Intellectual functioning of childhood leukemia survivors - relation to Tau protein - a marker of white matter injury

PurposeChemo- and radiotherapy used in acute lymphoblastic leukemia (ALL) can influence on brain functioning in the future. In a prospective study we analysed the cognitive functions of ALL survivors in relation to Tau protein as a marker of white matter injury.Material and methodsThirty-one survivors of childhood ALL (6.3 years after diagnosis); without the signs of CNS involvement, treated with chemotherapy alone, rested in first remission; underwent Intelligence tests- Wechsler Intelligence Scales (WISC-R, WAIS-R). Their results were analyzed in relation to the levels of Tau in cerebrospinal fluid (CSF) obtained during the treatment.ResultsThe analysis showed that all survivors attained the average scores in intelligence tests. A negative correlation was found between methotrexate (MTX) doses and Freedom from Distractibility (FFD). Females had higher values of Performance Intelligence Quotient (PIQ) than males. A negative correlation was noted of Tau protein levels obtained from the last CSF with: Total and Verbal Intelligence Quotient, PIQ, Perceptual Organisation Index and FFD but not with Verbal Comprehension Index.ConclusionOur results suggest the possibility of white matter injury during the treatment for ALL with chemotherapy alone. Elevated Tau protein level in CSF at the end of treatment might indicate future difficulties in neurocognitive functioning.     

Epstein-Barr virus latent infection membrane protein 1 TRAF-binding site induces NIK/IKK alpha-dependent noncanonical NF-kappaB activation

Epstein-Barr virus (EBV) latent infection membrane protein 1 (LMP1)-induced NF-kappaB activation is important for infected cell survival. LMP1 activates NF-kappaB, in part, by engaging tumor necrosis factor (TNF) receptor-associated factors (TRAFs), which also mediate NF-kappaB activation from LTbetaR and CD40. LTbetaR and CD40 activation of p100/NF-kappaB2 is now known to be NIK/IKKalpha-dependent and IKKbeta/IKKgamma independent. In the experiments described here, we found that EBV LMP1 induced p100/NF-kappaB2 processing in human lymphoblasts and HEK293 cells. LMP1-induced p100 processing was NIK/IKKalpha dependent and IKKbeta/IKKgamma independent. Furthermore, the LMP1 TRAF-binding site was required for p100 processing and p52 nuclear localization, whereas the LMP1 death domain-binding site was not. Moreover, the LMP1 TRAF-binding site preferentially caused RelB nuclear accumulation. In murine embryo fibroblasts (MEFs), IKKbeta was essential for LMP1 up-regulation of macrophage inflammatory protein (MIP)-2, TNFalpha, I-TAC, ELC, MIG, and CXCR4 RNAs. Interestingly, in IKKalpha knockout MEFs, LMP1 hyperinduced MIP-2, TNFalpha, and I-TAC expression, consistent with a role for IKKalpha in down-modulating canonical IKKbeta activation or its effects. In contrast, LMP1 failed to up-regulate CXCR4 and MIG RNA in IKKalpha knockout MEFs, indicating a dependence on noncanonical IKKalpha activation. Furthermore, LMP1 up-regulation of MIP-2 RNA in MEFs was both IKKbeta- and IKKgamma-dependent, whereas LMP1 upregulation of MIG and I-TAC RNA was fully IKKgamma independent. Thus, LMP1 induces typical canonical IKKbeta/IKKgamma-dependent, atypical canonical IKKbeta-dependent/IKKgamma-independent, and noncanonical NIK/IKKalpha-dependent NF-kappaB activations; NIK/IKKalpha-dependent NF-kappaB activation is principally mediated by the LMP1 TRAF-binding site.     

Multidimensional fetal flow imaging with cardiovascular magnetic resonance: a feasibility study

Purpose

To image multidimensional flow in fetuses using golden-angle radial phase contrast cardiovascular magnetic resonance (PC-CMR) with motion correction and retrospective gating.

Methods

A novel PC-CMR method was developed using an ungated golden-angle radial acquisition with continuously incremented velocity encoding. Healthy subjects (n?=?5, 27?±?3 years, males) and pregnant females (n?=?5, 34?±?2 weeks gestation) were imaged at 3 T using the proposed sequence. Real-time reconstructions were first performed for retrospective motion correction and cardiac gating (using metric optimized gating, MOG). CINE reconstructions of multidimensional flow were then performed using the corrected and gated data.

Results

In adults, flows obtained using the proposed method agreed strongly with those obtained using a conventionally gated Cartesian acquisition. Across the five adults, bias and limits of agreement were ??1.0 cm/s and [??5.1, 3.2] cm/s for mean velocities and???1.1 cm/s and [??6.5, 4.3] cm/s for peak velocities. Temporal correlation between corresponding waveforms was also high (R~?0.98). Calculated timing errors between MOG and pulse-gating RR intervals were low (~?20 ms). First insights into multidimensional fetal blood flows were achieved. Inter-subject consistency in fetal descending aortic flows (n =?3) was strong with an average velocity of 27.1?±?0.4 cm/s, peak systolic velocity of 70.0?±?1.8 cm/s and an intra-class correlation coefficient of 0.95 between the velocity waveforms. In one fetal case, high flow waveform reproducibility was demonstrated in the ascending aorta (R =?0.97) and main pulmonary artery (R =?0.99).

Conclusion

Multidimensional PC-CMR of fetal flow was developed and validated, incorporating retrospective motion compensation and cardiac gating. Using this method, the first quantification and visualization of multidimensional fetal blood flow was achieved using CMR.