Analysis of K-<Emphasis Type="Italic">ras</Emphasis> Codon 12 Mutation in Flat and Nodular Variants of Serrated Adenoma in the Colon

PURPOSE: The developmental process of serrated adenomas is obscure, and the importance of genetic alterations has not been elucidated clearly. The possibility that the developmental process and genetic alterations of serrated adenomas could differ from those of ordinary tubular adenomas was explored in this work. METHODS: Serrated adenomas were obtained by endoscopic resection (n = 57) and divided into two groups: flat (n = 10) and nodular (n = 47). Mutation of the K-ras gene was analyzed by enriched polymerase chain reaction–enzyme-linked mini-sequence assay, which can detect not only the presence of a mutation but also the mutation type of K-ras codon 12 with high sensitivity. Methylation-specific polymerase chain reaction was performed with specific primers for the DNA repair gene O6-methylguanine-DNA methyltransferase. RESULTS: Serrated adenomas located in the rectum were more likely to have a K-ras mutation (9/12, 75 percent), whereas serrated adenomas of the flat type were less likely to have one (1/10, 10 percent). Furthermore, nodular serrated adenomas that occurred in the rectum possessed a high frequency of K-ras gene codon 12 point mutation (8/10, 80 percent) despite an overall frequency of 46.8 percent (22/47). A mutation of the K-ras codon 12 gene was detected in 23 (40.4 percent) of 57 serrated adenomas. Three types of point mutations of codon 12 were detected, with the mutation of GAT being observed most frequently. CONCLUSIONS: This study shows that development of nodular serrated adenomas may depend on the mutation of the K-ras codon 12 gene, whereas development of flat serrated adenomas may not. Additionally, serrated adenomas that occur in the rectum are closely related to the mutation of the K-ras codon 12 gene. K-ras mutations in serrated adenomas may be unaffected by the epigenetic silencing of O6-methylguanine-DNA methyltransferase by promoter hypermethylation.     

Rheologic predictors of the severity of the painful sickle cell crisis

Deformable sickle erythrocytes have been reported by Mohandas and Evans to be more adherent to vascular endothelium than rigid irreversibly sickled cells (ISC). To define the clinical implications of this finding we have determined genetic, hematological, clinical, and rheological characteristics of sickle erythrocytes obtained from 65 patients with sickle cell anemia and fetal hemoglobin (Hb F) levels less than 15%. The alpha-globin gene number had a significant effect on the hematological parameters, the percentage of dense cells, ISC number, and HB A2 levels. The presence or absence of alpha thalassemia, however, had no effect on the frequency and severity of the sickle cell painful crisis (r = 0.06, P greater than .05). RBC deformability, determined by an ektacytometer, showed great heterogeneity among patients with three or four alpha-globin genes. Linear regression analyses of the data showed significant positive correlation of the frequency and severity of the painful crisis with RBC deformability (r = 0.49, P less than .001), and negative correlations with the percentage of dense cells (r = -0.37, P = .002), and the percentage of ISC (r = -0.46, P less than .001). We propose that the more deformable the sickle RBC are, the greater their adherence to vascular endothelium, and the more they cause vaso-occlusive crises, RBC deformability and the percentage of dense cells (or ISC) seem to have a predictive value of the frequency and severity of painful crises in sickle cell anemia.     

Unusual left ventricular dilatation without functional or biochemical impairment in normotensive extremely overweight Japanese professional sumo wrestlers

To explore the physiologic limit of left ventricular (LV) enlargement, we performed echocardiography and air displacement plethysmography to respectively assess LV dimension and function and the body composition of Japanese professional sumo wrestlers. After excluding subjects with cardiovascular disease, hypertension, plasma brain natriuretic peptide (BNP) > or =17.9 pg/ml, diabetes mellitus, or asthma, 331 subjects (mean +/- SD age, 21.6 +/- 3.7 years; height 179.2 +/- 5.3 cm; weight 1,17.9 +/- 21.5 kg; percent fat, 29.6 +/- 6.6%) were analyzed. LV end-diastolic dimension averaged 58.4 +/- 3.7 mm and was within the generally regarded normal limit (< or =54 mm) in 14.5% of subjects, but was > or =60 mm in 41.1% of subjects. LV septal and posterior wall thicknesses were 10.3 +/- 0.9 and 10.2 +/- 0.9 mm, respectively. Peak E- and A-wave velocities, E/A ratio, LV fractional shortening, and BNP were 96 +/- 16 and 51 +/- 13 cm/s, 2.0 +/- 0.7, 33.5 +/- 4.5%, and 3.1 +/- 3.7 pg/ml, respectively. LV end-diastolic dimension was not correlated with these indexes of LV function or with plasma BNP levels, but was significantly correlated with height, weight, body surface area, fat-free mass, and fat mass. These results show that among very large, highly trained, professional athletes, LV end-diastolic dimension frequently exceeds the traditionally accepted upper limit of normal for the general population. This increase in LV end-diastolic dimension may thus represent an extreme example of the physiologic adaptation of the athlete's heart.     

Clinical features of Japanese type 1 autoimmune hepatitis patients with zone III necrosis

Aim: In Caucasians in northern Europe and North America, type 1 autoimmune hepatitis is characterized by susceptibility to human leukocyte antigens DR3 and DR4, and patients with zone III necrosis more frequently have an acute onset of the disease and a lower frequency of cirrhosis than those without. In Japanese patients, however, type 1 autoimmune hepatitis is primarily associated with DR4, and there are almost no DR3-positive patients. Thus, the clinical features of Japanese patients with type 1 autoimmune hepatitis and zone III necrosis may be different from those reported previously for Caucasians. Methods: We investigated 160 consecutive patients with type 1 autoimmune hepatitis (20 males and 140 females; median age, 55 years; range, 16-79 years). Results: Forty-seven patients (29%) had zone III necrosis, and these patients had lower serum levels of albumin and higher serum levels of total bilirubin, aspartate aminotransferaseand alanine aminotransferase. Histologically, zone III necrosis was found more frequently in patients with acute hepatitis than in those with chronic hepatitis. However, there was no difference in the frequency of cirrhosis between patients with and without zone III necrosis. In addition, normalization of serum alanine aminotransferase levels within six months after the introduction of corticosteroid treatment was slightly more frequent in patients with zone III necrosis (95% vs. 88%). Conclusion: In Japanese patients, zone III necrosis may reflect not only acute autoimmune hepatitis, but also acute exacerbation of pre-existing chronic disease. Furthermore, patients with zone III necrosis may respond better to corticosteroid treatment than those without.     

Changes in calcium homeostasis in acromegaly treated by pituitary adenomectomy

Patients with acromegaly have alterations in mineral metabolism. To determine the effect of correction of excess GH secretion on calcium metabolism, we studied 12 acromegalic patients before and 3-4 weeks after pituitary adenomectomy. Treatment of acromegaly resulted in significant decreases in both serum calcium [from 9.3 +/- 0.2 to 8.7 +/- 0.1 mg/dl (mean +/- SEM); P less than 0.01] and urinary calcium excretion (from 200 +/- 24 to 88 +/- 12 mg/24 h; P less than 0.0002). Serum phosphate also decreased significantly (P less than 0.01) from 4.8 +/- 0.2 to 4.3 +/- 0.2 mg/dl. Both serum immunoreactive PTH and calcitonin levels were normal initially and did not change after surgery. The mean serum 25-hydroxyvitamin D (25OHD) level was significantly (P less than 0.01) lower and the 1,25-dihydroxyvitamin D [1,25-(OH)2D] level was significantly (P less than 0.0001) higher in acromegaly compared with measurements in 25 normal subjects. After surgery, the serum 25OHD level did not change; however, the serum 1,25-(OH)2D concentration fell significantly (P less than 0.0001) from 60 +/- 4 to 43 +/- 2 pg/ml. A positive correlation was found between the decrements in urinary calcium excretion and the serum 1,25-(OH)2D level when the comparison was made between the decrements as percentages of pretreatment values (r = 0.64; P less than 0.05). The accumulated data suggest that the hypercalciuria in acromegaly might be due to intestinal calcium hyperabsorption, which could be attributed to the elevated circulating 1,25-(OH)2D level. Excessive GH secretion might stimulate the production of 1,25-(OH)2D and might also directly stimulate calcium absorption.     

Effect of radioactivity outside the field of view on image quality of dedicated breast positron emission tomography: preliminary phantom and clinical studies

Annals of Nuclear Medicine - Semi-quantitative positron emission tomography (PET) values, such as the maximum standardized uptake value (SUVmax), are widely used to identify malignant lesions and...     

Identification of an oncogenic form of the thrombopoietin receptor MPL using retrovirus-mediated gene transfer

Thrombopoietin and its receptor (MPL) are important regulators of megakaryopoiesis. We have identified an activating mutation of MPL using a combination of a retrovirus-mediated gene transfer and polymerase chain reaction-driven random mutagenesis. This point mutation causes a single amino acid substitution from Ser498 to Asn498 in the transmembrane region and abrogates factor-dependency of all interleukin-3-dependent cell lines tested. Murine interleukin-3- dependent Ba/F3 cells expressing the mutated but not the normal form of MPL were tumorigenic when transduced into syngeneic mice. Analysis of intracellular signaling pathways indicated that the mutant MPL protein constitutively activated two distinct signaling pathways, SHC-Raf-MAPK and JAK2-STAT3/STAT5.     

Role of radial strain and displacement imaging to quantify wall motion dyssynchrony in patients with left ventricular mechanical dyssynchrony and chronic right ventricular pressure overload

Left ventricular (LV) deformation with ventricular septal shift is one of the most distinctive echocardiographic observations in patients with chronic right ventricular (RV) pressure overload (PO). However, little is known about the effects of RVPO on LV performance and regional synchrony. Accordingly, our objective was to test the hypothesis that chronic RVPO affects regional wall motion, synchronicity, and global LV function using a novel speckle-tracking approach to quantify and characterize regional LV wall motion dyssynchrony. Displacement and strain imaging echocardiographic studies were performed in 20 patients with RVPO from pulmonary arterial hypertension or pulmonic stenosis (mean age 53 +/- 16 years, New York Heart Association class 2.6 +/- 0.7, and peak RV systolic pressure 73 +/- 28 mm Hg) and 20 age-matched normal subjects (mean age 47 +/- 16 years). Segmental signals from 6 segments around the mid-LV short axis were defined as dyssynchronous if their changes were opposite to that of the global LV signal at each time frame, and overall LV dyssynchrony was calculated as the percentage of dyssynchrony in all 6 segments within the specified time interval from onset of QRS to the end of isovolumic relaxation. RVPO was associated with a large degree of regional dyssynchrony with paradoxical ventricular septal motion observed by displacement imaging (21 +/- 6%, p <0.05 vs control group), which was closely associated with LV eccentricity index (r = 0.79, p <0.05) and LV myocardial performance index with linear regression (r = 0.76, p <0.05). In contrast, strain imaging showed uniform segmental radial thickening in the RVPO group, which was similar to the control group, and suggests that there was no intrinsic LV contractile dyssynchrony. In conclusion, LV wall motion dyssynchrony assessed by displacement imaging, not intrinsic contractile dyssynchrony by strain imaging, coexists with LV chamber deformation with ventricular septal shift and is closely associated with impairment of LV performance.     

Serum inhibition of complement derived leukocyte chemotaxis and levels of immunoglobulin A subclass in alcoholic liver disease

Serum inhibition of complement-derived leukocyte chemotaxis was examined in alcoholic liver disease with or without cirrhosis. Chemotactic inhibitory activity (CIA) was detected with higher frequency and degree in alcoholic liver disease, especially with liver cirrhosis compared with normal subjects and non-alcoholic liver cirrhosis. CIA was found in anti-IgA adsorbed fractions in the sera of patients with alcoholic liver cirrhosis. Serum concentrations of IgAl and IgA2 in alcoholic liver disease were statistically higher than in non-alcoholic liver cirrhosis. However, no correlation between CIA and the concentrations of IgA subclasses was demonstrated in alcoholic liver disease. This serum inhibitor may partly explain the high susceptibility to bacterial infection in alcoholic liver disease.     

An epidemiologic and histopathological study of sudden cardiac death in Osaka Medical Examiner's Office

From 1982 to 1986, 1230 sudden death cases were autopsied in Osaka Medical Examiner's Office. Among them, 810 cases were sudden cardiac deaths (SCD) including coronary heart disease (77%), cardiomyopathy (7%), valvular disease (3%). All SCD cases were dead within 24 hours of the appearance of the fatal symptoms, and most of them (72%) were considered instantaneous death. Many of the fatal symptoms began in bed (31%), at bath (17%), at toilet (8%), or at work (8%). Thirty-four percent of them were thought by themselves or by their families to be healthy before the death. Hypertension (38%), coronary heart disease (13%) and diabetes mellitus (11%) were the major past history recorded. Microscopic observation of the hearts of 200 cases autopsied in 1986 showed various cardiac lesions: hypertrophy, atrophy, degenerations of myocytes, cellular and fatty infiltrations of the interstitium. According to their cardiac lesions and degrees of severity of coronary sclerosis, patients who died suddenly were divided into 8 groups as follows: 1. myocardial infarction (41) 2. myocarditis (6) 3. hypertrophic cardiomyopathy (19) 4. chronic ischemia with severe coronary sclerosis (65) 5. chronic ischemia with moderate coronary sclerosis (27) 6. small vessel disease (18) 7. amyloidosis (1) 8. unknown (23). These results suggest that coronary heart disease and hypertension play an important role in SCD.