CCR7-mediated LFA-1 functions in T cells are regulated by 2 independent ADAP/SKAP55 modules

The β2-integrin lymphocyte function-associated antigen-1 (LFA-1) plays a crucial role within the immune system. It regulates the interaction between T cells and antigen-presenting cells and facilitates T-cell adhesion to the endothelium, a process that is important for lymphocyte extravasation and homing. Signals mediated via the T-cell receptor and the chemokine receptor CCR7 activate LFA-1 through processes known as inside-out signaling. The molecular mechanisms underlying inside-out signaling are not completely understood. Here, we have assessed the role of the ADAP/SKAP55 module for CCR7-mediated signaling. We show that loss of the module delays homing and reduces intranodal T-cell motility in vivo. This is probably because of a defect in CCR7-mediated adhesion that affects both affinity and avidity regulation of LFA-1. Further analysis of how the ADAP/SKAP55 module regulates CCR7-induced integrin activation revealed that 2 independent pools of the module are expressed in T cells. One pool interacts with a RAPL/Mst1 complex, whereas the other pool is linked to a RIAM/Mst1/Kindlin-3 complex. Importantly, both the RAPL/Mst1 and the RIAM/Mst1/Kindlin-3 complexes require ADAP/SKAP55 for binding to LFA-1 upon CCR7 stimulation. Hence, 2 independent ADAP/SKAP55 modules are essential components of the signaling machinery that regulates affinity and avidity of LFA-1 in response to CCR7.     

Do different perceptual task sets modulate electrophysiological correlates of masked visuomotor priming? Attention to shape and color put to the test

According to classical theories, automatic processes operate independently of attention. Recent evidence, however, shows that masked visuomotor priming, an example of an automatic process, depends on attention to visual form versus semantics. In a continuation of this approach, we probed feature‐specific attention within the perceptual domain and tested in two event‐related potential (ERP) studies whether masked visuomotor priming in a shape decision task specifically depends on attentional sensitization of visual pathways for shape in contrast to color. Prior to the masked priming procedure, a shape or a color decision task served to induce corresponding task sets. ERP analyses revealed visuomotor priming effects over the occipitoparietal scalp only after the shape, but not after the color induction task. Thus, top‐down control coordinates automatic processing streams in congruency with higher‐level goals even at a fine‐grained level.     

Susceptibility-weighted imaging of the brain: Does gadolinium administration matter?

Objective

Susceptibility-weighted MR imaging (SWI) is usually obtained without administration of intravenous gadolinium (Gd). However, it is occasionally necessary to perform SWI after Gd is injected. The effects of Gd on SWI have not been systematically examined. The aim of this prospective study was to investigate whether performing SWI after Gd would influence the diagnostic image quality, parenchymal signal and vascular enhancement. An additional aim is to suggest potential future applications for Gd-enhanced SWI.

Methods

SWI was performed in 31 subjects before and after Gd administration. 17 cases were examined in a 1.5 T scanner and the remaining 14 were scanned at 3 T. The pre- and post-Gd images were analysed for signal changes in the cerebral grey matter (GM), white matter (WM) as well as for enhancement in the superficial and deep venous system. The visibility of the veins was graded on subtraction maps.

Results

The Gd-enhanced images showed no image quality degradation and no significant signal intensity change in the GM and WM as compared to the pre-Gd images (p > 0.05). After Gd-administration significant enhancement of the venous sinuses was noticed (p < 0.005), while the deep and cortical veins were poorly enhanced as confirmed by the calculated subtraction maps. The results showed no significant difference at variable MRI field strengths.

Conclusion

It is possible to perform SWI after Gd injection without information loss or signal change in the parenchyma. The most significant difference is the enhancement of the cerebral venous sinuses. Potential future applications are discussed.     

Quantitative evaluation of liver cirrhosis using T1 relaxation time with 3 tesla MRI before and after oxygen inhalation

Purpose:

To quantify liver T1 relaxation times before and after oxygen inhalation in patients with and without liver cirrhosis using a 3 Tesla (T) MRI.

Materials and Methods:

Institutional Review Board approval and written informed consent were obtained. Ninety‐two noncirrhotic patients and 87 patients with hepatitis B viral liver cirrhosis (72 Child‐Pugh class A and 15 Child‐Pugh class B or C) underwent MRI with a 3.0T system before and after the supply of 100% oxygen at a rate of 15 L/min by means of a nonrebreather ventilation mask for 3 min. T1 maps were acquired using three‐dimensional spoiled gradient echo sequences with two different flip angles (2° and 14°) and a fixed TR/TE (2.54 ms/0.95 ms). Liver T1 values were obtained using a T1 processing tool (MapIT software). The mean baseline T1 values of three groups (control, Child‐Pugh class A, and Child‐Pugh class B/C) were compared using an analysis of variance test. Liver T1 value before and after oxygenation was compared using a paired t‐test for each group.

Results:

The baseline liver T1 value was significantly higher in the control group (941 ± 136 ms) than in Child‐Pugh A (858 ± 143 ms) and Child‐Pugh B/C (783 ± 164 ms) group (P < 0.001 and P < 0.0001). The reduction in the liver T1 value after oxygen inhalation was significant in the control group (P = 0.012) but not significant in Child‐Pugh class A (P = 0.079) and Child‐Pugh class B/C (P = 0.752).

Conclusion:

The baseline liver T1 relaxation time was significantly different between the patients with and without liver cirrhosis. The shortening effect of oxygen on the liver T1 value was significant in the control group but not in the cirrhotic patients. J. Magn. Reson. Imaging 2012;36:405–410. © 2012 Wiley Periodicals, Inc.     

MTHFR C677T genotype and cardiovascular risk in a general population without mandatory folic acid fortification

Purpose

Meta-analyses have suggested an effect of MTHFR C677T genotype (rs1801133), a proxy for blood total homocysteine, on cardiovascular disease (CVD) in populations with low population dietary folate. The aim was to examine the association and effect modification by serum folate and vitamin B12 levels between MTHFR and CVD-related outcomes in a general population with no mandatory folic acid fortification policy.

Methods

The study population included 13,748 adults retrieved from pooling of four population-based studies conducted in Denmark. MTHFR genotype, serum folate (measured in approximately 9,356 individuals), and serum vitamin B12 (9,215 individuals), hypertension, and dyslipidemia were measured at baseline, and participants were followed for a mean of 10.5–11.7 years in central registries for diagnoses of stroke (623 incidents), ischaemic heart disease (IHD) (835 incidents), and all-cause mortality (1,272 incidents).

Results

The MTHFR genotype (TT vs. CC/CT) was not associated with hypertension [OR (95 % CI) 1.09 (0.95–1.25)], dyslipidemia [OR (95 % CI) 0.97 (0.84–1.11)], stroke [HR (95 % CI) 0.92 (0.69–1.23)], and all-cause mortality [HR (95 % CI) 0.94 (0.77–1.14)], either overall, or in participants with low serum folate or B12 status (P values for interactions 0.15–0.94). Individuals with the MTHFR TT genotype had a higher risk of IHD (HR (95 % CI) 1.38 (1.11–1.71)), but this association was not modified by folate status (P value for interaction 0.45).

Conclusions

Our results do not support a causal relationship between homocysteine and CVD. However, we cannot exclude a direct causal effect of MTHFR C677T genotype on IHD.     

Impact of Custodiol-N cardioplegia on acute kidney injury after cardiopulmonary bypass

Myocardial protection during cardiopulmonary bypass (CPB) can be achieved using cardioplegic solutions. Although, acute kidney injury (AKI) is a common complication following CPB, the effects of cardioplegic solutions on AKI have rarely been investigated. Within this study, the effects of the cardioplegic solutions histidine-tryptophan-ketoglutarate (HTK; Custodiol) and HTK-N (Custodiol-N) on AKI in a large animal model were compared. Therefore, Landrace pigs underwent median sternotomy, CPB at 34°C, 90 minutes of cardiac arrest and 120 minutes of reperfusion. Animals were randomized for single-shot cardioplegia with either HTK (n = 10) or HTK-N (n = 10). Renal biopsies and sera were analyzed to determine AKI biomarkers and apoptosis. Compared to HTK, HTK-N induced a decreased extent of proximal tubule swelling (48.3 ± 1.6 µm vs 52.3 ± 1.1 µm, P = .05) and decreased cytochrome c release (0.26 ± 0.04 vs 0.46 ± 0.08, P = .04) without reaching statistical significance due to Bonferroni correction. Comparing baseline and postreperfusion levels, the hemoglobin (Hb) and blood calcium levels were lower in HTK-N (Hb_baseline: 6.0 ± 0.6 mmol/L, Hb_reperfusion: 6.2 ± 0.7 mmol/L, P = .12; Ca²⁺_baseline: 1.36 ± 0.05 mmol/L, Ca²⁺_reperfusion: 1.28 ± 0.05 mmol/L, P = .16) compared to the HTK group (Hb_baseline: 5.9 ± 0.4 mmol/L, Hb_reperfusion: 4.7 ± 0.8 mmol/L, P < .01; Ca²⁺_baseline: 1.34 ± 0.07 mmol/L, Ca²⁺_reperfusion: 1.24 ± 0.06 mmol/L, P < .01). The present study showed that HTK-N could positively affect the kidney during CPB. Hb and calcium levels were stabilized. A statistical trend was found showing that AKI-related proximal tubule swelling and cytochrome c release were diminished.     

Epidemiology and Clinical Manifestations of Enteroaggregative Escherichia coli

SUMMARY

Enteroaggregative Escherichia coli (EAEC) represents a heterogeneous group of E. coli strains. The pathogenicity and clinical relevance of these bacteria are still controversial. In this review, we describe the clinical significance of EAEC regarding patterns of infection in humans, transmission, reservoirs, and symptoms. Manifestations associated with EAEC infection include watery diarrhea, mucoid diarrhea, low-grade fever, nausea, tenesmus, and borborygmi. In early studies, EAEC was considered to be an opportunistic pathogen associated with diarrhea in HIV patients and in malnourished children in developing countries. In recent studies, associations with traveler''s diarrhea, the occurrence of diarrhea cases in industrialized countries, and outbreaks of diarrhea in Europe and Asia have been reported. In the spring of 2011, a large outbreak of hemolytic-uremic syndrome (HUS) and hemorrhagic colitis occurred in Germany due to an EAEC O104:H4 strain, causing 54 deaths and 855 cases of HUS. This strain produces the potent Shiga toxin along with the aggregative fimbriae. An outbreak of urinary tract infection associated with EAEC in Copenhagen, Denmark, occurred in 1991; this involved extensive production of biofilm, an important characteristic of the pathogenicity of EAEC. However, the heterogeneity of EAEC continues to complicate diagnostics and also our understanding of pathogenicity.