Gene Expression in Rat Hearts Following Oral Administration of a Single Hepatotoxic Dose of Acetaminophen

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.

Acetaminophen Induced Cytotoxicity and Altered Gene Expression in Cultured Cardiomyocytes of H9C2 Cells

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 (H9C2 cells) after exposure to acetaminophen. METHODS: H9C2 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 H9C2 cells.

Recurrent Gastric Cancer at the Duodenal Stump after Billroth II Subtotal Gastrectomy / 대한소화기내시경학회지

Many studies have shown that gastric stump cancer develops after distal gastrectomy, particularly after Billroth II reconstruction. But, recurrent cancer at the duodenal stump following Billroth II type distal gastrectomy for gastric cancer is extremely rare. We report a case of duodenal stump cancer in a 64-year-old man underwent Billroth II distal gastrectomy.

A study of the development of macrovascular complications and factors related to these complications in young adults with childhood/adolescence-onset type 1 diabetes mellitus / 소아과

PURPOSE: Macrovascular complications are the main cause of mortality in type 1 diabetes mellitus (T1DM). The purpose of this study was to clarify the presence of early vascular changes and to assess the risk factors of macrovascular complications in young adults with T1DM diagnosed in childhood and adolescence. METHODS: Seventy-two patients (23.9+/-2.4 years) with T1 DM diagnosed before 18 years of age and twenty normal controls were included. The incidence of hypertension, dyslipidemia, and other risk factors of macrovascular complication were reviewed. Flow-mediated vasodilation (FMD) and mean intima-media thickness (IMT) measured by ultrasound were compared between patients and control subjects, and their correlations with macrovascular risk factors were analyzed. RESULTS: Of the 72 patients, 32 (44.4%) had hypertension. The proportions of maleness (P=0.03) and mean body mass index (P=0.04) were higher in the hypertensive patients than in normotensive patients. Thirty-one (N=69, 44.9%) patients had dyslipidemia and LDL-cholesterol was positively correlated with mean HbA1c (r=0.32, P=0.008) and total daily insulin dose (r=0.27, P=0.02). The mean IMT was significantly higher in patients than in control subjects (0.43+/-0.06 mm vs 0.39+/-0.06 mm, P=0.03). There was no difference in the value of FMD between patients and controls, but the duration of the disease after pubertal onset was negatively correlated with FMD (r=-0.34, P=0.01). CONCLUSION: Hypertension, dyslipidemia and atherosclerotic vascular change were observed in young adults with T1DM diagnosed during childhood and adolescence; this strongly suggests that meticulous screening of macrovascular complications and control of their risk factors should be conducted.

Endothelial Dysfunction and Microvascular Complications in Type 1 Diabetes Mellitus

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.

Decreased Left Ventricular Torsion and Untwisting in Children with Dilated Cardiomyopathy

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 twodimensional (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+/-4.6degrees vs. 0.3+/-2.1degrees, 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+/-4.1degrees vs. -0.9+/-3.1degrees, 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.

Alterations in Left Ventricular Circumferential Motion in Children with Dilated Cardiomyopathy

PURPOSE: The purpose of this study is to analyze left ventricular (LV) circumferential strain (S) and strain rate (SR) in children with dilated cardiomyopathy (DCM) and to evaluate whether the impairment of circumferential wall motion correlates with global ventricular dysfunction in DCM. METHODS: Ten DCM children (range 0.6-15 years, median 6.5 years, 3 females) and 17 age and sex matched normal controls were examined. After conventional echocardiography and tissue Doppler imaging analysis, segmental and global circumferential S and SR were measured using two dimensional speckle tracking imaging (STI) method at three levels of LV. RESULTS: Circumferential S and SR were markedly heterogeneous and decreased in almost all segments of LV in DCM. Peak global Sc (Sc G) was significantly reduced at three levels of LV (basal level; -15.7+/-3.8% vs. -9.5+/-3.6%, P=0.001, midventricular level; -13.5+/-3.5% vs. -6.5+/-3.3%, P<0.001, apical level; 14+/-5.1% vs. 6.2+/-4.1%, P=0.005). Global circumferential S and SR were correlated closely with other indices of global LV function and longitudinal and radial motion in normal and DCM children. CONCLUSION: In DCM, decreased circumferential S and SR are the major components of LV dysfunction. Analysis of circumferential S and SR with STI method can give further information on 3 dimensional LV mechanics in DCM.

Left Ventricular Radial Strain in Children with Dilated Cardiomyopathy: Analyzed with Two Dimensional Speckle Tracking Imaging Method

PURPOSE: The purpose of this study is to analyze left ventricular (LV) radial strain (S) and strain rate (SR) in children with dilated cardiomyopathy (DCM) and to evaluate whether the impairment of global radial wall motion correlates with global ventricular dysfunction in DCM. METHODS: In 10 DCM patients (range 0.6-15 years, median age 6.5 years, 3 females) and 17 age and sex matched normal controls (range 0.5-14 years, median age 5 years, 5 females) conventional echocardiography and real time tissue Doppler imaging analysis were performed. Using an automatic two dimensional speckle tracking imaging (STI) method radial S and SR were calculated for each LV segment in 18 segment model. To evaluate the correlation between the impairment of radial motion and LV global function, the average values of radial S and SR of each LV level were obtained, and defined as global (G) S or SR. RESULTS: LV radial S and SR were markedly heterogeneous and decreased in almost all segments of LV in DCM. Impaired radial S and SR were associated with global LV dysfunction. CONCLUSION: In DCM, decreased and disorganized radial S and SR contribute to LV dysfunction. Analysis of radial S and SR with STI method can give further information on LV function in DCM.

Heart Poblems of Newborns with Nonimmune Hydrops Fetalis

PURPOSE: To understand the pathophysiology of nonimmune hydrops fetalis, retrospective study was achieved. We evaluated cardiac anomalies and heart functions of newborns with nonimmune hydrops fetalis admitted to our neonatal intensive care unit. METHODS: A retrospective study was conducted on the newborn diagnosed as nonimmune hydrops fetalis (NIHF) between January 1995 and December 2005. To analyze cardiac structures and heart functions of the study population, echocardiographic data were used that carried out within 2 days after birth. RESULTS: During the study period, 29 newborns (18 males and 11 females; mean birth weight 2,877 g; mean gestational age 34.4 weeks) were identified as NIHF. There were 15 cases of structural cardiac anomaly, 5 cases of cardiomegaly, 2 cases of arrhythmia and one case of pericardial effusion. Among those patent ductus arteriosus were observed in 12 cases and there were 10 cases of patent foramen ovale (PFO) or atrial septal defect. Ebstein's anomaly with PFO and atrioventricular septal defect was one case respectively. Most cases appeared hypoalbuminemia and anemia. Difference of heart functions between neonatal survival group and neonatal death group had no statistical significance. CONCLUSION: Because there was no significant difference in cardiac function between neonatal survival group and neonatal death group, simple decline of the heart function is not sufficient for the explanation of pathophysiologic mechanisms. Nevertheless, NIHF remains a challenging entity to improve perinatal outcome.

Surgical Outcome and Time of Operation in Ebstein's Anomaly

PURPOSE: Ebstein's anomaly is characterized by ongoing tricuspid regurgitation and right ventricular dysfunction. It is difficult to decide the proper time of surgical correction. The purpose of this study is to evaluate the advantage of early surgical correction of Ebstein's anomaly. METHODS: The clinical records of the sixteen patients, who had undergone tricuspid valvuloplasty with plication of the atrialized RV and followed-up for more than five years, were reviewed. Surgical outcome was analysed as regards year of surgery, age of the patients, echocardiographic grade of severity, Carpentier type, associated cardiac defects, and type of surgery. RESULTS: Of sixteen patients, eight patients underwent tricuspid valve repair before 5 years(8 months to 5 years, mean 2.4 years) of age(group A), and eight patients underwent tricuspid valve repair after 5 years(6 to 23 years, mean 12.9 years) of age(group B). Immediately after the operation, tricuspid incompetence regressed significantly in 5 of group A, and 5 of group B, and reduction in heart size was usual. After short and mid- term follow-up period, four of group A showed mild tricuspid valve regurgitation and right ventricular dilatation and relatively well preserved right ventricular function. However, all of group B showed severe right ventricular dilatation with severe tricuspid regurgitation and both ventricular dysfunction. All of group A were in New York Heart Association class I. However, in group B, only three were in class I. Two of group B died of right heart failure 10 and 16 years after the surgical correction, respectively. The year of surgery, mean follow-up periods, associated cardiac defects, and the preoperative echocardiographic grade of the severity were not different significantly between two groups. But there was a difference between two groups in the mean age of the patients, 12.7+/-5.2 years in group A, 21.7+/-5.5 years in group B. The surgical outcome was not closely related to Carpentier types of Ebstein's anomaly. CONCLUSION: Early repair of tricuspid valve may be advantageous to prevent progressive dilatation of the right side heart and to preserve right ventricular function after surgical correction. But the aging factor was not corrected in our study and it is still necessary to follow-up for a longer period in larger patients group.

Clinical Characteristics of Long-Standing Foreign Body in Airway

PURPOSE: Although the diagnosis of foreign bodies in the airway can be made early, retained and neglected foreign bodies are a common occurrence. The objective of this study was to characterize the clinical features of children diagnosed beyond 14 days following inhalation of a foreign body, long-standing foreign body in airway(LFB). METHODS: We reviewed the records of 180 cases of airway foreign body, noting the age, symptoms and signs, types and location of foreign body, chest radiographs, and lung perfusion scan findings, and compared these findings of children diagnosed within 14 day(short-term foreign body in airway : SFB, n=130) with those of LFB(n=50). RESULTS: Of chief complaints on admission, sputum was more frequent in LFB(24.0%) than in SFB(6.9%). The age distribution was similar, but the proportion of patients aged 3 to 6 years was higher in LFB(16.0%) compared with SFB(3.9%). Of the types of foreign body, plastic was more common in LFB. Abnormal chest radiographic findings were more frequent in LFB(94.0%) than in SFB(80.6%), while the location within the bronchial tree was similar. Hypoperfusion on lung scan was noted in all patients except one in LFB(93.8%). CONCLUSION: There was some difference in age distribution, sputum production, type of foreign body, and abnormal radiographic and perfusion scan findings between SFB and LFB. This suggests that retained foreign bodies may present atypical clinical manifestation and physicians should be alert to the possibility of airway foreign body in children with chronic respiratory symptoms or signs.

Basophil Histamine Releasability in Asthmatic Children

PURPOSE: The release of histamine from human basophils is controlled by an intrinsic, as yet unidentified, cellular property termed "releasability." We carried out this study to ascertain whether there was any difference in the releasability of basophils from asthmatic children compared to those from normal children. We intended also to clarify the correlation between the releasability and the atopic status of asthma. METHODS: We selected nineteen atopic asthmatic, eighteen nonatopic asthmatic and fourteen normal children for this study. Suspensions of leukocytes were isolated and stimulated with calcium ionophore A23187, anti-IgE and D. pteronyssinus antigen. After incubation, the supernatant was assayed for histamine with an automated fluorometric technique. RESULTS: Basophil histamine release with anti-IgE was different in three groups. Anti-IgE caused significantly more basophil histamine release in asthmatic children than in nomal children. Atopic asthmatic group showed greater basophil histamine release with anti-IgE than nonatopic asthmatic group. D. pteronyssinus antigen caused the significant amount of histamine release only in atopic asthmatic group. CONCLUSIONS: Our data suggests that basophils from asthmatic children are characterized by a specific increase in IgE mediated histamine releasability. The difference of histamine releasability with anti-IgE between atopic and nonatopic asthmatic children may be due to the heterogeneity of IgE bound to cell surface, or may be due to the degree of the basophil activation by cytokines such as IL3. The specific release of histamine with D. pteronyssinus antigen in atopic asthmatic group suggests that the basophil histamine release test can be used to diagnose the causing antigen.