Effects of Extracellular Calcium Concentration on Hepatic Ischemia-Reperfusion Injury in a Rat Model.

OBJECTIVES: Hypocalcemia is frequently identified during liver transplant. However, supplementation of extracellular calcium could induce increased intracellular calcium concentration, as a potential factor for injury to the liver graft. We evaluated the effects of regulating extracellular calcium concentrations on hepatic ischemia-reperfusion injury. MATERIALS AND METHODS: We randomly divided 24 Sprague-Dawley rats into 3 groups: group C received normal saline (n = 8), group L received citrate to induce hypocalcemia (n = 8), and group L-Co received citrate followed by calcium gluconate to ameliorate hypocalcemia (n = 8). Liver enzyme levels and extracellular calcium were measured before surgery, 1 hour after ischemia, and 2 hours after reperfusion. The primary outcome was liver enzyme levels measured 2 hours after reperfusion. In addition, we evaluated intracellular calcium levels, lactate dehydrogenase activity, and histopathological results in liver tissue. RESULTS: Three groups demonstrated significant differences in extracellular calcium concentrations, but intracellular calcium concentrations in liver tissue were not significantly different. Group L showed significantly lower mean arterial pressure than other groups at 1 hour after ischemia (93.6 ± 20.8 vs 69.4 ± 14.2 vs 86.6 ± 10.4 mmHg; P = .02, for group C vs L vs L-Co, respectively). At 2 hours after reperfusion, group L showed significantly higher liver enzymes than other groups (aspartate aminotransferase 443.0 ± 353.2 vs 952.3 ± 94.8 vs 502.4 ± 327.3 U/L, P = .01; and alanine aminotransferase 407.9 ± 406.5 vs 860.6 ± 210.9 vs 333.9 ± 304.2 U/L, P = .02; for group C vs L vs L-Co, respectively). However, no significant difference was shown in lactate dehydrogenase and histological liver injury grade. CONCLUSIONS: Administering calcium to rats with hypocalcemia did not increase intracellular calcium accumulation but instead resulted in less hepatic injury compared with rats with low extracellular calcium concentrations in this rat model study.

Evaluation of Factors Affecting Illumination Intensity in Lightwand Endotracheal Intubation.

BACKGROUND/AIM: A lightwand is a stylet with a light bulb at its tip that can be used to guide intubation by confirming the illumination through the anterior neck. We aimed to determine the factors affecting the illumination intensity during lightwand endotracheal intubation. PATIENTS AND METHODS: We retrospectively collected data from 180 patients who underwent lightwand endotracheal intubation. We recorded illumination intensity on a 5-point scale. The patients were categorized into weak (score <3) and bright (score ≥3) groups based on the illumination intensity scale score. RESULTS: A total of 176 patients were analyzed, of whom 125 (71.1%) were enrolled in the bright group, and 51 (29.0%) were enrolled in the weak group. Multivariable logistic regression analysis revealed that an increased body mass index (BMI) and mask ventilation grade were associated with light intensity. For mask ventilation, moderate vs. easy (p=0.010) and difficult vs. easy (p=0.008) were associated with the weak group. Receiver operating characteristic curve analysis showed that BMI ≥24.6 kg/m2 was correlated with the weak group. CONCLUSION: BMI ≥24.6 kg/m2 or mask ventilation grade above moderate indicates increased odds of weak illumination intensity in lightwand intubation. Pre-intubation examination of these factors helps increase the chances of successful intubation.

Inhibition of EZH2 exerts antitumorigenic effects in renal cell carcinoma via LATS1.

The most common type of kidney cancer in adults is renal cell carcinoma (RCC), which accounts for approximately 90% of cases. RCC is a variant disease with numerous subtypes; the most common subtype is clear cell RCC (ccRCC, 75%), followed by papillary RCC (pRCC, 10%) and chromophobe RCC (chRCC, 5%). To identify a genetic target for all subtypes, we analyzed The Cancer Genome Atlas (TCGA) databases of ccRCC, pRCC, and chromophobe RCC. Enhancer of zeste homolog 2 (EZH2), which encodes a methyltransferase, was observed to be significantly upregulated in tumors. The EZH2 inhibitor tazemetostat induced anticancer effects in RCC cells. TCGA analysis revealed that large tumor suppressor kinase 1 (LATS1), a key tumor suppressor of the Hippo pathway, was significantly downregulated in tumors; the expression of LATS1 was increased by tazemetostat. Through additional experiments, we confirmed that LATS1 plays a crucial role in EZH2 inhibition and has a negative association with EZH2. Therefore, we suggest that epigenetic control could be a novel therapeutic strategy for three subtypes of RCC.

Effect of α1D-adrenoceptor blocker for the reduction of ureteral contractions.

PURPOSE: Urolithiasis is a common urinary tract disease with growing prevalence. Alpha1-adrenoceptors (α1-ARs) are abundant in ureteral smooth muscle, distributed with different α1-AR subtypes. α1D-AR is the most widely distributed in the ureter. However, the effect of α1D-AR blockade on ureteric contraction remains unknown. MATERIALS AND METHODS: We dissected smooth muscle tissues (3 mm×3 mm) from the rat bladder and human ureter, tied silk strips on both tissue ends, and measured contraction in an organ bath chamber. Contraction activity in ureteral smooth muscle cells (USMCs) was immunocytochemically examined using primary rat and human USMC cultures. RESULTS: Using the organ bath system, we determined the inhibitory effects of silodosin, tamsulosin, and naftopidil. Naftopidil significantly decreased contractility of rat bladder tissue; similar results were observed in human ureteral tissue. To confirm ex vivo experimental results in vitro , we examined the phosphorylation of myosin light chain (MLC), a marker of contractility, in a primary human USMC culture. The examined drugs decreased phospho-MLC levels in human USMCs; however, naftopidil profoundly increased MLC dephosphorylation. CONCLUSIONS: We studied the effects of naftopidil, an α1D-AR inhibitor, on the ureter. Compared with alpha-blockers, naftopidil significantly relaxed ureteral smooth muscle. Therefore, naftopidil could be an effective therapy for patients with ureteral stones.

Therapeutic Efficacy of YM155 to Regulate an Epigenetic Enzyme in Major Subtypes of RCC.

Renal cell carcinoma (RCC) is the most common type of kidney cancer and includes more than 10 subtypes. Compared to the intensively investigated clear cell RCC (ccRCC), the underlying mechanisms and treatment options of other subtypes, including papillary RCC (pRCC) and chromogenic RCC (chRCC), are limited. In this study, we analyzed the public databases for ccRCC, pRCC, and chRCC and found that BIRC5 was commonly overexpressed in a large cohort of pRCC and chRCC patients as well as ccRCC and was closely related to the progression of RCCs. We investigated the potential of BIRC5 as a therapeutic target for these three types of RCCs. Loss and gain of function studies showed the critical role of BIRC5 in cancer growth. YM155, a BIRC5 inhibitor, induced a potent tumor-suppressive effect in the three types of RCC cells and xenograft models. To determine the mechanism underlying the anti-tumor effects of YM155, we examined epigenetic modifications in the BIRC5 promoter and found that histone H3 lysine 27 acetylation (H3K27Ac) was highly enriched on the promoter region of BIRC5. Chromatin-immunoprecipitation analysis revealed that H3K27Ac enrichment was significantly decreased by YM155. Immunohistochemistry of xenografted tissue showed that overexpression of BIRC5 plays an important role in malignancy in RCC. Furthermore, high expression of P300 was significantly associated with the progression of RCC. Our findings demonstrate the P300-H3K27Ac-BIRC5 cascade in three types of RCC and provide a therapeutic path for future research on RCC.

Ginsenoside Rh2 sensitizes the anti-cancer effects of sunitinib by inducing cell cycle arrest in renal cell carcinoma.

Sunitinib, a VEGF blockade, is used to treat clear cell renal cell carcinoma (ccRCC). However, the anti-cancer treatment effects of sunitinib do not last long in ccRCC patients. Ginsenoside, a natural medicine extracted from ginseng, has been studied in cancer treatment and shown to have anti-tumor effects and low toxicity. We assessed cell viability and cell cycle analysis in ccRCC cell lines after treatment with ginsenoside and sunitinib. DNA damage was evaluated by measuring 8-OHdG levels and comet assay. ROS levels, reflecting the cause of oxidative stress, were also measured. Ginsenoside significantly enhanced the inhibition of cell viability by sunitinib, a result that was also confirmed in the xenograft model. In cell cycle analysis, combination treatment of ginsenoside and sunitinib enhanced G2M arrest in comparison with single-treatment groups. In addition, DNA damage was increased by ginsenoside and sunitinib according to the comet assay, and the level of 8-OHdG, which reflects oxidative DNA damage, also increased. We verified that ginsenoside enhances the efficacy of sunitinib to inhibit the proliferation of ccRCC cells via induction of oxidative DNA damage. The combination therapy of sunitinib and ginsenoside suggested the possibility of effectively treating ccRCC patients.

Synergic Effect of Metformin and Everolimus on Mitochondrial Dynamics of Renal Cell Carcinoma.

Renal cell carcinoma (RCC) frequently recurs or metastasizes after surgical resection. Everolimus, an mTOR inhibitor, is used as a second-line treatment, but the response of RCC to everolimus is insufficient. Metformin is an antidiabetic drug; recent reports have indicated its anti-cancer effects in various cancers, and it is known to have synergistic effects with other drugs. We investigated the possibility of coadministering everolimus and metformin as an effective treatment for RCC. RCC cells treated with a combination of the two drugs showed significantly inhibited cell viability, cell migration, and invasion, and increased apoptosis compared to those treated with each drug alone. An anti-cancer synergistic effect was also confirmed in the xenograft model. Transcriptome analysis for identifying the underlying mechanism of the combined treatment showed the downregulation of mitochondrial fusion genes and upregulation of mitochondrial fission genes by the combination treatment. Changes in mitochondrial dynamics following the combination treatment were observed using LysoTracker, LysoSensor, and JC-1 staining. In conclusion, the combination of everolimus and metformin inhibited RCC growth by disrupting mitochondrial dynamics. Therefore, we suggest that a treatment combining metformin and everolimus disrupts mitochondrial dynamics in RCC, and may be a novel strategy for RCC treatment.

Lenticular fungal infection caused by Aspergillus in a patient with traumatic corneal laceration: a case report.

BACKGROUND: To report a case of lenticular infection caused by Aspergillus, which was diagnosed 13 weeks after traumatic corneal laceration. CASE PRESENTATION: A 60-year-old woman presented with traumatic corneal laceration including anterior lens capsule rupture and traumatic cataract after being hit with a chestnut in the right eye. There were multiple injuries due to tiny thorns of the chestnut, including the conjunctiva, sclera, cornea, and anterior lens capsule. But no visible foreign body was detected by slit-lamp examination. Topical corticosteroid was prescribed to resolve the conjunctival inflammation induced by the thorns of chestnut, which could have caused persistent irritation. As conjunctival injection and edema being decreased during outpatient clinical follow-up, embedded conjunctival foreign body was detected and surgically removed (1st surgery). Approximately 10 weeks after the trauma, severe inflammation of the anterior segment accompanied with hypopyon developed suddenly and at the same time embedded scleral foreign body was revealed. After removal of scleral foreign body (2nd surgery), unspecified mold species was cultured from the scleral foreign body in SDA (Sabouraud dextrose agar) plate. Suspicious corneal foreign body was removed as 3rd surgery and phacoemulsification of traumatic cataract was planned as 4th surgery. Aspergillus was finally detected from removed anterior capsule and fibrotic membrane during the operation. Fungal infection resolved successfully after administration of topical (1% voriconazole and 5% natamycin) and systemic (fluconazole) antifungal agents and phacoemulsification of traumatic cataract. CONCLUSION: Chestnut thorns can damage multiple ocular tissues simultaneously. Lens capsular rupture could result in fungal inoculation and lead to delayed lenticular fungal infection with complicated cataract formation. In cases of ocular trauma due to organic substances such as thorns and branches, the possibility of fungal infection should be considered.

Assessment of the trueness and tissue surface adaptation of CAD-CAM maxillary denture bases manufactured using digital light processing.

STATEMENT OF PROBLEM: Limited information is available evaluating the trueness and tissue surface adaptation of computer-aided design and computer-aided manufacturing (CAD-CAM) maxillary denture bases fabricated using digital light processing (DLP). PURPOSE: The purpose of this in vitro study was to evaluate the trueness of DLP-fabricated denture bases and to compare the tissue surface adaptation of DLP with milling (MIL) and pack and press (PAP). MATERIAL AND METHODS: The maxillary denture bases were virtually designed on the reference cast and were fabricated using DLP and MIL. Their intaglio surfaces were scanned and superimposed on the reference computer-aided design denture base to evaluate the trueness. A total of 20 denture bases (10 per technique) were also fabricated on the duplicated master casts using DLP and MIL. Ten denture bases were additionally made using PAP. The intaglio surfaces of the dentures were scanned and superimposed on the corresponding casts to compare the degree of tissue surface adaptation among the 3 techniques. The Mann-Whitney test and Kruskal-Wallis ANOVA were used for statistical analyses (α=.05). RESULTS: The trueness of the DLP denture base was significantly better than that of the MIL denture base (P<.001). Statistically significant differences were detected with respect to tissue surface adaptation of the denture base among the groups (P<.001). The DLP denture base showed the best denture base fit among the 3 techniques with a small interquartile range. CONCLUSIONS: Within the limitations of this in vitro study, the DLP maxillary denture base showed better trueness and tissue surface adaptation of ≤100 µm of the 3-dimensional surface deviation than the MIL and PAP denture bases.

Evaluation of the trueness and tissue surface adaptation of CAD-CAM mandibular denture bases manufactured using digital light processing.

STATEMENT OF PROBLEM: Studies assessing the trueness and tissue surface adaptation of computer-aided design and computer-aided manufacturing (CAD-CAM) mandibular complete denture bases fabricated using digital light processing (DLP) are lacking. PURPOSE: The purpose of this in vitro study was to evaluate the trueness of DLP-generated denture bases and to compare the tissue surface adaptation of DLP with milling and pack and press. MATERIAL AND METHODS: The mandibular denture bases were virtually designed on a reference cast and were fabricated using DLP. Their intaglio surfaces were scanned and superimposed on the reference CAD denture base to evaluate the trueness. The reference cast was duplicated to create 10 identical master casts that were scanned to design 10 virtual denture bases. Twenty denture bases were fabricated with DLP and milling (10 specimens per technique). In addition, 10 denture bases were fabricated with the pack and press technique. The intaglio surfaces of the denture bases were scanned and superimposed on the corresponding master casts to compare tissue surface adaptation among the 3 techniques. The Mann-Whitney test and Kruskal-Wallis analysis of variance (α=.05) were used for statistical analyses. RESULTS: For trueness, the milled denture base was better than the DLP denture base (P<.001). However, no statistically significant difference was detected with respect to tissue surface adaptation of the denture base, regardless of the fabrication technique (P>.05). The DLP denture base showed comparable tissue surface adaptation with the milled base, one with a small interquartile range. CONCLUSIONS: The intaglio surfaces of DLP and milled denture bases corresponded within a 100-µm accuracy compared with the master cast. Although the DLP denture base exhibited tissue compression on the ridge crest, it showed comparable tissue adaptation to the milled denture base.

MACULAR EDEMA AFTER CATARACT SURGERY IN EYES WITH PREOPERATIVE RETINAL VEIN OCCLUSION.

PURPOSE: To evaluate the incidence of pseudophakic macular edema (PME) in eyes with a history of retinal vein occlusion before cataract surgery and to identify any associated risk factors. METHODS: The records of 21,332 eyes that underwent cataract surgery were retrospectively reviewed. Eyes that had retinal vein occlusion preoperatively with no evidence of macular pathology on optical coherence tomography at the time of surgery and no macular edema treatment at least 6 months before surgery were included. Eyes with diabetes or diabetic retinopathy, those with a history of previous intraocular surgery or with intraoperative complications, and those administered glaucoma and nonsteroidal antiinflammatory eye drops were excluded. RESULTS: Pseudophakic macular edema developed in 31 (27.4%) of 113 eyes within 3 months of cataract surgery. Mean visual acuity for eyes with PME (0.48 logarithm of the minimum angle of resolution [logMAR; 20/60 Snellen equivalent]) at 3 months after surgery was significantly worse than that for eyes without PME (0.28 logMAR; 20/38, P = 0.020). However, there was no significant difference in the visual acuity between the 2 groups 6 months after the surgery. Taking into consideration various baseline factors, a history of previous treatment of macular edema was significantly associated with an increased risk of PME (odds ratio, 11.022; 95% confidence interval, 7.258-17.712; P = 0.009). A higher number of intravitreal injections used to treat macular edema also significantly increased the risk of PME (odds ratio, 1.902; 95% confidence interval, 1.032-4.227; P = 0.031). CONCLUSION: Pseudophakic macular edema frequently developed after phacoemulsification cataract surgery in patients with a history of retinal vein occlusion. The risk of PME further increased when the patient had undergone macular edema treatment and had a higher prevalence of intravitreal injection treatment.

INTRAVITREAL AFLIBERCEPT AND RANIBIZUMAB INJECTIONS FOR TYPE 3 NEOVASCULARIZATION.

PURPOSE: To compare the effectiveness of intravitreal injection of aflibercept with ranibizumab in patients with Type 3 neovascularization. METHODS: Sixty-three treatment-naive eyes with Type 3 neovascularization (58 patients) were retrospectively analyzed. The eyes had received intravitreal aflibercept or ranibizumab injections. All patients were treated using an initial series of three monthly loading injections, followed by further injections as required. The visual and anatomical outcomes of treatment were evaluated after 12 months. RESULTS: The mean best-corrected visual acuity in the aflibercept-treated group (21 eyes), expressed as the logarithm of the minimum angle of resolution, improved from 0.71 ± 0.42 (Snellen equivalent; 20/102) to 0.54 ± 0.39 (20/69) after 12 months of treatment (P = 0.022). Similarly, in the ranibizumab-treated group (42 eyes), the best-corrected visual acuity improved from 0.68 ± 0.38 (20/95) to 0.53 ± 0.36 (20/67) (P = 0.013) at 12 months. The central foveal thickness decreased in the aflibercept-treated group from 356 ± 139 µm to 212 ± 155 µm and in the ranibizumab-treated group from 348 ± 177 µm to 208 ± 161 µm (P = 0.014 and P = 0.017, respectively). There was no significant difference between the groups about improvement in best-corrected visual acuity or decrease in central foveal thickness. However, geographic atrophy was significantly more frequent in the aflibercept-treated group, occurring in 42.9% of eyes, than in the ranibizumab-treated group (19.0% of eyes; P = 0.045). CONCLUSION: There was no difference between the aflibercept and ranibizumab treatments in terms of visual acuity improvement after 12 months in patients with Type 3 neovascularization. However, geographic atrophy developed more frequently in the aflibercept-treated group.

Polypoidal Choroidal Vasculopathy with Feeder Vessels: Characteristics, Fellow Eye Findings, and Long-term Treatment Outcomes.

PURPOSE: To evaluate the long-term outcomes of anti-vascular endothelial growth factor (VEGF) therapy for polypoidal choroidal vasculopathy (PCV) with feeder vessels and to investigate fellow-eye findings. METHODS: This retrospective observational study included 14 eyes with treatment-naïve PCV accompanied by feeder vessels that were treated with anti-VEGF monotherapy. The best-corrected visual acuity (BCVA) at baseline was compared with that at the last follow-up. The fellow-eye indocyanine green angiography findings were also analyzed. RESULTS: The mean follow-up period was 28.1 ± 19.2 months (range, 12 to 60 months). During the follow-up period, 5.9 ± 2.5 anti-VEGF injections were administered. The logarithm of the minimal angle of resolution (logMAR) BCVAs at the time of diagnosis, at 3 months, and at the last follow-up were 0.81 ± 0.49, 0.55 ± 0.44, and 0.71 ± 0.54, respectively. Although the BCVA at the last follow-up was not different from the baseline value (p=0.809), an improvement of ≥0.2 logMAR BCVA was observed in seven eyes (50.0%). In 11 eyes that underwent bilateral indocyanine green angiography at diagnosis, PCV, branching vascular networks, and late geographic hyperfluorescence were noted in two (18.2%), five (45.4%), and three (27.3%) fellow eyes, respectively. During the follow-up period, the development of polypoidal lesions in the fellow eye was observed in three patients. CONCLUSIONS: In this study, long-term improvement in BCVA was noted in 50% of the included patients who received anti-VEGF monotherapy. A relatively high incidence of pathological findings in the fellow eye and bilateral involvement suggest the need for bilateral examinations.