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Mutations in the mitochondrial kinase PINK1 and the cytosolic E3 ligase Parkin can cause Parkinson's disease. Damaged mitochondria accumulate PINK1 on the outer membrane where, dependent on kinase activity, it recruits and activates Parkin to induce mitophagy, potentially maintaining organelle fidelity. How PINK1 recruits Parkin is unknown. We show that endogenous PINK1 forms a 700 kDa complex with the translocase of the outer membrane (TOM) selectively on depolarized mitochondria whereas PINK1 ectopically targeted to the outer membrane retains association with TOM on polarized mitochondria. Inducibly targeting PINK1 to peroxisomes or lysosomes, which lack a TOM complex, recruits Parkin and activates ubiquitin ligase activity on the respective organelles. Once there, Parkin induces organelle selective autophagy of peroxisomes but not lysosomes. We propose that the association of PINK1 with the TOM complex allows rapid reimport of PINK1 to rescue repolarized mitochondria from mitophagy, and discount mitochondrial-specific factors for Parkin translocation and activation., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Cerebrotendinous Xanthomatosis (CTX) is a rare autosomal recessive lipid storage disease caused by sterol 27-hydroxylase (CYP27) deficiency. We report three CTX siblings that shared a novel mutation of the CYP27A1 gene. These siblings presented with elevated cholestanol levels and typical manifestations such as tendon xanthomas, cataracts, osteopenia, mental retardation, cerebellar ataxia and peripheral neuropathy. All shared the same genetic mutation, c.1146_1151delins and c.1214G>A of CYP27A1. All were treated with 750 mg/day chenodeoxycholic acid (CDCA). In conclusion, one should consider the possibility of CTX in any individual with normocholesterolemic xanthomatosis, early-onset cataracts, mental retardation, cerebellar ataxia and peripheral neuropathy., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Objectives: Hepatotoxicity of acetaminophen has been widely studied. However, the adverse effects on the heart have not been sufficiently evaluated. This study was performed to investigate cytotoxicity and alterations of gene expression in cultured cardiomyocytes (H(9)C(2) cells) after exposure to acetaminophen., Methods: H(9)C(2) cells were incubated in a 10 mM concentration of acetaminophen for the designated times (6, 12, and 24 hours), and cytotoxicity was determined by the 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. Alteration of gene expression was observed by microarray analysis, and RT-PCR was performed for the three representative oxidative stress-related genes at 24 hours after treatment., Results: It revealed that acetaminophen was toxic to cardiomyocytes, and numerous critical genes were affected. Induced genes included those associated with oxidative stress, DNA damage, and apoptosis. Repressed genes included those associated with cell proliferation, myocardial contraction, and cell shape control., Conclusions: These findings provide the evidences of acetaminophen-induced cytotoxicity and changes in gene expression in cultured cardiomyocytes of H(9)C(2) cells.

Purpose: Toxicity caused by acetaminophen and its toxic mechanisms in the liver have been widely studied, including effects involving metabolism and oxidative stress. However, its adverse effects on heart have not been sufficiently investigated. This study evaluated the cardiac influence and molecular events occurring within the myocardium in rats treated with a dose of acetaminophen large enough to induce conventional liver damage., Materials and Methods: Male rats were orally administered a single dose of acetaminophen at 1,000 mg/kg-body weight, and subsequently examined for conventional toxicological parameters and for gene expression alterations to both the heart and liver 24 hours after administration., Results: Following treatment, serum biochemical parameters including aspartate aminotransferase and alanine aminotransferase were elevated. Histopathological alterations of necrosis were observed in the liver, but not in the heart. However, alterations in gene expression were observed in both the liver and heart 24 hours after dosing. Transcriptional profiling revealed that acetaminophen changed the expression of genes implicated in oxidative stress, inflammatory processes, and apoptosis in the heart as well as in the liver. The numbers of up-regulated and down-regulated genes in the heart were 271 and 81, respectively, based on a two-fold criterion., Conclusion: The induced expression of genes implicated in oxidative stress and inflammatory processes in the myocardium reflects molecular levels of injury caused by acetaminophen (APAP), which could not be identified by conventional histopathology.

Background: In clinical trials using adult porcine islet products, islets should be isolated from the designated pathogen-free (DPF) pigs under the current good manufacturing practice (GMP) regulations. Our previous studies suggested that male DPF pigs are better donors than retired breeder pigs and histomorphometrical parameters of donor pancreas predict the porcine islet quality. We aimed to investigate whether the use of the newer bovine nervous tissue-free enzymes and a revised donor selection strategy could improve the islet graft function in the context of islet isolation with DPF pigs., Methods: Using 30 DPF pigs within a closed herd, we compared the islet yield of porcine islets isolated with Liberase PI (n = 11, as a historical control group), Liberase MTF C/T, which is a GMP-grade enzyme (n = 12), and CIzyme collagenase MA/BP protease (n = 7). We analyzed the relationship between the diabetes reversal rate of recipient NOD/SCID mice (n = 75) and histomorphometric parameters of each donor pancreas as well as donor characteristics., Results: Proportion of islets larger than 200 μm from the biopsied donor pancreas (P = 0.006) better predicted islet yield than age (P = 0.760) or body weight (P = 0.371) of donor. The proportion of islets larger than 200 μm from the biopsied donor pancreas was not related to the sex of the donor miniature pig (P = 0.358). The islet yield obtained with the three enzymes did not differ, even after stratification of the donor with the histomorphometric parameters of the biopsied donor pancreas and the sex of donor. The use of the newer bovine nervous tissue-free enzymes (P < 0.001), a higher proportion of large islets in donor pancreas (P = 0.006), and a male sex of the donor (P = 0.025) were independent predictors of earlier diabetes reversal., Conclusions: Use of the newer bovine nervous tissue-free enzymes including a GMP-grade enzyme resulted in better islet quality than that of islet isolated using Liberase PI. To obtain high-quality islet from DPF pigs, the donor should be male pig and histomorphometrical parameters from donor pancreas should be considered., (© 2011 John Wiley & Sons A/S.)

Conclusion: Injection of injured rabbit vocal folds with human adipose-derived stem cells (hADSCs) led to improved wound healing and fewer signs of scarring as demonstrated by a decreased collagen content in the treated folds compared with the untreated folds. hADSCs remained viable for up to 12 weeks in rabbit vocal folds., Objective: The aim of this study was to investigate the morphologic and histologic properties of scarred rabbit vocal folds following injection of hADSCs., Methods: This was a randomized, controlled animal study. Twenty-four vocal folds from 12 New Zealand rabbits were scarred using a CO(2) laser and injected with either hADSCs (left vocal fold) or phosphate-buffered saline (right vocal fold). Every 4 weeks for the first 12 weeks after injection, an endoscopic examination was performed to assess the morphology of the vocal folds. Twelve weeks later the animals were euthanized and the tissues were stained for histology., Results: In comparison with the right vocal folds, there was significantly less granulation tissue in the hADSCs-injected left vocal folds (p < 0.05). Histological examination revealed excessive collagen deposition and perichondral fibrosis in the right vocal folds, whereas the left vocal folds exhibited better wound healing and less collagen deposition (p < 0.05). Among the 12 specimens injected with hADSCs, 4 specimens demonstrated viable hADSCs under immunofluorescent cytochemistry.

The purpose of this study was to investigate risk factors of postoperative pneumonia (POP) after lung cancer surgery. The 417 lung cancer patients who underwent surgical resection in a tertiary referral hospital were included. Clinical, radiological and laboratory data were reviewed retrospectively. Male and female ratio was 267:150 (median age, 65 yr). The incidence of POP was 6.2% (26 of 417) and in-hospital mortality was 27% among those patients. By univariate analysis, age ≥ 70 yr (P < 0.001), male sex (P = 0.002), ever-smoker (P < 0.001), anesthesia time ≥ 4.2 hr (P = 0.043), intraoperative red blood cells (RBC) transfusion (P = 0.004), presence of postoperative complications other than pneumonia (P = 0.020), forced expiratory volume in 1 second/forced vital capacity (FEV(1)/FVC) < 70% (P = 0.002), diffusing capacity of the lung for carbon monoxide < 80% predicted (P = 0.015) and preoperative levels of serum C-reactive protein ≥ 0.15 mg/dL (P = 0.001) were related with risk of POP. Multivariate analysis showed that age ≥ 70 yr (OR = 3.563, P = 0.014), intraoperative RBC transfusion (OR = 4.669, P = 0.033), the presence of postoperative complications other than pneumonia (OR = 3.032, P = 0.046), and FEV(1)/FVC < 70% (OR = 3.898, P = 0.011) were independent risk factors of POP. In conclusion, patients with advanced age, intraoperative RBC transfusion, postoperative complications other than pneumonia and a decreased FEV(1)/FVC ratio have a higher risk for pneumonia after lung cancer surgery.

Background: Patients with stage I-II non-small cell lung cancer (NSCLC) show variability in recurrence after curative resection. Several factors have been proposed as prognostic of recurrence in previous studies. However, because of the heterogeneity of the populations studied, these reports did not yield consistent results. The aim of our study was to identify risk factors for recurrence in patients with curatively resected stage I-II NSCLC., Methods: We reviewed the medical records of pathological stage I-II NSCLC patients after curative surgery performed in a tertiary referral center (Seoul National University Hospital) from January 2002 to December 2004. Demographic factors, radiological, histopathological, and laboratory findings, and surgery-related factors were analyzed. Patients with invasive cancer other than lung cancer that was present 5 years prior to surgery were excluded. The Cox proportional hazard regression model was used for multivariate analyses., Results: Three hundred and ten patients were included. Among them, local recurrence occurred in 27 patients (8.7%), whereas distant recurrence occurred in 79 patients (25.5%). Adenocarcinoma histology (OR, 2.74; 95% CI, 1.14-6.58; P=0.024), carcinoembryonic antigen (CEA) level>2.3 ng/mL (OR, 2.26; 95% CI, 1.02-5.00; P=0.045), and standard uptake values (SUV) of tumor in positron emission tomography (PET)>4.5 (OR, 5.45; 95% CI, 1.82-16.31; P=0.002) were independent predictors of recurrence in addition to TNM stage. We also constructed a recurrence prediction model based on these findings, which yielded better diagnostic performance than the TNM staging system., Conclusion: Adenocarcinoma histology, CEA level, and SUV of PET could be considered as prognostic factors for recurrence in patients with curatively resected stage I-II NSCLC., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Purpose: With the increase in vancomycin use, adverse drug reactions (ADRs) associated with vancomycin have been reported increasingly more often. However, the characteristics of cutaneous ADRs with and without systemic reactions (SRs) have not been described. This study investigated the characteristics of spontaneously reported and assessed ADRs associated with vancomycin by a pharmacovigilance center., Methods: ADRs (n=121) associated with vancomycin in 96 patients were collected from 2008 to 2009. Records from physician- and nurse-reported suspected cases of vancomycin ADRs, ADR type, latent period, and laboratory results were compared between cutaneous ADRs with and without SRs., Results: The main vancomycin-related ADRs were skin rashes (47.9%), hematologic abnormalities (17.36%), fever (12.4%), and elevated serum creatinine (12.4%). Significant differences were observed in latent period (days) and the mean change in eosinophils (%) between cutaneous (9.21±9.71 and 1.4±3.4, respectively) and other ADRs (14.03±11.71 and -0.5±3.5, respectively). Twelve cases of cutaneous ADRs with SRs had been initially reported as cutaneous ADRs only. Mean changes in the eosinophil count were significantly higher for cutaneous ADRs with SRs compared to those without SRs., Conclusions: Skin rashes accompanied by peripheral eosinophilia, representing suspected immune-mediated delayed hypersensitivity reactions, are a common vancomycin ADR. For the early and exact detection of ADRs associated with vancomycin administration, close monitoring of laboratory tests, including complete blood counts with differential analysis, is recommended.

Intraductal administration of a c-Jun NH(2)-terminal kinase (JNK) inhibitor enhances islet viability. However, its role in reducing the inflammatory response in islets is unknown. It is also unknown whether a JNK inhibitor could act in synergy with statins. We examined if the sequential combination of a JNK inhibitor and simvastatin would reduce islet inflammation and improve islet viability. We performed porcine islet isolation with or without intraductal administration of SP600125, a JNK inhibitor. This was followed by culture medium supplementation with either nicotinamide alone or nicotinamide plus simvastatin. We assessed the viability of islets by flow cytometry, islet loss during overnight culture, graft function in NOD/SCID mice, and expression of inflammation-related genes in islets. The sequential combination of a JNK inhibitor and simvastatin increased the β-cell viability index of porcine islets cultured overnight (p = 0.015) as well as islet viability as assessed by a DNA binding dye staining (p = 0.011). The combination of a JNK inhibitor and simvastatin significantly increased the islet survival rate (p = 0.027) when the histomorphometry of donor pancreas indicated a large islet proportion of greater than 50.55%. When we transplanted the same islet mass per recipient for each group, there was no difference in overall islet graft function. Intraductal administration of JNK inhibitor significantly suppressed mRNA expression levels of interleukin-1β (IL-1β), interferon-γ, tumor necrosis factor-α, IL-6, IL-8, and macrophage chemoattractant protein-1. It also decreased the concentration of IL-1β (p = 0.040) and IL-8 (p = 0.023) in the culture supernatant. In conclusion, the sequential combination of a JNK inhibitor and simvastatin protected porcine islets from peritransplant apoptosis. Inhibition of JNK reduced the inflammatory response and could be considered an alternative target for suppression of porcine islet inflammation.

PINK1 is a mitochondrial kinase mutated in some familial cases of Parkinson's disease. It has been found to work in the same pathway as the E3 ligase Parkin in the maintenance of flight muscles and dopaminergic neurons in Drosophila melanogaster and to recruit cytosolic Parkin to mitochondria to mediate mitophagy in mammalian cells. Although PINK1 has a predicted mitochondrial import sequence, its cellular and submitochondrial localization remains unclear in part because it is rapidly degraded. In this study, we report that the mitochondrial inner membrane rhomboid protease presenilin-associated rhomboid-like protein (PARL) mediates cleavage of PINK1 dependent on mitochondrial membrane potential. In the absence of PARL, the constitutive degradation of PINK1 is inhibited, stabilizing a 60-kD form inside mitochondria. When mitochondrial membrane potential is dissipated, PINK1 accumulates as a 63-kD full-length form on the outer mitochondrial membrane, where it can recruit Parkin to impaired mitochondria. Thus, differential localization to the inner and outer mitochondrial membranes appears to regulate PINK1 stability and function.

Objective: To investigate the relationship between chromosomal genomic DNA imbalance in medulloblastoma (MB), and the age and gender., Methods: The gains and losses of chromosomal genomic DNA in 16 MBs were analyzed using comparative genomic hybridization., Results: The gains and(or) losses were found in 15 of the 16 cases. There was not significant difference (P > 0.05) between the total gains (10/16) and losses (11/16). Both of their differences had also no significance between different age and gender groups (P > 0.05). In 15 cases with gains and(or) losses, single-, two-, three- and multi-chromosome genomic DNA imbalances were 3/15, 4/15, 1/15 and 7/15 respectively. Eleven gain zones (+5q, +6q, +7q, +11q, +15q, +17p, +17q, +19q, +20q, +21q, +Xp) and twenty-five loss zones (-1p, -1q, -2p, -2q, -3q, -4p, -6p, -6q, -8p, -8q, -10p, -10q, -11p, -14q, -16p, -16q, -17p, -18p, -18q, -19p, -19q, -20p, -20q, -Xp, -Xq) were detected in those tumors. +7q (6/16), +17q (6/16), -14q (5/16) and -10q (3/16) were the most frequent, but -14q only occurred in the cases of > 10-year-old., Conclusions: Most MBs have chromosomal genomic DNA imbalances. The frequent imbalance zones are mainly at the long arms of some chromosomes. +7q, +17q, -14q and -10q correlate closely to development of the tumors. -14q is important factor to result in MBs of > 10-year-old group. MB has possibly different molecular genetics subtype.

Purpose: To establish a three dimensional finite element model of a maxillary impacted canine and its support tissues by means of finite element method (FEM) and spiral CT which can offer digital model for orthodontic traction., Methods: A patient with a completely bony impacted maxillary canine was chosen. The CAD model of the canine and its surrounding tissues was established using spiral CT equipment, Mimics and Unigraphic. The CAD model was changed to FEM models by MSC. Mentat which could cut nets in CAD models., Results: With the use of spiral CT,Mimics,UG and MSC, FEM model of the maxillary impacted canine and its support tissues and the whole maxilla was constructed and the model was of high geometrical similarity., Conclusion: The FEM model of maxillary impacted canine established by spiral CT,Mimics,UG and MSC has high accuracy, integrated constitution and optimized mesh which can be taken into account in the course of the treatment planning prior to starting therapy.

Loss-of-function mutations in PINK1 and Parkin cause parkinsonism in humans and mitochondrial dysfunction in model organisms. Parkin is selectively recruited from the cytosol to damaged mitochondria to trigger their autophagy. How Parkin recognizes damaged mitochondria, however, is unknown. Here, we show that expression of PINK1 on individual mitochondria is regulated by voltage-dependent proteolysis to maintain low levels of PINK1 on healthy, polarized mitochondria, while facilitating the rapid accumulation of PINK1 on mitochondria that sustain damage. PINK1 accumulation on mitochondria is both necessary and sufficient for Parkin recruitment to mitochondria, and disease-causing mutations in PINK1 and Parkin disrupt Parkin recruitment and Parkin-induced mitophagy at distinct steps. These findings provide a biochemical explanation for the genetic epistasis between PINK1 and Parkin in Drosophila melanogaster. In addition, they support a novel model for the negative selection of damaged mitochondria, in which PINK1 signals mitochondrial dysfunction to Parkin, and Parkin promotes their elimination., Competing Interests: The authors have declared that no competing interests exist.

Prediction of islet yield and posttransplant outcome is essential for clinical porcine islet xenotransplantation. Although several histomorphometric parameters of biopsied porcine pancreases are predictive of islet yield, their role in the prediction of in vivo islet potency is unknown. We investigated which histomorphometrical parameter best predicts islet yield and function, and determined whether it enhanced the predictive value of in vitro islet function tests for the prediction of posttransplant outcome. We analyzed the histomorphometry of pancreases from which 60 adult pig islet isolations were obtained. Islet function was assessed using the beta-cell viability index based on flow cytometry analysis, oxygen consumption rate, ADP/ATP ratio, and/or concurrent transplantation into NOD/SCID mice. Receiver operating characteristic (ROC) analysis revealed that only islet equivalent (IEQ)/cm(2) and the number of islets >200 microm in diameter significantly predicted an islet yield of >2000 IEQ/g (p < 0.001 for both) and in vivo islet potency (p = 0.024 and p = 0.019, respectively). Although not predictive of islet yield, a high proportion of large islets (>100 microm in diameter) best predicted diabetes reversal (p = 0.001). Multiple regression analysis revealed that the beta-cell viability index (p = 0.003) and the proportion of islets >100 microm in diameter (p = 0.048) independently predicted mean posttransplant blood glucose level (BGL). When BGL was estimated using both these parameters [area under the ROC curve (AUC), 0.868; 95% confidence interval (CI), 0.730-1.006], it predicted posttransplant outcome more accurately than the beta-cell viability index alone (AUC, 0.742; 95% CI, 0.544-0.939). In conclusion, we identified the best histomorphometric predictors of islet yield and posttransplant outcome. This further enhanced the predictive value of the flow cytometry analysis. These parameters should be useful for predicting islet yield and in vivo potency before clinical adult porcine islet xenotransplantation.

Objective: This study was conducted to identify anatomical variations of the spinal accessory nerve (SAN) in the upper neck, the landmark of the anterior and inferior border of level IIb, and to evaluate the nerve's effect on the border and the number of lymph nodes (LNs) in level IIb., Study Design and Setting: Case series with planned data collection., Subjects and Methods: A total of 181 neck dissections (NDs) were prospectively enrolled in this study. The relation between the SAN and adjacent structures (internal jugular vein [IJV], sternocleidomastoid muscle [SCM], cervical plexus) and the number of LNs in level IIb was investigated., Results: The SAN crossed the IJV ventrally in 72 cases (39.8%) and dorsally in 104 cases (57.4%), and passed through the IJV in five cases (2.8%). The SAN ran along the inner surface of the SCM and sent branches to the SCM without penetration of the muscle in 83 cases (45.9%), whereas in 98 cases (54.1%) the nerve sent branches to the SCM by penetration. Cervical plexus contribution to the SAN was seen from C2 in 96 cases (53.1%), C2 and C3 in 69 cases (38.1%), and C3 in 16 cases (8.8%). The mean number of LNs of level IIa and level IIb was 6.5 and 8.2 in cases in which the SAN crossed the IJV ventrally, and 6.8 and 5.4 in dorsally crossing cases. LNs included in the neck level IIb in ventrally crossing SAN cases were significantly larger than the dorsally crossing cases (P < 0.05)., Conclusions: Our results may help to minimize the incidence of injuring the SAN in the upper neck during ND. Neck level IIb would contain more LNs if the course of the nerve leans toward the ventral side.

Ectopic thyroid tissue is an uncommon embryologic aberration characterized by the presence of thyroid tissue in a site other than its usual pre-tracheal location. Single ectopic thyroid tissue is the most common variant, and the base of the tongue is the most frequent ectopic location. Dual ectopic thyroid is extremely rare, and only eleven cases have been reported in the English literature. Furthermore, adenomatous hyperplasia has never been reported to arise from dual ectopic thyroid. There has been only one reported case of adenomatous hyperplasia arising from a single intratracheal ectopic thyroid. We report a case of adenomatous hyperplasia arising from dual ectopic thyroid tissue that presented as a sublingual mass in a 37-yr-old woman. The diagnosis was made through pathologic examination after surgical resection. We also discuss the diagnosis and treatment of ectopic thyroid, along with a review of the literature.

Objectives: OK-432 has been widely used to treat lymphangioma and ranula; however, there are few studies for its use in treatment of branchial cleft cyst (BCC). We conducted this study to evaluate the effectiveness of sclerotherapy using OK-432 in treatment of BCC., Study Design and Setting: Case series with planned data collection., Subjects and Methods: From 2004 to 2007, we treated 23 patients with BCC using OK-432 sclerotherapy. Of these 23 patients, 18 had unilocular cysts and five had multilocular cysts. The sizes of the BCCs were measured and compared before and after treatment., Results: Of the 23 cases, 14 (60.8%) showed complete regression; all of these were unilocular cysts. Of the remaining individuals with unilocular cysts, only one patient failed to show any response. This individual subsequently underwent surgical excision. A total of five patients with multilocular cysts showed no or partial response and subsequently underwent surgical excision. Minor adverse effects including fever and local pain were reported by 13 (56.5%) patients., Conclusion: These results suggest that sclerotherapy using OK-432 is an effective and safe treatment modality for BCC, especially for unilocular cysts. Sclerosing of unilocular BCC with OK-432 should therefore be considered before surgical excision.

The protease BACE1 (beta-site APP-cleaving enzyme 1) is essential for the generation of amyloid beta (Abeta) from amyloid precursor protein (APP). Although BACE1 is expressed primarily in neurons, which are a principal source of Abeta in the brain, the mechanism that underlies basal expression of BACE1 in neurons has not been studied thoroughly. In the present study, we found that endogenous BACE1 expression was mediated by constitutive JAK2/STAT1 activation in neurons. Inhibition of the JAK2/STAT1 signaling pathway, using AG490 (a JAK2 inhibitor), a dominant-negative form of STAT1, and SOCS1 and SOCS3 overexpression, reduced levels of BACE1 promoter activity, expression of endogenous BACE1, and generation of Abeta. These results were recapitulated in the SH-SY5Y neuronal cell line, primary cultured neurons, and mouse brains. Therefore, we propose that constitutive JAK2/STAT1 activation mediates endogenous BACE1 expression in neurons and that inhibition of JAK2/STAT1 signaling abrogates basal levels of BACE1 expression and Abeta generation.

The receptor for advanced glycation end products (RAGE) is a multiligand cell surface receptor, and amyloid beta peptide (Abeta) is one of the ligands for RAGE. Because RAGE is a transporter of Abeta from the blood to the brain, RAGE is believed to play an important role in Alzheimer's disease (AD) pathogenesis. In the present study, the role of RAGE in Abeta production was examined in the brain tissue of an AD animal model, Tg2576 mice, as well as cultured cells. Because beta-site APP-cleaving enzyme 1 (BACE1), an essential protease for Abeta production, is up-regulated in cells overexpressing RAGE and in RAGE-injected brains of Tg2576 mice, the molecular mechanisms underlying RAGE, BACE1 expression, and Abeta production were examined. Because RAGE stimulates intracellular calcium, nuclear factor of activated T-cells 1 (NFAT1) was examined. NFAT1 was activated following RAGE-induced BACE1 expression followed by Abeta generation. Injection of soluble RAGE (sRAGE), which acts as a competitor with full-length RAGE (fRAGE), into aged Tg2576 mouse brains reduced the levels of plaques, Abeta, BACE1, and the active form of NFAT1 compared with fRAGE-injected Tg2576 mice. Taken together, RAGE stimulates functional BACE1 expression through NFAT1 activation, resulting in more Abeta production and deposition in the brain.

Objective: To investigate genomic DNA imbalances in ependymomas (EDMs) and their correlations with the tumor histological types, grades, locations, patients' gender and age., Methods: Chromosomal gains and losses in 16 cases of EDM were analyzed using comparative genomic hybridization., Results: Chromosomal regional gain and loss were found in 15 and 13 of 16 EDM cases respectively including totally 24 regional gains and 19 regional losses in all the tumors studied. Both regional gains and losses were mostly seen in myxopapillary EDMs (MPE, WHO grade I), more commonly seen in cellular EDMs (CE, WHO grade II) and tanycytic EDMs (TE, WHO grade II) than in anaplastic EDMs (AE, WHO grade III). Some of the regional gains and losses appeared only in one subtype of MPE, CE, TE and AE cases resulting in development of specific imbalance profiles of certain subtype in these cases. MPE, CE and TE often had +7. Chromosomal +5 occurred only in MPE and CE, and -22q was only seen in CE and TE. AE frequently had +1q, but none had +5, +7, -4q, -19q and -22q. The frequencies of any regional gain or loss were not affected by patients' genders (P > 0.05). Chromosomal +1q and +7p happened predominantly in intracranial EDMs with an averagely onset age of

Background and Objective: Connective tissue diseases are the most common disorders causing diffuse alveolar haemorrhage (DAH) confirmed by open lung biopsy. However, it is not known whether these diseases are also the most common causes of DAH in patients presenting with the features of ARDS/acute lung injury (ALI). This study evaluated the frequency of concomitant disease in patients with ARDS/ALI and DAH., Methods: The sampling frame comprised all patients in a tertiary referral hospital diagnosed with ARDS/ALI and who underwent BAL between January 2000 and July 2006. The medical records of those patients who had BAL fluid findings compatible with DAH were reviewed., Results: Of the 97 patients diagnosed with ARDS/ALI and who underwent BAL, 27 had BAL fluid findings compatible with DAH. Sixteen of the 27 patients did not have connective tissue diseases (59%); of these 12 patients had concomitant haematological malignancies or solid tumours. Of the seven patients who presented with DAH and no known underlying disease, only two were subsequently diagnosed with a connective tissue disorder. The in-hospital mortality rate was 55% and 63% for patients with DAH with and without connective tissue diseases, respectively (P = 0.710)., Conclusions: The majority of patients with DAH presenting with the features of ARDS/ALI did not have underlying connective tissue diseases. Concomitant malignancies were found frequently in these patients. The outcome did not differ between patients with DAH with or without connective tissue diseases.

Background: Islet cell transplantation is a novel therapeutic modality for the cure of diabetes. Pig islet cells are an attractive substitute for human islet cells; however, they are known to be particularly difficult to isolate because of a weak islet capsule and a tendency to be fragmented during enzymatic digestion. Therefore, parameters favoring successful pig islet isolation were investigated using specific-pathogen-free (SPF) miniature pigs., Methods: Sixty-eight SPF miniature pigs were used for islet isolation. Birth weight, body weight, age, sex, pregnancy history, and the fasting blood glucose levels of each pig were determined. Each pig's general condition was assessed with regard to feeding status and physical activity. Pancreas procurement was performed by one surgical team. Anesthesia duration, operation duration, procedure quality, and perfusate type were recorded. After pancreatectomy, a biopsy was performed for islet density analysis. Decapsulation, cannulation duration, degree of distension, and cold ischemic time were assessed. During islet isolation, pancreas weight, digestion time, and digested tissue proportion were recorded. Isolation results were evaluated by total islet equivalents (IEQ), islet equivalents per gram of pancreas (IEQ/g), isolation index, islet recovery rate, purity, and visual grade. To identify the predictors of higher islet isolation yield, we performed binary logistic regression analysis with significant (P < 0.05) variables from the univariate analysis., Results: The pigs were categorized into high (n = 34) and low yield (n = 34) groups according to the median IEQ/g or total IEQ values. Body weight and age were significantly different between the two groups. Being male or a positive history of pregnancy in females was factors favoring successful islet isolation. General condition assessments failed to estimate islet isolation results. Long anesthesia duration, which might have caused ischemic injury to the pancreas, negatively affected islet isolation results. Decapsulation, cannulation duration, and subsequent pancreas distension were significantly important in successful islet isolation. Inter-lot variability of Liberase was not observed because of screening processes performed before purchase. Isolation index and islet recovery rate correlated well with islet yields., Conclusions: Multivariate analysis using total IEQ and IEQ/g as outcome variables indicated that age older than 2, being male and moderate distension by Liberase injection are major determinants influencing successful islet isolation.

To amplify the difference in localized surface plasmon resonance (LSPR) spectra of gold nano-islands due to intermolecular binding events, gold nanoparticles were used. LSPR-based optical biosensors consisting of gold nano-islands were readily made on glass substrates using evaporation and heat treatment. Streptavidin (STA) and biotinylated bovine serum albumin (Bio-BSA) were chosen as the model receptor and the model analyte, respectively, to demonstrate the effectiveness of this detection method. Using this model system, we were able to enhance the sensitivity in monitoring the binding of Bio-BSA to gold nano-island surfaces functionalized with STA through the addition of gold nanoparticle-STA conjugates. In addition, SU-8 well chips with gold nano-island surfaces were fabricated through a conventional UV patterning method and were then utilized for image detection using the attenuated total reflection mode. These results suggest that the gold nano-island well chip may have the potential to be used for multiple and simultaneous detection of various bio-substances.

Background: Miliary pulmonary nodules are commonly caused by various infections and cancers. We sought to identify the relative frequencies of various aetiologies and the clinical and radiographic predictors of miliary tuberculosis (TB) in patients with miliary pulmonary nodules., Methods: We performed a retrospective cohort study of patients who presented with micronodules occupying more than two-thirds of the lung volume, based on computed tomography (CT) of the chest, between November 2001 and April 2007, in a tertiary referral hospital in South Korea., Results: We analyzed 76 patients with miliary pulmonary nodules. Their median age was 52 years and 38 (50%) were males; 18 patients (24%) had a previous or current malignancy and five (7%) had a history of TB. The most common diagnoses of miliary nodules were miliary TB (41 patients, 54%) and miliary metastasis of malignancies (20 patients, 26%). Multivariate analysis revealed that age 25% of total lung volume increased the probability of miliary TB. However, a history of malignancy decreased the probability of miliary TB., Conclusion: Miliary TB accounted for approximately half of all causes of miliary pulmonary nodules. Young age, an immune-compromised state, and several clinical and radiographic characteristics increased the probability of miliary TB.

Purpose: To detect the changes of MMP-1 and MMP-9 in gingival crevicular fluid (GCF) of the rats in different age groups with orthodontic appliances., Methods: 40 female Wistar rats were selected as the animal model, in which there were 20 6-week-old rats and 20 12-week-old rats. The orthodontic appliances were fixed onto the maxilla of the rats after general anesthesia. The maxillary first molar in the experimental side was drawn medially by applying an excess force of 50 g, with both of the maxillary central incisors as anchorage. In the control side, the maxillary first molar was winded around the dental cervix with ligature wire. The GCF was collected every week, and MMP-1 and MMP-9 were assayed in quantitation by SDS-PAGE, Western blot and Gel Doc quantitative analysis system,respectively. The data were analyzed for ANOVA using SPSS11.0 software package., Results: No statistical difference of the original concentration of MMP-1 and MMP-9 in GCF was found between adolescent group and adult group (P>0.05), but the adult group's contents were a little more than adolescent group's, and is the same as the 1st week's content. The concentration of MMPs in adult group changed more greatly than that in adolescent group. At the beginning of the experiment, the MMPs' increasing speed of adult group was higher than that of adolescent group. But at the end, the rate of descent of adult group was lower than that of adolescent group., Conclusions: The expression of MMPs in gingival crevicular fluid of adult rats is higher than that of adolescent rats. It may be more serious of the orthodontic root resorption in adult rats than in adolescent rats. Supported by Shandong Provincial Natural Science Foundation (Grant No.Y2007C023) and Jinan Science and Technology Development Plan (Grant No.200705089-9).

Chronic tympanic membrane (TM) perforations are a common problem in otolaryngology. However, there are controversies of how best to treat TM perforation. Recently, we successfully managed TM perforation with paper patch after trimming the perforated TM margin with the CO2 laser. The purpose of this report is to demonstrate the trial of this method and effectiveness. The authors conducted a retrospective case series from March 2000 to January 2005. Ninety patients underwent paper-patch myringoplasty with the CO2 laser. The procedure was performed in an office setting under local anesthesia. We investigated perforation size and postoperative success rate. Successful closure of the TM was achieved in 52.2% of cases (47/90) without any severe complication. The procedure was successful in 16 of 19 (84.2%) cases in perforation smaller than 2 mm, 19 of 29 (63.0%) cases when the size was 2-4 mm, 10 of 25 (40.0%) cases when the size was 4-6 mm, and 2 of 17 (11.8%) cases when the size was > or =6 mm. A significant difference was found: Perforation with <4 mm had the higher closure rate (chi2 test, P < 0.01). There was no correlation between the size of perforation and the number of patch graft (chi2 test, P > 0.05). The results showed paper-patch myringoplasty after CO2 laser trimming is simple and safe to perform, and suitable as an outpatient procedure, especially in small perforations (<4 mm).

According to the amyloid cascade hypothesis, Alzheimer's disease is the consequence of neuronal cell death induced by beta-amyloid (Abeta), which accumulates by abnormal clearance or production. On the other hand, recent studies have shown cell death-induced alteration in amyloid precursor protein (APP) processing, suggesting potential mutual interactions between APP processing and cell death. We have shown previously that the cell death caused by DNA damage-inducing agents (DDIAs) facilitated gamma-secretase activity and Abeta generation in a Bax/Bcl-2-dependent, but caspase-independent manner. Here, we attempted to elucidate the downstream mechanism that modulates gamma-secretase activity in DDIA-treated cells. N-acetyl cysteine, a potent antioxidant, attenuated DDIA-induced enhancement of gamma-secretase activity but failed to rescue cell death. Overexpression of heat shock protein 70, which blocks cytochrome c release from mitochondria, also reduced gamma-secretase activity. Moreover, glutathione depletion significantly facilitated gamma-secretase activity and Abeta generation by enhancing the formation of higher molecular weight gamma-secretase complex before signs of cell death developed. Finally, Abeta treatment, a known inducer of oxidative stress, also increased gamma-secretase activity. Taken together, these results indicate that DDIA-induced gamma-secretase activation is dependent on augmented oxidative stress, and that Abeta and gamma-secretase may activate each other. On the basis of these results, we propose a feed-back loop between oxidative stress and Abeta generation mediated by gamma-secretase activation.

This paper documents a study of an Au nano-dot array that was fabricated by electron beam lithography on a glass wafer. The patterns that had features of 100 nm dots in diameter with a 2-mum pitch comprised a total area of 200 x 200 microm(2). The dot-shaped Cr underlayer was open to the air after developing Poly(methyl methacrylate) (PMMA). When dipped into the Cr etchant, the exposed Cr layer was eliminated from the glass wafer in a short period of time. In order to ultimately fabricate the Ti/Au dot arrays, Ti and Au were deposited onto the arrays with a thickness of 2 and 40 nm, respectively. The lift-off procedure was carried out in the Cr etchant using sonication in order to completely remove the residual Cr/PMMA layer. The fabricated Au nano-dot array was then immersed in an Ag enhancing solution and then into an ethanol solution containing (N-(6-(Biotinamido)hexyl)-3'-(2'-pyridyldithio)-propionamide (Biotin-HPDP). The substrate was analyzed using a correlated atomic force microscopy (AFM) and confocal Raman spectroscopy. Through this procedure, position-dependent surface-enhanced Raman spectroscopy (SERS) signals could be obtained.

Purpose: Many studies have shown that subjects show a change of vocal fundamental frequency (F0) when phonating subjects hear their vocal pitch feedback shifted upward or downward. This study was performed to demonstrate whether vocal parameters [F0, intensity, jitter, shimmer, and noise to harmonic ratio (NHR)] in normal males respond to changes in frequency of pure tone masking., Materials and Methods: Twenty healthy male subjects participated in this study. Subjects vocalized /a/ vowel sounds while listening to a pitch- shift pure tone through headphones (upward pitch-shift in succession: 1 kHz to 2 kHz and 1 kHz to 4 kHz at 50 dB or 80 dB, respectively, downward pitch-shift in succession: 1 kHz to 250 Hz and 1 kH to 500 Hz at 50 dB or 80 dB, respectively)., Results: Vocal intensity, F0, was increased, whereas jitter was decreased as the pitch of pure tone was shifted upward. However, there was no correlation between shimmer and NHR with pitch-shift feedback for pure tones. Unlike vocal pitch- shift feedback in other studies, upward pitch-shift feedback of pure tones caused the vocal F0 and intensity to change in the same direction as pitch-shift., Conclusion: The results of this study demonstrated that auditory kinesthetic feedback is affected by pitch-shift in pure tone.

Objectives: We previously showed that a trained tenor's voice has the conventional singer's formant at the region of 3 kHz and another energy peak at 8-9 kHz. Singers in other operatic voice ranges are assumed to have the same peak in their singing and speaking voice. However, to date, no specific measurement of this has been made., Methods: Tenors, baritones, sopranos and mezzo sopranos were chosen to participate in this study of the singer's formant and the speaker's ring resonance. Untrained males (n=15) and females (n=15) were included in the control group. Each subject was asked to produce successive /a/ vowel sounds in their singing and speaking voice. For singing, the low pitch was produced in the chest register and the high notes in the head register. We collected the data on the long-term average spectra of the speaking and singing voices of the trained singers and the control groups., Results: For the sounds produced from the head register, a significant energy concentration was seen in both 2.2-3.4 kHz and 7.5-8.4 kHz regions (except for the voices of the mezzo sopranos) in the trained singer group when compared to the control groups. Also, the chest register had a significant energy concentration in the 4 trained singer groups at the 2.2-3.1 kHz and 7.8-8.4 kHz. For speaking sound, all trained singers had a significant energy concentration at 2.2-5.3 kHz and sopranos had another energy concentration at 9-10 kHz., Conclusion: The results of this study suggest that opera singers have more energy concentration in the singer's formant/speaker's ring region, in both singing and speaking voices. Furthermore, another region of energy concentration was identified in opera singer's singing sound and in sopranos' speaking sound at 8-9 kHz. The authors believe that these energy concentrations may contribute to the rich voice of trained singers.

Purpose: Numerous methods have been utilized to repair nasal septal perforation with varying degrees of success; however, no consensus has been reached on nasoseptal perforation repair. Here, the authors describe a surgical method based on human dermal allograft (Surederm, Hans Biomed Corp. Korea) for the repair of nasal septal perforations., Materials and Methods: Eleven patients with a nasal septal perforation were included in this study. The causes of these septal perforations included previous nasal surgery, trauma, foreign body (button battery), and idiopathy. There were several sites of perforation: 9 in the central area, 1 in the posterior-central area, and 1 in the anterior area. An interpositional graft incorporating Surederm was positioned between bilateral mucoperichondrial flaps using an intranasal approach. A silastic sheet was then left in the nasal septum bilaterally until complete healing had occurred through new nasal mucosa, which took a mean duration of 6 weeks., Results: Outcomes in ten of the eleven patients were successful, with complete septal perforation closure. The remaining perforation, which was caused by a button battery, closed incompletely; however, its initial size of 2 cm was reduced to 5 mm., Conclusion: The described technique has a high success rate and can be performed under local anesthesia without external scarring. In the absence of donor site morbidity, this technique can also be utilized to repair posterior or multiple septal perforations without difficulty.

Objective: We examined the incidence of nodal involvement and attempted to determine the predictive factors for central compartment lymph node (LN) metastasis in thyroid papillary microcarcinoma (PMC)., Study Design: Retrospective chart review., Methods: We undertook a retrospective study of 52 patients treated between January 2000 and December 2005 for PMC by total thyroidectomy and elective central compartment LN dissection with or without comprehensive lateral neck dissection (n = 9). There were 45 women and 7 men whose mean age was 47.6 +/- 11.5 years. The following criteria were used to study the predictive value of central compartment LN metastasis: sex, age, multifocality of the tumor, extracapsular spread (ECS), the involvement of the lateral neck LN, tumor size, and tumor location., Results: In 16 of 52 (31%) patients, central compartment LN metastasis was found. With use of univariate and multivariate analysis, ECS, lateral LN metastasis, and tumor size (>5 mm) were independent correlates of central compartment metastasis. Sex, age, multifocality, and tumor location were not associated with central compartment LN metastasis and did not significantly influence the predictive value of these variables., Conclusions: We found a significant association among ECS, lateral LN metastasis, tumor size (>5 mm), and central compartment LN metastasis in patients with PMC. A prophylactic neck dissection of the central compartment should be considered particularly in patients with ECS of the tumors, metastatic LN in the lateral neck, and a greater than 5 mm tumor size.

A variety of approaches have been introduced to perform injection laryngoplasty under local anesthesia. Among these reported methods, transcutaneous injection through the cricothyroid space offers many advantages, but it possesses some technical difficulties during access to the vocal fold. The aim of this study was to assess the anatomic references related to transcutaneous injection laryngoplasty through cricothyroid space using 3-dimensionally reconstructed computed tomography to provide guidelines and to achieve higher efficacy during the procedure. The study group consisted of 14 patients (7 male, 7 female) with unilateral vocal fold paralysis and who had undergone multi-detector array computed tomography (MDCT) between January 2004 and December 2005. Assumption was made that transcutaneous injection is approached from the surface at lower margin of the thyroid cartilage and 7 mm lateral to the midline through the cricothyroid membrane and spot at the posterior 1/3 of true vocal cord is the target for injection laryngoplasty. From the surface of the injection point to the target, a line was drawn. Its length and the angle formed between it and the approach direction of needle was measured. Based on these measurements, 15 patients (8 male, 7 female) with unilateral vocal fold paralysis received 15 trials of transcutaneous injection laryngoplasty through the cricothyroid space. The average length from the surface of the injection point (7 mm lateral to the midline) to the posterior 1/3 of the true vocal cord (target of the injection) was 15.75 mm in men and 13.91 mm in women. The average of the angle in medial direction at the surface needed to reach the target of the injection was 10.57 degrees in men and 12.71 degrees in women, and in superior direction was 47.57 degrees in men and 47.43 degrees in women. Injection laryngoplasty performed under acquired reference measurements were successful in 14 trials (93.3%) out of 15 trials in 15 patients. We suggest that knowledge of the anatomic references regarding the transcutaneous injection laryngoplasty through cricothyroid space will provide guidelines for beginners and improve the understanding of the procedure, eventually leading to easier and more precise access to the vocal cord.

Beta-site APP-cleaving enzyme 1 (BACE1) expression is elevated in the brains of Alzheimer's disease (AD) patients and in aged-animal models. Because both AD and aging are associated with disrupted calcium homeostasis, we investigated the role of nuclear factor of activated T cells (NFAT) - a transcription factor regulated by the calcium- and calmodulin-dependent phosphatase calcineurin - in BACE1 expression. BACE1 expression was stimulated by a calcium ionophore in primary cortical cultures, and by SH-SY5Y neuroblastoma cells, which was both blocked by pretreatment with either cyclosporin A, an inhibitor of calcineurin, or ethyleneglycotetraacetic acid, a calcium chelator. Gel shift assays revealed direct binding of NFAT1 to specific DNA sequences within the BACE1 gene promoter region. Treatment with amyloid beta (Abeta), one of the major factors in AD pathogenesis, stimulated activation and nuclear translocation of NFAT1 following up-regulation of BACE1 expression. In addition, primary cortical cultures from Tg2576 mouse brains generated more Abeta by ionophore stimulation, which was reversed by cyclosporin A treatment. Furthermore, NFAT1 activation was observed in Tg2576 mouse brains. These results suggest that calcium ionophore- or Abeta-induced increases in intracellular calcium concentration stimulate BACE1 expression, resulting in accelerated Abeta generation, and that this process is mediated through the calcineurin-NFAT1 signaling pathway. This process may play a significant role in the pathogenesis of AD and aging.

We examined whether alterations in vascular endothelial function and early structural changes in atherosclerosis are associated with microvascular complications in patients with type 1 diabetes mellitus (DM). Flow-mediated dilation (FMD) of the brachial artery and carotid intima-media thickness (IMT) measurement were performed in 70 young adults (aged 19 to 35 yr), 48 with type 1 DM, and 22 normal controls. Patients with diabetes had a lower peak FMD response (7.8+/-3.9 vs. 11.1+/-1.9%, p<0.001) and increased IMT (0.51+/-0.10 vs. 0.42+/-0.07 mm, p<0.001) compared with controls. Twenty (41.7%) of the patients had microvascular complications including neuropathy, nephropathy, or retinopathy. In these complicated diabetic patients, we found a lower FMD response (6.1+/-2.5 vs. 9.9+/-3.5%, p=0.001) compared with diabetics without microvascular complications. The presence of microvascular complications was also associated with older age and longer duration of the disease. However, no differences were observed in IMT, body size, blood pressure, HbA1c, C-reactive protein, low-density lipoprotein or high-density lipoprotein cholesterol levels between complicated and non-complicated patients. Endothelial dysfunction and early structural atherosclerotic changes are common manifestations in type 1 DM, and endothelial dysfunction is thought to be an early event in the atherosclerotic process and important in the pathogenesis of microvascular complications.

This prospective study attempts to explore the effect of glycerol on vestibular evoked myogenic potential (VEMP) in patients with definite unilateral Meniere's disease (MD) and to investigate whether the test reflects different pathologic states of endolymphatic hydrops (EH) in the inner ear by comparing the results of glycerol pure tone audiometry (PTA). Twenty-eight patients with definite unilateral MD were studied. As a control group, 11 patients with vestibular neuritis were selected. Sixteen ears of normal volunteers were enrolled to acquire normal range of the test. Each MD patient underwent glycerol testing measure with both conventional PTA and VEMP testing. Eleven vestibular neuritis patients also underwent glycerol-VEMP testing. The difference ratio was adopted to compare the changes in p1-n1 amplitude and latency of VEMP after the administration of glycerol (1.3 g/kg). Significant changes in the VEMP wave after the glycerol loading were seen in amplitude, but not in latency with MD patients. On the affected side, the amplitude of the p1-n1 biphasic wave significantly increased in 11 of 28 (39.3%) ears and decreased in 2 (7.1%) ears. On the unaffected side, 5 (17.9%) ears showed significant increase in amplitude. Significant changes in PTA were noted after administration of glycerol in 14 of 28 (50%) patients with MD. However, there was no statistically significant correlation between the test results. Glycerol administration had no significant effect on VEMP in patients with vestibular neuritis. The amplitude of VEMP in some patients with MD was increased, but the latency was not influenced by oral administration of glycerol. The severity of EH appears to vary in different parts of the inner ear. Glycerol-VEMP test results in patients with vestibular neuritis suggest that the VEMP reflects potential abnormality in the sacculocollic pathway, while glycerol-VEMP identifies the existence of EH in the saccule. VEMP and PTA after glycerol administration provide potential status of MD.

We aimed to determine the outcome of small (<10 mm) solid noncalcified pulmonary nodules detected by chest computed tomography (CT) scans. Reports of low-dose chest CT scans performed from October 2003 to April 2005 at the Seoul National University Hospital Healthcare System Gangnam Center were reviewed to identify patients with solid noncalcified pulmonary nodules smaller than 10 mm. Partly solid and nonsolid nodules or nodules without follow-up imaging within 1 year were excluded. Records were studied to determine if the initial nodules had changed in size. A total of 3478 chest CT examinations were performed, with 232 patients having small noncalcified nodules (6.7%). One hundred and thirty-eight patients met the criteria (104 men and 34 women) and 213 nodules were identified. The median age was 54 years (range 32-80) and at least 86 patients (62%) were at low to intermediate risk for developing lung cancer. The largest nodule was less than 5 mm in diameter in 87 patients (63%) and 5 mm or more in 51 patients (37%). None of the nodules grew and 29 (14%) decreased in size at follow-up CT scans performed within 12 months. When those individuals at low to intermediate risk for lung cancer were included, solid noncalcified subcentimeter nodules were less frequently found in low-dose CT screening and were nearly unchanged in size when a follow-up CT scan was done within 12 months.

Background: This study was performed to evaluate the endothelial function in Fontan patients, and to investigate the associated factors which influence the endothelial function in these patients., Methods: Flow mediated dilatation (FMD) and nitroglycerin induced dilatation (NG) of the brachial artery, and intima media thickness (IMT) of common carotid artery (CCA) were measured in nonselected Fontan patients (n=44, age 5 to 29 years, median 14 years, 18 females) by means of high-resolution ultrasound according to the standard protocols. The results were compared to age and sex matched controls (n=25, age 5 to 27 years, median 13 years, 10 females)., Results: Fontan patients presented significantly reduced FMD and NG compared with controls (FMD; 6.5+/-2.4 vs. 11.1+/-1.4%, p<0.001, NG; 13.3+/-5.2 vs. 19.4+/-6.2%; p=0.035). Twenty two percent of Fontan patients presented pure endothelial dysfunction, and 34% of patients presented combined endothelial and smooth muscle dysfunction. Although there was no correlation between FMD and IMT, Fontan patients presented increased carotid IMT (0.44+/-0.07 vs. 0.38+/-0.06 mm, p=0.008). In multivariate analysis, duration of exposure to chronic hypoxia was inversely correlated with FMD (p=0.117, hazards ratio=1.294, 95% confidence interval=0.938-1.786). There was higher FMD in patients receiving angiotensin-converting enzyme inhibitors (ACEi) compared with those not receiving ACEi (7.0+/-2.5 vs. 5.5+/-2.2%, p=0.069)., Conclusions: Endothelial dysfunction is more prevalent in Fontan patients compared with healthy controls, and the previous hypoxia is an independent factor. Although it is not statistically significant, those patients on treatment with ACEi seem to have better endothelial function.

Objective: The purpose of this study was to analyze the psychological characteristics of patients with vocal nodules and to establish the relationship between these characteristics and the development of vocal nodules., Setting: A tertiary medical centre., Design and Method: The patient group consisted of 41 housewives with vocal nodules, and the control group consisted of 35 housewives who did not have any vocal pathology. The subjects completed questionnaires related to the voice disorder and the Symptom Checklist-90-Revision., Outcome Measures: The scores of the patient group with less than 1 year of symptom duration (acute) and more than 1 year of symptom duration (chronic) were also compared with those of the controls., Results and Conclusion: The total patient group differed statistically from the control group on seven neurotic dimensions (p < .001) and one psychotic dimension (p < .05). The acute group differed on two neurotic dimensions (p < .05). We suggest that the neurotic traits found in the acute group may play a role in the development of vocal nodules. The dimensions in which the total patient group differed significantly from the control group may indicate the changes that occur in the psychological characteristics following voice change. The collective results indicate that psychological characteristics play an important role in the pathogenesis of vocal nodules. Hence, greater attention should be given to the psychological and emotional aspects of patients for the treatment and prevention of vocal nodules.

The purpose of this study was to analyze left ventricular (LV) torsion and untwisting, and to evaluate the correlation between torsion and other components of LV contraction in children with dilated cardiomyopathy (DCM). Segmental and global rotation, rotational rate (Vrot) were measured at three levels of LV using the two dimensional (2D) speckle tracking imaging (STI) method in 10 DCM patients (range 0.6-15 yr, median 6.5 yr, 3 females) and 17 age- and sex-matched normal controls. Global torsion was decreased in DCM (peak global torsion; 10.9 +/- 4.6 degrees vs. 0.3 +/- 2.1 degrees , p<0.001). Loss of LV torsion occurred mainly by the diminution of counterclockwise apical rotation and was augmented by somewhat less reduction in clockwise basal rotation. In DCM, the normal counterclockwise apical rotation was not observed, and the apical rotation about the central axis was clockwise or slightly counterclockwise (peak apical rotation; 5.9 +/- 4.1 degrees vs. -0.9 +/- 3.1 degrees , p<0.001). Systolic counterclockwise Vrot and early diastolic clockwise Vrot at the apical level were decreased or abolished. In DCM, decreased systolic torsion and loss of early diastolic recoil contribute to LV systolic and diastolic dysfunction. The STI method may facilitate the serial evaluation of the LV torsional behavior in clinical settings and give new biomechanical concepts for better management of patients with DCM.

The observation that human matrix metalloproteinase (MMP)-8 is over-expressed in ectatic bronchi in patients with bronchiectasis suggests that polymorphisms altering the expression of MMP-8 may contribute to the susceptibility to development of bronchiectasis. We evaluated the association between the presence of bronchiectasis in a Korean population and two single nucleotide polymorphisms (SNPs) (-799C/ T and -381A/G) on the promoter region of the MMP-8 gene that are reported to alter the promoter activity and thereby the gene expression. Genotyping through polymerase chain reaction (PCR) and subsequent automatic sequencing was done in 167 patients with bronchiectasis and their age-, sex-matched healthy controls to reveal that only -799C/T is polymorphic among Koreans. In the patient group with bronchiectasis, the frequency of -799C/C, C/T, and T/T genotypes were 41.9%, 49.7%, and 8.4%, respectively. A similar distribution was observed in the control group: C/C (49.7%), C/T (43.1%), and T/T (7.2%) (p=0.36). In subgroup analysis, no significant difference was observed among the patients according to; the extent of disease (p=0.76), colonization of microorganisms (p=0.56), or association of mycobacteria (p=0.17). From these results, we conclude that -799C/T on the promoter region of MMP-8 lacks association with development of bronchiectasis in Koreans.

Combined micro-Raman/UV-visible (vis)/fluorescence spectroscopy system, which can evaluate an integrated array of more than 10,000 microsamples with a minimuma size of 5 microm within a few hours, has been developed for the first time. The array of microsamples is positioned on a computer-controlled XY translation microstage with a spatial resolution of 1 mum so that the spectra can be mapped with micron precision. Micro-Raman spectrometers have a high spectral resolution of about 2 cm(-1) over the wave number range of 150-3900 cm(-1), while UV-vis and fluorescence spectrometers have high spectral resolutions of 0.4 and 0.1 nm over the wavelength range of 190-900 nm, respectively. In particular, the signal-to-noise ratio of the micro-Raman spectroscopy has been improved by using a holographic Raman grating and a liquid-nitrogen-cooled charge-coupled device detector. The performance of the combined spectroscopy system has been demonstrated by the high-throughput screening of a combinatorial ferroelectric (i.e., BaTi(x)Zr(1-x)O(3)) library. This system makes possible the structure analysis of various materials including ferroelectrics, catalysts, phosphors, polymers, alloys, and so on for the development of novel materials and the ultrasensitive detection of trace amounts of pharmaceuticals and diagnostic agents.

Basaloid squamous cell carcinoma (BSCC) is a rare malignancy, with features of both basal cell carcinoma and squamous cell carcinoma. The tumor has a predilection for the upper aerodigestive tract, and has been suggested to behave more aggressively than squamous cell carcinoma (SCC). To the author's knowledge, BSCC confined to the external auditory canal (EAC) has not been previously described. BSCC of EAC manifests similar characteristics as the conventional EAC cancer, presenting a mass with chronic otorrhea and itching sense. Excision of the tumor was accomplished by modified lateral temporal bone resection. This report describes the first case of BSCC in this location, and includes reviews of the pathologic and clinical aspects of this disease.

Beta-site APP cleaving enzyme 1 (BACE1) is an essential enzyme for the production of beta amyloid. Since we found that injection of interferon-gamma (IFN-gamma) into young mouse brains increased BACE1 expression in astrocytes, we investigated molecular mechanisms underlying this process by cloning a putative BACE1 promoter. BACE1 promoter activity was differentially regulated by IFN-gamma in a region specific manner and down-regulated by an inhibitor of Janus kinase 2 (JAK2). A dominant negative mutant of signal transducer and activator of transcription 1 (STAT1) expression suppressed BACE1 promoter activity, and this was rescued by transfecting wild type STAT1. Electrophoretic mobility shift assay and promoter activity assays indicated that STAT1 binds directly to the putative STAT1 binding sequence of BACE1 promoter. Because IFN-gamma treatment induced STAT1 phosphorylation, we examined whether the expression of a suppressor of cytokine signaling (SOCS), negative regulator of JAK2, suppresses BACE1 promoter activity. The results show that SOCS1 or SOCS3 expression suppressed BACE1 promoter by blocking phosphorylation of Tyr701 residue in STAT1. Also, because IFN-gamma treatment specifically potentiated extracellular signal regulated MAP kinase (ERK) 1/2 activation, pretreatment of mitogen-activated or extracellular signal-regulated protein kinase (MEK) inhibitor, PD98059, significantly attenuated IFN-gamma-induced BACE1 promoter activity and protein expression through blocking phosphorylation of Ser727 residue in STAT1, suggesting that ERK1/2 is associated with IFN-gamma-induced STAT1 signaling cascade. Taken together, our results suggest that IFN-gamma activates JAK2 and ERK1/2 and then phosphorylated STAT1 binds to the putative STAT1 binding sequences in BACE1 promoter region to modulate BACE1 protein expression in astrocytes., (Copyright 2006 Wiley-Liss, Inc.)

Background: Chronic airway inflammation and airway remodeling are important features of bronchial asthma. IL-11 is one of the important mediators involved in the process of airway inflammation and remodeling. Cysteinyl leukotrienes (cysLTs) play roles in recruitment of inflammatory cells, airway smooth muscle contraction, vascular leakage, increased mucus secretion, decreased mucociliary clearance, and airway fibrosis., Objective: An aim of the present study was to determine the effect of the cysLTs on the regulation of IL-11 expression., Methods: We used a C57BL/6 mouse model of allergic airway disease and murine tracheal epithelial cells to examine the effects of cysLTs on the regulation of IL-11 expression., Results: Our present study with an ovalbumin-induced murine model of allergic airway disease revealed that levels of leukotriene C(4) (LTC(4)) in bronchoalveolar lavage fluids were increased and that administration of montelukast or pranlukast reduced the increased levels of LTC(4); the increased expression of IL-11 protein and mRNA in lung tissues; airway inflammation, bronchial hyperresponsiveness; the increased levels of TGF-beta(1), IL-4, and IL-13 in bronchoalveolar lavage fluids and lung tissues; and airway fibrosis. In addition, LTC(4) stimulates epithelial cells to produce IL-11. Our results also showed that cysLT type 1 receptor antagonists downregulated the activity of a transcription factor, nuclear factor kappaB, and BAY 11-7085 substantially reduced the increased levels of IL-11 after ovalbumin inhalation., Conclusion: These results suggest that cysLTs regulate the IL-11 expression in allergic airway disease., Clinical Implications: These findings provide one of the molecular mechanisms for the effects of cysLTs on airway inflammation and fibrosis in allergic airway diseases.