Steatohepatitic hepatocellular carcinoma: imaging findings with clinicopathological correlation.

AIM: To evaluate the clinicopathological and computed tomography (CT) and magnetic resonance imaging (MRI) findings of steatohepatitic hepatocellular carcinoma (SH-HCC). MATERIALS AND METHODS: Clinicopathological and radiological features were evaluated in 20 patients with SH-HCC. The diagnosis of SH-HCC was made histologically if the tumour had four of the following five characteristics: steatosis (>5% tumour cells), ballooning, Mallory-Denk bodies, interstitial fibrosis, and inflammation. All patients underwent dynamic CT and MRI. CT and MRI images were reviewed for morphological features including tumour size, presence, and distribution of fat, and patterns and degree of contrast enhancement. RESULTS: Obesity, hypertension, and history of heavy alcohol intake were common clinical findings observed in 10 (50%), 13 (65%), and 11 (55%) of the 20 patients, respectively. Steatosis and steatohepatitis were pronounced in the background liver in 12 (60%) and 10 (50%) patients, respectively. SH-HCC was moderately differentiated in 18 patients (90%) and well differentiated in two (10%). Pathologically, steatohepatitic features were diffuse in 12 (60%) of the 20 tumours and focal in eight (40%). Tumour size and the percentage of intratumoural steatosis were not correlated (r=0.17, p=0.47). On CT, 16 (80%) patients showed arterial phase enhancement and delayed washout. On MRI, 16 (80%) of 20 tumours showed prominent fatty deposition (10 diffusely, six focally) with arterial phase enhancement. CONCLUSIONS: SH-HCC is likely to show prominent fatty deposits with arterial phase enhancement on CT and MRI. A hypervascular lesion with prominent fatty change should raise the diagnostic suspicion of SH-HCC.

Virtual monochromatic image at lower energy level for assessing pancreatic ductal adenocarcinoma in fast kV-switching dual-energy CT.

AIM: To evaluate the value of virtual monochromatic images (VMIs) at lower energy levels in fast-voltage-switching dual-energy computed tomography (DECT) for assessing pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS: The institutional review board approved this prospective study. Written informed consent was obtained from all patients. Seventy-four consecutive patients with PDAC underwent dynamic contrast-enhanced DECT. Two radiologists reviewed eight energy levels (40, 45, 50, 55, 60, 65, 70, and 75 keV) of the pancreatic parenchymal phase VMIs. CT attenuation of the PDAC and pancreatic parenchyma, background noise, signal-to-noise ratio (SNR) of the pancreas, tumour-to-pancreas contrast-to-noise ratio (CNR), major and minor axes of PDAC, and qualitative tumour conspicuity were compared among the VMIs at eight energy levels. RESULTS: CT attenuation of PDAC and pancreatic parenchyma, background noise, SNR, and CNR peaked on VMIs at 40 keV with statistically significant difference (p<0.0001) and gradually decreased with increasing energy levels. The reproducibility in measuring tumour size was better on VMIs at 40 keV (28.8 and 29.2 mm of major axis in readers 1 and 2, respectively) and tended to be overestimated at higher energy levels (29.8 and 30.9 mm of major axis at 75 keV in readers 1 and 2, respectively). Qualitative tumour conspicuity was also significantly superior on VMIs at 40 keV than at all other energy levels (p<0.0001). CONCLUSION: VMIs at 40 keV demonstrated significantly increased SNR of the pancreas, CNR, and tumour conspicuity and high reproducibility in measuring tumour size for assessing PDAC.

Pancreatic MRI associated with pancreatic fibrosis and postoperative fistula: comparison between pancreatic cancer and non-pancreatic cancer tissue.

AIM: To evaluate the potential value of magnetic resonance imaging (MRI) for predicting postoperative pancreatic fistula (POPF) in patients with pancreatic cancer (PC) and non-pancreatic cancer (non-PC). MATERIAL AND METHODS: This retrospective study was approved by the institutional review board and written informed consent was waived. Forty patients underwent pancreatoduodenectomy due to PC (n=31) and non-PC (n=9). The pancreas-to-muscle signal intensity ratio (SIR) on three-dimensional (3D)- fast field echo (FFE) T1-, in- and opposed-phase T1-, and T2-weighted images, as well as the apparent diffusion coefficient (ADC) value of the pancreas were measured. The frequency of POPF and MRI measurements were compared between patients with PC and non-PC. The MRI measurements were also compared with the grade of pancreatic fibrosis on pathological findings, fat deposition, and interstitial oedema. RESULTS: The frequency of POPF was significantly higher in patients with non-PC than in those with PC (p=0.0067), with an odds ratio of 10.4. The SIR on 3D-FFE T1-weighted images was significantly higher in patients with non-PC (p=0.0001) and those with POPF (p=0.017) than in those with PC and those without POPF, respectively. Multiple regression analysis demonstrated that the SIR on 3D-FFE T1-weighted image was independently associated with the grade of pancreatic fibrosis (p<0.0001). CONCLUSION: The frequency of POPF was significantly higher in patients with non-PC than in those with PC was inversely related to the grade of pancreatic fibrosis. The SIR on 3D-FFE T1-weighted image might be a potential imaging biomarker for predicting POPF.

Right adrenal vein: comparison between adaptive statistical iterative reconstruction and model-based iterative reconstruction.

AIM: To compare right adrenal vein (RAV) visualisation and contrast enhancement degree on adrenal venous phase images reconstructed using adaptive statistical iterative reconstruction (ASiR) and model-based iterative reconstruction (MBIR) techniques. MATERIAL AND METHODS: This prospective study was approved by the institutional review board, and written informed consent was waived. Fifty-seven consecutive patients who underwent adrenal venous phase imaging were enrolled. The same raw data were reconstructed using ASiR 40% and MBIR. The expert and beginner independently reviewed computed tomography (CT) images. RAV visualisation rates, background noise, and CT attenuation of the RAV, right adrenal gland, inferior vena cava (IVC), hepatic vein, and bilateral renal veins were compared between the two reconstruction techniques. RESULTS: RAV visualisation rates were higher with MBIR than with ASiR (95% versus 88%, p=0.13 in expert and 93% versus 75%, p=0.002 in beginner, respectively). RAV visualisation confidence ratings with MBIR were significantly greater than with ASiR (p<0.0001, both in the beginner and the expert). The mean background noise was significantly lower with MBIR than with ASiR (p<0.0001). Mean CT attenuation values of the RAV, right adrenal gland, IVC, and hepatic vein were comparable between the two techniques (p=0.12-0.91). Mean CT attenuation values of the bilateral renal veins were significantly higher with MBIR than with ASiR (p=0.0013 and 0.02). CONCLUSION: Reconstruction of adrenal venous phase images using MBIR significantly reduces background noise, leading to an improvement in the RAV visualisation compared with ASiR.

P450 oxidoreductase deficiency with maternal virilization during pregnancy.

PURPOSE: The authors report on a rare case of maternal virilization during pregnancy caused by autosomal recessive P450 oxidore- ductase (POR) deficiency. MATERIALS AND METHODS: A 24-year-old primigravida developed a deepening voice and hirsutism in the second trimester. Prenatal ultrasonography failed to detect any fetal abnormality and fetal growth was normal. POR deficiency was suspected, but the mother declined fetal genetic testing. A female neonate was delivered by cesarean section at 41 weeks' gestation. RESULTS: The neonate had skeletal abnormalities. Mutational analysis of the POR gene demonstrated homozygosity for c.1370 G>A and p.R457H in the patient and heterozygosity in her parents. POR deficiency was confirmed in the neonate. CONCLUSION: POR deficiency should be suspected in cases of maternal virilization. Maternal urinary estriol, fetal magnetic resonance imaging, and parental genetic testing should be performed. Parental consent for fetal genetic testing should be sought to ensure prompt diagnosis and early treatment.

Roles of M2 and M3 muscarinic receptors in the generation of rhythmic motor activity in mouse small intestine.

BACKGROUND: The roles of M2 and M3 muscarinic receptor subtypes in the regulation of gut motor activity were investigated. METHODS: We simultaneously recorded changes in the intraluminal pressure (IP) and longitudinal tension (LT) in small intestinal segments from M2 or M3 receptor knockout (KO) and wild-type (WT) mice. KEY RESULTS: In the WT preparations, luminal distension induced a continuous rhythmic contractile activity that was characterized by synchronous rises in IP and LT, occurring periodically at a constant interval. Tetrodotoxin completely abolished the response, whereas atropine either abolished or attenuated it. In the majority of the M2 KO preparations, however, no rhythmic activity was observed in response to the luminal distention, even though networks of enteric neurons and interstitial cells of Cajal (ICC) seemed to be intact. Where rhythmic activity did occur in M2 KO preparations, it was atropine resistant. In the M3 KO preparations, the IP and LT were synchronously changed by the luminal distention, but the changes occurred at irregular intervals. The W/W(v) mutant preparations, which lack ICC in the myenteric plexus (ICC-MY), showed results similar to those of the M3 KO preparations. In some of the M2 /M3 double-KO preparations, rhythmic activity was not observed, but in the others, an atropine-resistant rhythmicity appeared. CONCLUSIONS & INFERENCES: These results suggest that M2 and M3 muscarinic receptors differentially regulate the intestinal motor activity: M2 receptors play an essential role in the generation of rhythmic motor activity, and M3 receptors have a modulatory role in controlling the periodicity of the rhythmic activity together with the ICC-MY.

Development of a bioassay system for human growth hormone determination with close correlation to immunoassay.

Serum growth hormone (GH) level is measured largely through immunoassays in clinical practice. However, a few cases with bioinactive and immunoreactive GH have also been reported. We describe here a new bioassay system for GH determination using the BaF/GM cell line, which proliferates in a dose-dependent manner on hGH addition; cell proliferation was blocked by anti-hGH antibody. This bioassay had the lowest detection limit (∼0.02 ng/ml) reported thus far and the highest specificity for GH. The bioassay results were compared with those of an immunoradiometric assay across 163 patient samples in various endocrine states. A close correlation (the ratio of bioactivity/immunoreactivity was 1.04 ± 0.33, mean ± SD) was observed between bioactivity and immunoreactivity in these samples. The newly developed system is a specific, sensitive, easy, and fast bioassay system for GH determination; we consider it useful for evaluating GH bioactivity in various endocrine states.

Design Considerations for Optimizing Storyline Visualizations.

Storyline visualization is a technique used to depict the temporal dynamics of social interactions. This visualization technique was first introduced as a hand-drawn illustration in XKCD's "Movie Narrative Charts" [21]. If properly constructed, the visualization can convey both global trends and local interactions in the data. However, previous methods for automating storyline visualizations are overly simple, failing to achieve some of the essential principles practiced by professional illustrators. This paper presents a set of design considerations for generating aesthetically pleasing and legible storyline visualizations. Our layout algorithm is based on evolutionary computation, allowing us to effectively incorporate multiple objective functions. We show that the resulting visualizations have significantly improved aesthetics and legibility compared to existing techniques.

Glycated albumin but not HbA1c reflects glycaemic control in patients with neonatal diabetes mellitus.

AIMS/HYPOTHESIS: It is difficult to use HbA(1c) as an indicator of glycaemic control in patients with neonatal diabetes mellitus (NDM) because of high levels of fetal haemoglobin (HbF) remaining in the blood. In this study, glycated albumin (GA), which is not affected by HbF, and HbA(1c) were compared to evaluate whether they reflect glycaemic control in patients with NDM. METHODS: This study included five patients with NDM. Age at diagnosis was 38 ± 20 days. Insulin therapy was started in all patients, and levels of GA, HbA(1c) and HbF were measured monthly for 6 months. One-month average preprandial plasma glucose (aPPG) was calculated using self-monitoring of blood glucose. RESULTS: Plasma glucose and GA were elevated (29.7 ± 13.1 mmol/l [n = 5] and 33.3 ± 6.9% [n = 3], respectively) but HbA(1c) was within normal limits (5.4 ± 2.6% [35.5 ± 4.9 mmol/mol]; n = 4) at diagnosis. With diabetes treatment, aPPG (r = -0.565, p = 0.002), GA (r = -0.552, p = 0.003) and HbF (r = -0.855, p < 0.0001) decreased with age, whereas HbA(1c) increased (r = 0.449, p = 0.004). GA was strongly positively correlated with aPPG (r = 0.784, p < 0.0001), while HbA(1c) showed no correlation with aPPG (r = 0.221, p = 0.257) and was significantly inversely correlated with HbF (r = -0.539, p = 0.004). CONCLUSIONS/INTERPRETATION: GA is a useful indicator of glycaemic control in patients with NDM, whereas HbA(1c) is influenced by age-related changes in HbF and does not accurately reflect glycaemic control.

Partial paternal uniparental disomy of chromosome 6 in monozygotic twins with transient neonatal diabetes mellitus and macroglossia.

Transient neonatal diabetes mellitus (TNDM) usually develops within the first few weeks of life and resolves at a median age of 3 months. In most of the cases, TNDM is caused by the over-expression of a paternally expressed imprinted PLAGL1 locus on chromosome 6q24. The most frequent manifestation other than TNDM is intrauterine growth retardation (IUGR), and in some cases macroglossia. We investigated monozygotic twins who had macroglossia without IUGR. Both of the twins developed insulin-dependent hyperglycemia within the first week of life, which subsequently resolved. DNA profiling with polymerase chain reaction amplification was performed for polymorphic microsatellite markers of chromosome 6. The six informative markers, located between 6p24 and 6q15, showed normal biparental inheritance. However, the six distal informative markers, located between 6q23.2 and the 6q telomeric region, showed the absence of a maternal allele and the presence of a single paternal allele. The monosomy of the 6q telomeric region was not confirmed by chromosome banding showing 46, XX. These findings provide further evidence that partial paternal uniparental disomy of chromosome 6 (pUPD6) causes TNDM. The phenotypes other than diabetes observed in patients with partial pUPD6 may differ from those observed in patients with complete pUPD6.

Muscarinic cationic current in gastrointestinal smooth muscles: signal transduction and role in contraction.

1 The muscarinic receptor plays a key role in the parasympathetic nervous control of various peripheral tissues including gastrointestinal tract. The neurotransmitter acetylcholine, via activating muscarinic receptors that exist in smooth muscle, produces its contraction. 2 There is the opening of cationic channels as an underlying mechanism. The opening of cationic channels results in influxes of Ca2+ via the channels into the cell and also via voltage-dependent Ca2+ channels which secondarily opened in response to the depolarization, providing an amount of Ca2+ for activation of the contractile proteins. 3 Electrophysiological and pharmacological studies have shown that the cationic channels as well as muscarinic receptors exist in many visceral smooth muscle cells. However, the activation mechanisms of the cationic channels are still unclear. 4 In this article, we summarize the current knowledge of the muscarinic receptor-operated cationic channels, focusing on the receptor subtype, G protein and other signalling molecules that are involved in activation of these channels and on the molecular characteristics of the channel. This will improve strategies aimed at developing new selective pharmacological agents and understanding the activation mechanism and functions of these channels in physiological systems.

Results of duct-to-mucosa pancreaticojejunostomy for pancreaticoduodenectomy Billroth I type reconstruction in 100 consecutive patients.

BACKGROUND: This study retrospectively analyzed 100 consecutive patients who underwent pancreaticoduodenectomy (PD) and pylorus-preserving PD (PPPD) with a Billroth I type reconstruction and pancreaticojejunostomy by duct-to-mucosal anastomosis using a continuous running suture. STUDY DESIGN: Seventy patients underwent PD and 30 patients PPPD for pancreatic cancer in 33, bile duct cancer in 28, ampullary or duodenal tumor in 22, chronic pancreatitis in 8, and other gastrointestinal cancer in 9. Postoperative pancreatic anastomotic leakage was diagnosed from skin excoriation around the drain site, and was defined as a high concentration of amylase in drainage fluid or leakage demonstrated on x-ray. RESULTS: The mortality rate was 2% overall (2.8% in PD, 0% in PPPD). The morbidity rate was 23% overall (12.8% in PD, 46.7% in PPPD). Pancreatic anastomotic leakage was 4.0% overall (2.8% in PD, 6.7% in PPPD).. The incidence in the ampullary or duodenal tumors was 9.1% overall (0% in PD, 14.3% in PPPD). Biliary leakage occurred in four patients, 4.0% overall (4.3% in PD, 3.3% in PPPD), intraabdominal hemorrhage in 2% (2.8% in PD, 0% in PPPD), and lethal anastomotic leakage in one patient, overall rate 1% (1.4% in PD, 0% in PPPD). Delayed gastric emptying had the highest morbidity and was seen exclusively in PPPD (39.3%). CONCLUSIONS: A simple continuous running suture and parachuting for duct-to-mucosal pancreaticojejunostomy makes pancreaticoduodenectomy a safe procedure, even in a Billroth I type reconstruction.

Ab initio structure determination of monoclinic 2,2-dihydroxymethylbutanoic acid from synchrotron radiation powder diffraction data: combined use of direct methods and the Monte Carlo method.

The crystal structure of 2,2-dihydroxymethylbutanoic acid (C(6)H(12)O(4)) in monoclinic form has been determined ab initio from synchrotron radiation powder diffraction data. Two O and five C atoms were first derived by direct methods. Two missing O atoms and one C atom were found by the Monte Carlo method without applying constraint to their relative positions. Positional and isotropic displacement parameters of these non-H atoms were refined by the Rietveld method. Molecules are linked by hydrogen bonds and they make sheet-like networks running parallel to the (010) plane. The Monte Carlo method is demonstrated to be a powerful tool for finding missing atoms in partially solved structure.

Continuous measurement of targeted promoter activity by a secreted bioluminescence reporter, Vargula hilgendorfii luciferase.

The promoter activity of growth hormone (GH) was continuously monitored in rat pituitary adenoma cells (GH3) by a secreted bioluminescence reporter, Vargula hilgendorfii (Vh) luciferase. The sensitivity of the reporter was approximately 60-times higher than that of the firefly luciferase. GH3 cells were transfected with a plasmid containing a DNA sequence of the GH promoter (1.8 kb) and a full length of the Vh luciferase cDNA. Using the stable transformants, the Vh luciferase activity was monitored in the plate culture through the bioluminescence of Vh luciferase secreted into the culture medium. The reporter activity was well correlated with GH mRNA as well as GH when the GH promoter activity was activated by thyroid hormone. To develop a continuous monitoring system of the promoter, the reporter activity was sequentially measured in the perfusion system. When the promoter activity of the stable transformants was suppressed by a transcription inhibitor, the reporter activity and GH in the perfusate were simultaneously decreased. The Vh luciferase reporter is a sensitive and convenient tool for continuous and prolonged measurement of promoter activity in living cell culture systems.

Inhibitory effect of TAS-301, a new synthesized constrictive remodeling regulator, on renarrowing after balloon overstretch injury of porcine coronary artery.

The purpose of this study was to determine the efficacy and the possible mechanism of action of a recently synthesized drug, TAS-301 [3-bis(4-methoxyphenyl)methylene-2-indolinone], on stenosis after balloon overstretch injury of porcine arteries. We measured the diameter of vessels by angiography and conducted histological analysis. The oral administration of TAS-301 kept dilated the angiographic luminal diameter of injured segment 4 weeks after overstretch injury and reduced calculated stenosis ratio in a dose-dependent manner, significantly reducing it at doses of 30 and 100 mg/kg. Histopathological analysis showed that TAS-301 significantly reduced the adventitial area at doses of 30 and 100 mg/kg with moderate reduction of the neointimal area, resulting in the larger residual lumen. In an in vitro assay, TAS-301 dose dependently inhibited the proliferation of adventitial fibroblasts stimulated by basic fibroblast growth factor or transforming growth factor-beta(1). In addition, the drug reduced adventitial fibroblast-mediated three-dimensional collagen gel contraction. These findings indicate that TAS-301, the first compound developed for targeting the constrictive remodeling, showed a high inhibitory potency on coronary artery stenosis of micropigs after injury, mainly due to inhibition of adventitial fibroblast proliferation and of the contractile ability of myofibroblasts. Our results suggest the strong possibility that TAS-301 may be efficacious for prevention of restenosis after angioplasty and the need to examine the therapeutic usefulness of this drug in clinical trials.

[Diagnosis of urinary disorders using ultra-thin ultrasound probe].

We have developed a new diagnostic instrument, to visualize small or early lesions from inside by introducing a flexible ultra-thin probe (2 mm in diameter) into the urinary system. The frequency of the oscillator is 20 to 30 MHz, so the tomogram obtained by the method is extremely fine compared with the ultrasonogram obtained by the scanning from outside of the body. Three-dimensional reconstruction of tomogram is also realized. This display method is valuable to plan operations, follow the progress of therapy, and obtain well informed consent from the patient. We are now developing systems to bend and twist the tip of the intraureteral probe. They are applications of shape memory alloy, thermo-electric actuator and magnetic torque.

[Development of a new method for sequential monitoring of transcriptional activities of growth hormone genes by a secreted bioluminescence reporter].

The genetic reporter system has been introduced as a tool for sensitive and convenient monitoring of gene expression. In the present study, the promoter activity of growth hormone (GH)-coding gene was sequentially monitored in GH3 cells (rat pituitary adenoma cell-line) by means of bioluminescence which was evoked by a secreted reporter, Vargula hilgendorfii (VH) luciferase. Three kinds of expression plasmids were constructed, which consisted of a rat GH promoter fragment and VH luciferase cDNA, and transfected into GH3 cells. The sensitivity of the reporter was revealed to be extremely high from the dose-response curve of VH luciferase. With the use of the stable transformant, the reporter activity as well as that of GH was sequentially measured in plate culture. The intracellular dynamics of reporter signals was analyzed through the response to inhibitors of transcription, protein synthesis and vesicle transport, which suggested that the overall time from transcription to secretion was essentially identical to those of the VH luciferase and GH although the both proteins took different time course at different intracellular stages. When the GH promoter was activated by triiodothyronine (T3), the reporter activity was enhanced, and well correlating with the amount of GH mRNA, which indicated a reliability of the reporter system. Furthermore, in the present reporter system, a synergistic effect of T3 and dexamethasone was observed not only on the GH transcription but also on the stability of mRNA. It is concluded that the bioluminescence reporter system using the VH luciferase is an excellent tool for sequential monitoring of the GH transcriptional activity.