Clinical characteristics of responders to intravitreal bevacizumab in central serous chorioretinopathy patients.

PURPOSE: To investigate factors associated with good response to intravitreal bevacizumab (IVB) in central serous chorioretinopathy (CSC) patients. METHODS: We retrospectively reviewed 42 eyes of CSC patients of symptom duration more than 3 months who received a single or multiple successive IVBs on an as-needed basis (0.05 ml, 1.25 mg). High responders (HRs) were defined as complete resolution of subretinal fluid (SRF) on spectral domain optical coherence tomography (SD-OCT). Moderate responders (MRs) were defined as SRF resolution of 50-99% of pretreatment volume and poor responders (PRs) as SRF resolution <50%. Clinical, SD-OCT, fluorescein, and indocyanine green angiography findings were analyzed to find factors associated with HR. Descriptive statistics for all demographic and clinical variables were calculated, and comparisons were made using Wilcoxon's matched-pairs signed-rank test, the Mann-Whitney U-test for means with continuous data, Pearson's χ(2) test, and Fisher's exact test for categorical data. RESULTS: The mean number of IVB was 1.9. At postoperative 1 month, there were 10 (24%) HRs, 18 (43%) MRs, and 14 (33%) PRs. At the last follow-up (the mean 8.6 months), there were 25 HRs (60%), 9 MRs (21%), and 8 PRs (19%). Thicker subfoveal choroid (P=0.036), smaller lesion diameter (P=0.019), and better baseline best-corrected visual acuity (P=0.002) predicted HRs at postoperative 1 month. HR at the last follow-up was associated with classic pattern fluorescein angiography finding. CONCLUSIONS: Suboptimal effects of IVB on persistent CSC suggest primary IVB on selective cases with better vision, smaller lesion, and thicker choroid at baseline.

The sparing effect of low-dose esmolol on sevoflurane during laparoscopic gynaecological surgery.

This double-blind, randomized, placebo-controlled study evaluated the sparing effect of esmolol on sevoflurane during laparoscopic gynaecological surgery in 54 patients between December 2009 and May 2010. The concentration of sevoflurane required to maintain adequate anaesthesia was determined. Patients received either a 0.5 mg/kg esmolol intravenous loading dose followed by infusion of 30 µg/kg per min or an identical volume of normal saline (placebo). During surgery the input concentration of sevoflurane was adjusted every 5 min to maintain systolic blood pressure within 15% of baseline and bispectral index at 50 - 60. Infusion of esmolol resulted in an 18.2% decrease in mean sevoflurane input concentration. Patients receiving esmolol had an earlier discharge from the postanaesthetic care unit and a lower mean fentanyl dose. In conclusion, intraoperative esmolol infusion decreased both the requirement for sevoflurane and postoperative administration of fentanyl.

The analysis of lacquer crack in the assessment of myopic choroidal neovascularization.

OBJECTIVE: The aim of this study was to clarify the characteristic findings in myopic choroidal neovascularization (CNV) and the relationship with lacquer crack (LC). METHODS: In all, 66 consecutive myopic CNV patients treated with photodynamic therapy and/or intravitreal anti-vascular endothelial growth factor injection in one eye were reviewed. Data from fluorescein angiography (FA) and indocyanine green angiography (ICGA), obtained simultaneously using the Heidelberg retina angiograph 2 (HRA2), were analyzed. RESULTS: LCs were associated with a relatively large extent (≥3000 µm) of peripapillary choroidal atrophy and a dark rim, the proliferation of retinal pigment epithelial cells surrounding the neovascular membrane was accompanied by a small extent. Myopic CNV usually developed in the LC area surrounded by tiny crack fragments. In all, 35 patients with LCs received FA and ICGA at least twice during follow-up. LC progression was observed in nine (25.7%) treated eyes and six (23.1%) non-CNV fellow eyes. Crack fragments progressed in three distinct forms such as elongation, branching, or bridging pattern. Newly diagnosed myopic CNV was reported in 18 treated eyes and 3 fellow eyes. Progression of LCs and development of CNV occurred simultaneously in eight eyes. By multivariate Cox's regression, a statistically significant association was observed between recurrence of myopic CNV and the absence of a dark rim on ICGA. CONCLUSIONS: The HRA2 instrument affords detailed high-resolution images of FA and ICGA. Notably, recurrence of myopic CNV developed in areas surrounded by new small crack fragments and LCs are considered to be important in the development of myopic CNV.

Factors influencing the concentration of cytokines during liver transplantation.

Not only does the underlying disease that requires surgery constitute a significant stress to the human body, but also the surgery itself serves as a stressor. Cytokine secretion is activated in response to the surgical stress during liver transplantation. We examined 44 patients to compare cytokine levels, according to the underlying diseases causing liver failure (viral hepatitis vs alcoholic hepatitis), examining whether the values differed according to the model for end-stage liver disease (MELD) score [high (≥20) vs low (<20)]. Pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)1ß, and IL-6 and anti-inflammatory cytokines IL-4 and IL-10 were quantified using sandwich enzyme- linked immunoassays at three times: (1) after inducing anesthesia, (2) 60 minutes after the start of the anhepatic period, and (3) 60 minutes after reperfusion. No difference in the level of any cytokine measured in our study was detected at any time point between the viral and the alcoholic hepatitis groups. Among the high MELD group, IL-1ß and IL-4 contents were higher than in the low MELD group at all time points (P < .05). IL-10 concentrations at time 1 and TNF-α at time 2 were higher among the high MELD group (P < .05). In conclusion, the severity of the inflammatory and stress reactions expressed as cytokine concentrations did not differ according to the underlying liver disease, but did associate with the MELD score.

Axial length and intraoperative posterior vitreous detachment as predictive factors for surgical outcomes of diabetic vitrectomy.

AIMS: To evaluate the relationship of axial length (AXL), intraoperatively assessed posterior vitreous detachment (PVD) status, and surgical outcomes of diabetic vitrectomy. METHODS: Retrospective, consecutive case series. Clinical records were reviewed for 115 eyes (50 males, 65 females) with more than a 6-month follow-up who underwent diabetic vitrectomy from a single surgeon. Thirty-three eyes had vitreous haemorrhage, 37 had tractional retinal detachment (TRD) threatening the macula, 43 had TRD involving the macula, and two had neovascular glaucoma. AXL was measured preoperatively by ultrasonography, and PVD status was classified intraoperatively: broad vitreo-retinal adhesion as no PVD, PVD at the macular area with attachment at the disc as incomplete PVD, and complete PVD. RESULTS: Forty-four eyes had no PVD, 23 had incomplete PVD, and 48 had complete PVD. A majority of the no PVD group had macula off TRD (97.7%), whereas vitreous haemorrhage (68.7%) predominated in the complete PVD group. Longer AXLs were noted in the complete PVD group compared with the no PVD and incomplete PVD groups (ANOVA in three groups P=0.0001). Univariate analysis showed that AXL had an influence on anatomical success (P=0.02). Multiple logistic regression analysis yielded that PVD status is a significant predictor of the final best corrected visual acuity (BCVA)>20/100, and BCVA>20/40 (P=0.01, P=0.02). CONCLUSIONS: Intraoperatively assessed PVD status is a prognostic factor for functional outcomes of diabetic vitrectomy. Shorter AXL was associated with lesser PVD. In eyes with a lack of PVD, careful timing and decision of surgery are mandatory.

Inhibition of choroidal neovascularisation in mice by systemic administration of the multikinase inhibitor, sorafenib.

BACKGROUND: To investigate the effect of orally administered sorafenib, a multikinase inhibitor, in a mouse model of choroidal neovascularisation (CNV). METHODS: Sorafenib or vehicle was administered orally to female C57BL/6 mice at the onset (day 0) of experiments. CNV was induced by laser photocoagulation the following day. After 14 days, mice were perfused with fluorescein-labelled dextran, and the area of CNV was measured on choroidal flat mounts by image analysis. In some groups of mice, treatments were started 7 days after the laser photocoagulation to determine the effect of the agent on established CNV. Expression of phosphorylated extracellular signal-regulated kinase (p-ERK) in choroidal tissues was measured by Western blot analysis to demonstrate the kinase-inhibitory effect of sorafenib in intracellular signalling pathways involved in CNV formation. RESULTS: Sorafenib significantly reduced the extent of CNV in a dose-dependent manner. The area of CNV was reduced by 43% in the 30 mg/kg/day group and by 61% in the 60 mg/kg/day group compared with vehicle-treated controls (both p<0.0001). Oral administration of sorafenib also caused significant regression of established CNV. The area of CNV was reduced by 59% in the 30 mg/kg/day group and by 66% in the 60 mg/kg/day group compared with both baseline and control measurements (p<0.0001). The expression of p-ERK in choroidal tissues was increased within 1 day of laser photocoagulation and remained elevated for 2 weeks. The expression of p-ERK was suppressed by sorafenib. CONCLUSIONS: Sorafenib demonstrated antiangiogenic properties in a mouse model of CNV and may be useful in the treatment of CNV.

Objective evaluation of cataract progression associated with a high dose intravitreal triamcinolone injection.

PURPOSE: To investigate the progression of cataract after a high dose (25 mg) intravitreal triamcinolone acetonide injection in patients with macular oedema secondary to diabetes and retinal vein occlusion. METHODS: This prospective interventional case series study included 38 patients (76 eyes) with diabetic retinopathy or retinal vein occlusion diagnosed with clinical examination and fluorescein angiography. The patients were treated with 25 mg IVTA in their one eye with macular oedema and the fellow eyes served as a control. Patients were asked to return the next day and weekly for 1 month and monthly thereafter by 6 months post-operative. The progression of the cataract using photographic evaluation according to the Lens Opacities Classification System III was documented and statistical analysis was done using the Kaplan-Meier survival analysis and the log-rank test. RESULTS: Among the 38 treated eyes, there was an increase of cataract degree by 1 grade at the end of 6 months in 10 patients. The types of progressed cataract were PSC in seven patients, cortical in six patients, and nuclear sclerosis in one patient. Six months after the injections, there was a significantly higher rate of progression of PSC (P=0.023, log-rank test) and cortical opacities (P=0.011) in the treated group while the progression of nuclear cataract was not significantly different between the treated eye and the control eye. CONCLUSION: A high-dose (25 mg) intravitreal triamcinolone acetonide injection induces the progression of cortical and posterior subcapsular opacity in patients with diabetic macular oedema and retinal vein occlusion.

Bran extracts from pigmented rice seeds inhibit tumor promotion in lymphoblastoid B cells by phorbol ester.

Using flow cytometry, we quantitatively evaluated anti-tumor-promoting activity of rice bran extracts by measuring inhibition of Epstein-Barr virus early-antigen activation (EBV-EA) induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). This assay measures anti-tumor-promoting activity and cytotoxicity of target substances using the same batch of cells. Using this short-term procedure, we have determined the anti-tumor-promoting activity of 70% ethanol-water extracts of bran (outer layer) from seeds of five pigmented rice cultivars: Jumlalocal-1, DZ 78, Elwee, LK1-3-6-12-1-1, and LK1A-2-12-1-1. The results show that, compared to an extract from the non-pigmented white cooking rice variety Chuchung, the extracts from the pigmented varieties strongly inhibited phorbol ester-induced tumor promotion in marmoset lymphoblastoid cells B95-8 in vitro. These findings may facilitate development and use of new health-promoting rice varieties.

Role of NADP+-dependent isocitrate dehydrogenase (NADP+-ICDH) on cellular defence against oxidative injury by gamma-rays.

PURPOSE: To investigate the regulation of NADPH-producing isocitrate dehydrogenase (ICDH) in cytosol (IDPc) and mitochondria (IDPm) upon gamma-ray irradiation, and the roles of IDPc and IDPm in the protection against cellular damage induced by gamma-ray irradiation. MATERIALS AND METHODS: Changes of IDPc and IDPm proteins upon gamma-ray irradiation to NIH3T3 cells were analysed by immunoblotting. To increase or decrease the expression of IDPc or IDPm, NIH3T3 cells were stably transfected with mouse IDPc or IDPm cDNA in either the sense or the antisense direction. The transfected cells with either increased or decreased IDPc or IDPm were exposed to gamma-rays, and the levels of reactive oxygen species generation, protein oxidation and lipid peroxidation were measured. RESULTS: Both IDPc and IDPm activities were induced by gamma-ray in NIH3T3 cells. Cells with decreased expression of IDPc or IDPm had elevated reactive oxygen species generation, lipid peroxidation and protein oxidation. Conversely, overproduction of IDPc or IDPm protein partially protected the cells from oxidative damage induced by gamma-ray irradiation. CONCLUSIONS: The protective role of IDPc and IDPm against gamma-ray-induced cellular damage can be attributed to elevated NADPH, reducing equivalents needed for recycling reduced glutathione in the cytosol and mitochondria. Thus, a primary biological function of the ICDHs may be production of NADPH, which is a prerequisite for some cellular defence systems against oxidative damage.

Enhanced expression of transglutaminase 2 in anterior polar cataracts and its induction by TGF-beta in vitro.

BACKGROUND/AIMS: Transglutaminase activity has long been implicated in the cataract formation. However, the precise mechanism of how it is produced and involved in this process remains unclear. Here the authors sought to examine whether transglutaminase 2 (TGase 2) is expressed in lens epithelial cells from patients with anterior polar cataracts, to determine whether TGase 2 expression is induced by transforming growth factor (TGF-beta) in cultured lens epithelial cells, and to determine whether TGase 2 participates in the crosslinking of fibronectin in lens epithelial cells in vitro. METHODS: Lens epithelial cells from anterior polar cataracts, nuclear cataracts, and non-cataractous clear lenses were examined for the expression of TGase 2 using reverse transcription-polymerase chain reaction, western blot analysis, and immunohistochemical analysis. The modulation of extracellular TGase 2 activity by TGF-beta was measured by the formation of fibronectin polymers and the incorporation of fluorescein cadaverine into extracellular matrix proteins. The effect of TGase 2 overexpression was analysed by immunofluorescence staining and western blot analysis of human lens epithelial (HLE) B-3 cells transiently transfected with TGase 2 gene. RESULTS: The expression of TGase 2 mRNA and its protein was markedly enhanced in lens epithelial cells from patients with anterior polar cataracts. Treatment of HLE B-3 cells with TGF-beta caused an increase in TGase 2 protein, its extracellular activity, and the crosslinking of fibronectin. Transient transfection of HLE B-3 cells with the TGase 2 gene led to the increased production of fibronectin monomers and polymers. CONCLUSIONS: This study shows that TGase 2 is overexpressed in lens epithelial cells from anterior polar cataracts and that TGF-beta may be a causative factor in the induction of TGase 2. The enhanced expression of TGase 2 might cause the accumulation and crosslinking of the extracellular matrix proteins and might play a part in anterior polar cataract development.

Isolation, characterization, and mapping of the stay green mutant in rice.

Leaf color turns yellow during senescence due to the degradation of chlorophylls and photosynthetic proteins. A stay green mutant was isolated from the glutinous japonica rice Hwacheong- wx through N-methyl-N-nitrosourea mutagenesis. Leaves of the mutant remained green, while turning yellow in those of the wild-type rice during senescence. The stay green phenotype was controlled by a single recessive nuclear gene, tentatively symbolized as sgr(t). All the phenotypic characteristics of the mutant were the same as those of the wild-type lines except for the stay green trait. The leaf chlorophyll concentration of the mutant was similar to that of the wild-type before heading, but decreased steeply in the wild-type during grain filling, while very slowly in the mutant. However, no difference in photosynthetic activity was observed between the stay green mutant and the yellowing wild-type leaves, indicating that senescence is proceeding normally in the mutant leaves and that the mutation affects the rate of chlorophyll degradation during the leaf senescence. Using phenotypic and molecular markers, we mapped the sgr(t) locus to the long arm of chromosome 9 between RFLP markers RG662 and C985 at 1.8- and 2.1-cM intervals, respectively.

Effects of risperidone on information processing and attention in first-episode schizophrenia.

Risperidone appears to have a beneficial effect in several areas of cognitive function in schizophrenic patients. In previous studies, however, the clinical characteristics of the subjects differed between studies, and were heterogeneous even in single study. Most of the subjects were previously exposed to different kinds of neuroleptics and some of them were treatment-resistant. The aim of this study is to evaluate the effect of risperidone on attention and information processing in a homogeneous subgroup of schizophrenic patients, i.e. drug-naïve first-episode inpatients. In the patient group (n=17), cognitive tests and clinical assessments were performed before and after 8 weeks of risperidone treatment. The same cognitive tests were administered to the control group (n=24). The delay between test and retest was 8 weeks. Before treatment, the patient group performed significantly worse than control group on the tests measuring continuous attention, vigilance, and the speed of information processing. After treatment (the average dose of risperidone was 7.3mg/day), in spite of significant improvement of the clinical symptoms, the patients did not show any significant improvement or worsening in most of the items of these tests. The control group did not show any practice effect. These results suggest that first-episode schizophrenic patients have deficits in sustained attention and vigilance to visual stimuli, as well as the speed of information processing to visual and auditory stimuli, and these deficits are unrelated to clinical symptoms and remain stable during the early phase of treatment. This study did not receive pharmaceutical company financial support.

Structure-reactivity relationships in the pyridinolysis of N-methyl-N-arylcarbamoyl chlorides in dimethyl sulfoxide.

Nucleophilic substitution reactions of N-methyl-N-arylcarbamoyl chlorides (YC(6)H(4)N(CH(3))COCl) with pyridines (XC(5)H(4)N) have been investigated in dimethyl sulfoxide at 45.0 degrees C. A striking trend in the selectivity parameters is that they are constant within experimental errors, rho(X) = -2.25 +/- 0.03, beta(X) = 0.42 +/- 0.01, and rho(Y) = 1.10 +/- 0.06, with changing reactivities of the electrophiles (deltasigma(Y)) and nucleophiles (deltasigma(X)), respectively, and this leads to a vanishingly small cross-interaction constant, rho(XY) approximately equals beta(XY) approximately equals 0. The rate data can be expressed in the Ritchie N(+) type equation. Based on this and other results, the mechanism of nucleophile (pyridine) addition to the resonance- stabilized carbocation is proposed. It has been shown from the definition of beta(XY) (and rho(XY)) together with the Marcus equation that the high intrinsic barrier, DeltaG(0), in the intrinsic-barrier controlled reaction series is a prerequisite for such reactions in which the cross-interaction vanishes and the N(+) relationship holds.

TGF-betas synthesized by RPE cells have autocrine activity on mesenchymal transformation and cell proliferation.

The present study investigated the effects of transforming growth factor (TGF)-beta on retinal pigment epithelial (RPE) transformation in a simplified model and also whether or not TGF-beta exhibits similar proliferation effects on transformed RPE cells that it has on primary RPE cells. Furthermore, we examined the cell proliferation effects of RPE-conditioned medium (CM). A vertical wound measuring 2 mm in diameter was made on primary RPE monolayers. The expression of alpha-smooth muscle actin (SMA) by the cells located at the wound edges was observed using a confocal microscope under immunofluorescent staining. Cell proliferation was measured by incorporating 3H-thymidine into DNA. The presence of alpha-SMA was observed in the cells within the wound after treatment with TGF-beta2, while negative expression was observed in control cells. TGF-betas inhibited the proliferation of the primary cultures of RPE cells in a dose-dependent manner, but the spindle-shaped late-passaged RPE cells were not inhibited by these growth factors. The medium conditioned by RPE cells stimulated the proliferation of subconjunctival fibroblasts and inhibited the proliferation of primary RPE cells, in a manner similar to TGF-beta. These findings demonstrate that TGF-beta-stimulated RPE cells may evoke proliferative vitreoretinopathy through mesenchymal transformation and cell proliferation.

Translimbal approach for intravitreal injection in endophthalmitis after phacoemulsification.

We describe a corneal limbal technique of intravitreal injection for use in cases in which it is difficult to confirm the position of the needle. Using this translimbal approach, the needle's position is easily identified and the intravitreal injection can be given using topical anesthesia. This technique is an option in eyes with a cloudy cornea or a large iridectomy.

Control of mitochondrial redox balance and cellular defense against oxidative damage by mitochondrial NADP+-dependent isocitrate dehydrogenase.

Mitochondria are the major organelles that produce reactive oxygen species (ROS) and the main target of ROS-induced damage as observed in various pathological states including aging. Production of NADPH required for the regeneration of glutathione in the mitochondria is critical for scavenging mitochondrial ROS through glutathione reductase and peroxidase systems. We investigated the role of mitochondrial NADP(+)-dependent isocitrate dehydrogenase (IDPm) in controlling the mitochondrial redox balance and subsequent cellular defense against oxidative damage. We demonstrate in this report that IDPm is induced by ROS and that decreased expression of IDPm markedly elevates the ROS generation, DNA fragmentation, lipid peroxidation, and concurrent mitochondrial damage with a significant reduction in ATP level. Conversely, overproduction of IDPm protein efficiently protected the cells from ROS-induced damage. The protective role of IDPm against oxidative damage may be attributed to increased levels of a reducing equivalent, NADPH, needed for regeneration of glutathione in the mitochondria. Our results strongly indicate that IDPm is a major NADPH producer in the mitochondria and thus plays a key role in cellular defense against oxidative stress-induced damage.

Scleral fixation technique using 2 corneal tunnels for a dislocated intraocular lens.

Several techniques are used to reposition dislocated intraocular lenses (IOLs). Most place a suture loop around the end of the haptic. However, in cases of a dislocated capsular bag containing the IOL, a dislocated IOL with a large haptic, or a miotic pupil, it is not easy to see the haptic ends to place the suture loop. We describe a scleral fixation technique that uses 2 corneal tunnels. A double-armed 10-0 polypropylene suture loop can be introduced through 1 corneal tunnel and placed around any accessible part of the haptic with the help of a bent 26 gauge needle. This modified technique is an easy and effective way to reposition the IOL.