Vascular endothelial growth factor (VEGF) plays a pivotal role in pathologic ocular neovascularization and vascular leakage via activation of VEGF receptor 2 (VEGFR2). This study was undertaken to evaluate the therapeutic mechanisms and effects of the tetrapeptide Arg-Leu-Tyr-Glu (RLYE), a VEGFR2 inhibitor, in the development of vascular permeability and choroidal neovascularization (CNV). In cultured human retinal microvascular endothelial cells (HRMECs), treatment with RLYE blocked VEGF-A-induced phosphorylation of VEGFR2, Akt, ERK, and endothelial nitric oxide synthase (eNOS), leading to suppression of VEGF-A-mediated hyper-production of NO. Treatment with RLYE also inhibited VEGF-A-stimulated angiogenic processes (migration, proliferation, and tube formation) and the hyperpermeability of HRMECs, in addition to attenuating VEGF-A-induced angiogenesis and vascular permeability in mice. The anti-vascular permeability activity of RLYE was correlated with enhanced stability and positioning of the junction proteins VE-cadherin, β-catenin, claudin-5, and ZO-1, critical components of the cortical actin ring structure and retinal endothelial barrier, at the boundary between HRMECs stimulated with VEGF-A. Furthermore, intravitreally injected RLYE bound to retinal microvascular endothelium and inhibited laser-induced CNV in mice. These findings suggest that RLYE has potential as a therapeutic drug for the treatment of CNV by preventing VEGFR2-mediated vascular leakage and angiogenesis.
Actins ; Animals ; Capillary Permeability ; Choroid ; Choroidal Neovascularization ; Claudin-5 ; Endothelial Cells ; Endothelium ; Humans ; Macular Degeneration ; Mice ; Nitric Oxide Synthase Type III ; Permeability ; Phosphorylation ; Receptors, Vascular Endothelial Growth Factor ; Retinaldehyde ; Vascular Endothelial Growth Factor A

STUDY DESIGN: Retrospective radiographic study. OBJECTIVES: To evaluate the characteristics of concurrent degenerative cervical and lumbar spondylolisthesis. SUMMARY OF LITERATURE REVIEW: Concurrent degenerative cervical and lumbar spondylotic diseases have been reported. Given that severe spondylosis can result in spondylolisthesis, one might expect that concurrent spondylolisthesis of the cervical and lumbar spines might also be prevalent. However, the incidence of spondylolistheses in the lumbar and cervical spines might differ due to anatomical differences between the 2 areas. Nonetheless, there is minimal information in the literature concerning the incidence of concurrent cervical and lumbar spondylolisthesis. MATERIAL AND METHODS: We evaluated standing cervical and lumbar lateral radiographs of 2510 patients with spondylosis. Concurrence, age group, gender, and direction of spondylolisthesis were evaluated. Lumbar spondylolisthesis was defined as at least Meyerding grade I and degenerative cervical spondylolisthesis was defined as over 2 mm of displacement on standing lateral radiographs. RESULTS: Lumbar spondylolisthesis was found in 125 patients (5.0%) and cervical spondylolisthesis was found in 193 patients (7.7%). Seventeen patients had both degenerative cervical and lumbar spondylolistheses (0.7%). Lumbar spondylolisthesis is a risk factor for co-existing cervical spondylolisthesis. Lumbar spondylolisthesis was more common in females than males, independent of advancing age. In contrast, degenerative cervical spondylolisthesis was more common in older patients, independent of gender. Anterolisthesis was more common in the lumbar spine. Retrolisthesis was more common in the cervical spine. CONCLUSIONS: There was a higher prevalence of degenerative cervical spondylolisthesis in patients with degenerative lumbar spondylolisthesis.
Cervical Vertebrae ; Female ; Humans ; Incidence ; Lumbar Vertebrae ; Male ; Prevalence ; Retrospective Studies ; Risk Factors ; Spine ; Spondylolisthesis ; Spondylosis

OBJECTIVES: To evaluate the characteristics of concurrent degenerative cervical and lumbar spondylolisthesis.SUMMARY OF LITERATURE REVIEW: Concurrent degenerative cervical and lumbar spondylotic diseases have been reported. Given that severe spondylosis can result in spondylolisthesis, one might expect that concurrent spondylolisthesis of the cervical and lumbar spines might also be prevalent. However, the incidence of spondylolistheses in the lumbar and cervical spines might differ due to anatomical differences between the 2 areas. Nonetheless, there is minimal information in the literature concerning the incidence of concurrent cervical and lumbar spondylolisthesis.MATERIAL AND METHODS: We evaluated standing cervical and lumbar lateral radiographs of 2510 patients with spondylosis. Concurrence, age group, gender, and direction of spondylolisthesis were evaluated. Lumbar spondylolisthesis was defined as at least Meyerding grade I and degenerative cervical spondylolisthesis was defined as over 2 mm of displacement on standing lateral radiographs. RESULTS: Lumbar spondylolisthesis was found in 125 patients (5.0%) and cervical spondylolisthesis was found in 193 patients (7.7%). Seventeen patients had both degenerative cervical and lumbar spondylolistheses (0.7%). Lumbar spondylolisthesis is a risk factor for co-existing cervical spondylolisthesis. Lumbar spondylolisthesis was more common in females than males, independent of advancing age. In contrast, degenerative cervical spondylolisthesis was more common in older patients, independent of gender. Anterolisthesis was more common in the lumbar spine. Retrolisthesis was more common in the cervical spine. CONCLUSIONS There was a higher prevalence of degenerative cervical spondylolisthesis in patients with degenerative lumbar spondylolisthesis.

Heme oxygenase-1-derived carbon monoxide prevents inflammatory vascular disorders. To date, there is no clear evidence that HO-1/CO prevents endothelial dysfunction associated with the downregulation of endothelial NO synthesis in human endothelial cells stimulated with TNF-α. Here, we found that the CO-releasing compound CORM-2 prevented TNF-α-mediated decreases in eNOS expression and NO/cGMP production, without affecting eNOS promoter activity, by maintaining the functional activity of the eNOS mRNA 3′-untranslated region. By contrast, CORM-2 inhibited MIR155HG expression and miR-155-5p biogenesis in TNF-α-stimulated endothelial cells, resulting in recovery of the 3′-UTR activity of eNOS mRNA, a target of miR-155-5p. The beneficial effect of CORM-2 was blocked by an NF-κB inhibitor, a miR-155-5p mimic, a HO-1 inhibitor and siRNA against HO-1, indicating that CO rescues TNF-α-induced eNOS downregulation through NF-κB-responsive miR-155-5p expression via HO-1 induction; similar protective effects of ectopic HO-1 expression and bilirubin were observed in endothelial cells treated with TNF-α. Moreover, heme degradation products, except iron and N-acetylcysteine prevented H₂O₂-mediated miR-155-5p biogenesis and eNOS downregulation. These data demonstrate that CO prevents TNF-α-mediated eNOS downregulation by inhibiting redox-sensitive miR-155-5p biogenesis through a positive forward circuit between CO and HO-1 induction. This circuit may play an important preventive role in inflammatory endothelial dysfunction associated with human vascular diseases.
Acetylcysteine ; Bilirubin ; Carbon Monoxide* ; Carbon* ; Down-Regulation* ; Endothelial Cells ; Heme ; Humans ; Iron ; RNA, Messenger ; RNA, Small Interfering ; Vascular Diseases

A 35-year-old woman visited the emergency department for a pedestrian traffic accident. Severe tenderness was noted at the posterior sacrum area, without open wound or initial neurologic deficit. Fracture of the left sacral ala extended to the S1 foramen, anterior acetabulum, and pubic ramus. Two weeks after the injury, she presented aggravating radiculopathy with the weakness of the left great toe plantar flexion. The S1 nerve root was compressed by the fracture fragments in the left S1 foramen. Decompressive S1 foraminotomy was performed. The postoperative follow-up computed tomography scan showed successful decompression of the encroachment, and the patient recovered well from the radiculopathy with motor weakness. She was able to resume her daily routine activity. We suggest that early decompressive sacral foraminotomy could be a useful additional procedure in selective sacral zone II fractures that are accompanied by radiculopathy with a motor deficit.
Accidents, Traffic ; Acetabulum ; Adult ; Decompression ; Emergency Service, Hospital ; Female ; Follow-Up Studies ; Foraminotomy* ; Humans ; Neurologic Manifestations ; Radiculopathy ; Sacrum ; Toes ; Wounds and Injuries

A 35-year-old woman visited the emergency department for a pedestrian traffic accident. Severe tenderness was noted at the posterior sacrum area, without open wound or initial neurologic deficit. Fracture of the left sacral ala extended to the S1 foramen, anterior acetabulum, and pubic ramus. Two weeks after the injury, she presented aggravating radiculopathy with the weakness of the left great toe plantar flexion. The S1 nerve root was compressed by the fracture fragments in the left S1 foramen. Decompressive S1 foraminotomy was performed. The postoperative follow-up computed tomography scan showed successful decompression of the encroachment, and the patient recovered well from the radiculopathy with motor weakness. She was able to resume her daily routine activity. We suggest that early decompressive sacral foraminotomy could be a useful additional procedure in selective sacral zone II fractures that are accompanied by radiculopathy with a motor deficit.
Accidents, Traffic ; Acetabulum ; Adult ; Decompression ; Emergency Service, Hospital ; Female ; Follow-Up Studies ; Foraminotomy* ; Humans ; Neurologic Manifestations ; Radiculopathy ; Sacrum ; Toes ; Wounds and Injuries

Concentrations of heavy metals exceed safety thresholds in the soil near Janghang Copper Refinery, a smelter in Korea that operated from 1936 to 1989. This study was conducted to evaluate the level of exposure to toxic metals and the potential effect on health in people living near the smelter. The study included 572 adults living within 4 km of the smelter and compared them with 413 controls group of people living similar lifestyles in a rural area approximately 15 km from the smelter. Urinary arsenic (As) level did not decrease according to the distance from the smelter, regardless of gender and working history in smelters and mines. However, in subjects who had no occupational exposure to toxic metals, blood lead (Pb) and cadmium (Cd) and urinary Cd decreased according to the distance from the smelter, both in men and women. Additionally, the distance from the smelter was a determinant factor for a decrease of As, Pb, and Cd in multiple regression models, respectively. On the other hands, urinary Cd was a risk factor for renal tubular dysfunction in populations living near the smelter. These results suggest that Janghang copper smelter was a main contamination source of As, Pb, and Cd, and populations living near the smelter suffered some adverse health effects as a consequence. The local population should be advised to make efforts to reduce exposure to environmental contaminants, in order to minimize potential health effects, and to pay close attention to any health problems possibly related to toxic metal exposure.
Acetylglucosaminidase/urine ; Adult ; Aged ; Arsenic/*urine ; Bone Density ; Cadmium/*blood ; Case-Control Studies ; Chemical Industry ; Creatinine/urine ; *Environmental Exposure ; Environmental Pollutants/*analysis/blood/urine ; Female ; Humans ; Lead/*blood ; Male ; Middle Aged ; Regression Analysis ; Republic of Korea ; Spectrophotometry, Atomic

PURPOSE: Limited traction has been an obstacle in the advancement of single incision laparoscopic cholecystectomy (SILC). Adequate retraction is necessary for safe performance of a cholecystectomy. In this study, we introduce our method for securing CVS for prevention of bile duct injury during performance of SILC and evaluated the effectiveness of the snake liver retractor. METHODS: A total of 148 patients who underwent needlescopic assisted SILC (nSILC) from February 2011 to February 2012 at Uijeongbu St. Mary's Hospital, Uijeongbu, Korea were analyzed. Patients were categorized into two groups: G roup I consisted of patients who underwent nSILC without use of a snake liver retractor from February 2011 to October 2011 (n=51) and group II consisted of patients who underwent nSILC using a snake liver retractor from October 2011 to February 2012 (n=97). Patient characteristics and operative outcomes were compared between groups in order to evaluate the effectiveness of use of a snake liver retractor during performance of SILC. RESULTS: There were no differences in age, sex, BMI, and history of previous abdominal surgery. However, more difficult surgeries for acute cholecystitis were performed in group II. Nevertheless, no differences in operative outcomes, such as operative time, rate of bile spillage, open conversion rate, intraoperative complication, and postoperative hospital stay were observed between groups. In addition, CVS identification time was rather shorter in group II, compared with group I. CONCLUSION: Results of this study showed that nSILC using a snake liver retractor can allow for achievement of CVS safely and for expansion of indication for SILC through improvement of exposure and obtaining adequate traction.
Achievement ; Bile ; Bile Ducts ; Cholecystectomy ; Cholecystectomy, Laparoscopic ; Cholecystitis, Acute ; Humans ; Intraoperative Complications ; Korea ; Length of Stay ; Liver ; Operative Time ; Snakes ; Traction

Nitric oxide (NO) produced by endothelial NO synthase (eNOS) plays an important role in vascular functions, including vasorelaxation. We here investigated the pharmacological effect of the natural product syringaresinol on vascular relaxation and eNOS-mediated NO production as well as its underlying biochemical mechanism in endothelial cells. Treatment of aortic rings from wild type, but not eNOS-/- mice, with syringaresinol induced endothelium-dependent relaxation, which was abolished by addition of the NOS inhibitor NG-monomethyl-L-arginine. Treatment of human endothelial cells and mouse aortic rings with syringaresinol increased NO production, which was correlated with eNOS phosphorylation via the activation of Akt and AMP kinase (AMPK) as well as elevation of intracellular Ca2+ levels. A phospholipase C (PLC) inhibitor blocked the increases in intracellular Ca2+ levels, AMPK-dependent eNOS phosphorylation, and NO production, but not Akt activation, in syringaresinol-treated endothelial cells. Syringaresinol-induced AMPK activation was inhibited by co-treatment with PLC inhibitor, Ca2+ chelator, calmodulin antagonist, and CaMKKbeta siRNA. This compound also increased eNOS dimerization, which was inhibited by a PLC inhibitor and a Ca2+-chelator. The chemicals that inhibit eNOS phosphorylation and dimerization attenuated vasorelaxation and cGMP production. These results suggest that syringaresinol induces vasorelaxation by enhancing NO production in endothelial cells via two distinct mechanisms, phosphatidylinositol 3-kinase/Akt- and PLC/Ca2+/CaMKKbeta-dependent eNOS phosphorylation and Ca2+-dependent eNOS dimerization.
Animals ; Aorta/*drug effects/physiology ; Enzyme Activation/drug effects ; Furans/*pharmacology ; Gene Deletion ; Human Umbilical Vein Endothelial Cells/drug effects/metabolism ; Humans ; Lignans/*pharmacology ; Mice ; Mice, Inbred C57BL ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type III/genetics/*metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphoinositide Phospholipase C/metabolism ; Phosphorylation/drug effects ; Protein Multimerization/*drug effects ; Proto-Oncogene Proteins c-akt/metabolism ; Vasodilation/*drug effects

This study was designed to investigate the effects of the prenylated flavonoid kurarinone on TNF-related apoptosis inducing ligand (TRAIL)-induced apoptosis and its underlying mechanism. A low dose of kurarinone had no significant effect on apoptosis, but this compound markedly promoted tumor cell death through elevation of Bid cleavage, cytochrome c release and caspase activation in HeLa cells treated with TRAIL. Caspase inhibitors inhibited kurarinone-mediated cell death, which indicates that the cytotoxic effect of this compound is mediated by caspase-dependent apoptosis. The cytotoxic effect of kurarinone was not associated with expression levels of Bcl-2 and IAP family proteins, such as Bcl-2, Bcl-xL, Bid, Bad, Bax, XIAP, cIAP-1 and cIAP-2. In addition, this compound did not regulate the death-inducing receptors DR4 and DR5. On the other hand, kurarinone significantly inhibited TRAIL-induced IKK activation, IkappaB degradation and nuclear translocation of NF-kappaB, as well as effectively suppressed cellular FLICE-inhibitory protein long form (cFLIPL) expression. The synergistic effects of kurarinone on TRAIL-induced apoptosis were mimicked when kurarinone was replaced by the NF-kappaB inhibitor withaferin A or following siRNA-mediated knockdown of cFLIPL. Moreover, cFLIP overexpression effectively antagonized kurarinone-mediated TRAIL sensitization. These data suggest that kurarinone sensitizes TRAIL-induced tumor cell apoptosis via suppression of NF-kappaB-dependent cFLIP expression, indicating that this compound can be used as an anti-tumor agent in combination with TRAIL.
Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; CASP8 and FADD-Like Apoptosis Regulating Protein/*genetics/metabolism ; Caspase 3/metabolism ; Caspase 8/metabolism ; Drug Synergism ; Enzyme Activation/drug effects ; Flavonoids/*pharmacology ; Gene Expression/drug effects ; Gene Knockdown Techniques ; HeLa Cells ; Humans ; NF-kappa B/antagonists & inhibitors/*metabolism ; Protein Transport/drug effects ; RNA, Small Interfering/genetics ; Signal Transduction ; TNF-Related Apoptosis-Inducing Ligand/*physiology ; Up-Regulation/drug effects