Overexpression of long noncoding RNA Malat1 ameliorates traumatic brain injury induced brain edema by inhibiting AQP4 and the NF-κB/IL-6 pathway

Brain edema is a major traumatic brain injury (TBI)-related neurological complication. In the initiation stage of TBI, brain edema is characterized by astrocyte swelling (cytotoxic edema). We studied the impact of a long noncoding RNA, Malat1, on the TBI-induced astrocyte swelling and brain edema. Our results showed that Malat1 was downregulated in both the TBI rat model and the astrocyte fluid percussion injury (FPI) model, which concurred with brain edema and astrocyte swelling. Overexpression of Malat1 significantly inhibited rat brain edema, meanwhile reducing interleukin-6 (IL-6), nuclear factor-κB (NF-κB), and aquaporin 4 (AQP4) expression after TBI. In addition, overexpression of Malat1 ameliorated FPI-induced astrocyte swelling and reduced IL-6 release. Quantitative real-time polymerase chain reaction and Western blot analysis also corroborated the inhibitory effects of Malat1 on NF-κB and AQP4 expression after FPI. Our results highlighted the protective effects of Malat1 on the TBI-induced brain edema, which were mediated through regulating IL-6, NF-κB, and AQP4 expression. Our study could provide a novel approach for TBI treatment.     

Octanoic Acid Inhibits Astrocyte Volume Control: Implications for Cerebral Edema in Reye's Syndrome

Abstract Octanoic acid has been implicated in the pathogenesis of cytotoxic cerebral edema in Reye's syndrome. Using astrocytes from primary culture, we studied the dose-dependent effects of octanoate on cellular volume regulation and metabolism. Astrocyte volume recovery following hypoosmotic swelling was stimulated by 1.0 m M octanoate and inhibited by 3.0 m M octanoate. Parallel effects were obtained at these concentrations on the activity of the Na⁺,K⁺-depen-dent ATPase. Cellular ATP concentrations also were reduced 36% with the higher octanoate concentration. These effects of octanoate may contribute to the severe astrocyte swelling observed in the brains of Reye's syndrome patients.     

The Mode of Attachment of Trypanosoma vivax in the Proboscis of the Tsetse Fly Glossina fuscipes: an Ultrastructural Study of the Epimastigote Stage of the Trypanosome*

SYNOPSIS. The ultrastructure of attached Trypanosoma vivax epimastigote clusters in the proboscis of the tsetse fly Glossina fuscipes is described from electron micrographs of thin sections. Some flagellates are attached directly to the lining of the insect's labrum by their flagella, most of which are aligned along the long axis of the proboscis. Other trypanosomes are attached indirectly, their flagella adhering to those of flagellates which are directly attached. Junctional complexes similar to those described from metazoan epithelia are found on the flagellar membrane. A long zonular hemidesmosome attaches the flagellum to the proboscis wall and a series of closely set macular desmosomes link the flagellar membranes of adjacent flagellates. Unlike the trypomastigote stages of T. vivax, more than one row of macular desmosomes may be present along the flagellum-body junction of the trypanosome. It is suggested that all these Junctional complexes serve to buttress the flagellate's attachment to its insect host and so maintain anchorage of the parasite during the fly's blood meals. The ability of the flagellum of trypanosomatids to form Junctional complexes may be a factor contributing to their success as parasites, this adaptation enabling them to multiply while attached to host surfaces.     

Age-related macular degeneration: a target for nanotechnology derived medicines

Despite the fact that the retina is a fairly accessible portion of the central nervous system, there are virtually no treatments for early age-related macular degeneration (AMD). AMD is a degenerative retinal disease that causes progressive loss of central vision and is the leading cause of irreversible vision loss and legal blindness in individuals over the age of 50. Both environmental and genetic components play a role in its development. AMD is a multifactorial disease with characteristics that include drusen, hyperpigmentation and/or hypopigmentation of the retinal pigment epithelium (RPE), geographic atrophy and, in a subset of patients, late-stage choroidal neovascularization (CNV). Drugs that inhibit vascular endothelial growth factor (VEGF) have proven effective in treating late-stage CNV, but optimal means of drug delivery remains to be determined. Microscopic particles, whose size is on the nanometer scale, show considerable promise for drug delivery to the retina, for gene therapy, and for powering prosthetic "artificial retinas." This article summarizes the pathophysiology of AMD stressing potential applications from nanotechnology.     

年龄相关性黄斑变性患者黄斑区脉络膜新生血管特征分析

目的:探讨年龄相关性黄斑变性黄斑区脉络膜新生血管(CNV)的特征。方法:对41例(41只眼)年龄相关性黄斑变性患者CNV进行荧光素眼底血管造影(FFA)和相干光断层扫描(OCT)检查,并对两种不同的图像检查结果进行对比分析。结果:FFA发现典型CNV29眼,FFA早期黄斑区可见边界清晰的高荧光区,FFA晚期荧光扩大并增强;隐匿型CNV10眼,FFA早期可见边界欠清的强荧光,FFA晚期持续为荧光素渗漏或染色,边界多不清晰。OCT发现典型CNV33眼,显示CNV多位于视网膜神经上皮层下,呈边界清晰的纺锤形或圆形强反射,隐匿型CNV8眼,表现为视网膜色素上皮层平面不规则增强紊乱的反射信号。两种检查对黄斑区CNV的检出率对比差异无统计学意义(P0.05)。结论:结合FFA和OCT的图像特征对年龄相关性黄斑变性黄斑区脉络膜新生血管形态学改变进行对比分析,有助于明确病变的性质,为临床诊疗提供帮助。     

ELOVL4 protein preferentially elongates 20:5n3 to very long chain PUFAs over 20:4n6 and 22:6n3

We hypothesized that reduction/loss of very long chain PUFAs (VLC-PUFAs) due to mutations in the ELOngase of very long chain fatty acid-4 (ELOVL4) protein contributes to retinal degeneration in autosomal dominant Stargardt-like macular dystrophy (STGD3) and age-related macular degeneration; hence, increasing VLC-PUFA in the retina of these patients could provide some therapeutic benefits. Thus, we tested the efficiency of elongation of C20-C22 PUFA by the ELOVL4 protein to determine which substrates are the best precursors for biosynthesis of VLC-PUFA. The ELOVL4 protein was expressed in pheochromocytoma cells, while green fluorescent protein-expressing and nontransduced cells served as controls. The cells were treated with 20:5n3, 22:6n3, and 20:4n6, either individually or in equal combinations. Both transduced and control cells internalized and elongated the supplemented FAs to C22-C26 precursors. Only ELOVL4-expressing cells synthesized C28-C38 VLC-PUFA from these precursors. In general, 20:5n3 was more efficiently elongated to VLC-PUFA in the ELOVL4-expressing cells, regardless of whether it was in combination with 22:6n3 or with 20:4n6. In each FA treatment group, C34 and C36 VLC-PUFAs were the predominant VLC-PUFAs in the ELOVL4-expressing cells. In summary, 20:5n3, followed by 20:4n6, seems to be the best precursor for boosting the synthesis of VLC-PUFA by ELOVL4 protein.     

Features of anti‐inflammatory effects of modulated extremely high‐frequency electromagnetic radiation

Using a model of acute zymosan‐induced paw edema in NMRI mice, we test the hypothesis that anti‐inflammatory effects of extremely high‐frequency electromagnetic radiation (EHF EMR) can be essentially modified by application of pulse modulation with certain frequencies. It has been revealed that a single exposure of animals to continuous EHF EMR for 20 min reduced the exudative edema of inflamed paw on average by 19% at intensities of 0.1–0.7 mW/cm² and frequencies from the range of 42.2–42.6 GHz. At fixed effective carrier frequency of 42.2 GHz, the anti‐inflammatory effect of EHF EMR did not depend on modulation frequencies, that is, application of different modulation frequencies from the range of 0.03–100 Hz did not lead to considerable changes in the effect level. On the contrary, at “ineffective” carrier frequencies of 43.0 and 61.22 GHz, the use of modulation frequencies of 0.07–0.1 and 20–30 Hz has allowed us to restore the effect up to a maximal level. The results obtained show the critical dependence of anti‐inflammatory action of low‐intensity EHF EMR on carrier and modulation frequencies. Within the framework of this study, the possibility of changing the level of expected biological effect of modulated EMR by a special selection of combination of carrier and modulation frequencies is confirmed. Bioelectromagnetics 30:454–461, 2009. © 2009 Wiley‐Liss, Inc.     

Retinal carotenoids can attenuate formation of A2E in the retinal pigment epithelium

A2E, an important constituent of lipofuscin in human retinal pigment epithelium (RPE), is thought to mediate light-induced oxidative damage associated with aging and other ocular disorders. Ocular carotenoids in overlying retinal tissues were measured by HPLC and mass spectrometry and were correlated with levels of RPE A2E. We observed a statistically significant increase in total A2E levels in human RPE/choroid with age, and A2E levels in macular regions were approximately 1/3 lower than in peripheral retinal regions of the same size. There was a statistically significant inverse correlation between peripheral retina carotenoids and peripheral RPE/choroid A2E. Prospective carotenoid supplementation studies in Japanese quail demonstrated nearly complete inhibition of A2E formation and oxidation. These findings support current recommendations to increase dietary intake of xanthophyll carotenoids in individuals at risk for macular degeneration and highlight a new potential mechanism for their protective effects—inhibition of A2E formation and oxidation in the eye.     

The need for validation of large administrative databases: Veterans Health Administration ICD-9CM coding of exudative age-related macular degeneration and ranibizumab usage

We performed a validation study by chart review of data for exudative age-related macular degeneration (eAMD) and, because of the Veterans Administration (VA) therapy policy, ranibizumab usage in the largest electronic medical record system in the USA. We reviewed 5,854 distinct patients who visited an ophthalmology clinic within VA Connecticut from January 2006-December 2008. We randomly selected 98 of 138 distinct eAMD patients and 265 of 5,588 non-eAMD patients who did not receive ranibizumab. International Classification of Diseases, Ninth Revision, Clinical Modification coding of eAMD had an excellent positive predictive value of 97.8% (95% confidence interval (CI), 93.5-99.4%). The national Decision Support System (DSS) had an excellent positive predictive value of 100% (95% CI, 79.9-100%) for ranibizumab. However, the negative predictive value of the DSS dispensed ranibizumab decreased to 67.5 (95% CI, 62.1-72.4) because of a change in the way local values were stored that led to errors. Therefore, validation of clinical information over time in large databases is necessary.