Epigenetically Upregulated T-Type Calcium Channels Contribute to Abnormal Proliferation of Embryonic Neural Progenitor Cells Exposed to Valproic Acid

Valproic acid is a clinically used mood stabilizer and antiepileptic drug. Valproic acid has been suggested as a teratogen associated with the manifestation of neurodevelopmental disorders, such as fetal valproate syndrome and autism spectrum disorders, when taken during specific time window of pregnancy. Previous studies proposed that prenatal exposure to valproic acid induces abnormal proliferation and differentiation of neural progenitor cells, presumably by inhibiting histone deacetylase and releasing the condensed chromatin structure. Here, we found valproic acid up-regulates the transcription of T-type calcium channels by inhibiting histone deacetylase in neural progenitor cells. The pharmacological blockade of T-type calcium channels prevented the increased proliferation of neural progenitor cells induced by valproic acid. Differentiated neural cells from neural progenitor cells treated with valproic acid displayed increased levels of calcium influx in response to potassium chloride-induced depolarization. These results suggest that prenatal exposure to valproic acid up-regulates T-type calcium channels, which may contribute to increased proliferation of neural progenitor cells by inducing an abnormal calcium response and underlie the pathogenesis of neurodevelopmental disorders.

T-Type Calcium Channels Are Required to Maintain Viability of Neural Progenitor Cells

T-type calcium channels are low voltage-activated calcium channels that evoke small and transient calcium currents. Recently, T-type calcium channels have been implicated in neurodevelopmental disorders such as autism spectrum disorder and neural tube defects. However, their function during embryonic development is largely unknown. Here, we investigated the function and expression of T-type calcium channels in embryonic neural progenitor cells (NPCs). First, we compared the expression of T-type calcium channel subtypes (CaV3.1, 3.2, and 3.3) in NPCs and differentiated neural cells (neurons and astrocytes). We detected all subtypes in neurons but not in astrocytes. In NPCs, CaV3.1 was the dominant subtype, whereas CaV3.2 was weakly expressed, and CaV3.3 was not detected. Next, we determined CaV3.1 expression levels in the cortex during early brain development. Expression levels of CaV3.1 in the embryonic period were transiently decreased during the perinatal period and increased at postnatal day 11. We then pharmacologically blocked T-type calcium channels to determine the effects in neuronal cells. The blockade of T-type calcium channels reduced cell viability, and induced apoptotic cell death in NPCs but not in differentiated astrocytes. Furthermore, blocking T-type calcium channels rapidly reduced AKT-phosphorylation (Ser473) and GSK3β-phosphorylation (Ser9). Our results suggest that T-type calcium channels play essential roles in maintaining NPC viability, and T-type calcium channel blockers are toxic to embryonic neural cells, and may potentially be responsible for neurodevelopmental disorders.

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.

Relationship between Chronic Kidney Disease and Depression in Elderly Koreans Using the 2013 Korea National Health and Nutrition Examination Survey Data / 가정의학회지

BACKGROUND: Depression is prevalent in patients with chronic kidney disease (CKD) and continues to increase in elderly adults. Therefore, the aim of our study was to examine the relationship between CKD and depression in older patients. METHODS: We conducted a cross-sectional study based on 2013 Korea National Health and Nutrition Examination Survey data. In total, data of 973 subjects aged ≥65 years were analyzed, and the estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. RESULTS: The prevalence of depression in older adults was 4.1% in men and 8.8% in women (P=0.004). The prevalence of depression did not differ according to CKD stage in women (normal eGFR and CKD stages 1 and 2 women, 41/474 [8.6%]) vs. CKD stages 3–5 women, 6/63 [9.5%]); however, the prevalence of depression in men with CKD stages 3–5 (8/83 [9.6%]) was significantly higher than in men with normal eGFR and CKD stage 1 and 2 (10/353 [2.8%], P=0.010). Multivariate logistic regression analysis showed that the odds ratio for depression in men with CKD stages 3–5 was 3.822 (95% confidence interval, 1.229 to 11.879) after adjusting for social status and chronic diseases (P=0.021). CONCLUSION: The prevalence of depression was higher in elderly women than in men, while the prevalence of depression increased in elderly men with CKD stages 3–5 and was almost equal to that of women. Therefore, elderly men with progressive renal function impairment should be counseled and monitored for psychological problems.

Plerocercoids of Nybelinia surmenicola (Cestoda: Tentacularidae) in Squids, Todarodes pacificus, from East Sea, the Republic of Korea

A visceral helminth of the squid, Todarodes pacificus, is reported from the East Sea, the Republic of Korea. Total 39 squid samples were purchased from a fish market in Jumunjin-eup, Gangneung-si (City) from August 2014 to July 2015 and were examined for helminth parasites with naked eyes and under a stereomicroscope after opening the abdominal cavity with a pair of scissors. Whitish larval worms were mainly found in the stomach and abdominal cavity of the squid. They were detected in 25 (64.1%) out of 39 squids examined, and the infection density was 7 larvae per infected squid. Spatula-shaped larvae were 8.2×2.0 mm in average size, round to slightly flattened anteriorly, with round hatching posteriorly, and had characteristic 4 tentacles with numerous hooklets in the scolex. The larvae were identified as the plerocercoid stage of Nybelinia surmenicola by their morphological features. This finding represents a new host record and the first report of N. surmenicola infection in T. pacificus squids from the east coast of Korea.

Exploring the Validity of Valproic Acid Animal Model of Autism

The valproic acid (VPA) animal model of autism spectrum disorder (ASD) is one of the most widely used animal model in the field. Like any other disease models, it can't model the totality of the features seen in autism. Then, is it valid to model autism? This model demonstrates many of the structural and behavioral features that can be observed in individuals with autism. These similarities enable the model to define relevant pathways of developmental dysregulation resulting from environmental manipulation. The uncovering of these complex pathways resulted to the growing pool of potential therapeutic candidates addressing the core symptoms of ASD. Here, we summarize the validity points of VPA that may or may not qualify it as a valid animal model of ASD.

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.

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.

A Case of Membranous Glomerulonephritis Presenting with Right Common Iliac Artery Thrombosis as the Initial Sign / 대한내과학회지

Most patients with nephrotic syndrome visit the hospital because of edema due to hypoalbuminemia induced by severe proteinuria. However, rare cases have reported arterial thrombosis as the main problem complicating nephrotic syndrome. Arterial thrombosis combined with nephrotic syndrome is rarer than venous thrombosis, and it usually develops during treatment with steroids or diuretics. Arterial thrombosis is rarely diagnosed as the initial sign of nephrotic syndrome. We report the case of a 38-year-old-woman with membranous glomerulonephritis presenting with right common iliac artery thrombosis as the initial sign.

Serum Cystatin C Reflects the Progress of Albuminuria

BACKGROUND: Research on the relationship between urinary albumin excretion and serum cystatin C in diabetes is restricted to cross-sectional studies. In this study, we investigated how well serial measurements of serum cystatin C level reflect changes in the urinary albumin excretion rate. METHODS: We enrolled and retrospectively collected data on 1,058 participants with type 2 diabetes who were older than 18 years and who had more than 3 years of follow-up with serial measurements of albuminuria and serum cystatin C at an outpatient clinic. RESULTS: With the use of a linear mixed model, we found that the albuminuria level for each patient over time corresponded with the annual change in serum cystatin C-based estimated glomerular filtration rate (cysC-eGFR) but did not correspond with the creatinine-based eGFR calculated by the modification of diet in renal disease formula (MDRD-eGFR). The discrepancy in the direction of the trend was smaller with cysC-eGFR than with MDRD-eGFR. CONCLUSION: Serum cystatin C level reflects the trend in albuminuria level more accurately than serum creatinine level in Korean type 2 diabetes mellitus patients.

A Case of Paroxysmal Atrial Fibrillation after Electric Injury / 대한내과학회지

Electrical injuries can cause cardiac abnormalities, ranging from dysrhythmias to myocardial infarction. Atrial fibrillation after electrical injury is extremely rare. The mechanisms underlying electrical current-induced arrhythmias are unclear. However, due to differences in electrical resistance, current travels preferentially along blood vessels and nerves, making the heart the most susceptible organ to electrical injury. Cardiac arrhythmias may occur at the time of electrical injury or later, but most occur within the first day of injury. Almost all patients described in previous reports with atrial fibrillation developed the condition after high voltage injuries (> 1,000 V). In our case, however, atrial fibrillation developed after a low voltage injury (220 V). Atrial fibrillation was detected and the rate was controlled with intravenous digoxin infusion. A normal sinus rhythm was restored 21 h after the electrical injury.

Renal cell carcinoma developed in a patient treated with huge simple renal cyst sclerotherapy / 대한내과학회지

Simple renal cysts are a common cystic disease of the kidneys, which is not symptomatic in most cases and is diagnosed by radiological examination. However, if the cyst is huge or symptomatic, it must be treated. Renal cyst aspiration and alcohol sclerotherapy is a safe and effective treatment for symptomatic simple renal cysts. Simple renal cysts have benign clinical features in the main and transformation of a simple renal cyst into renal cell carcinoma has rarely been reported. However, one case of renal cell carcinoma during renal cyst follow-up has been reported. We report a case of renal cell carcinoma that developed in a patient who was being treated with huge simple renal cyst sclerotherapy.

The Clinical Characteristics of the Newly Diagnosed Early Onset (< 40 Years Old) Diabetes in Outpatients' Clinic / 당뇨병

BACKGROUND: The prevalence of type 2 diabetes in young adults and adolescents has increased in the last decade according to the increasing obese population. The aim of this study was to examine the clinical characteristics of patients diagnosed with diabetes mellitus before the age of 40 years as compared with patients diagnosed at older ages. METHODS: This was a cross-sectional, retrospective study using data from 350 diabetic patients who were diagnosed with diabetes in an outpatient setting between January 2005 and December 2007. Patients were diagnosed according to the criteria set forth by the American Diabetes Association. We examined the clinical characteristics and laboratory data of the patients through review of medical records and compared the early-onset diabetic patients ( or = 40 years old). RESULTS: The frequency of early-onset diabetes and usual-onset diabetes were 31.1% (n=109) and 68.9% (n=241), respectively. The early-onset diabetic patients more often had a positive family history of diabetes; higher HbA1c, fasting glucose, and postprandial glucose levels; experienced typical symptoms more frequently; had microalbuminuria more frequently; and required insulin therapy as initial treatment more frequently as compared to usual-onset diabetic patients, and these differences were significant. Conversely, hypertension was significantly more common in the usual-onset diabetic patients. CONCLUSION: It could be concluded that we should control early onset diabetes more strictly to prevent its complication because early onset diabetic patients represented more severe hyperglycemia and had more prevalent microalbuminuria.

A Case of Malignant Lymphoma in Patient with Ulcerative Colitis / 대한소화기내시경학회지

Ulcerative colitis has been recognized as a premalignant condition because a considerable proportion of patients with colitis eventually develop colorectal carcinoma at the site of the inflammatory disease. Malignant lymphoma occurring in cases of long-standing ulcerative colitis is rare. Cancer risk is positively correlated with duration and anatomic extent of colitis, but do not appear to be increased by early age at onset of disease. Patients with chronic ulcerative colitis should have periodic rectal and colonoscopic biopsies, and those with moderate to marked dysplasia require colectomy because of the increased risk of colon carcinoma. We report a case of malignant lymphoma in patient with ulcerative colitis.

A Clinical Investigation of Community-Acquired Pneumonia in Mokpo Area / 결핵

BACKGROUND: Community-acquired pneumonia(CAP) remains a leading cause of morbidity and mortality worldwide. Recently, the evolution of drug-resistant microorganisms has become a serious problem in CAP management. Specific antimicrobial therapy is the cornerstone of CAP management. However, obtaining an accurate etiologic diagnosis clinically is not easy and empirical antimicrobial treatment is usually administered prior to the correct microbiologic diagnosis. In this study, the clinical usefulness of empirical CAP treatment was investigated. METHODS: A total 35 cases were studied prospectively over a 16-month period in Mokpo Catholic Hospital from Dec. 1995 to Mar. 1997. The microbiologic diagnosis was made by sputum, blood culture, a specific serum antibody test and an immunologic study. RESULTS: The causative organisms were isolated in 10 (30%) out of 33 cases: 8 cases and 1 case on the sputum culture and blood culture respectively, and 1 case by an indirect hemagglutinin test. 12 cases had underlying diseases: pulmonary tuberculosis 4, alcoholism 4, diabetes mellitus 3, and liver cirrhosis 1. Antimicrobial treatment was given empirically and all cases recovered. CONCLUSION: A definite microbiologic diagnosis before commencing the appropriate treatment in CAP is not straightforward. Empirical therapy according to a clinical assessment is important and helpful. However, every effort to make the correct etiologic diagnosis should be taken.

A comparative study on initial pleural fluid findings of tuberculous pleurisy between patients with and those without pleural thickening / 대한내과학회지

BACKGROUND: Indicator that can predict pleural thickening in pleural tuberculosis has not been known clearly. By the previous study, patients with pleural thickening > or =10 mm had significantly lower glucose and pH values and higher lysozyme and TNF-alpha values than those with pleural thickening or =10 mm and 12 patient (54.5%) had pleural thickening > or =3 mm. Initial pleural fluid protein, LDH, pH, glucose and IFN-gamma, Interleukin-1alpha (IL-1alpha) were studied. RESULTS: Pleural fluid levels of protein, LDH, glucose, and IFN-gamma were not statistically significant different not only between the group of pleural thickening > or =3 mm and the group of pleural thickening or =10 mm and the group of pleural thickening or =3 mm (85.9+/- 37.1 U/mL) was significantly higher than without thickening (44.8+/-32.0 U/mL) (p or =10 mm (106.9+/-8.6 U/mL) was significantly higher than without thickening (58.5+/-8.6 U/mL)(p< 0.001). CONCLUSION: Although patient number of our study was smaller than the previous study, IFN-gamma level in initial pleural fluid of pleural tuberculosis may be considered as the predictive factor of pleural thickening.

The Comparison among Low and High Doses of Imidapril, and Combined Imidapril with Losartan in Patients with Ischemic Heart Failure after Coronary Intervention

BACKGROUND AND OBJECTIVES: Angiotensin converting enzyme inhibitor and aniotensin II receptor blocker have been used in the treatment of heart failure. However, the effects of both agents are not known exactly in patients with ischemic heart failure. The clinical effects of Imidapril, Losartan and its combination on ischemic heart failure were observed after percutaneous coronary interventions (PCI). METHODS: Thirty six patients (58+/-8.8 year-old, 30 male) with myocardial infarction who underwent PCI with ejection fraction less than 45% by echocardiogram were included. The patients were divided into four groups; low (5 mg) and high (10 mg) doses of Imidapril (Group I: 58+/-6.1 years, M:F=:2 and II: 61+/-6 years, M:F=:1), combination of low dose Imidapril and 50 mg Losartan (Group III: 56+/-13 years, M:F=:0), and Losartan alone (Group IV: 57+/-9.3 years, M:F=:3). Clinical symptoms of angina and dyspnea, laboratory changes, exercise tolerance by treadmill test, and left ventricular function with dimension, and wall motion score by echocardiogram were observed at 4-week interval for 12 weeks. RESULTS: There were no significant differences among 4 groups in baseline clinical characteristics. In Group I, dyspnea and ejection fraction improved 12 weeks after therapy. Dyspnea and exercise tolerance improved in Group II. However, dyspnea and left ventricular function were unchanged in Group III, and 4 of them developed hypotension. In Group IV, left ventricular ejection fraction improved after therapy. Dry cough observed in 3 of Imidapril-treated patients, but withdrawal of drug was performed only in one of Group II. CONCLUSIONS: Monotherapy of Imidapril or Losartan is effective in the management of ischemic heart failure, but its combination shows no additional benefit.

The Comparison among Low and High Doses of Imidapril, and Combined Imidapril with Losartan in Patients with Ischemic Heart Failure after Coronary Intervention

BACKGROUND AND OBJECTIVES: Angiotensin converting enzyme inhibitor and aniotensin II receptor blocker have been used in the treatment of heart failure. However, the effects of both agents are not known exactly in patients with ischemic heart failure. The clinical effects of Imidapril, Losartan and its combination on ischemic heart failure were observed after percutaneous coronary interventions (PCI). METHODS: Thirty six patients (58+/-8.8 year-old, 30 male) with myocardial infarction who underwent PCI with ejection fraction less than 45% by echocardiogram were included. The patients were divided into four groups; low (5 mg) and high (10 mg) doses of Imidapril (Group I: 58+/-6.1 years, M:F=:2 and II: 61+/-6 years, M:F=:1), combination of low dose Imidapril and 50 mg Losartan (Group III: 56+/-13 years, M:F=:0), and Losartan alone (Group IV: 57+/-9.3 years, M:F=:3). Clinical symptoms of angina and dyspnea, laboratory changes, exercise tolerance by treadmill test, and left ventricular function with dimension, and wall motion score by echocardiogram were observed at 4-week interval for 12 weeks. RESULTS: There were no significant differences among 4 groups in baseline clinical characteristics. In Group I, dyspnea and ejection fraction improved 12 weeks after therapy. Dyspnea and exercise tolerance improved in Group II. However, dyspnea and left ventricular function were unchanged in Group III, and 4 of them developed hypotension. In Group IV, left ventricular ejection fraction improved after therapy. Dry cough observed in 3 of Imidapril-treated patients, but withdrawal of drug was performed only in one of Group II. CONCLUSIONS: Monotherapy of Imidapril or Losartan is effective in the management of ischemic heart failure, but its combination shows no additional benefit.

A Case of a Gastric Bezoar Regurgitated from the Stomach to the Esophagus / 대한소화기내시경학회지

Bezoars are persistent concretions of indigestible material, usually seen in the stomach. Esophageal bezoars are very rare and generally occur in elderly patients with anatomic defects such as diverticulum or stricture, or with esophageal motility disorders. However, it is quite unusual that a gastric bezoar would be regurgitated into a normal esophagus during forceful vomiting. Endoscopic removal of a bezoar is safe and successful in most cases. A case of a gastric bezoar regurgitated into the esophagus was recently experienced and removed by an endoscopic polypectomy snare and bezoar (lithotripsy) basket.