Absence of donor CD40 protects renal allograft epithelium and preserves renal function

Blocking the CD40‐CD154 pathway prevents allograft rejection and induces donor‐specific tolerance in various experimental models. However, the translation to clinical studies has been hampered by unexpected thromboembolic complications of CD154‐blocking antibodies. Thus, blocking CD40 instead is now considered as an alternative strategy. Here, we evaluated the role of donor CD40 in allospecific T‐cell responses in vitro and in an in vivo model for renal transplantation. Fully MHC‐mismatched allografts from CD40‐deficient donors displayed better renal function than wild type. These functional data correlated with a lower level of apoptosis in renal tubular epithelial cells and higher expression of PD‐L1, which is most probably because of a reduced Th17 response in recipients of a CD40‐deficient donor. This hypothesis was supported in vitro, where donor CD40 expression was important for the induction of direct allospecific T‐cell responses. Especially the induction of Th17 cells was critically dependent on donor CD40. IL‐17A in conjunction with interferon‐γ in turn rendered renal tubular epithelial cells to a more costimulatory state by upregulating CD40 and downregulating PD‐L1 expression. In conclusion, CD40 blockade not only reduces the allospecific T‐cell responses, but might also lead to protection of tubular epithelium from apoptosis and thereby preserve kidney allograft function.     

Enhanced thrombin generation in women with a history of oral contraception-related venous thrombosis

Introduction

In women who suffer venous thrombosis (VT) during oral contraceptive (OC) use, a transient risk factor (OC) is removed during the acute event, while most co-existing forms of thrombophilia persist and presumably continue to maintain hypercoagulability. The aim of this study was to establish if hypercoagulability persists long after OC-related VT and if it could be attributed to thrombophilia.

Materials and Methods

60 women (age 33.0 ± 8.5 years) were investigated 5 – 64 (median 33) months after OC-related VT (patients) and compared to 63 apparently healthy women (controls). All women were tested for thrombophilia, activated partial thromboplastin time (APTT), fibrinogen, D-dimer, P-selectin and C-reactive protein. Thrombin generation was measured by Technothrombin® TGA assay. Overall haemostasis potential (OHP) assay with overall coagulation potential (OCP) and overall fibrinolytic potential (OFP) as supplementary parameters were measured by repeated fibrin formation and degradation registration.

Results

In patients increased endogenous thrombin potential (4205 ± 440 nM x min vs 4015 ± 421 nM x min, p = 0.017), increased OCP (22.6 ± 4.6 Abs-sum vs 20.8 ± 4.1 Abs-sum, p = 0.025), shorter APTT (30.9 ± 3.8 s vs 33.4 ± 3.6 s, p < 0.001) and lower antithrombin activity (99, 93-105% vs 104, 100-109%, p < 0.05) were observed. Thrombophilia was observed in 22/60 (36%) patients and in 5/63 (7.9%, p < 0.001) controls. The only significant difference between thrombophilic and non-thrombophilic patients was higher soluble P-selectin in the former subgroup (22, 20-33 μg/L vs 17, 12-22 μg/L, p = 0.012).

Conclusions

In women with a history of OC-related VT persistent hypercoagulability was observed, which, however was not augmented by the presence of thrombophilia.     

The role of linguistic context in deriving word meanings in individuals with Down Syndrome

Deriving the meaning of unknown words from context and its relationship to text comprehension was investigated in 24 individuals with Down syndrome and in 24 typically developing children matched for the Peabody Picture Vocabulary Test (PPVT) score.The study consisted of three phases. Unknown words were identified during the first phase (PPVT). Those words were presented embedded in brief linguistic contexts during the second phase. Recognition (maintenance) of word meanings was verified in the third and final phase. Both groups of participants recognized the meanings of a noteworthy number of words in contexts and a high percentage of these was maintained when they were presented at a later date without the support of context. Over and above group differences and basic linguistic skills, text comprehension seems to predict the ability to use context. Context provides the semantic information necessary to extract word meaning by activating relevant world knowledge.     

Deep brain stimulation in the globus pallidus compensates response inhibition deficits: evidence from pantothenate kinase-associated neurodegeneration

Fronto-striatal loops are important for many cognitive control processes, like response inhibition, and it has been suggested that the globus pallidus is of particular importance for these processes. In the current study, we investigate the effect of deep brain stimulation in the GP on response inhibition processes by means of neurophysiological (EEG) methods. We perform a case–control study in neuroaxonal dystrophy pantothenate kinase-associated neurodegeneration (PKAN) using single-case statistics. We control the signal-to-noise ratio of the EEG data. The data show that disease-related changes in the globus pallidus lead to dysfunctions in response inhibition processes. Dysfunctions in the GP seem to affect controlled, but not automatized behavior as evidenced by an increased rate of false alarms and attenuation of inhibition-related neurophysiological correlates. With respect to controlled behavior in terms of response inhibition, it seems that pre-motor subprocesses and not evaluation subprocesses are affected. Deep brain stimulation in the globus pallidus seems to be able to compensate the effects of disease-related changes in this structure and normalizes response inhibition performance and their electrophysiological correlates in PKAN.