Image quality and radiation exposure in CT of the pancreas: 320-MDCT with and without adaptive iterative dose reduction versus 64-MDCT.

AIM: To compare the image quality and radiation exposure in computed tomography (CT) of the pancreas acquired using 320-multidetector (MD)CT versus 64-MDCT and to demonstrate the effects of adaptive iterative dose reduction (AIDR) on 320-MDCT. MATERIALS AND METHODS: One hundred and fifty patients were randomized into three groups including 320-section volume imaging using AIDR (group A), 320-slice volume scan without AIDR (group B), and 64-section helical imaging without AIDR (group C). Transaxial arterial, pancreatic phase, and volume-rendered CT angiographic images were reconstructed. CT radiodensity of the abdominal aorta, pancreas, signal-to-noise ratios (SNR), dose-length products (DLPs; mGy cm), and image quality were measured. RESULTS: No significant difference in CT radiodensity of the abdominal aorta or pancreas was noted between groups. Mean DLPs were 600.9 ± 145.8, 681.6 ± 97.5, and 1231.5 ± 271.4 in groups A, B, and C, respectively. The DLP was reduced by 51% in group A and 45% in group B compared to group C (p < 0.001). SNRs of the pancreas during the pancreatic phase were comparable between groups A and C, but were significantly lower in group B (p < 0.001). Image quality, including the depiction of some small arterial branches on the arterial and CT angiographic images and the main pancreatic duct on the pancreatic-phase images, were significantly lower in group B than in groups A and C (p = 0.008-0.038). CONCLUSION: Radiation dose can be markedly reduced for contrast-enhanced CT imaging of the pancreas without compromising image quality using a 320-MDCT with AIDR, compared with 64-section helical CT.

Comparison of sensitivity of lung nodule detection between radiologists and technologists on low-dose CT lung cancer screening images.

OBJECTIVES: The objective of this study was to compare the sensitivity of detection of lung nodules on low-dose screening CT images between radiologists and technologists. METHODS: 11 radiologists and 10 technologists read the low-dose screening CT images of 78 subjects. On images with a slice thickness of 5 mm, there were 60 lung nodules that were ≥5 mm in diameter: 26 nodules with pure ground-glass opacity (GGO), 7 nodules with mixed ground-glass opacity (GGO with a solid component) and 27 solid nodules. On images with a slice thickness of 2 mm, 69 lung nodules were ≥5 mm in diameter: 35 pure GGOs, 7 mixed GGOs and 27 solid nodules. The 21 observers read screening CT images of 5-mm slice thickness at first; then, 6 months later, they read screening CT images of 2-mm slice thickness from the 78 subjects. RESULTS: The differences in the mean sensitivities of detection of the pure GGOs, mixed GGOs and solid nodules between radiologists and technologists were not statistically significant, except for the case of solid nodules; the p-values of the differences for pure GGOs, mixed GGOs and solid nodules on the CT images with 5-mm slice thickness were 0.095, 0.461 and 0.005, respectively, and the corresponding p-values on CT images of 2-mm slice thickness were 0.971, 0.722 and 0.0037, respectively. CONCLUSION: Well-trained technologists may contribute to the detection of pure and mixed GGOs ≥5 mm in diameter on low-dose screening CT images.

Change in carrier type in high-k gate carbon nanotube field-effect transistors by interface fixed charges.

We study the phenomenon of change in carrier type in carbon nanotube field-effect transistors (CNFETs) caused by the atomic layer deposition (ALD) of a HfO(2) gate insulator. When a HfO(2) layer is deposited on a CNFET, the type of carrier changes from p-type to n-type. The so-obtained n-type device has good performance and stability in air. The conductivity of such a device with a channel length of 0.7 microm is 11% of the quantum conductance 4e(2)/h. The contact resistance for electron current is estimated to be 14 kOmega. The n-type conduction of this CNFET is maintained for more than 100 days. The change in carrier type is attributed to positive fixed charges introduced at the interface between the HfO(2) and SiO(2) layers. We also propose a novel technique to control the type of conduction by utilizing interface fixed charges; this technique is compatible with Si CMOS process technology.

A simple image processing approach for electronic cleansing in computed tomographic colonography.

The prevalence of colon cancer has seen strong demand in screening for colorectal neoplasia, and this has drawn considerable attention to the technological advances in Computed Tomographic Colonography (CTC). With the assistance of an oral contrast agent, an imaging technique known as Electronic Cleansing (EC), can affect virtual cleaning of the computed tomography (CT) images, to remove fecal material that is tagged by the agent. Technical problems can arise with electronic cleansing however, when the air lumen causes distortions to the tagged regions which result in partial volume effects.Combining the simple image arithmetic of an electronic cleansing algorithm, with a vertical motion filter at the fluid level of the bowel, artifacts such as those caused by an air lumen are eliminated. Essentially, the filter becomes a vector for that carries the measurement of vertical motion to neutralise the artifact that is causing partial volume effects. Results demonstrate that despite its simplicity, this technique offers accuracy and is able to successfully maintain the normal intra-colonic structure, while supporting digital leaning of tagged residual material appearing on the colon wall.

Evaluation of 18F-2-deoxy-2-fluoro-glucose positron emission tomography for gastric cancer screening in asymptomatic individuals undergoing endoscopy.

(18)F-2-deoxy-2-fluoro-glucose Positron Emission Tomography (FDG-PET) has been recently proposed as a promising cancer-screening test. However, the validity of FDG-PET in cancer screening has not been evaluated. We investigated the sensitivity of FDG-PET compared with upper gastric endoscopy in gastric cancer screening for asymptomatic individuals. A total of 2861 consecutive subjects (1600 men and 1261 women) who were asymptomatic and who underwent both FDG-PET and upper gastrointestinal endoscopy between 1 February 2004 and 31 January 2005 were included in this study. Both endoscopists and a radiologist were unaware of the results of the other diagnostic tests. The FDG-PET images were examined using criteria determined by the pattern of FDG accumulation. Sensitivity and specificity of FDG-PET were calculated compared with endoscopic diagnosis as the gold standard. Among 2861 subjects enrolled in the study, there were 20 subjects with gastric cancer, of whom 18 were T1 in depth of cancer invasion. Positive FDG-PET results were obtained only in 2 of the 20 cancer subjects. The calculated sensitivity and specificity for overall gastric cancers were 10.0% (95% confidence interval (CI): 1.2-31.7%) and 99.2% (95% CI: 98.8-99.5%), respectively. (18)F-2-deoxy-2-fluoro-glucose Positron Emission Tomography was poorly sensitive for detection of gastric cancer in the early stages.

Sentinel node biopsy in primary breast cancer: radioactive detection and metastatic disease.

AIM: To examine the relationship between the intensity of the radioactive counts and the presence of tumor metastasis in sentinel lymph nodes (SLNs) in order to correctly identify the number of SLNs to be removed. PATIENTS AND METHODS: Five hundred three breast cancer patients with successful radioisotope localization of SLNs using the combined blue dye and radioisotope method were analyzed. SLN biopsy was continued until all the blue-stained and radioactive nodes were removed. RESULTS: The mean number of harvested SLNs was 1.7+/-0.9, and the number of radioactive SLNs among the harvested nodes was 1.6+/-0.8. SLN metastasis was found in 123 of the 503 cases. The metastasis was detected in the SLN with the highest radioactive count (the hottest SLN) in 94 of the 123 cases with positive SLNs. The positive rate in the hottest SLN was 89% in 61 cases with a single radioactive SLN, and 65% in 62 cases with multiple radioactive SLNs. Of the 29 cases with positivity in other than the hottest SLNs, the metastasis was detected in the second hottest SLN in 16 cases, in the third hottest SLN in one case, in a mixture of negative radioactive SLNs and blue-dye-stained in four cases, and in the negative SLNs and positive non-SLNs (false-negative) in eight cases. Of 123 node-positive cases, 111 cases had metastasis that was detected within the first three hottest SLNs. CONCLUSIONS: These data suggest that lymph node metastasis may not always be detected in the hottest SLN. Thus, in practice, all radioactive and/or blue-dye-stained nodes should be removed for further examination.

PTOV1: a novel testosterone-induced atherogenic gene in human aorta.

There are gender differences in the development of atherosclerosis, possibly owing to differences in sex steroid hormone action and/or metabolism. One of the atherogenic effects of testosterone is thought to be androgen receptor (AR)-mediated vascular smooth muscle cell (VSMC) proliferation. However, the detailed mechanism of this effect, particularly the identity of the genes associated with VSMC proliferation, remains largely unknown. Therefore, we first employed microarray analysis and, subsequently, quantitative RT-PCR to analyse RNA expression in AR-positive human VSMCs treated with testosterone in order to detect testosterone-induced genes associated with cell proliferation. We further examined whether the genes identified were involved in cell proliferation using small interfering RNA (siRNA) transfection. Expression of the gene products was then evaluated in human aorta with various degrees of atherosclerosis in order to evaluate the clinical relevance of the findings. Both microarray and quantitative RT-PCR analyses demonstrated marked induction of the human prostate overexpressed protein 1 (PTOV1) gene by testosterone in the cell lines: this gene was recently identified as a novel androgen-induced gene involved in prostate tumour cell proliferation. Inhibition of PTOV1 by transfection of its corresponding siRNA suppressed testosterone-induced cell proliferation. In human aorta, PTOV1 immunoreactivity in the nuclei of neointimal VSMCs was abundantly detected in male aorta with mild atherosclerotic changes compared with female aorta or male aorta with severe atherosclerotic changes. These findings indicate that the PTOV1 gene is androgen-responsive in VSMCs and that it may play an important role in androgen-related atherogenesis in the human aorta, particularly early atherosclerosis in the male aorta, through regulating proliferation of neointimal VSMCs.

Expression of vascular endothelial growth factor in hepatocellular carcinoma and the surrounding liver: correlation with MR imaging and angiographically assisted CT.

We summarize and discuss our previous research results on the correlation between findings on magnetic resonance (MR) imaging and angiographically assisted computed tomography (CT) and the intensity of vascular endothelial growth factor (VEGF) expression in hepatocellular carcinoma (HCC) and in the surrounding nontumorous liver. MR images (n = 22), CT during arterial portography (n = 20), and CT hepatic arteriography (n = 17) were retrospectively correlated quantitatively and qualitatively with VEGF expression in HCCs and in the surrounding liver assessed by western blotting. HCC-to-liver contrast-to-noise ratio correlated with VEGF expression index (VEGF(IND)) values of HCCs inversely on opposed-phase, T1-weighted, spoiled gradient recalled-echo (GRE) images, directly on T2-weighted, fast spin-echo images, and marginally and inversely on gadolinium-enhanced hepatic arterial-phase GRE images. On T2-weighted fast spin-echo images, standard deviation ratio of HCCs correlated directly with VEGF(IND) values of HCCs. By CT hepatic arteriography, the contrast-enhancement index of HCCs showed a moderate inverse correlation with VEGF(IND) values of HCCs, and the contrast-enhancement index of the liver showed marginal, moderate direct correlation with VEGF(IND) values in the liver. Heterogeneities of HCCs on images correlated directly with VEGF(IND) values of HCCs on opposed-phase T1-weighted GRE images, T2-weighted fast spin-echo images, hepatic arterial-phase GRE images, equilibrium-phase GRE images, and CT hepatic arteriogram. Our results may reflect that MR signal intensity, hepatic arterial vascularity, and heterogeneity of HCCs on CT or MR images are closely related to the intensity of VEGF expression in HCC as upregulated by hyper- or hypoxia in HCCs. Although the real effects of our results on radiologic practice are debatable at this moment, we believe that our results may help future radiologic practice in conjunction with biomolecular or genetic treatment for HCCs.

A new approach towards volumetric assessment of left ventricular function with MSCT.

Cardiovascular CT is considered the diagnostic standard for establishing the presence of a functional and dynamic imaging system. It is difficult, however, to estimate the ventricular motion and volumes that are processed using hundreds and thousands of CT images, in a few moments.The main concept and design of our work are two fold - the development of effective semi-automatic tools for measuring the sequential left ventricular volumes from the hundreds or thousands of cardiac trans-axial images, and providing a simple interface with an interactive diagnostic tool for the volumetry of left ventricle and valuable cardiac 4D visualisation.We converted ten and more sequential volume data sets of the heart acquired from retrospective ECG-gating helical scan into 3D images by volume rendering. These sequential 3D images could be displayed as a movie (4D cardiac image) file. Furthermore, we developed a method for semi-automatic calculation of ejection fraction (EF) and cardiac cycle (%)-volume (ml) curve for estimation of the motion and the volume of the left ventricle. This method involved the use an interactive selection tool in the region of interest (ROI). All 3D processing methods, such as, cutting objects, segmentation, and image fusion were based on mask processing data. We now describe the software developed for cardiac 4D imaging and the estimation of ventricular volume.

[Reusable imaging plate (IP) for swift and automatic measurement of X-ray CT dose profiles].

PURPOSE: In multi-slice CT, over beaming by penumbra effect has been reported, and measurements of X-ray CT beam profiles are very important for accurate performance assessment. This study was conducted in order to facilitate and economize on the measurement of CT dose profiles. METHODS: The imaging plate (IP: HR-V type, Fuji) was placed in its case, X-rayed, and then read with a digital IP reader, which then erased the data in preparation for reuse. The values were then compared with the values obtained with the standard one-use imaging film. The CT scanner used was a Toshiba Aquilion Multi (4 rows). RESULTS: The shape of the beam profile obtained using the IP method was for all practical purposes identical to that obtained using the film method. The FWHM values for 2.0, 4.0, 8.0, 12.0, 16.0, 20.0 and 32-mm beam were 4.88, 6.61, 10.2, 14.9, 18.2, 22.4 and 35.0 mm for the IP method and 4.81, 6.66, 10.2, 14.7, 18.1, 22.3 and 34.8 mm for the film method. In addition, in the IP method, the results obtained for the shape of the beam profile and the FWHM were found to be extremely similar irrespective of the X-ray tube used or individual differences between IPs. CONCLUSION: We have developed a new X-ray CT beam profile measurement system using an IP. This IP method permits data processing to be performed entirely in the digital domain, allowing high-precision measurements to be obtained with ease.

Which types of non-bleeding visible vessels in gastric peptic ulcers should be treated by endoscopic hemostasis?

BACKGROUND AND AIMS: Because non-bleeding visible vessels (NBVV) of gastric peptic ulcers have the potential to re-bleed, endoscopic hemostatic treatment may be necessary during the first emergency endoscopy. However, not all NBVV re-bleed, and endoscopic hemostasis sometimes causes fatal side-effects. Therefore, we have evaluated the risk of re-bleeding from various NBVV in gastric peptic ulcers to determine which types should be treated by endoscopy to prevent re-bleeding. METHODS: A total of 227 NBVV in 202 patients with gastric peptic ulcers that were endoscopically followed without endoscopic hemostatic procedures were classified by the following factors: vessel color, form, location of the NBVV in the ulcer crater, and location of the ulcer in the stomach. The re-bleeding rate was then analyzed for each type of NBVV. RESULTS: Significantly high rates of re-bleeding were observed in cases with white, protruded and peripheral NBVV. In particular, white NBVV located in the peripheral zone of the ulcer crater were frequent re-bleeding sources. The location of the ulcer in the stomach was not a statistically significant factor in determining re-bleeding rates. CONCLUSION: We found that white, protruded and peripherally located NBVV in gastric ulcers have a higher chance of re-bleeding if preventive endoscopic hemostatic procedures are not performed.

Hepatic metastases of soft tissue angiosarcoma: CT and MR imaging findings.

BACKGROUND: We describe the computed tomographic (CT) and magnetic resonance imaging (MRI) findings of hepatic metastases caused by soft tissue angiosarcomas to clarify the relation between radiologic appearances and clinicopathologic features. METHODS: CT and MR examinations of 13 patients with hepatic metastases of soft tissue angiosarcoma were retrospectively analyzed. RESULTS: Contrast-enhanced CT images showed multiple hypoattenuating lesions relative to the adjacent liver parenchyma. Lesions contained peripheral areas of enhancement in eight patients (62%). Tumors showed cystic attenuation with fluid-fluid levels, which were suggestive of hemorrhage in five patients (38%). In one patient (8%) with cystic attenuation and fluid-fluid levels, lesions also contained marked enhanced nodular portions located centrally or peripherally. On T1-weighted MR images, all four liver tumors appeared heterogeneous and hypointense relative to adjacent liver parenchyma. Fluid-fluid levels were identified on T2-weighted MR images in five patients (38%). After an intravenous bolus of gadolinium-based contrast material was administered, slight peripheral enhancement was seen in three patients (75%). CONCLUSION: The common CT findings of metastatic angiosarcoma in our series were multiple hypoattenuating lesions often associated with nodular enhancement and cystic lesions with hemorrhagic change.

Early-enhancing non-neoplastic lesions on gadolinium-enhanced MRI of the liver.

AIM: To assess the frequency, cause, and significance of early-enhancing, non-neoplastic (EN) lesions on gadolinium-enhanced magnetic resonance imaging (MRI) of the liver performed for the detection of malignant hepatic tumours. MATERIALS AND METHODS: From September 1997 to September 2000, we reviewed the images of 125 patients, suspected of having hepatic tumours, in whom (1) gadolinium-enhanced triphasic dynamic gradient-recalled-echo (GRE) imaging in addition to unenhanced T1- and T2-weighted MRI was performed, (2) conventional angiography and combination computed tomography (CT) hepatic arteriography and CT during arterial portography were performed within 2 weeks of the MRI, and (3) definitive surgery within 2 weeks of the MRI or follow-up study by means of intravenously contrast-enhanced CT or MRI in 10 months or more was performed. Angiographic studies were correlated to determine the underlying causes of the EN lesions. RESULTS: We found 78 EN lesions in 36 patients (29%), ranging in size from 4 and 50 mm (mean, 12.2 mm). From the MR reports, our radiologists had prospectively diagnosed EN lesions as probable malignant tumours in eight (10%), possible malignant tumours in 36 (46%), and probable non-neoplastic lesion in 34 (44%). EN lesions were found in 27 of 81 (33%) cirrhotic patients and in nine of 44 (20%) non-cirrhotic patients. Fifty-one EN lesions (65%) were located along the liver edge. The shape was circular in 42 (54%), oval in 14 (18%), irregular in 12 (15%), wedge-shaped in seven (9%), and fan-shaped in three (4%). Twenty EN lesions (26%) appeared slightly hyperintense on T2-weighted images. The causes were non-neoplastic arterio-portal shunting in 48 (62%), cystic venous drainage in four (5%), rib compression in four (5%), aberrant right gastric venous drainage in two (3%), and unknown in 20 (26%). CONCLUSION: Over half the number of EN lesions were caused by non-neoplastic arterio-portal shunting, occasionally showing slight hyperintensity on T2-weighted images. On MR images the non-neoplastic nature of the EN lesion was often ascertained. Radiologists should not overcall EN lesions as malignant as the patients involved would be inappropriately considered inoperable. In problematic cases, further investigation with angiographic CT or follow-up imaging studies should be performed.

Early invasive colorectal carcinomas with submucosal invasion: radiographic characteristics with barium double contrast images.

BACKGROUND: We assessed the radiographic characteristics of early colorectal carcinomas with submucosal invasion (CCSI) with the use of double-contrast images. METHODS: From 1989 to 1997, 193 patients with 196 CCSI lesions underwent double-contrast barium enema examinations. Three gastrointestinal radiologists retrospectively reviewed the radiographic characteristics of the lesions and classified them as protruding and depressed types by consensus. Further, subclassifying the protruding into lobular and smooth types was accomplished on the basis of surface structure. Each type was compared with pathologic findings of resected specimens. RESULTS: The incidence of the protruding type was 98.0%, and that of the depressed type was only 2.0%. The proportion of smooth lesions was 49.0% for the protruding type; these had a mean diameter of 17.9 mm, which was significantly smaller than the 23.1 mm mean observed for lobular lesions (p < 0.01). Of the smooth lesions, 44.7% demonstrated massive invasion, whereas 91.8% of lobular lesions exhibited only slight or moderate invasion into the submucosa (p < 0.01). The extent of invasion of the smooth lesions was greater than that for their lobular counterparts in terms of venous and lymph node involvement. CONCLUSION: Almost all CCSIs could be identified radiologically as protruding lesions; these had a smooth rather than a lobulated surface and demonstrated greater malignancy, despite the smaller size. It is clinically important to discriminate these from other polypoid lesions in establishing patient treatment. Double-contrast imaging is useful for evaluation of the surface characteristics of CCSIs in barium enema studies.

Prognostic significance of grading (MIB-1 system) in patients with myxoid liposarcoma.

AIMS: To determine the relation between clinical outcome and tumour grade defined by a MIB-1 (Ki-67) score based grading system. METHOD: The clinical and pathological features of 50 patients with myxoid liposarcoma were evaluated, and MIB-1 immunostaining was performed to grade these patients' tumours. Univariate and multivariate analyses were conducted to evaluate survival. Clinical follow up details were available for all patients (median, 46.5 months; range, 9-408). RESULTS: Univariate analysis revealed that the tumour site (p < 0.05), round cell component content (p < 0.01), necrosis (p < 0.01), mitosis (p < 0.01), MIB-1 labelling index (p < 0.001), and tumour grade (p < 0.001) had a significant impact on overall survival. Multivariate analysis showed that, of the variables evaluated, the tumour grade defined by a MIB-1 score based grading system was the most significant adverse prognostic factor. CONCLUSION: Tumour grade determined by the grading system using the MIB-1 score (MIB-1 system) is a very strong prognostic factor in patients with myxoid liposarcoma.

Engineered IGF-I expression induces glandular enlargement in the murine prostate.

IGF-I has been implicated as a factor that may predispose one to prostate cancer and to benign prostatic hypertrophy (BPH). We established murine IGF-I transgenic mice under the control of rat probasin promoter and analysed the histology of the murine IGF-I-overexpressing prostate. Immunohistochemically, IGF-I was expressed in prostatic epithelial cells or basement membranes of the ventral, dorsal and lateral lobes in a line of IGF-I transgenic mice, but not in their control littermates. The anterior lobe did not express IGF-I. IGF-binding protein-3 (IGFBP-3), inhibitory to the mitogenic action of IGF-I, was detected in epithelial cells of prostatic ventral lobes, but not in those of the dorsal, lateral or anterior lobes of IGF-I transgenic mice. In controls, IGFBP-3 was not detected in epithelial cells of any prostatic lobe. Macroscopic prostatic size and the appearance of IGF-I transgenic mice were comparable with those of their control littermates of the same age. With a computed morphometric analysis, epithelial glands and intraglandular lumens in the prostatic lobes except the ventral lobe were smaller at 17 Months of age than at 14 Months both in IGF-I transgenic mice and controls. Glands and intraglandular lumens in the ventral prostatic lobes of IGF-I transgenic mice expressing more IGF-I protein in the prostate than controls were dense and enlarged similar to cysts compared with those of non-transgenic littermates without showing epithelial growth. Glands and lumens in the dorsal and lateral lobes of the IGF-I transgenic mice were also larger than controls at 14 and/or 17 Months of age. Glands in the anterior prostatic lobe of the IGF-I transgenic mice were not morphologically or morphometrically different from those of non-transgenic littermates. In conclusion, IGF-I transgenic mice under the control of rat probasin promoter showed more dense and enlarged epithelial glands in their prostatic ventral, dorsal and lateral lobes.

Sentinel node biopsy for breast cancer patients in Japan.

Sentinel node biopsy may become a standard procedure to detect lymph node metastases in early breast cancer. Numerous studies have confirmed and demonstrated the reliability of the hypothesis of sentinel node biopsy, with a high identification rate and overall accuracy connected with dye-guided and radio-guided sentinel node biopsy. To assess the benefit of sentinel node biopsy, randomized clinical trials are underway in Western countries comparing sentinel node biopsy with conventional axillary lymph node dissection. In Japan, feasibility studies on sentinel node biopsy started in the mid-1990s. The dye and radiopharmaceuticals associated with sentinel node biopsy commonly used in Western countries are not available in Japan. Japanese investigators have attempted to perform sentinel node biopsy using other dyes and radiopharmaceuticals. The results from feasibility studies have been similar to those reported previously. In conclusion, sentinel node biopsy for breast cancer patients is successful in Japan. The current status and the problems are discussed.

Renal damage and salt-dependent hypertension in aged transgenic mice overexpressing endothelin-1.

The recent development of endothelin-1 (ET-1) antagonists and their potential use in the treatment of human disease raises questions as to the role of ET-1 in the pathophysiology of such cardiovascular ailments as hypertension, heart failure, renal failure and atherosclerosis. It is still unclear, for example, whether activation of an endogenous ET-1 system is itself the primary cause of any of these ailments. In that context, the phenotypic manifestations of chronic ET-1 overproduction may provide clues about the tissues and systems affected by ET-1. We therefore established two lines of transgenic mice overexpressing the ET-1 gene under the direction of its own promoter. These mice exhibited low body weight, diminished fur density and two- to fourfold increases in the ET-1 levels measured in plasma, heart, kidney and aorta. There were no apparent histological abnormalities in the visceral organs of young (8 weeks old) transgenic mice, nor was their blood pressure elevated. In aged (12 months old) transgenic mice, however, renal manifestations, including prominent interstitial fibrosis, renal cysts, glomerulosclerosis and narrowing of arterioles, were detected. These pathological changes were accompanied by decreased creatinine clearance, elevated urinary protein excretion and salt-dependent hypertension. It thus appears that mild, chronic overproduction of ET-1 does not primarily cause hypertension but triggers damaging changes in the kidney which lead to the susceptibility to salt-induced hypertension.

Mutation screening for Japanese Lafora's disease patients: identification of novel sequence variants in the coding and upstream regulatory regions of EPM2A gene.

The progressive myoclonus epilepsy of Lafora type (LD) is an autosomal recessive disorder caused by mutations in the EPM2A gene. We demonstrated recently that EPM2A encodes a dual-specificity phosphatase that is primarily associated with polyribosomes. In the present study, we screened for mutations in the EPM2A gene in 4 Japanese LD families and identified a novel mis-sense mutation, Ala46Pro (136G-->C), in heterozygous condition in one patient. In addition, sequence analyses in the patient and control DNA samples identified 4 single nucleotide polymorphisms (SNPs) (75G/A, 120G/T, 159C/G, 171C/T) in the coding region and a novel insertion/deletion polymorphic site (-483[T](11/10)[A](2/3)) and a SNP (-547A/G) in the putative regulatory region of the EPM2A gene. None of the sequence variants, however, co-segregated with the LD phenotype. Haplotype analysis for the 6q24 region in the affected families revealed lack of homozygosity at the EPM2A locus. Our studies suggest that EPM2A is not involved in the disease phenotype of the 4 families studied and that locus heterogeneity for LD may exist in Japanese population also. A simple test described for the detection of Ala46Pro mutation present heterozygously in Japanese population (allele frequency 0.026) can be used for screening this novel allele in a larger sample size.

Vascular abnormalities and elevated blood pressure in mice lacking adrenomedullin gene.

BACKGROUND: Adrenomedullin (AM) is a vasodilating peptide involved in the regulation of circulatory homeostasis and in the pathophysiology of certain cardiovascular diseases. Levels of AM are markedly increased in the fetoplacental circulation during pregnancy, although its function there remains unknown. To clarify the physiological functions of AM, we chose a gene-targeting strategy in mice. METHODS AND RESULTS: Targeted null mutation of the AM gene is lethal in utero: the mortality rate among AM(-/-) embryos was >80% at E13.5. The most apparent abnormality in surviving AM(-/-) embryos at E13.5 to E14.0 was severe hemorrhage, readily observable under the skin and in visceral organs. Hemorrhage was not detectable at E12.5 to E13.0, although the yolk sac lacked well-developed vessels. Electron microscopic examination showed endothelial cells to be partially detached from the basement structure at E12.5 in vitelline vessels and hepatic capillaries, which allowed efflux of protoerythrocytes through the disrupted barrier. The basement membrane was not clearly recognizable in the aorta and cervical artery, and the endothelial cells stood out from the wall of the lumen, only partially adhering to the basement structure. AM(+/-) mice survived to adulthood but exhibited elevated blood pressures with diminished nitric oxide production. CONCLUSIONS: AM is indispensable for the vascular morphogenesis during embryonic development and for postnatal regulation of blood pressure by stimulating nitric oxide production.