Triggered Electrooculography for Identification of Oculomotor and Abducens Nerves during Skull Base Surgery.

OBJECTIVE: Electrooculography (EOG) records eyeball movements as changes in the potential difference between the negatively charged retina and the positively charged cornea. We aimed to investigate whether reliable EOG waveforms can be evoked by electrical stimulation of the oculomotor and abducens nerves during skull base surgery. METHODS: We retrospectively reviewed the records of 18 patients who had undergone a skull base tumor surgery using EOG (11 craniotomies and seven endonasal endoscopic surgeries). Stimulation was performed at 5 Hz with a stimulus duration of 200 µs and an intensity of 0.1-5 mA using a concentric bipolar probe. Recording electrodes were placed on the upper (active) and lower (reference) eyelids, and on the outer corners of both eyes; the active electrode was placed on the contralateral side. RESULTS: Reproducibly triggered EOG waveforms were observed in all cases. Electrical stimulation of cranial nerves (CNs) III and VI elicited positive waveforms and negative waveforms, respectively, in the horizontal recording. The median latencies were 3.1 and 0.5 ms for craniotomies and endonasal endoscopic surgeries, respectively (p=0.007). Additionally, the median amplitudes were 33.7 and 46.4 µV for craniotomies and endonasal endoscopic surgeries, respectively (p=0.40). CONCLUSION: This study showed reliably triggered EOG waveforms with stimulation of CNs III and VI during skull base surgery. The latency was different according to the point of stimulation and thus predictable. As EOG is noninvasive and relatively easy to perform, it can be used to identify the ocular motor nerves during surgeries as an alternative of electromyography.

Cerebrospinal Fluid Biomarkers for the Diagnosis of Alzheimer Disease in South Korea.

Laboratory-specific reference values for cerebrospinal fluid (CSF) Alzheimer disease (AD) biomarkers are necessary. Our objective was to apply well-known CSF biomarkers and redetermine their diagnostic cutoff values for AD in South Korea. CSF samples from matched control subjects (n=71), patients with AD dementia (ADD, n=76), and other neurological disorders with cognitive decline (OND, n=47) were obtained from 6 Korean dementia clinics according to a standardized protocol. CSF biomarker concentrations were measured using enzyme-linked immunosorbent assay. CSF biomarkers differed significantly between the ADD and control groups (P<0.001 for all), and between the ADD and OND groups (P<0.001 for all). The areas under the curve in differentiation of ADD from control subjects were 0.97 for Aß42, 0.93 for total tau (tTau), 0.86 for pTau, and 0.99 for both tTau/Aß42 and pTau/Aß42 ratios. Our revised cutoff value for Aß42 was higher than our previous one, whereas the values for the Tau proteins were similar. The tTau/Aß42 ratio had the highest accuracy, 97%. Our findings highlight the usefulness of CSF AD biomarkers in South Korea, and the necessity of continually testing the reliability of cutoff values.

Suppression of Toll-Like Receptor 4 Dimerization by 1-[5-Methoxy-2-(2-nitrovinyl)phenyl]pyrrolidine.

Toll-like receptor 4 (TLR4) recognizes lipopolysaccharide (LPS) and triggers the activation of myeloid differention factor 88 (MyD88) and the Toll/interleukin-1 receptor domain-containing adapter, inducing interferon-ß (TRIF)-dependent major downstream signaling pathways. To evaluate the therapeutic potential of 1-[5-methoxy-2-(2-nitrovinyl)phenyl]pyrrolidine (MNP), previously synthesized in our laboratory, its effect on signal transduction via the TLR signaling pathways was examined. Here, we investigated whether MNP modulates the TLR4 signaling pathways and which anti-inflammatory target in TLR4 signaling is regulated by MNP. MNP inhibited the activation of nuclear factor-κB (NF-κB) induced by LPS (TLR4 agonist), and it also inhibited the expression of cyclooxygenase-2 and inducible nitric oxide synthase. MNP inhibited LPS-induced NF-κB activation by targeting TLR4 dimerization in addition to IKKß. These results suggest that MNP can modulate the TLR4 signaling pathway at the receptor level to decrease inflammatory gene expression.

Tau mis-splicing in the pathogenesis of neurodegenerative disorders.

Tau proteins, which stabilize the structure and regulate the dynamics of microtubules, also play important roles in axonal transport and signal transduction. Tau proteins are missorted, aggregated, and found as tau inclusions under many pathological conditions associated with neurodegenerative disorders, which are collectively known as tauopathies. In the adult human brain, tau protein can be expressed in six isoforms due to alternative splicing. The aberrant splicing of tau pre-mRNA has been consistently identified in a variety of tauopathies but is not restricted to these types of disorders as it is also present in patients with non-tau proteinopathies and RNAopathies. Tau mis-splicing results in isoform-specific impairments in normal physiological function and enhanced recruitment of excessive tau isoforms into the pathological process. A variety of factors are involved in the complex set of mechanisms underlying tau mis-splicing, but variation in the cis-element, methylation of the MAPT gene, genetic polymorphisms, the quantity and activity of spliceosomal proteins, and the patency of other RNA-binding proteins, are related to aberrant splicing. Currently, there is a lack of appropriate therapeutic strategies aimed at correcting the tau mis-splicing process in patients with neurodegenerative disorders. Thus, a more comprehensive understanding of the relationship between tau mis-splicing and neurodegenerative disorders will aid in the development of efficient therapeutic strategies for patients with a tauopathy or other, related neurodegenerative disorders. [BMB Reports 2016; 49(8): 405-413].

Suppression of TLRs signaling pathways by 1-[5-methoxy-2-(2-nitrovinyl)phenyl]pyrrolidine.

Toll-like receptors (TLRs) play significant roles in recognizing the pathogen-associated molecular patterns that induce innate immunity, and subsequently, acquired immunity. In general, TLRs have two downstream signaling pathways, the myeloid differential factor 88 (MyD88)-dependent and toll-interleukin-1 receptor domain-containing adapter-inducing interferon-ß (TRIF)-dependent pathways, which lead to the activation of nuclear factor-kappa B (NF-κB) and interferon regulatory factor 3 (IRF3). 1-[5-methoxy-2-(2-nitrovinyl)phenyl]pyrrolidine (MNP) has been previously synthesized in our laboratory. To evaluate the therapeutic potential of MNP, its effect on signal transduction via the TLR signaling pathways was examined. MNP was shown to inhibit the activation of NF-κB and IRF3 induced by TLR agonists, as well as to inhibit the expression of cyclooxygenase-2, inducible nitric oxide synthase, and interferon inducible protein-10. MNP also inhibited the activation of NF-κB and IRF3 induced by the overexpression of downstream signaling components of the MyD88- or TRIF-dependent signaling pathways. These results suggest that MNP can modulate MyD88- and TRIF-dependent signaling pathways of TLRs, leading to decreased inflammatory gene expression.

Surgical Outcomes of Additional Ahmed Glaucoma Valve Implantation in Refractory Glaucoma.

PURPOSE: To evaluate the surgical outcomes of the implantation of an additional Ahmed glaucoma valve (AGV) into the eyes of patients with refractory glaucoma following previous AGV implantation. METHODS: This study is a retrospective review of the clinical histories of 23 patients who had undergone a second AGV implantation after a failed initial implantation. Age, sex, prior surgery, glaucoma type, number of medications, intraocular pressure (IOP), visual acuity, and surgical complications were analyzed. Surgical success was defined as IOP maintained below 21 mm Hg, with at least a 20% overall reduction in IOP, regardless of the use of IOP-lowering medications. RESULTS: Following the implantation of a second AGV, the mean IOP decreased from 39.3 to 18.5 mm Hg (52.9% reduction, P<0.001). The mean number of postoperative IOP-lowering medications administered decreased from 2.8 to 1.7 after the second AGV implantation (P<0.001). The cumulative probability of success for the procedure was 87% after 1 year and 52% after 3 years. Three patients (13.0%) experienced bullous keratopathy after the second AGV implantation. None of the patients showed any evidence of diplopia or ocular movement limitation as a result of the presence of 2 AGVs in the same eye. Prior trabeculectomy was found to be a significant risk factor for failure (P=0.027). CONCLUSIONS: A second AGV implantation can be a good choice of surgical treatment when the first AGV has failed to control IOP.

Diagnostic ability of macular ganglion cell asymmetry for glaucoma.

BACKGROUND: Using spectral-domain optical coherence tomography (OCT), this study aims to investigate the glaucoma diagnostic ability of macular ganglion cell asymmetry analysis. DESIGN: A cross-sectional study was conducted. This study was performed to investigate glaucoma diagnostic ability of macular ganglion cell asymmetry analysis in eyes with various degrees of glaucoma. PARTICIPANTS: We enrolled 181 healthy eyes and 265 glaucomatous eyes. METHODS: Glaucomatous eyes were subdivided into pre-perimetric, early, moderate and advanced-to-severe glaucoma based on visual field test results. For each eye, macular ganglion cell-inner plexiform layer (GCIPL) thickness was measured using OCT. Average GCIPL thickness, GCIPL thicknesses in superior and inferior hemispheres, absolute difference in GCIPL thickness between superior and inferior hemispheres and GCIPL asymmetry index calculated as the absolute value of log10 (inferior hemisphere thickness/superior hemisphere thickness) were analysed. MAIN OUTCOME MEASURES: Areas under the receiver operating characteristics curves (AUCs) of GCIPL parameter were calculated and compared. RESULTS: All of the GCIPL parameters showed good glaucoma diagnostic ability (AUCs ≥ 0.817, P < 0.01). AUCs of average, superior and inferior GCIPL thickness increased as the severity of glaucoma increased. GCIPL thickness difference and asymmetry index showed the highest AUCs in early and moderate glaucoma and lower AUCs in pre-perimetric and advanced-to-severe glaucoma. GCIPL thickness difference and asymmetry index showed better glaucoma diagnostic ability than other GCIPL parameters only in early stage of glaucoma (P < 0.05); in other stages, these parameters had similar to or worse glaucoma diagnostic ability than other GCIPL parameters. CONCLUSIONS: Macular ganglion cell asymmetry analysis showed good glaucoma diagnostic ability, especially in early-stage glaucoma. However, it has limited usefulness in other stages of glaucoma.

Suppression of the TRIF-dependent signaling pathway of Toll-like receptor by CDr10b in RAW264.7 macrophages.

Toll-like receptors (TLRs) recognize distinct pathogen-associated molecular patterns and play a critical role in innate immune responses. TLR signaling pathways can be largely classified as either myeloid differential factor 88 (MyD88)- or toll-interleukin-1 receptor domain-containing adapter inducing interferon-ß (TRIF)-dependent pathways. Compound of Designation red 10 binding (CDr10b) was synthesized to investigate its role in neuroinflammatory diseases. This study was conducted to determine whether CDr10b can affect TLR signaling pathways. CDr10b suppressed NF-κB activation as well as COX-2 and iNOS expression induced by TLR3 or TLR4 agonists. CDr10b also suppressed the activation of interferon regulatory factor 3 (IRF3) and the expression of interferon inducible protein-10 (IP-10) induced by TLR3 or TLR4 agonists. These results indicate that CDr10b can modulate the TRIF-dependent pathway of TLRs and has the potential to become a new therapeutic drug for chronic inflammatory diseases.

Suppressive effects of 1-[4-fluoro-2-(2-nitrovinyl)phenyl]pyrrolidine on the Toll-like receptor signaling pathways.

When various pathogens invade a host, toll-like receptors (TLRs) play a significant role in recognizing the pathogen-associated molecular patterns carried by the pathogens to induce innate immune reaction, followed by acquired immunity reaction. TLRs have two downstream signaling pathways, the myeloid differential factor 88 (MyD88)-dependent and toll-interleukin-1 receptor domain-containing adapter inducing interferon-ß (TRIF)-dependent pathways. To evaluate the therapeutic potential of 1-[4-fluoro-2-(2-nitrovinyl)phenyl]pyrrolidine (FPP), previously synthesized in our laboratory, its effect on signal transduction via the TLR signaling pathways was examined. FPP inhibited the activation of nuclear factor-κB (NF-κB) and interferon regulatory factor 3 (IRF3) induced by TLR agonists, as well as inhibited the expression of cyclooxygenase-2, inducible nitric oxide synthase, and interferon inducible protein-10. FPP also inhibited the activation of NF-κB and IRF3 when induced by the overexpression of downstream signaling components of the TLRs. As a result, FPP has potential to become a new therapeutic drug for many inflammatory diseases.

CDr10b inhibits the expression of cyclooxygenase-2 and inducible nitric oxide synthase induced by lipopolysaccharide.

The pathophysiological processes of inflammation can lead to a host of diseases, such as periodontitis, atherosclerosis, rheumatoid arthritis, and even cancer. The dysregulated inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) activation play important roles in the development of certain inflammatory diseases. Here, we investigated the effects of CDr10b which is originally developed for a microglia staining probe on inflammation, by modulating NF-κB activation and iNOS and COX-2 expression induced by lipopolysaccharide (LPS) in murine macrophages. The CDr10b suppressed NF-κB activation and iNOS and COX-2 expression induced by LPS. All the results suggest that CDr10b is a promising novel agent for the treatment of inflammatory diseases.

Visual prognostic value of photopic negative response and optical coherence tomography in central retinal vein occlusion after anti-VEGF treatment.

OBJECTIVE: To investigate the potential of optical coherence tomography (OCT) and photopic negative response (PhNR) for predicting visual outcome after intravitreal bevacizumab in patients with macular edema secondary to central retinal vein occlusion (CRVO). METHODS: Thirty-two consecutive patients with macular edema secondary to unilateral CRVO who were treated with three times of 6 weeks interval intravitreal bevacizumab were enrolled. LogMAR visual acuity (Va), OCT and PhNR were done before and 4 weeks after first and third injection. Stepwise multiple regression analysis was conducted between pre-treatment Va, central retinal thickness, b wave amplitude, PhNR amplitude, PhNR relative amplitude (affected eye/unaffected fellow eye, % presentation) and post-treatment Va at 4 weeks after the third injection. The predictive values of pre-treatment parameters for good visual outcome (0.2 ≤ LogMAR Va) were assessed using receiver-operating characteristics (ROC) analysis. RESULTS: In multiple regression analysis, pre-treatment Va (ß = 0.615, P = 0.001) and PhNR relative amplitude (ß = -0.352, P = 0.032) were correlated significantly with post-treatment Va. In ROC analysis, pre-treatment Va showed a 80 % sensitivity and 80 % specificity for predicting good visual outcome, at a cutoff value of 0.52 LogMAR. Pre-treatment PhNR relative amplitude demonstrated a 88 % sensitivity and 75 % specificity for predicting good visual outcome, at a cutoff value of 40.00 %. CONCLUSIONS: The PhNR relative amplitude can be a useful prognostic factor for visual outcome after intravitreal bevacizumab therapy in patient with macular edema secondary to CRVO. Patients with larger pre-treatment PhNR relative amplitude with better pre-treatment Va showed a better post-treatment visual outcome.

Inhibition of homodimerization of toll-like receptor 4 by 6-shogaol.

Toll-like receptors (TLRs) play a critical role in sensing microbial components and inducing innate immune and inflammatory responses by recognizing invading microbial pathogens. Lipopolysaccharide-induced dimerization of TLR4 is required for the activation of downstream signaling pathways including nuclear factor-kappa B (NF-kappaB). Therefore, TLR4 dimerization may be an early regulatory event in activating ligand-induced signaling pathways and induction of subsequent immune responses. Here, we report biochemical evidence that 6-shogaol, the most bioactive component of ginger, inhibits lipopolysaccharide-induced dimerization of TLR4 resulting in the inhibition of NF-kappaB activation and the expression of cyclooxygenase-2. Furthermore, we demonstrate that 6-shogaol can directly inhibit TLR-mediated signaling pathways at the receptor level. These results suggest that 6-shogaol can modulate TLR-mediated inflammatory responses, which may influence the risk of chronic inflammatory diseases.

Guggulsterone suppresses the activation of transcription factor IRF3 induced by TLR3 or TLR4 agonists.

Toll-like receptors (TLRs) are vital in the induction of innate immune responses. The microbial components trigger the activation of the myeloid differential factor 88 (MyD88)- and toll-interleukin-1 receptor domain-containing adapter inducing interferon-beta (TRIF)-dependent downstream TLR signaling pathways. Guggulsterone, which has been used for centuries to treat many chronic diseases, inhibits the MyD88-dependent pathway by inhibiting the activity of inhibitor-kappaB kinase. However, it is not known whether guggulsterone inhibits the TRIF-dependent pathway. Presently, we sought to identify the molecular targets of guggulsterone in this pathway. Guggulsterone inhibited nuclear factor-kappaB and IRF3 activation induced by lipopolysaccharide or poly[I:C] and activation of IRF3 induced by the overexpression of TRIF, TBK1 or constitutively active IRF3. Guggulsterone also suppressed the lipopolysaccharide-induced phosphorylation of IRF3. These results suggest that guggulsterone can modulate both MyD88- and TRIF-dependent signaling pathways of TLRs leading to decreased inflammatory gene expression.