Inhibition of HIF-1alpha by the anticancer drug TAS106 enhances X-ray-induced apoptosis in vitro and in vivo.

In a previous study, we showed that a novel anticancer drug, 1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine (TAS106, ECyd) increased the antitumour efficacy of X-irradiation. However, its effects on hypoxic cells in tumours remain unclarified. Here, we show that TAS106 enhances the induction of apoptosis in X-irradiated human gastric adenocarcinoma MKN45 and MKN28 cells under hypoxia in vitro. At the same time, the accumulation of HIF-1alpha observed under hypoxia was shown to be decreased to the level of normoxia in the presence of 0.1 microM TAS106. To study the function of HIF-1alpha protein in apoptosis of hypoxic cells, we employed an HIF-1alpha reductive approach using its specific antisense oligodeoxynucleotide. The reduction of HIF-1alpha gene expression dramatically enhanced X-ray-induced apoptosis in hypoxic cells. In in vivo experiments in which MKN45 cells were transplanted into severe combined immunodeficient (SCID) mice, TAS106 (0.5 mg kg(-1)) suppressed HIF-1alpha expression and subsequently reduced the area of the hypoxic region in the tumour and enhanced the induction of apoptosis in the hypoxic region when combined with 2 Gy of X-irradiation. These results suggest the possibility that TAS106 acts as a potent radiosensitiser through the inhibition of HIF-1alpha expression and can be a useful agent against radiotherapy-resistant hypoxic cells in solid tumours.

Effects of supine and lateral recumbent positions on pulmonary venous flow in healthy subjects evaluated by transesophageal Doppler echocardiography.

OBJECTIVES: This study attempted to evaluate the effects of supine and lateral recumbent positions on pulmonary venous flow by transesophageal Doppler echocardiography in healthy subjects. BACKGROUND: Although transesophageal echocardiographic examination is usually performed with the patient lying in the left lateral decubitus or supine position, little attention has been paid to the effects of these positions on pulmonary venous flow. METHODS: We performed pulsed Doppler transesophageal echocardiography of the left and right pulmonary veins in 16 normal subjects as they lay in the left and right lateral decubitus and supine positions. RESULTS: Data are reported as mean value +/- SD. Adequate recordings were obtained in 12 subjects (75%). In the left pulmonary vein, peak systolic velocity and time-velocity integral of systolic flow increased significantly in the left compared with the right lateral decubitus position (56 +/- 12 vs. 44 +/- 13 cm/s, p < 0.05, and 15 +/- 4 vs. 9 +/- 4 cm, p < 0.05, respectively). In the right pulmonary vein, peak systolic velocity and time-velocity integral of systolic flow decreased significantly in the left compared with the right lateral decubitus position (38 +/- 10 vs. 48 +/- 9 cm/s, p < 0.05, and 9 +/- 2 vs. 12 +/- 2 cm, p < 0.05, respectively). There were no significant differences between positions in peak diastolic flow velocity, time-velocity integral of diastolic flow or peak velocity of flow reversal at atrial contraction. CONCLUSIONS: Pulmonary venous systolic peak velocities and time-velocity integrals of systolic flow increase when the pulmonary venous recording is from the recumbent subject's lower side. Therefore, the effects of position should be considered in evaluating left ventricular diastolic function by transesophageal Doppler echocardiography.

Guidelines from the Japanese Society of Echocardiography: Guidance for the management and maintenance of echocardiography equipment.

Echocardiography plays a pivotal role as an imaging modality in modern cardiology practice. Information derived from echocardiography is definitely helpful for patient care. The Japanese Society of Echocardiography has promoted echocardiography in routine clinical and research use. One of the missions of the Society is to provide information that is useful for high-quality examinations. To ensure this, we believe that equipment in good condition and a comfortable environment are important for both patient and examiner. Here, the Guideline Preparation Committee of the Japanese Society of Echocardiography has established brief guidance for the routine use of echocardiography equipment.

The effects of alpha-phenyl-tert-butyl nitrone (PBN) on copper-induced rat fulminant hepatitis with jaundice.

In the present study we demonstrated the protective effects of the spin-trapping agent alpha-phenyl-tert-butyl nitrone (PBN) against fulminant hepatitis with jaundice in LEC rats. In LEC rats an excess amount of copper is accumulated in the liver and causes hepatitis with severe jaundice. PBN was subcutaneously administered every 2 d at the concentration of 128 mg/kg, beginning with 13-week-old rats and continuing for 17 weeks. PBN prevented the loss of body weight, reduced death rate, and suppressed the increase in GTP and GOT values reflecting hepatic cell destruction. Ocular inspection also confirmed the suppressive effects of PBN on jaundice. In parallel with these phenomena, the amounts of thiobarbituric acid-reactive substances (TBARS) in livers of PBN-administered rats were found to be lower than those of non-PBN-administered rats. Little histological changes were observed in PBN-administered rats in comparison with non-PBN-administered rats. The protective effect of PBN on the formation of oxidative damage in liver DNA was observed but not so remarkable as that on lipid peroxidation. From these results, it was concluded that PBN had the liver-protective effects against fulminant hepatitis with jaundice. This suggested that free radicals play an important role in abnormally accumulated copper-induced liver injury and that PBN potentially has therapeutic value for the treatment of hepatitis.

Intravascular ultrasound evaluation of plaque distribution at curved coronary segments.

Although the distribution of atherosclerosis at the curved coronary segments has implications for atherogenesis and interventional procedures, few data exist regarding the plaque distribution in these sites. Therefore, we prospectively analyzed the intravascular ultrasound images of 55 coronary sites from 37 patients where the atherosclerotic plaque and pericardium were simultaneously demonstrated by intravascular ultrasound. The pericardial images were defined as a high-intensity linear echo image moving during cardiac cycles outside the vessel wall. By the line that was parallel to the pericardial image, the vessel area was divided into 2 semicircles with the same area, namely myocardial and pericardial sides. In each side, the maximal thickness, area, and percent area of plaque were measured. The plaque thickness and area of the myocardial side were significantly greater (1.5 +/- 0.5 mm, 4.9 +/- 2.1 mm or 66%, mean +/- SD) than those of the pericardial side (1.1 +/- 0.4 mm, 3.5 +/- 2.1 mm2 or 45%, p < 0.01). The maximal plaque thickness was positioned at the point with a mean angle of 139 +/- 37 degrees from the point just facing the pericardial image, indicating that atherosclerosis was eccentrically located on the opposite side of the pericardium in these coronary segments, and suggesting that the side of the pericardial image represents the outer curvature of the coronary artery. These results indicate that the pericardial images can be seen by intravascular ultrasound, facilitating the recognition of the disease distribution in situ. The eccentric plaque located on the inner wall at the curved coronary segments, probably due to uneven local shear stress, may have implications for the interventional procedures for these segments.

Doppler estimation of pulmonary artery end-diastolic pressure using contrast enhancement of pulmonary regurgitant signals.

Pulmonary artery (PA) end-diastolic pressure is used as an estimate of PA wedge pressure. We evaluated contrast enhanced pulmonary regurgitant signals in the assessment of PA end-diastolic pressure in 24 patients in a critical care unit. Right atrial pressure was estimated by the percent decrease of the inferior vena caval diameter with inspiration. Weak or absent pulmonary regurgitant signals were enhanced by sonicated albumin (Albunex) in 23 patients (96%). The Doppler-determined PA end-diastolic pressure (the sum of the pulmonary regurgitant pressure gradient at end-diastole and the right atrial pressure) was significantly correlated with the catheter-determined PA end-diastolic pressure (y = 0.85x + 1.72, r = 0.93). Compared with invasive hemodynamic monitoring, the contrast-enhanced Doppler technique using Albunex is effective for measuring PA end-diastolic pressure, even in critically ill patients.

The suppression of age-related accumulation of lipid peroxides in rat brain by administration of Rooibos tea (Aspalathus linearis).

The protective effects of Rooibos tea (RT), Aspalathus linearis, against damage to the central nervous system (CNS) accompanying aging were examined by both the thiobarbituric acid reaction (TBA) and magnetic resonance imaging (MRI) methods in brains of chronically RT-treated rats. Ad libitum administration of RT was begun with 3-month-old Wistar female rats and continued for 21 months. The contents of TBA reactive substances (TBARS) in the frontal cortex, occipital cortex, hippocampus and cerebellum in 24-month-old rats after administration with water were significantly higher than those in young rats (5 weeks old). However, no significant increase of TBARS was observed in RT-administered aged rats. When MR images of the brains of 24-month-old rats with and without RT as well as 5-week-old rats were taken, a decrease of the signal intensity was observed in the cerebral cortex, hippocampus and cerebellum in MR images of aged rats without RT, whereas little change of the signal intensity was observed in MR images of the same regions of 24-month-old rats treated with RT, whose images were similar to those of young rats. These observations suggested that (1) the age-related accumulation of lipid peroxides in the brain was closely related to the morphological changes observed by MRI, and (2) chronic RT-administration prevented age-related accumulation of lipid peroxides in several regions of rat brain.

Fatal cardiac rupture: a case of subepicardial aneurysm after myocardial infarction.

We report a case in which 2-dimensional echocardiography established the diagnosis of a left ventricular subepicardial aneurysm that was followed by rupture and sudden death before surgery. Two-dimensional echocardiography is of great help in detecting this rare complication after myocardial infarction. Urgent surgical treatment is warranted for this condition.

Left atrial thrombus formation immediately after cardioversion of atrial fibrillation despite adequate anticoagulant therapy.

We observed a patient who exhibited de novo left atrial thrombus formation after cardioversion, despite administration of adequate anticoagulant therapy. Preexisting atrial thrombus was excluded by transesophageal echocardiography. Preexisting severe left atrial mechanical dysfunction may be considered as a risk factor for de novo thrombus formation after cardioversion, as well as the poor outcome of cardioversion.

Radiofrequency spectral analysis of attenuated ultrasound signals in experiments with echo contrast microbubbles.

Conventional gray-scale myocardial contrast echocardiography cannot distinguish perfused but attenuated from nonperfused myocardium because both may appear similar at low image intensity. We hypothesized that with radiofrequency spectral analysis of attenuated ultrasound signals, the harmonic-to-fundamental frequency ratio of the peak power spectrum (HFR(P)) could determine the presence of contrast microbubbles. We measured frequency responses of Optison microbubbles at defined degrees of ultrasound signal attenuation with different formulations of silicone (55D, 80A, and 3M); gray-scale intensities of Optison plus water compared with degassed water were analyzed at different attenuation settings (-25, -32, and -44 dB, respectively). HFR(P) values of Optison plus water were significantly higher than reference values of degassed water at each attenuation setting (55D, -14 +/- 2 dB versus -30 +/- 2 dB, P <.001; 80A, -19 +/- 2 dB versus -30 +/- 3 dB, P <.01; 3M, -22 +/- 2 dB versus -30 +/- 3 dB, P <.05), even though conventional videodensitometric analysis could not distinguish them. HFR(P) analysis objectively detects microbubbles in clinically relevant conditions of attenuation.

Improved visualization of the left atrial appendage by transthoracic 2-dimensional tissue harmonic compared with fundamental echocardiographic imaging.

We compared fundamental and tissue harmonic transthoracic echocardiographic imaging for the delineation of the left atrial appendage (LAA) in 32 subjects. The LAA images recorded in the parasternal short-axis view were divided into 4 segments and 2 observers independently graded for each segment using a visual scoring system ranging from 0 to 3 (0 = no, 3 = clearly visible over the entire length of the segment). For the 128 segments, the averaged segment scores were significantly increased after switching to harmonic imaging (1.32 +/- 0.69 versus 1.60 +/- 0.81 for fundamental and tissue harmonic imaging, respectively; P <.0005 for observer 1, and 1.38 +/- 0.65 versus 1.61 +/- 0.82, respectively; P <.001 for observer 2). In a patient with LAA thrombus, the image contrast of the thrombus was improved in harmonic compared with fundamental imaging. These data suggest that tissue harmonic imaging significantly improves image quality of the LAA.

Three-dimensional magnetic resonance imaging of lung and liver tumors in mice by use of transversal multislice magnetic resonance images.

PURPOSE: To diagnose lung and liver tumors experimentally induced in mice in three-dimensional magnetic resonance (MR) images constructed by superimposing transversal multislice MR images of thoracic and abdominal regions taken under a high magnetic field of 7.05 tesla (T). METHODS: Lung and liver tumors were induced by administration of urethane to A/J mice and implantation of transplantable colon-26 cells into BALB/c mice, respectively. Two-dimensional (2-D) multislice MR images from the thoracic to abdominal regions were taken under the proton density-weighted conditions. Each organ in the 2-D MR images was pseudocolored, and a three-dimensional (3-D) image was constructed by superimposing them on a UNIX computer, using volume-rendering software. RESULTS: In the normal mouse, each organ in the thoracic and abdominal regions was three-dimensionally imaged and was clearly distinguished from the others. In mice with tumors in the lung or liver, the pathologic changes in the tissue could be visualized in 3-D images. CONCLUSIONS: The MR images three-dimensionally constructed by use of a method combining MR imaging under a high magnetic field of 7.05 T and a computer technique using volume-rendering software was useful for diagnosis of lung and liver tumors experimentally induced in mice.

Visualization of the topographical structure of the anesthetized mouse brain by MR microimaging.

A nuclear magnetic resonance (NMR) spectrometer equipped with a magnet producing a high and extremely uniform magnetic field (7.05 T) was combined with a strong field gradient coil (3.5 mT/cm) and applied to MR microimaging of the mouse brain to visualize its topographical structure. Since the proton-density-weighted condition (long repetition time (TR) and short echo time (TE); TR/TE = 3,000 ms/10.4 ms) was found to be the most suitable for imaging the mouse brain, mid-sagittal and coronal sections in 1-mm- or 0.3-mm-thick slices were imaged according to the multislice spin echo sequence with 2 or 8 acquisitions, a 2 kHz pulse width and a 256 x 256 data matrix. As expected, the resolution of MR microimaging was comparable to that of the histological sections. The white matter especially, could be distinguished from the gray matter in some regions of the brain. Coronal sections of the brain also showed that the hippocampal CA1-CA3 regions were distinguishable from the other regions. The results suggested that the present MR microimaging technique might be a useful tool for the study of topological anatomy and submicroscopic research using brains of small laboratory animals.

Magnetic resonance imaging of young and aged rat brains under a magnetic field of 7.05 T.

Using a homemade MR imaging probe (Helmoholtz coil), MR images of brains of 5-week-old and 23- or 24-month-old Wistar rats were taken under a magnetic field of 7.05 T (Tesla). The probe was designed to fit the rat head and made by winding thin copper film round an acrylic tube with a 5-cm i.d., 10-cm length and 2-mm thickness. This was adjusted to resonate with the 300 MHz radiofrequency corresponding to the resonance frequency of 1H under a magnetic field of 7.05 T. MR images were obtained by T1-weighted and two-dimensional Fourier transformation techniques. The sagittal and coronal sections were imaged in 1-mm-thick slices. The size of the data matrix was 128 phase-encoded steps. Each image was obtained through eight acquisitions. A comparison of the MR images with those semi-microscopically taken at the same position of the coronal section revealed that the cerebral cortex, hippocampus, hypothalamus and thalamus were clearly imaged by this probe. With aging, MR images of cerebral cortices were observed with decreased signal intensities. Enlargement of the third ventricles and hypertrophy of cranical parietal bones were also recognized in sagittal MR images of aged rats. These observations were more marked in males than in females. From these observations it was concluded that this probe was applicable for MR imaging of rat brains under a magnetic field of 7.05 T.

MR imaging of hepatic injury in the LEC rat under a high magnetic field (7.05 T).

Visualization of copper-induced hepatitis (CuH) in LEC rats was performed by using an MRI apparatus equipped with a magnet producing a high magnetic field of 7.05 T. When three groups of LEC rats (6-16 [pre-hepatitis], 15-26 [acute hepatitis] and 40-77 [chronic hepatitis] weeks old) were examined by MRI under T2-weighted imaging conditions which are suitable for the diagnosis of human hepatitis, hypointense MR images of the livers were, as a whole, obtained in all groups, suggesting that these conditions were not adequate for imaging of CuH of LEC rats. The shortening of the T1 and T2 relaxation times of livers due to an excess amount of paramagnetic irons under the high magnetic field was responsible for the lowering of MR signal intensities of the livers, especially those of 15 to 26-week old rats showing acute hepatitis. However, theoretical calculation of the MR signal intensities using the T1 and T2 relaxation times of the livers indicated that their imaging might be possible under proton density-weighted conditions even with a high magnetic field. Experimental results showed that hepatic injury was visualized as hyperintense regions in the MR image of the liver in the acute-phase rat.

Beneficial effect of combination therapy with ozagrel and pranlukast in exercise-induced asthma demonstrated by krypton-81 m ventilation scintigraphy--a case report.

INTRODUCTION: We evaluated the effect of combination therapy with thromboxane A2 synthesis inhibitor and leukotriene receptor antagonist in a patient with exercise-induced asthma using krypton-81 m ventilation scintigraphy. CLINICAL PICTURE: In a patient with exercise-induced asthma, we found exercise-induced abnormalities of respiratory function test and ventilation scintigraphy, and increases in plasma concentrations of thromboxane B2 and leukotriene C4 with exercise. TREATMENT: A thromboxane A2 synthesis inhibitor (ozagrel) and a leukotriene receptor antagonist (pranlukast) were prescribed. OUTCOME: After treatment for 2 weeks, abnormalities of respiratory function test and ventilation scintigraphy improved. CONCLUSIONS: The combination therapy with ozagrel and pranlukast might be useful for the relief of symptoms in patients with exercise-induced asthma, and krypton-81 m ventilation scintigraphy could be a useful tool for visible evaluation of treatment.

Magnetic resonance imaging of hepatocellular carcinoma in Long-Evans cinnamon rats under a magnetic field of 7.05 T.

Magnetic resonance (MR) images of livers in 3-, 12- and 29-month-old Long-Evans Cinnamon(LEC) rats (male) were taken under a magnetic field of 7.05 T. MR images of sagittal and transversal sections were obtained in 1-mm-thick slices by T1-weighted and two-dimensional Fourier transformation techniques. The data matrix size was 256 phase-encoded steps. Each image was obtained through four acquisitions. Three-month-old rats gave MR images with low signal intensity over the liver probably due to the shorting of its T1 and T2 relaxation times. However, 12-month-old rats gave hyperintense regions around hepatic veins in right hepatic lobe, which was assigned to hepatocellular carcinoma. In 29-month-old rats, MR images with hyperintensity throughout the hepatic lobe were observed. These MR images, therefore, suggested that hepatocellular carcinoma in LEC rats developed from the restricted regions surrounding hepatic veins. In the present study, T1-weighted MR imaging under a magnetic field of 7.05 T was shown to be applicable to the diagnosis of hepatic cancer in LEC rats.

[Endoscopic resection with local injection of hypertonic saline epinephrine for the treatment of early gastric cancer].

We have developed a new method of endoscopic resection of early gastric carcinomas and other tumors. Characteristics of the new method are summarized as follows. 1. In order to prevent bleeding after endoscopic resection of the tumors, local injection of hypertonic saline epine phrine (HSE) solution was applied to the lesion. Even a depressed lesion like II c type early gastric carcinoma was artificially protruded by local injection of HSE solution. 2. Instead of a single fiberscope, double fiberscopes were employed simultaneously for endoscopic resection of the lesion. 3. Prior to resection of the lesion by high frequency current snare method, incision of the mucosa along the marking line around the lesion performed, enabling the area to be resected precisely. 4. Because tissue damage is mild, resected materials removed are suitable for pathological study. Endoscopic resection was performed on a total of 113 cases in early gastric carcinomas; 103 cases among them (91.2%) were curative resections. Ten cases of the rest underwent surgical gastrectomy for the endoscopic non-curative resections. Rate of five-year survival in 103 cases was 85.2%. Endoscopic resection by our method seems to be effective for the treatment of early gastric carcinomas in any lymph node metastasis and in patients at high surgical risk.

[Hemostatic effect of an endoscopic local injection of hypertonic saline-epinephrine (HS-E) solution on upper gastrointestinal bleeding--comparative study of this effect with and without visible vessel detection].

One hundred and ninety seven patients with upper gastrointestinal bleeding were each administered and endoscopic local injection of hypertonic saline epinephrine (HS-E) solution at our hospital over a 5-year period, from the Spring of 1981 to March of 1986. Peptic ulcers were found in 162 of the patient. Vessels could be visibly detected in the 148 (91.4%)-A group, but not in the 14 (8.6%)-B group. A comparison of the number of endoscopic local injections to each of these groups indicated no significant differences in types of bleeding, systemic complications, or sites of bleeding. The excellent hemostatic effect of HS-E is due to the fact that local injection of its solution can be repeated in large quantities for various types of bleeding.