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Inhibition of cAMP/PKA Pathway Protects Optic Nerve Head Astrocytes against Oxidative Stress by Akt/Bax Phosphorylation-Mediated Mfn1/2 Oligomerization.
Glaucoma is characterized by a progressive optic nerve degeneration and retinal ganglion cell loss, but the underlying biological basis for the accompanying neurodegeneration is not known. Accumulating evidence indicates that structural and functional abnormalities of astrocytes within the optic nerve head (ONH) have a role in glaucomatous neurodegeneration. Here, we investigate the impact of activation of cyclic adenosine 3',5'-monophosphate (cAMP)/protein kinase A (PKA) pathway on mitochondrial dynamics of ONH astrocytes exposed to oxidative stress. ONH astrocytes showed a significant loss of astrocytic processes in the glial lamina of glaucomatous DBA/2J mice, accompanied by basement membrane thickening and collagen deposition in blood vessels and axonal degeneration. Serial block-face scanning electron microscopy data analysis demonstrated that numbers of total and branched mitochondria were significantly increased in ONH astrocytes, while mitochondrial length and volume density were significantly decreased. We found that hydrogen peroxide- (H2O2-) induced oxidative stress compromised not only mitochondrial bioenergetics by reducing the basal and maximal respiration but also balance of mitochondrial dynamics by decreasing dynamin-related protein 1 (Drp1) protein expression in rat ONH astrocytes. In contrast, elevated cAMP by dibutyryl-cAMP (dbcAMP) or isobutylmethylxanthine treatment significantly increased Drp1 protein expression in ONH astrocytes. Elevated cAMP exacerbated the impairment of mitochondrial dynamics and reduction of cell viability to oxidative stress in ONH astrocytes by decreasing optic atrophy type 1 (OPA1), and mitofusin (Mfn)1/2 protein expression. Following combined treatment with H2O2 and dbcAMP, PKA inhibition restored mitochondrial dynamics by increasing mitochondrial length and decreasing mitochondrial number, and this promoted cell viability in ONH astrocytes. Also, PKA inhibition significantly promoted Akt/Bax phosphorylation and Mfn1/2 oligomerization in ONH astrocytes. These results suggest that modulation of the cAMP/PKA signaling pathway may have therapeutic potential by activating Akt/Bax phosphorylation and promoting Mfn1/2 oligomerization in glaucomatous ONH astrocytes
Elevated intracellular cAMP exacerbates vulnerability to oxidative stress in optic nerve head astrocytes.
Glaucoma is characterized by a progressive loss of retinal ganglion cells and their axons, but the underlying biological basis for the accompanying neurodegeneration is not known. Accumulating evidence indicates that structural and functional abnormalities of astrocytes within the optic nerve head (ONH) have a role. However, whether the activation of cyclic adenosine 3',5'-monophosphate (cAMP) signaling pathway is associated with astrocyte dysfunction in the ONH remains unknown. We report here that the cAMP/protein kinase A (PKA) pathway is critical to ONH astrocyte dysfunction, leading to caspase-3 activation and cell death via the AKT/Bim/Bax signaling pathway. Furthermore, elevated intracellular cAMP exacerbates vulnerability to oxidative stress in ONH astrocytes, and this may contribute to axonal damage in glaucomatous neurodegeneration. Inhibition of intracellular cAMP/PKA signaling activation protects ONH astrocytes by increasing AKT phosphorylation against oxidative stress. These results strongly indicate that activation of cAMP/PKA pathway has an important role in astrocyte dysfunction, and suggest that modulating cAMP/PKA pathway has therapeutic potential for glaucomatous ONH degeneration
Comparison of orthopaedic manifestations of multiple epiphyseal dysplasia caused by MATN3 versus COMP mutations: a case control study
Background : Multiple epiphyseal dysplasia (MED) is a relatively common skeletal dysplasia mainly involving the epiphyses of the long bones. However, it is a genetically heterogeneous group of diseases sharing certain aspects of the radiologic phenotype. In surveys conducted in East Asia, MATN3 was the most common causative gene, followed by COMP. In this study, the authors compared clinical manifestation of MED patients caused by MATN3 and COMP gene mutations, as well as subsequent orthopaedic interventions.
Methods : Fifty nine molecularly-confirmed MED patients were subjects of this study. The MATN3 gene mutation group comprised of 37 patients (9 female, 28 male). The COMP gene mutation consisted of 22 cases (15 females, 7 males). Medical records and radiographs were reviewed, and questionnaire surveys or telephone interviews were conducted.
Results : At the first presentation, the mean age was 8.8 ± 2.8 years (mean ± standard deviation) in the MATN3 group, and 8.5 ± 3.5 years in the COMP group (p = 0.670). The height in the COMP group was significantly shorter than those in the MATN3 group (p < 0.001). Gait abnormality at the first visit (p = 0.041) and the lastest follow-up (p = 0.037) were statistically significant difference. Hip pain (p = 0.084), limitation of daily activity (p = 0.075) at the latest follow-up tended to be more frequent in the COMP group. Hip dysplasia was more common in the COMP group, having significantly larger acetabular angle (p = 0.037), smaller center-edge angle (p = 0.002), severe Stulberg classification (p < 0.001), and smaller femoral head coverage (p < 0.001).
Conclusions : Clinical manifestations of MED caused by MATN3 were milder than manifestations of the COMP mutation group. These differences in clinical manifestation and prognosis justify molecular differentiation between the two genotypes.This study was supported by a grant from the SNUH Research Fund (No. 04-2013-0640).Peer Reviewe
Comparison of orthopaedic manifestations of multiple epiphyseal dysplasia caused by MATN3 versus COMP mutations: a case control study
Background : Multiple epiphyseal dysplasia (MED) is a relatively common skeletal dysplasia mainly involving the epiphyses of the long bones. However, it is a genetically heterogeneous group of diseases sharing certain aspects of the radiologic phenotype. In surveys conducted in East Asia, MATN3 was the most common causative gene, followed by COMP. In this study, the authors compared clinical manifestation of MED patients caused by MATN3 and COMP gene mutations, as well as subsequent orthopaedic interventions.
Methods : Fifty nine molecularly-confirmed MED patients were subjects of this study. The MATN3 gene mutation group comprised of 37 patients (9 female, 28 male). The COMP gene mutation consisted of 22 cases (15 females, 7 males). Medical records and radiographs were reviewed, and questionnaire surveys or telephone interviews were conducted.
Results : At the first presentation, the mean age was 8.8 ± 2.8 years (mean ± standard deviation) in the MATN3 group, and 8.5 ± 3.5 years in the COMP group (p = 0.670). The height in the COMP group was significantly shorter than those in the MATN3 group (p < 0.001). Gait abnormality at the first visit (p = 0.041) and the lastest follow-up (p = 0.037) were statistically significant difference. Hip pain (p = 0.084), limitation of daily activity (p = 0.075) at the latest follow-up tended to be more frequent in the COMP group. Hip dysplasia was more common in the COMP group, having significantly larger acetabular angle (p = 0.037), smaller center-edge angle (p = 0.002), severe Stulberg classification (p < 0.001), and smaller femoral head coverage (p < 0.001).
Conclusions : Clinical manifestations of MED caused by MATN3 were milder than manifestations of the COMP mutation group. These differences in clinical manifestation and prognosis justify molecular differentiation between the two genotypes.This study was supported by a grant from the SNUH Research Fund (No. 04-2013-0640).Peer Reviewe
Comparison of orthopaedic manifestations of multiple epiphyseal dysplasia caused by MATN3 versus COMP mutations: a case control study
This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly credited.Abstract
Background
Multiple epiphyseal dysplasia (MED) is a relatively common skeletal dysplasia mainly involving the epiphyses of the long bones. However, it is a genetically heterogeneous group of diseases sharing certain aspects of the radiologic phenotype. In surveys conducted in East Asia, MATN3 was the most common causative gene, followed by COMP. In this study, the authors compared clinical manifestation of MED patients caused by MATN3 and COMP gene mutations, as well as subsequent orthopaedic interventions.
Methods
Fifty nine molecularly-confirmed MED patients were subjects of this study. The MATN3 gene mutation group comprised of 37 patients (9 female, 28 male). The COMP gene mutation consisted of 22 cases (15 females, 7 males). Medical records and radiographs were reviewed, and questionnaire surveys or telephone interviews were conducted.
Results
At the first presentation, the mean age was 8.8 ± 2.8 years (mean ± standard deviation) in the MATN3 group, and 8.5 ± 3.5 years in the COMP group (p = 0.670). The height in the COMP group was significantly shorter than those in the MATN3 group (p < 0.001). Gait abnormality at the first visit (p = 0.041) and the lastest follow-up (p = 0.037) were statistically significant difference. Hip pain (p = 0.084), limitation of daily activity (p = 0.075) at the latest follow-up tended to be more frequent in the COMP group. Hip dysplasia was more common in the COMP group, having significantly larger acetabular angle (p = 0.037), smaller center-edge angle (p = 0.002), severe Stulberg classification (p < 0.001), and smaller femoral head coverage (p < 0.001).
Conclusions
Clinical manifestations of MED caused by MATN3 were milder than manifestations of the COMP mutation group. These differences in clinical manifestation and prognosis justify molecular differentiation between the two genotypes
Mo1421 High Hemoglobin A1c Level Is Associated With Worse Survival in Advanced Pancreatic Cancer Patients With Diabetes
Surface Roughness Measurement of Nonwovens Using 3D Profile Data
The surface friction property changes of nonwovens under repetitive abrasions were observed. Surface data were acquired using a threedimensional noncontact camera and fractal dimensions were calculated to evaluate surface roughness. The fractal dimension showed a tendency to
increase with the number of abrasions. They were compared with surface friction values measured by the KES-FB system [Textile Res. J. 58(3), 129–136,1988]. Pilling on the nonwoven surface prohibited accurate surface roughness measurement, so they were detected using high-pass filtering of the surface
data. The method needs instant measurement
time and is highly objective, and therefore it is suitable for real-time on-line manufacturing systems.This work was supported by the SRC/ERC program of MOST/KOSEF (R11-2005-065)
Mallory-Weiss Tear during Esophagogastroduodenoscopy
Mallory-Weiss tears (MWTs) are mucosal lacerations caused by forceful retching and are typically located at the gastroesophageal junction. Reported cases of MWT with serious complications seen in esophagogastroduodenoscopy are limited. We report MWT in an 81-year-old woman who presented with gastric perforation by esophagogastroduodenoscopy. We discuss and indicate that hiatal hernia, atrophic gastritis and old age may be associated with the gastric perforation in comparison to typical tears occurring at the gastroesophageal junction
Is endoscopic papillary large balloon dilation safe for treating large CBD stones?
In recent years, endoscopic papillary large balloon dilation (EPLBD) with endoscopic sphincterotomy (EST) has been shown to be an effective technique for the removal of large or difficult common bile duct (CBD) stones, as an alternative to EST. Reviewing the literature published since 2003, it is understood that EPLBD has fewer associated overall complications than EST. Bleeding occurred less frequently with EPLBD than with EST. There was no significant difference in postendoscopic retrograde cholangiopancreatography pancreatitis or perforation. Recent accumulated results of EPLBD with or even without EST suggest that it is a safe and effective procedure for the removal of large or difficult bile duct stones without any additional risk of severe adverse events, when performed under appropriate guidelines. Since use of a larger balloon can tear the sphincter as well as the bile duct, possibly resulting in bleeding and perforation, a balloon size that is equal to or smaller in diameter than the diameter of the native distal bile duct is recommended. The maximum transverse diameter of the stone and the balloon-stone diameter ratio have a tendency to affect the success or failure of complete removal of stones by large balloon dilation to prevent adverse effects such as perforation and bleeding. One should take into account the size of the native bile duct, the size and burden of stones, the presence of stricture of distal bile duct, and the presence of the papilla in or adjacent to a diverticulum. Even though the results of EPLBD indicate that it is a relatively safe procedure in patients with common duct stones with a dilated CBD, the recommended guidelines should be followed strictly for the prevention of major adverse events such as bleeding and perforation