were uncoupled as evident from simultaneous electromyographic recordings. In contrast, when the bimanual thumb-index oppositions were cued by a visual stimulus, the movements of both hands were tightly correlated. This synchronized activity was accompanied by additional activations bilateral in lateral occipital cortex, dorsal premotor cortex and cerebellum. The data suggest that the visually cued movements of both hands were recoupled by action of a bihemispheric motor network.     

Napping to renew learning capacity: enhanced encoding after stimulation of sleep slow oscillations

As well as consolidating memory, sleep has been proposed to serve a second important function for memory, i.e. to free capacities for the learning of new information during succeeding wakefulness. The slow wave activity (SWA) that is a hallmark of slow wave sleep could be involved in both functions. Here, we aimed to demonstrate a causative role for SWA in enhancing the capacity for encoding of information during subsequent wakefulness, using transcranial slow oscillation stimulation (tSOS) oscillating at 0.75 Hz to induce SWA in healthy humans during an afternoon nap. Encoding following the nap was tested for hippocampus‐dependent declarative materials (pictures, word pairs, and word lists) and procedural skills (finger sequence tapping). As compared with a sham stimulation control condition, tSOS during the nap enhanced SWA and significantly improved subsequent encoding on all three declarative tasks (picture recognition, cued recall of word pairs, and free recall of word lists), whereas procedural finger sequence tapping skill was not affected. Our results indicate that sleep SWA enhances the capacity for encoding of declarative materials, possibly by down‐scaling hippocampal synaptic networks that were potentiated towards saturation during the preceding period of wakefulness.