Growth arrest and DNA damage inducible protein 34 (GADD34) is induced by various cellular stresses, such as DNA damage, endoplasmic reticulum stress, and amino-acid deprivation. Although the major roles of GADD34 are regulating ER stress responses and apoptosis, a recent study suggested that GADD34 is linked to innate immune responses. In this report, we investigated the roles of GADD34 in inflammatory responses against bacterial infection. To explore the effects of GADD34 on systemic inflammation in vivo, we employed a lipopolysaccharide (LPS)-induced murine sepsis model and assessed the lethality, serum cytokine levels, and tissue injury in the presence or absence of GADD34. We found that GADD34 deficiency increased the lethality and serum cytokine levels in LPS-induced sepsis. Moreover, GADD34 deficiency enhanced tissue destruction, cell death, and pro-inflammatory cytokine expression in LPS-induced acute liver injury. Pro-inflammatory cytokine production after LPS stimulation is regulated by the Toll-like receptor 4 (TLR4)-mediated NF-κB signaling pathway. In vitro experiments revealed that GADD34 suppressed pro-inflammatory cytokine production by macrophages through dephosphorylation of IKKβ. In conclusion, GADD34 attenuates LPS-induced sepsis and acute tissue injury through suppressing macrophage activation. Targeting this anti-inflammatory role of GADD34 may be a promising area for the development of therapeutic agents to regulate inflammatory disorders.
The aim of this study is to determine the progress of the visual field defects obtained by the Humphrey Field Analyzer 10-2 program (HFA 10-2) in patients with retinitis pigmentosa (RP). The medical records of 45 eyes of 45 RP patients who had at least 3 visual field tests were reviewed. Linear mixed models were used to follow the changes of the mean deviation and the average sensitivity of 4, 12, and 20 points in three concentric squares, designated as S4, S12, and S20. The median follow-up time was 3.86 years [range: 1.93 to 9.86, IQR (Interquartile range): 3.01 to 4.93]. The median number of the visual field tests was 3 (range: 3 to 15, IQR: 3 to 4). The mean change of the MD was −0.46 dB/year (−5.80%/year). When the patients were grouped by the average initial MD, the less advanced group had slower progressions than the more advanced group in S4, S12, and S20. These results should be useful in understanding the pathological changes of RP in the central visual field.
PURPOSE. To evaluate the microvascular changes in eyes with RP quantitatively using optical coherence tomography angiography (OCTA) and to determine whether the correlations between these indices and the severity of RP are significant.METHODS. This was a retrospective, observational study. The medical records of 53 RP patients and 46 controls were reviewed. The OCTA images were obtained with the Cirrus 5000 with Angioplex, and an automated program was used to analyze the microvascular patterns. The perfusion density (PD) and vessel length density (VLD) were used as indices of the microvascular density, whereas the vessel diameter index (VDI) was used as a measure of the caliber of the vessels. The width of the ellipsoid zone (EZ) in the OCT images and the mean deviation (MD) of the Humphry Field Analyzer (HFA) were used to determine the severity of the RP. Student's t-tests and Spearman's correlation tests were used.RESULTS. Both the PD and VLD in the superficial and deep plexuses and the whole retina were significantly reduced, and the VDI was significantly increased in RP patients compared with the corresponding values of the controls (P < 0.001). Spearman's rank tests indicated the RP severity was significantly correlated with the PD and VLD in all three layers (P < 0.001, r ranging from 0.50 to 0.87) and significantly correlated with VDI in the deep and the whole retina (P < 0.001, ranging from À0.64 to À0.73).CONCLUSIONS. Quantitative changes in the microvascular density might be useful for examining the pathophysiology of RP.
Purpose: To report the clinical course of eyes with paraneoplastic retinopathy caused by an autoantibody against transient receptor potential cation channel, subfamily M, member 1 (TRPM1). Methods: Ten paraneoplastic retinopathy patients with retinal ON-bipolar cell dysfunction, including six melanoma-associated retinopathy, from eight institutions in Japan were evaluated for the presence of an anti-TRPM1 antibody. The results of ophthalmic examinations and the presence of anti-TRPM1 antibody were analyzed. Results: Five patients were positive for the anti-TRPM1 antibody. These patients had similar clinical findings in both eyes at the time of diagnosis; relatively preserved best-corrected visual acuity, absence of fundus and optical coherence tomography abnormalities, and specific abnormalities of the electroretinography (ERG); and negative-type ERGs with bright stimulus flashes. One patient whose retinal ON-bipolar cells remained dysfunctional for the entire testing period, although the anti-TRPM1 antibody had disappeared. On the other hand, the ERGs recovered in 2 cases within 2 years after the onset. One case progressed to additional impairment of the photoreceptors with deterioration of ERGs. One case died and the clinical course was unavailable. Conclusion: Paraneoplastic retinopathy patients with retinal ON-bipolar cell dysfunction possess autoantibodies against TRPM1 at the onset of the disease process; however, the clinical course of these eyes can be different.
In contrast to previous reports, the thickness of the OS reflected the retinal sensitivity better than the product of OS and ONL.
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