PDI regulates seizure activity via NMDA receptor redox in rats.

Redox modulation of cysteine residues is one of the post-translational modifications of N-methyl-D-aspartate receptor (NMDAR). Protein disulfide isomerases (PDI), an endoplasmic reticulum (ER) chaperone, plays a crucial role in catalyzing disulfide bond formation, reduction, and isomerization. In the present study, we found that PDI bound to NMDAR in the normal hippocampus, and that this binding was increased in chronic epileptic rats. In vitro thiol reductase assay revealed that PDI increased the amount of thiols on full-length recombinant NR1 protein. PDI siRNA, 5-5'-dithio-bis(2-nitrobenzoic acid) (DTNB), bacitracin and PDI antibody reduced seizure susceptibility in response to pilocarpine. In addition, PDI knockdown effectively ameliorated spontaneous seizure activity in chronic epileptic rats. Anticonvulsive effects of PDI siRNA were correlated to the reduction of the amount of free- and nitrosothiols on NMDAR, accompanied by the inhibition of PDI activity. However, PDI knockdown did not lead to alteration in basal neurotransmission or ER stress under physiological condition. These findings provide mechanistic insight into sulfhydration of disulfide bonds on NMDAR by PDI, and suggest that PDI may represent a target of potential therapeutics for epilepsy, which avoids a possible side effect on physiological receptor functionality.

PLPP/CIN regulates bidirectional synaptic plasticity via GluN2A interaction with postsynaptic proteins.

Dendritic spines are dynamic structures whose efficacies and morphologies are modulated by activity-dependent synaptic plasticity. The actin cytoskeleton plays an important role in stabilization and structural modification of spines. However, the regulatory mechanism by which it alters the plasticity threshold remains elusive. Here, we demonstrate the role of pyridoxal-5'-phosphate phosphatase/chronophin (PLPP/CIN), one of the cofilin-mediated F-actin regulators, in modulating synaptic plasticity in vivo. PLPP/CIN transgenic (Tg) mice had immature spines with small heads, while PLPP/CIN knockout (KO) mice had gigantic spines. Furthermore, PLPP/CIN Tg mice exhibited enhanced synaptic plasticity, but KO mice showed abnormal synaptic plasticity. The PLPP/CIN-induced alterations in synaptic plasticity were consistent with the acquisition and the recall capacity of spatial learning. PLPP/CIN also enhanced N-methyl-D-aspartate receptor (GluN) functionality by regulating the coupling of GluN2A with interacting proteins, particularly postsynaptic density-95 (PSD95). Therefore, these results suggest that PLPP/CIN may be an important factor for regulating the plasticity threshold.

P2X7 receptor-mediated PARP1 activity regulates astroglial death in the rat hippocampus following status epilepticus.

Poly(ADP-ribose) polymerase-1 (PARP1) plays a regulatory role in apoptosis, necrosis, and other cellular processes after injury. Recently, we revealed that PARP1 regulates the differential neuronal/astroglial responses to pilocarpine-induced status epilepticus (SE) in the distinct brain regions. In addition, P2X7 receptor (P2X7R), an ATP-gated ion channel, activation accelerates astroglial apoptosis, while it attenuates clasmatodendrosis (lysosome-derived autophagic astroglial death). Therefore, we investigated whether P2X7R regulates regional specific astroglial PARP1 expression/activation in response to SE. In the present study, P2X7R activation exacerbates SE-induced astroglial apoptosis, while P2X7R inhibition attenuates it accompanied by increasing PARP1 activity in the molecular layer of the dentate gyrus following SE. In the CA1 region, however, P2X7R inhibition deteriorates SE-induced clasmatodendrosis via PARP1 activation following SE. Taken together, our findings suggest that P2X7R function may affect SE-induced astroglial death by regulating PARP1 activation/expression in regional-specific manner. Therefore, the selective modulation of P2X7R-mediated PARP1 functions may be a considerable strategy for controls in various types of cell deaths.

Endothelial NOS activation induces the blood-brain barrier disruption via ER stress following status epilepticus.

The blood-brain barrier (BBB) maintains the unique brain microenvironment, which is separated from the systemic circulating system. Since the endoplasmic reticulum (ER) is an important cell organelle that is responsible for protein synthesis, the correct folding and sorting of proteins contributing to cell survivals, ER stress is a potential cause of cell damage in various diseases. Therefore, it would be worthy to explore the the relationship between the ER stress and BBB disruption during vasogenic edema formation induced by epileptogenic insults. In the present study, we investigated the roles of ER stress in vasogenic edema and its related events in rat epilepsy models provoked by pilocarpine-induced status epilepticus (SE). SE-induced eNOS activation induces BBB breakdown via up-regulation of GRP78 expression and dysfunction of SMI-71 (an endothelial BBB marker) in the piriform cortex (PC). In addition, caveolin-1 peptide (an eNOS inhibitor) effectively attenuated GRP78 expression and down-regulation of SMI-71. Taken together, our findings suggest that eNOS-mediated ER stress may participate in SE-induced vasogenic edema formation. Therefore, the modulation of ER stress may be a considerable strategy for therapy in impairments of endothelial cell function.

Elevated serum CA 19-9 at screening tests: underlying conditions and role of abdominopelvic CT.

OBJECTIVES: To investigate underlying conditions of patients with elevated CA 19-9 at screening tests and to evaluate diagnostic performance of abdominopelvic CT. METHODS: One hundred and thirteen patients with elevated CA 19-9 (>37 U/ml) who underwent abdominopelvic CT in a screening program were selected. Underlying conditions were determined by reviewing all available data and follow-up records. Patients were categorized into malignancy, benign, and normal/non-related disease groups. Their mean CA 19-9 and percent of patients with CA 19-9 ≥ 100 U/ml were compared. Diagnostic sensitivity of CT for detecting underlying conditions of elevated CA 19-9 was analysed. RESULTS: Seventeen patients (17/113, 15 %) had 17 elevated CA 19-9-related malignancies, and 55 patients (55/113, 48.7 %) had 70 benign diseases. Mean CA 19-9 and percent of patients with CA 19-9 ≥ 100 U/ml in the malignancy group were significantly higher than in the two other groups. CT detected all except one malignant lesion with a detection sensitivity of 94.1 % (16/17). Of 70 CA 19-9-related benign diseases, CT detected 34 benign diseases (48.6 %) providing an alternative diagnosis for elevated CA 19-9. CONCLUSION: Abdominopelvic CT is not only useful in detecting malignancies, but can also diagnose alternative benign causes of elevated CA 19-9 in asymptomatic screening tests. KEY POINTS: • Fifteen percent of asymptomatic patients with elevated CA19-9 may have intra-abdominal malignancies. • Mean value of CA19-9 is different among malignant, benign, and non-related groups. • CT shows excellent sensitivity for intra-abdominal malignancies as causatives of elevated CA19-9. • CT provides alternative benign diagnoses as causatives of elevated CA19-9. • Detection of causatives of elevated CA19-9 using CT alleviates concerns and uncertainty.

Endothelial transient receptor potential conical channel (TRPC)-3 activation induces vasogenic edema formation in the rat piriform cortex following status epilepticus.

Transient receptor potential canonical channel (TRPC) is a nonselective cation channel permeable to Ca(2+), which express in many cell types, including neurons. However the alterations in TRPC receptor expressions in response to status epilepticus (SE) have not been explored. Therefore, the present study was designated to elucidate the roles of TRPC3 in neuronal death and vasogenic edema within the rat piriform cortex (PC) following SE. In non-SE animals, TRPC3 immunoreactivity was abundantly detected in the PC. Following SE, TRPC3 immunoreactivity was increased in neurons. Furthermore, TRPC3 expression was detected in endothelial cells that did not contain it in non-SE animals. Loss of SMI-71 (a blood-brain barrier antigen) immunoreactivity was also observed in TRPC3 positive endothelial cells. In addition, FJB positive neurons and vasogenic edema were noticeably detected in the PC. To directly determine whether TRPC3 activation is correlated to SE-induced vasogenic edema formation and neuronal damages in the PC, the effect of Pyr-3 (a TRPC3 antagonist) on SE-induced insults were investigated. Pyr-3 infusion effectively attenuated vasogenic edema in the PC as compared to the vehicle. Therefore, our findings indicate that TRPC3 activation/overexpression induced by SE may involve BBB disruption and neuronal damages in the rat PC following SE. Therefore, the present study was TRPC3 may play an important role in SE-induced vasogenic edema formation through BBB disruptions in the rat PC.

Ultrasonographic criteria for fine needle aspiration of nonpalpable thyroid nodules 1-2 cm in diameter.

PURPOSE: To investigate the ultrasonographic (US) characteristics for nonpalpable thyroid nodules 1-2 cm in diameter and to evaluate the guideline for fine needle aspiration (FNA) in terms of US findings. MATERIALS AND METHODS: Between June 2005 and November 2006, FNA was performed in 919 thyroid nodules by radiologists. Of these nodules, 51 malignant nodules and 72 benign nodules were finally included. All 123 nodules were analyzed by 3 radiologists if there were the following US characteristics: marked hypoechogenecity, hypoechogenecity, isoechogenecity, hyperechogenecity, microcalcification, coarse calcification, rim calcification, spiculated margin, taller-than-wide shape, irregular shape, hypoechoic rim and honeycomb appearance. The maximum diameters of nodules and thickness of hypoechoic rim were measured. US characteristics relevant as predictors were identified using a Chi-square or Fisher's exact test and odds ratio. We compared the diagnostic efficacy of 3 US criteria for FNA indication. RESULTS: Microcalcification, taller-than-wide shape, marked hypoechogenecity, hypoechogenecity, coarse calcification, irregular shape and spiculated margin were significant characteristics of malignant nodules. Isoechogenecity, hypoechoic rim and honeycomb appearance was significant characteristics of benign nodules. Rim or arc calcification, hyperechogenecity and thickness of hypoechoic rim were insignificant. Among 3 US criteria for FNA indication, NFI showed the highest diagnostic efficacy, 98.0% in sensitivity, 75.0% in specificity and 150.0 in odds ratio. CONCLUSION: As for nonpalpable thyroid nodules 1-2 cm in diameter, US characteristics are useful for differentiating between malignant and benign nodules. Malignant US characteristics and honeycombing appearance have significant value in selecting nodules for biopsy and reducing the frequency of the FNA procedure.

Magnetic resonance pancreatography: comparison of two- and three-dimensional sequences for assessment of intraductal papillary mucinous neoplasm of the pancreas.

The purpose was to compare two-dimensional (2D) magnetic resonance pancreatography (MRP) with 3D MRP to evaluate intraductal papillary mucinous neoplasm (IPMN). Thirty-four patients (22 men, 12 women; age range, 45-80 years) with IPMN (n = 40) were examined with MRP on 2D and 3D sequences. Two readers independently reviewed the images to assess the overall image quality, artifacts, lesion location, communication with main pancreatic duct, and potential for malignancy. The readers assigned their confidence level (1-5) for predicting ductal communication of the lesion. The results of MRP were compared with endoscopic retrograde pancreatography and surgical and histopathologic findings. Studies obtained with 3D MRP were of significantly higher technical quality than those obtained with 2D MRP. Although 3D MRP showed higher area under the ROC curve (Az) values for predicting ductal communication of the lesion, there was no statistical significance between Az values of 2D and 3D MRP (Az for 2D = 0.821, 0.864 for readers 1 and 2, respectively, and Az for 3D= 0.964, 0.921). Accuracies for discriminating benign from malignant lesions were 70 and 67.5% (reader 1 and 2, respectively, for 2D) and 62.5 and 80.1% (3D). 3D MRP showed superior image quality to that of 2D MRP but did not increase the diagnostic accuracy for predicting ductal communication of the lesion.

Radiologic and pathologic findings of nonpalpable thyroid carcinomas detected by ultrasonography in a medical screening center.

OBJECTIVE: The purpose of this study was to investigate the ultrasonographic and pathologic findings of nonpalpable thyroid carcinomas and reliable guidelines for fine-needle aspiration (FNA). METHODS: Our study was approved by our Institutional Review Board, and written informed consent was waived. Between April 2004 and June 2006, screening ultrasonography was performed for 16,352 self-referred patients in the health care center. Among 1325 nonpalpable thyroid nodules in 1009 patients, pathologic results of FNA revealed 823 benign, 154 indeterminate, 198 nondiagnostic, and 150 malignant nodules. Fifty-eight malignant thyroid nodules (39 microcarcionomas and 19 carcinomas >1 cm, confirmed by both FNA and thyroidectomy) in 55 patients and 82 benign nodules (confirmed by both FNA and follow-up over 2 years) in 75 patients were included for the analysis. Three radiologists retrospectively analyzed the ultrasonographic features of these nonpalpable thyroid nodules for echogenicity, shape, margin, calcification, degree of cystic changes, and size. We compared the radiologic and pathologic findings between microcarcinomas and carcinomas larger than 1 cm for extra-capsular invasion, lymph node metastasis, bilaterality, and multicentricity using univariate analysis. RESULTS: Marked hypoechogenicity, an irregular shape, a taller-than-wide shape, a well-defined spiculated margin, microcalcification, and an entirely solid nature were significant predictors for malignancy (P < .05), whereas a cutoff value of 1 cm in the longest diameter was not significant (P = .184). However, extracapsular invasion (P = .024) and lymph node metastasis (P = .019) were observed more frequently in carcinomas larger than 1 cm (73.7% and 42.1%, respectively) than in microcarcinomas (38.5% and 12.8%). CONCLUSIONS: Ultrasonographic findings suggesting malignancy should be preferentially considered as indicators for FNA, regardless of size, in nonpalpable thyroid nodules. However, extracapsular invasion and lymph node metastasis are closely related to the size of the thyroid nodule.

Standardization of the korean version of the geriatric depression scale: reliability, validity, and factor structure.

OBJECTIVE: We developed a Revised Korean version of the Geriatric Depression Scale (GDS-KR) and examined its reliability, validity, and factor structures. We also estimated its optimal cutoff scores for major depressive disorder (MDD) and minor depressive disorder (MnDD) stratified by age and education. METHODS: The GDS-KR was administered to 888 subjects (61 MDD patients, 45 MnDD patients, and 782 normal elders). Its internal consistency and test-retest reliability were examined. Its concurrent validity was evaluated using Pearson correlation coefficients with the Korean version of the Center for Epidemiologic Studies Depression Scale (CES-D-K) and Hamilton Depression Rating Scale (HAM-D). The mean GDS-KR scores of the MDD patients, MnDD patients and normal elders were compared to evaluate its discriminant validity. To evaluate its construct validity, a principal component analysis with varimax rotation was performed. Receiver operator characteristic (ROC) curve analyses were performed to evaluate its diagnostic ability. RESULTS: Chronbach's coefficient alpha for the GDS-KR was 0.90 and the test-retest reliability was 0.91 (p<0.01). The Pearson correlation coefficients of the GDS-KR scores with the CES-D-K and HAM-D scores were 0.63 (p<0.01) and 0.56 (p<0.01), respectively. The GDS-KR consisted of 5 factors. The optimal cut-off scores of the GDS-KR were 16/17 for MDD only and 15/16 for both MDD and MnDD. The optimal cutoff scores of the GDS-KR were higher in the less educated and younger subjects. The diagnostic accuracy for MDD of the GDS-KR was higher than that of the CES-D. CONCLUSION: The GDS-KR was found to be a reliable and valid questionnaire for screening MDD and MnDD in late life.

Contrast-enhanced MRI combined with MR cholangiopancreatography for the evaluation of patients with biliary strictures: differentiation of malignant from benign bile duct strictures.

PURPOSE: To determine imaging criteria for the combined use of contrast-enhanced (CE)-MRI and MR cholangiopancreatography (MRCP) to differentiate malignant from benign biliary strictures. MATERIALS AND METHODS: A total of 44 patients with biliary stricture who had undergone unenhanced, MRCP, and dynamic MRI were identified from radiological and surgical databases. Two radiologists analyzed MR features for asymmetry, luminal irregularity, abrupt narrowing, outer margin, signal intensity (SI) on T2-weighted (T2W) images, and hyperenhancement relative to liver parenchyma during portal phase. The wall thickness and length of the narrowed segment were measured. MR findings relevant as predictors were identified using a Chi-square or Fisher's exact test and the odds ratio (OR). RESULTS: The presence of hyperenhancement relative to liver parenchyma, length > 12 mm, wall thickness > 3 mm, indistinct outer margin, luminal irregularity, and asymmetry of strictured bile duct were significant factors for malignancy (P < 0.05). Malignant strictures were significantly thicker (5.0 +/- 2.0 mm) and longer (27.0 +/- 13.6 mm) than benign strictures. When any three or more of these six criteria were used in combination, we could identify 100% of malignant strictures and 87.0% of benign strictures. CONCLUSION: The combined use of CE-MRI and MRCP helped to define the criteria for differentiating malignant from benign biliary strictures in our data.

Differentiating malignant from benign wall thickening in postoperative stomach using helical computed tomography: results of multivariate analysis.

OBJECTIVE: To determine significant computed tomography (CT) predictors for differentiating malignant from benign wall thickening in postoperative stomach. METHODS: Sixty-nine patients with perianastomotic wall thickening (25 malignant, 44 benign) after gastric surgery were identified. All patients underwent contrast-enhanced CT with the administration of oral contrast agents such as air, diluted barium, or water. Two radiologists analyzed CT images regarding enhancement of thickened wall, obliteration of wall layering, heterogeneity, asymmetry, perigastric infiltration, proximity to metallic suture material, lymphadenopathy, adjacent bowel thickening, and periceliac soft-tissue density. Another radiologist measured the wall thickness and the mean CT value of the lesion and normal mucosa. Individual CT findings relevant as predictors were determined using the univariate test. Multivariate analysis was used to determine the most predictable factors. RESULTS: Malignant wall thickening was significantly thicker than benign one. Isoattenuation and high attenuation of thickened wall were more frequently seen in malignant than in benign cases. Multivariate analysis showed that isoattenuation or high attenuation of thickened wall, proximity to suture material, and perigastric infiltration were only 3 variables that independently differentiated malignant from benign thickening in postoperative stomach. CONCLUSION: Isoattenuation or high attenuation of thickened wall, perigastric infiltration, and wall thickening without metallic suture material are the 3 main factors distinguishing malignant from benign thickening in postoperative stomach.

Evaluation of the longitudinal tumor extent of bile duct cancer: value of adding gadolinium-enhanced dynamic imaging to unenhanced images and magnetic resonance cholangiography.

OBJECTIVE: To determine the added value of gadolinium-enhanced dynamic magnetic resonance (MR) images compared with unenhanced and MR cholangiography (MRC) images, to evaluate the longitudinal extension of bile duct cancer. MATERIALS AND METHOD: Thirty-three patients with hilar cholangiocarcinoma or common duct cancer who had undergone MRC, unenhanced, and gadolinium-enhanced dynamic MR images and surgery were included in this study. Two experienced radiologists independently reviewed 2 image sets in 2 steps, that is, the MRC set (unenhanced and MRC) and the combined image set (MRC set with dynamic images). At each step, the readers determined the tumor status according to the Bismuth-Corlette classification. The readers assigned their confidence levels on a 5-point scale regarding whether the tumor involved the secondary confluence of the bile duct and the intrapancreatic common bile duct. The radiologists' diagnostic confidence of the 2 image sets was analyzed using receiver operating characteristic analysis. RESULTS: Receiver operating characteristic analysis showed higher areas under the curve values when the combined image set was interpreted (0.990 +/- 0.017 for reader 1 and 0.951 +/- 0.027 for reader 2) than when the MRC set was interpreted (0.982 +/- 0.017 for reader 1 and 0.902 +/- 0.038 for reader 2); however, the difference was not statistically significant for either reader (P > 0.05). In addition, regarding evaluation of the tumor status according to the Bismuth-Corlette classification, the overall accuracy was higher for the combined image set than for the MRC set alone, but the difference was not significant (P > 0.05). When dynamic images were added to the MRC images, interobserver agreement improved from 0.72 to 0.84. CONCLUSIONS: The addition of contrast-enhanced dynamic images to unenhanced and MRC images did not significantly improve the diagnostic accuracy for assessment of the longitudinal extent of bile duct cancer.