TNF-alpha induces thromboxane receptor signaling-dependent microcirculatory dysfunction in mouse liver

TNF-alpha is a critical mediator of hepatic microcirculatory dysfunction during endotoxemia. The present study was to investigate the role of thromboxane A2 (TXA2) and the biological significance of thromboxane prostanoid (TP) receptor signaling in TNF-alpha-mediated hepatic microcirculatory dysfunction in male C57Bl/6 mice. The number of leukocytes adhering to the endothelial cells of the hepatic microvessels (the portal venules, sinusoids, and central venules) and the percentage of nonperfused sinusoids were determined using in vivo fluorescence microscopy. FR167653, an inhibitor of TNF-alpha, was administered 0 and 2 h after LPS injection. A TXA2 synthase inhibitor, OKY-046, was administered 30 min before TNF-alpha injection. Thromboxane prostanoid receptor knockout mice were used to investigate whether TNF-alpha-induced hepatic microcirculatory dysfunction is mediated by endogenously produced TXA2. FR167653 reduced LPS-induced leukocyte adhesion (50%-80%) and the percentage of nonperfused sinusoids (55%). The leukocyte adhesion was increased in the portal venules (8-fold), sinusoids (51-fold), and central venules (73-fold) in TNF-alpha-treated mice, accompanied with an increase in sinusoidal perfusion deficits (8-fold). Alanine aminotransferase levels rose as the adhesion of leukocytes increased. OKY-046 administration before TNF-alpha administration reduced leukocyte adhesion (41%-49% decrease) and sinusoid perfusion deficits (34% decrease). In TP receptor knockout mice, the number of adhering leukocytes, the percentage of nonperfused sinusoids, and alanine aminotransferase levels were lower (by 43%-56%, 41%, and 29%, respectively) than in wild-type counterparts. The results suggest that TP receptor signaling may promote hepatic microcirculatory dysfunction elicited by TNF-alpha. Blockade of TNF-alpha generation and TP receptor signaling may be a good strategy for managing endotoxin-induced hepatic injury.     

The EFA6 family: guanine nucleotide exchange factors for ADP ribosylation factor 6 at neuronal synapses

ADP ribosylation factor 6 (ARF6) is a member of the ARF family of small GTPases, which mediates a variety of neuronal functions accompanying the structural changes of developing and mature neurons through its regulation of actin cytoskeleton reorganization and membrane traffic. The activation of ARF6 is strictly regulated by guanine nucleotide exchange factors (GEFs). The EFA6 family is the first member that was identified to be a specific GEF for ARF6 and comprises four structurally related polypeptides (EFA6A, EFA6B, EFA6C and EFA6D). Since the cellular and subcelllular localization of GEFs is a critical determinant for the spatiotemporal activation of ARF6 in neurons, I have focused on the EFA6 family from the anatomical point of view to understand the neuronal functions of ARF6. Three members of the EFA6 family (EFA6A, EFA6C and EFA6D) are abundantly expressed in the mouse brain with distinct spatiotemporal patterns. Interestingly, they are enriched particularly in the postsynaptic density fraction, shedding light on the importance of the EFA-ARF6 pathway in neuronal synapses. Here, I will review the recent advances in the expression and functions of the EFA6 family in the nervous system.     

Predictive Validity of the Classification Schema for Functional Mobility Tests in Instrumental Activities of Daily Living Decline Among Older Adults

Shimada H, Sawyer P, Harada K, Kaneya S, Nihei K, Asakawa Y, Yoshii C, Hagiwara A, Furuna T, Ishizaki T. Predictive validity of the classification schema for functional mobility tests in instrumental activities of daily living decline among older adults.

Objective

To determine predictive validity for cut points of the Timed Up & Go (TUG) test and life-space assessment (LSA) on decline in instrumental activities of daily living (IADLs) among older adults.

Design

Cross-sectional and 1-year follow-up study.

Setting

Preventive health care services.

Participants

In a cross-sectional study, 2404 older adults (65-100y) were recruited to determine cut points for the TUG and LSA for IADLs limitation. For longitudinal analysis, 436 older adults (65-100y) were followed over 1 year to explore the validity of a classification model using the cut points to predict incident IADLs decline.

Interventions

Not applicable.

Main Outcome Measures

The TUG, LSA, and Tokyo Metropolitan Institute of Gerontology index of IADLs measurement.

Results

The cut points associated with IADLs limitations for the TUG and LSA were 12 seconds and 56 points, respectively. Participants were classified into fast/high (most able; TUG <12 and LSA >56), fast/low, slow/high, and slow/low (vulnerable; TUG ≥12 and LSA ≤56) groups; there were 813 (34%), 385 (16%), 246 (10%), and 960 (40%) participants in each group, respectively. The proportions of participants with IADLs limitation in the most able, fast/low, slow/high, and vulnerable groups were 19%, 64%, 61%, and 89%, respectively. The vulnerable group included significantly more participants with IADLs limitation than any other group (P<.001). Compared with a most able group, the odds ratios of IADLs decline for the fast/low and vulnerable groups were 2.52 (95% confidence interval 1.15-5.53, P<.05) and 2.87 (95% confidence interval 1.38-5.96, P<.01), respectively.

Conclusions

The combination of TUG and LSA identifies persons with future IADLs decline and has the potential to be used by community health care services to target individualized interventions.