Erratum: Valproic Acid Induces Telomerase Reverse Transcriptase Expression during Cortical Development

In the ‘Acknowledgements’ section on page 263 of the original article, the grant number was incorrectly stated.

Sex Differences in Autism-Like Behavioral Phenotypes and Postsynaptic Receptors Expression in the Prefrontal Cortex of TERT Transgenic Mice

Autism spectrum disorder (ASD) remains unexplained and untreated despite the high attention of research in recent years. Aside from its various characteristics is the baffling male preponderance over the female population. Using a validated animal model of ASD which is the telomerase reverse transcriptase overexpressing mice (TERT-tg), we conducted ASD-related behavioral assessments and protein expression experiments to mark the difference between male and females of this animal model. After statistically analyzing the results, we found significant effects of TERT overexpression in sociability, social novelty preference, anxiety, nest building, and electroseizure threshold in the males but not their female littermates. Along these differences are the male-specific increased expressions of postsynaptic proteins which are the NMDA and AMPA receptors in the prefrontal cortex. The vGluT1 presynaptic proteins, but not GAD, were upregulated in both sexes of TERT-tg mice, although it is more significantly pronounced in the male group. Here, we confirmed that the behavioral effect of TERT overexpression in mice was male-specific, suggesting that the aberration of this gene and its downstream pathways preferentially affect the functional development of the male brain, consistent with the male preponderance in ASD.

Sex Differences in Autism-Like Behavioral Phenotypes and Postsynaptic Receptors Expression in the Prefrontal Cortex of TERT Transgenic Mice

Autism spectrum disorder (ASD) remains unexplained and untreated despite the high attention of research in recent years. Aside from its various characteristics is the baffling male preponderance over the female population. Using a validated animal model of ASD which is the telomerase reverse transcriptase overexpressing mice (TERT-tg), we conducted ASD-related behavioral assessments and protein expression experiments to mark the difference between male and females of this animal model. After statistically analyzing the results, we found significant effects of TERT overexpression in sociability, social novelty preference, anxiety, nest building, and electroseizure threshold in the males but not their female littermates. Along these differences are the male-specific increased expressions of postsynaptic proteins which are the NMDA and AMPA receptors in the prefrontal cortex. The vGluT1 presynaptic proteins, but not GAD, were upregulated in both sexes of TERT-tg mice, although it is more significantly pronounced in the male group. Here, we confirmed that the behavioral effect of TERT overexpression in mice was male-specific, suggesting that the aberration of this gene and its downstream pathways preferentially affect the functional development of the male brain, consistent with the male preponderance in ASD.

Valproic Acid Induces Telomerase Reverse Transcriptase Expression during Cortical Development

The valproic acid (VPA)-induced animal model is one of the most widely utilized environmental risk factor models of autism. Autism spectrum disorder (ASD) remains an insurmountable challenge among neurodevelopmental disorders due to its heterogeneity, unresolved pathological pathways and lack of treatment. We previously reported that VPA-exposed rats and cultured rat primary neurons have increased Pax6 expression during post-midterm embryonic development which led to the sequential upregulation of glutamatergic neuronal markers. In this study, we provide experimental evidence that telomerase reverse transcriptase (TERT), a protein component of ribonucleoproteins complex of telomerase, is involved in the abnormal components caused by VPA in addition to Pax6 and its downstream signals. In embryonic rat brains and cultured rat primary neural progenitor cells (NPCs), VPA induced the increased expression of TERT as revealed by Western blot, RT-PCR, and immunostainings. The HDAC inhibitor property of VPA is responsible for the TERT upregulation. Chromatin immunoprecipitation revealed that VPA increased the histone acetylation but blocked the HDAC1 binding to both Pax6 and Tert genes. Interestingly, the VPA-induced TERT overexpression resulted to sequential upregulations of glutamatergic markers such as Ngn2 and NeuroD1, and inter-synaptic markers such as PSD-95, α-CaMKII, vGluT1 and synaptophysin. Transfection of Tert siRNA reversed the effects of VPA in cultured NPCs confirming the direct involvement of TERT in the expression of those markers. This study suggests the involvement of TERT in the VPA-induced autistic phenotypes and has important implications for the role of TERT as a modulator of balanced neuronal development and transmission in the brain.

Effects of Triclosan on Neural Stem Cell Viability and Survival

Triclosan is an antimicrobial or sanitizing agent used in personal care and household products such as toothpaste, soaps, mouthwashes and kitchen utensils. There are increasing evidence of the potentially harmful effects of triclosan in many systemic and cellular processes of the body. In this study, we investigated the effects of triclosan in the survivability of cultured rat neural stem cells (NSCs). Cortical cells from embryonic day 14 rat embryos were isolated and cultured in vitro. After stabilizing the culture, triclosan was introduced to the cells with concentrations ranging from 1 muM to 50 muM and in varied time periods. Thereafter, cell viability parameters were measured using MTT assay and PI staining. TCS decreased the cell viability of treated NSC in a concentration-dependent manner along with increased expressions of apoptotic markers, cleaved caspase-3 and Bax, while reduced expression of Bcl2. To explore the mechanisms underlying the effects of TCS in NSC, we measured the activation of MAPKs and intracellular ROS. TCS at 50 muM induced the activations of both p38 and JNK, which may adversely affect cell survival. In contrast, the activities of ERK, Akt and PI3K, which are positively correlated with cell survival, were inhibited. Moreover, TCS at this concentration augmented the ROS generation in treated NSC and depleted the glutathione activity. Taken together, these results suggest that TCS can induce neurodegenerative effects in developing rat brains through mechanisms involving ROS activation and apoptosis initiation.

Clinical and Neurobiological Relevance of Current Animal Models of Autism Spectrum Disorders

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social and communication impairments, as well as repetitive and restrictive behaviors. The phenotypic heterogeneity of ASD has made it overwhelmingly difficult to determine the exact etiology and pathophysiology underlying the core symptoms, which are often accompanied by comorbidities such as hyperactivity, seizures, and sensorimotor abnormalities. To our benefit, the advent of animal models has allowed us to assess and test diverse risk factors of ASD, both genetic and environmental, and measure their contribution to the manifestation of autistic symptoms. At a broader scale, rodent models have helped consolidate molecular pathways and unify the neurophysiological mechanisms underlying each one of the various etiologies. This approach will potentially enable the stratification of ASD into clinical, molecular, and neurophenotypic subgroups, further proving their translational utility. It is henceforth paramount to establish a common ground of mechanistic theories from complementing results in preclinical research. In this review, we cluster the ASD animal models into lesion and genetic models and further classify them based on the corresponding environmental, epigenetic and genetic factors. Finally, we summarize the symptoms and neuropathological highlights for each model and make critical comparisons that elucidate their clinical and neurobiological relevance.

Repeated Neonatal Propofol Administration Induces Sex-Dependent Long-Term Impairments on Spatial and Recognition Memory in Rats

Propofol is an anesthetic agent that gained wide use because of its fast induction of anesthesia and rapid recovery post-anesthesia. However, previous studies have reported immediate neurodegeneration and long-term impairment in spatial learning and memory from repeated neonatal propofol administration in animals. Yet, none of those studies has explored the sex-specific long-term physical changes and behavioral alterations such as social (sociability and social preference), emotional (anxiety), and other cognitive functions (spatial working, recognition, and avoidance memory) after neonatal propofol treatment. Seven-day-old Wistar-Kyoto (WKY) rats underwent repeated daily intraperitoneal injections of propofol or normal saline for 7 days. Starting fourth week of age and onwards, rats were subjected to behavior tests including open-field, elevated-plus-maze, Y-maze, 3-chamber social interaction, novel-object-recognition, passive-avoidance, and rotarod. Rats were sacrificed at 9 weeks and hippocampal protein expressions were analyzed by Western blot. Results revealed long-term body weight gain alterations in the growing rats and sex-specific impairments in spatial (female) and recognition (male) learning and memory paradigms. A markedly decreased expression of hippocampal NMDA receptor GluN1 subunit in female- and increased expression of AMPA GluR1 subunit protein expression in male rats were also found. Other aspects of behaviors such as locomotor activity and coordination, anxiety, sociability, social preference and avoidance learning and memory were not generally affected. These results suggest that neonatal repeated propofol administration disrupts normal growth and some aspects of neurodevelopment in rats in a sex-specific manner.

Effects of Atomoxetine on Hyper-Locomotive Activity of the Prenatally Valproate-Exposed Rat Offspring

A substantial proportion of patients with autism spectrum disorder (ASD) display hyperactivity as a comorbid symptom. Exposure to valproic acid (VPA) during pregnancy produces ASD-like core behavioral phenotypes as well as hyperactivity in offspring both in human and experimental animals, which makes it a plausible model to study ASD-related neurobiological processes. In this study, we examined the effects of two of currently available attention defecit hyperactivity disorder (ADHD) medications, methylphenidate (MPH) and atomoxetine (ATX) targeting dopamine and norepinephrine transporters (DAT and NET), respectively, on hyperactive behavior of prenatally VPA-exposed rat offspring. In the prefrontal cortex of VPA exposed rat offspring, both mRNA and protein expression of DAT was increased as compared with control. VPA function as a histone deacetylase inhibitor (HDACi) and chromatin immunoprecipitation experiments demonstrated that the acetylation of histone bound to DAT gene promoter was increased in VPA-exposed rat offspring suggesting epigenetic mechanism of DAT regulation. Similarly, the expression of NET was increased, possibly via increased histone acetylation in prefrontal cortex of VPA-exposed rat offspring. When we treated the VPA-exposed rat offspring with ATX, a NET selective inhibitor, hyperactivity was reversed to control level. In contrast, MPH that inhibits both DAT and NET, did not produce inhibitory effects against hyperactivity. The results suggest that NET abnormalities may underlie the hyperactive phenotype in VPA animal model of ASD. Profiling the pharmacological responsiveness as well as investigating underlying mechanism in multiple models of ASD and ADHD may provide more insights into the neurobiological correlates regulating the behavioral abnormalities.

Valproic Acid Regulates alpha-Synuclein Expression through JNK Pathway in Rat Primary Astrocytes

Although the role of alpha-synuclein aggregation on Parkinson's disease is relatively well known, the physiological role and the regulatory mechanism governing the expression of alpha-synuclein are unclear yet. We recently reported that alpha-synuclein is expressed and secreted from cultured astrocytes. In this study, we investigated the effect of valproic acid (VPA), which has been suggested to provide neuroprotection by increasing alpha-synuclein in neuron, on alpha-synuclein expression in rat primary astrocytes. VPA concentration-dependently increased the protein expression level of alpha-synuclein in cultured rat primary astrocytes with concomitant increase in mRNA expression level. Likewise, the level of secreted alpha-synuclein was also increased by VPA. VPA increased the phosphorylation of Erk1/2 and JNK and pretreatment of a JNK inhibitor SP600125 prevented the VPA-induced increase in alpha-synuclein. Whether the increased alpha-synuclein in astrocytes is involved in the reported neuroprotective effects of VPA awaits further investigation.

Gastrointestinal Tract Abnormalities Induced by Prenatal Valproic Acid Exposure in Rat Offspring

In-utero exposure to valproic acid (VPA) has been known as a potent inducer of autism spectrum disorder (ASD), not only in humans, but also in animals. In addition to the defects in communication and social interaction as well as repetitive behaviors, ASD patients usually suffer from gastrointestinal (GI) problems. However, the exact mechanism underlying these disorders is not known. In this study, we examined the gross GI tract structure and GI motility in a VPA animal model of ASD. On embryonic day 12 (E12), 4 pregnant Sprague-Dawley (SD) rats were subcutaneously injected with VPA (400 mg/kg) in the treatment group, and with phosphate buffered saline (PBS) in the control group; the resulting male offspring were analyzed at 4 weeks of age. VPA exposure decreased the thickness of tunica mucosa and tunica muscularis in the stomach and ileum. Other regions such as duodenum, jejunum, and colon did not show a significant difference. In high-resolution microscopic observation, atrophy of the parietal and chief cells in the stomach and absorptive cells in the ileum was observed. In addition, decreased staining of the epithelial cells was observed in the hematoxylin and eosin (H&E)-stained ileum section. Furthermore, decreased motility in GI tract was also observed in rat offspring prenatally exposed to VPA. However, the mechanism underlying GI tract defects in VPA animal model as well as the association between abnormal GI structure and function with ASD is yet to be clearly understood. Nevertheless, the results from the present study suggest that this VPA ASD model undergoes abnormal changes in the GI structure and function, which in turn could provide beneficial clues pertaining to the pathophysiological relevance of GI complications and ASD phenotypes.

The Efficacy of Cimetropium Bromide as a Premedication before Esophagogastroduodenoscopy / 대한소화기내시경학회지

BACKGROUND/AIMS: Cimetropium bromide has been used widely as a premedication for endoscopy; however, there are no subjective data pertaining to the effects of cimetropum bromide as a premedication. Thus, the current study was undertaken to compare the effects of cimetropum bromide with placebo as a premedication for esophagogastroduodenoscopy (EGD). METHODS: Two hundred ninety-nine consecutive outpatients who had undergone EGD were enrolled in this study. Thirty minutes before EGD, the patients were randomly given an intramuscular injection of cimetropium bromide (5 mg) or saline using a placebo-controlled, double-blind, randomized technique. Immediately after EGD, all the patients and endoscopists were requested to fill out the questionnaire form. RESULTS: One-hundred patients were injected with cimetropium bromide and 150 patients were injected with placebo. There was no statistically significant difference in the degree of residual gastric secretions, the peristaltic activity detected by endoscopists, and the comfort experienced by the patients in each study group. CONCLUSIONS: The intramuscular injection of cimetropium bromide (5 mg) as a premedication for EGD was not significantly superior to placebo, at least with respect to subjective parameters, in spite of its broad use.

Prevalence and clinical characteristics of gastroesophageal reflux disease and reflux esophagitis in chuncheon city-Health care examination study / 대한내과학회지

BACKGROUND/AIMS: The aims of this study were to estimate the frequency of symptoms of gastroesophageal reflux disease and reflux esophagitis, to evaluate the difference in characteristics among groups subdivided by symptoms, and to compare clinical features between a reflux esophagitis group and a non reflux esophagitis group in Chuncheon City. METHODS: A total of 1,011 persons who underwent endoscopy for health check up were enrolled between July 1, 2005, and June 30, 2006. All persons were given a validated, self reported questionnaire, which inquired about the presence, frequency, and severity of typical symptoms (heartburn and acid regurgitation) and atypical symptoms. The questionnaire also inquired about smoking, alcohol intake, and Helicobacter pyroli eradication. The subjects were subdivided into typical symptomatic, atypical symptomatic, no discomfort, and asymptomatic groups. RESULTS: The prevalence of heartburn and acid regurgitation occurring at least weekly was 7.5%. Reflux esophagitis, hiatal hernia, smoking, and alcohol intake were more common in males (p<0.05). Ninety eight cases (9.7%) were endoscopically diagnosed as reflux esophagitis, and sixty nine cases (6.8%) were endoscopically suspected esophageal metaplasia (ESEM). Subjects in the symptomatic group more frequently manifested reflux esophagitis than subjects in the asymptomatic group (p<0.05). CONCLUSIONS: The presence of reflux induced symptoms is related to reflux esophagitis, but the intensity and frequency of symptoms are poor predictors of the presence or severity of endoscopic mucosal breaks.

Two Cases of Infective Endocarditis in Burn Patients Requiring Surgical Intervention / 감염과화학요법

No abstract available.

Two Cases of Infective Endocarditis in Burn Patients Requiring Surgical Intervention / 감염과화학요법

No abstract available.

The Early Prognosis of Burn Patients with Elevated Initial Arterial Carboxyhemoglobin Level / 결핵

BACKGROUND: Smoke inhalation injury is an important determinant of mortality in burn patients. The early detection of inhalation injury in burn patients is important because the incidence of respiratory failure after inhalation injury was known to be high, with hypoxemia, pneumonia, and prolonged ventilatory support being commonplace. Acute carbon monoxide poisoning was one feature of smoke inhalation. The purpose of our study were to investigate the clinical characteristics of burn patients whose initial arterial carboxyhemoglobin (COHb) level had been elevated, to assess the clinical impact of COHb for smoke inhalation injury. METHODS: Among 1,416 burn patients had been admitted at our institution from August 1, 2001 to July 31, 2002, 39 patients whose initial arterial COHb level have been more than 5% were included. We compared clinical scoring system for inhalation injury, percent total body surface area (%TBSA) burn, initial chest X-ray findings, APACHE II scores and SAPS II scores between survivors (n=27) and non-survivors (n=12) retrospectively. RESULTS: COHb level were 9.7(5.71% and 10.3(8.81% in survivors and in non-survivors (p>0.05). Mean %TBSA burn of survivors and non-survivors were 16.6+/-17.8% and 60.7+/-28.8% (p<0.001). We did not find any difference in clinical scoring system, initial chest X-ray findings in survivors and in non-survivors. But %TBSA burn, APACHE II and SAPS II scores were high in non-survivors than in survivors significantly. Important factors associated with death were %TBSA burn, APACHE II scores, SAPS II scores, and the most important factor in predicting mortality was %TBSA burn. CONCLUSION: Burn patients with elevated initial arterial COHb level showed poor prognosis, but further study may be performed to know that the effect of COHb on prognosis in burn patients accompanying smoke inhalation.

A Case of Granular Cell Tumor of the Ascending Colon / 대한소화기내시경학회지

A 40-year-old woman was admitted with a history of intermittent abdominal pain at the right lower quadrant area. Colonoscopy showed a 1.5 1.5 cm sized polypoid lesion that had yellowish surface, central depression, and normal mucosal covering. The tumor was removed by endoscopic tumorectomy following injection of hypertonic saline solution with epinephrine for lifting the lesion. The tumor consisted of granular tumor cells which were positive for S-100 protein, NSE, and PAS stain. We report a case of granular cell tumor of the ascending colon with a review of the literature.

Clinical Significance of Atrioventricular Plane Displacement for Evaluating Left Ventricular Diastolic Dysfunction

BACKGROUND AND OBJECTIVES: Atrioventricular plane displacement (AVPD) has been used for evaluating systolic function. However, its relations with other echocardiographic variables reflecting diastolic function are not well documented. This study was designed to assess the relations between AVPD and those echocardiographic variables known to reflect diastolic function, especially using mitral annulus velocity. SUBJECTS AND METHODS: Eighty-seven patients with normal left ventricular (LV) systolic function (normal echocardiography group (Group I, n=44), concentric left ventricular hypertrophy (LVH) group (Group II, n=43)) and 51 patients with LV dysfunction (Group III) were studied. To evaluate the correlation with echocardiographic variables reflecting LV systolic and diastolic function, we measured mitral inflow velocity and mitral annulus Doppler tissue velocity. RESULTS: AVPD was correlated negatively with age, the ratio of early diastolic mitral inflow velocity and early diastolic mitral annulus velocity (E/E'), isovolumic relaxation time, and E/A ratio. AVPD was correlated positively with deceleration time, ejection fraction, and systolic mitral annulus velocity (S'). By multivariate analysis, AVPD was independently correlated with S' (beta=0.4, p<0.001) and E' (beta=0.5, p<0.001) in the normal LV function group, and with S' (beta=0.6, p<0.001) and E/E'(beta=-0.3, p=0.005) in the LV dysfunction group. CONCLUSION: AVPD may be used as a diagnostic tool for evaluating LV diastolic function.

Clinical characteristics of acute renal failure occurring in major burns / 대한내과학회지

BACKGROUND: Acute renal failure (ARF) is not a rare occurrence in severe burns and is an important complication leading to an increase in mortality. This study was undertaken to characterize the ARF occurring in major burn patients and to investigate the impact of burn size and initial serum albumin concentration on the occurrence of ARF and patient survival in major burns. METHODS: The clinical characteristics of 147 adult patients with second- and third-degree burns covering 30% or more of their body surface area were analyzed retrospectively. All patients were admitted over a 1-year period to a single burn intensive care unit in Seoul, Korea. Logistic regression was used to estimate of the relative risks of ARF and mortality associated with the larger burn size and the lower serum albumin level at admission. RESULTS: Mean burned body surface was 60.0+/-21.8% (range, 30 to 100%). Twenty-eight (19.0%) out of 147 patients experienced ARF, defined as a serum creatinine > 2 mg/dL, during the admission. The ARF was preceded by significant hypotension (burn shock), rhabdomyolysis, sepsis or use of aminoglycosides. The occurrence of ARF was not associated with age, sex or burn type. The patients with ARF had larger burn size (79.5+/-15.4% vs. 55.3+/-20.5%, p 65% was associated with a risk of ARF that was 9.9 times and with a risk of death that was 14.2 times as high as that for the burn size 2.5 g/dL. CONCLUSION: When major burns are complicated by ARF, the mortality increases very high. Burn size is an independent predictor of ARF occurring in major burns. Initially depressed serum albumin level is associated with an increase in mortality in the major burn patients.