Biomedical subjects
T Hata
Publications and source records attributed to T Hata.
Targeted disruption of the tyrosine hydroxylase locus results in severe catecholamine depletion and perinatal lethality in mice.
Tyrosine 3-hydroxylase (TH, EC 1.14.16.2) catalyzes the first and rate-limiting step of the catecholamine biosynthetic pathway in the nervous and endocrine systems. The TH locus was disrupted in mouse embryonic stem cells by homologous recombination. Mice heterozygous for the TH mutation were apparently normal. In these mice, TH activity in the embryos and adult tissues was less than 50% of the wild-type values, but the catecholamine level was decreased only moderately in the developing animals and was maintained normally at adulthood, suggesting the presence of a regulatory mechanism for ensuring the proper catecholamine level during animal development. In contrast, the homozygous mutant mice died at a late stage of embryonic development or shortly after birth. Both TH mRNA and enzyme activity were lacking in the homozygous mutants, which thus explained the severe depletion of catecholamines. These changes, however, did not affect gross morphological development of the cells that normally express high catecholamine levels. Analysis of electrocardiograms of surviving newborn mutants showed bradycardia, suggesting an alteration of cardiac functions in the homozygous mice that may lead to the lethality of this mutation. In addition, transfer of a human TH transgene into the homozygous mice corrected the mutant phenotype, showing recovery of TH activity by expression of the human enzyme. These results indicate that TH is essential for survival of the animals during the late gestational development and after birth.
Effects of nisoldipine in silent myocardial ischemia after healing of acute myocardial infarction.
Silent myocardial ischemia occurring after acute myocardial infarction is classified as Cohn type II and has a frequency of 20-30% in all patients with acute myocardial infarction. Follow-up data of patients with either silent or anginal ischemia show a poor prognosis. Thus, all ischemic episodes occurring after myocardial infarction should be treated aggressively. Many multicenter studies have evaluated whether drug treatment can improve prognosis or protect from a nonfatal second attack. Calcium antagonists, especially those that increase heart rate, have not been considered as drugs of choice for this purpose, despite the many beneficial effects shown on myocardial tissue in experimental studies. In the study reported here, the effect of nisoldipine on postinfarction silent myocardial ischemia was evaluated by ambulatory left ventricular function monitoring. Ten patients were selected for study who showed silent myocardial ischemia after their first acute infarction. Blood pressure fell significantly (p < 0.05) after 4 weeks of treatment with nisoldipine (5-10 mg/day), but heart rate showed no change at rest. Exercise time improved (p < 0.05), with increased peak double products. During exercise, there was no significant change in end-diastolic volume but there was a marked improvement in end-systolic volume, and at the submaximal point the ejection fraction was significantly (p < 0.05) increased. Ejection fraction at rest also improved. The deterioration in ejection fraction due to dipyridamole was ameliorated by nisoldipine. Ejection fraction and blood pressure improved during the calculation test, and work performance also improved.(ABSTRACT TRUNCATED AT 250 WORDS)
Molecular detection of pre-ATL state among healthy HTLV-1 carriers in an endemic area of Japan.
Adult T-cell leukemia/lymphoma (ATL) usually develops after age 40 in Japan, suggesting a long latency since HTLV-I is considered to be transmitted mainly from mothers to babies via breast milk. Our previous studies had suggested that HTLV-I carriers who have a monoclonal integration of HTLV-I proviral DNA in the peripheral blood cells, designated pre-ATL, account for about 2% of healthy carriers and are at high risk of developing ATL. Their ages ranged from 32 to 80 (median 57). Nevertheless, many cases of pre-ATL showed a long-lasting carrier state (10-year probability around 90%). In the present investigation we conducted a large-scale molecular detection of monoclonal integration in a population (481 cases) of healthy carriers with ages ranging from 16 to 82 (median 49) for the purpose of clarifying the earliest onset of this pre-ATL state. Southern-blot analysis of DNA extracted from peripheral blood mononuclear cells revealed 6 cases (1.2%) with a monoclonal band. All of these 6 were older than 40; no single positive case was found in 220 carriers under age 40. These results indicate that the molecularly detectable pre-ATL state also develops after a long latency. Thus the pre-ATL state seems to be a subtype of ATL showing an extremely indolent course of disease development, but not merely an early phase of all subtypes of ATL. We propose that, in order to reveal a promoter(s) responsible for the development of ATL from the pre-ATL state, intensive epidemiological investigation of life style, eating habits, occupation and exposure to carcinogens must be conducted on this unique group prone to ATL. It is also important to perform such an epidemiological study on the general population of carriers by paying special attention to the first 3-4 decades of each carrier's life in Japan and by comparing the data with those from carriers in different geographical areas of the world.
Antenatal diagnosis of persistent right umbilical vein.
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Hypertensive intra-arterial chemotherapy for endometrial carcinoma assessed by transvaginal Doppler ultrasound and magnetic resonance imaging.
We examined the effectiveness of hypertensive intra-arterial chemotherapy for endometrial carcinoma using transvaginal Doppler ultrasound and magnetic resonance imaging. Angiotensin II, 100 mg cisplatin, and 40 mg doxorubicin were prescribed for 8 patients with endometrial carcinoma (3 stage Ia; 3 stage Ib; 2 stage II). The resistance index (RI) was obtained for intratumoral blood flow velocity waveforms by transvaginal Doppler ultrasound and changes in RI (delta RI: differences before and after chemotherapy) were calculated. The tumor volume (TV) was also evaluated, based on the T2-weighted image of magnetic resonance imaging (MRI). The decrease in tumor size [DR-T: (TV before chemotherapy--TV after chemotherapy)/TV before chemotherapy x 100] was determined. RI measurements did not correlate with TV, either before or after chemotherapy. The delta RI varied from 0.007 to 0.615 (mean: 0.207) and DR-T varied from 20.1% to 65.0% (mean: 45.5%). The correlation between delta RI and DR-T [DR-T = 23.5 + 167.2 (delta RI)-165.6 (delta RI)2; R2 = 0.772, p < 0.05] was significant. Therefore, we confirmed the effectiveness of hypertensive intra-arterial chemotherapy for endometrial carcinoma using both transvaginal Doppler ultrasound and MRI.
Intrauterine ultrasonographic assessments of embryonic development.
OBJECTIVE: Our purpose was to describe embryonal anatomic structures by use of intrauterine ultrasonography with a 20 MHz flexible catheter-based, high-resolution, real-time miniature transducer. STUDY DESIGN: Thirty-four women about to undergo therapeutic abortion from 7 to 9.9 weeks' gestation were studied with specially developed catheter-based, high-resolution, real-time miniature (2.4 mm outer diameter) ultrasonography transducer (20 MHz). A percentage of anatomic structures visualized at each gestational age is presented. RESULTS: The number and the clarity of structures increased from 7 to 8 weeks of gestation; however, the image quality was degraded because of the increasing fetal size at 9 weeks. At 8 weeks secondary brain vesicles, spine, midgut herniation, liver, upper and lower limb buds, and sacral tail were visualized in all fetuses. The four-chamber view was first identified at 8 weeks, as were fingers or toes. The stomach was first noted at 9 weeks. The umbilical cord cyst was visualized in 8% of embryos at 7 weeks' gestation and in 29% of embryos at 8 weeks. One cystic hygroma was diagnosed at 8 weeks 5 days. CONCLUSION: Intrauterine ultrasonography provides information on the visualization of anatomic structures of the embryo. In this limited series one embryonic malformation was demonstrated, and thus there is a potential for its use in the detection of malformations. These results suggest that intrauterine ultrasonography has the potential to be a supplement to transvaginal ultrasonography during the first trimester in high-risk pregnancies.
Intratumoral peak systolic velocity as a new possible predictor for detection of adnexal malignancy.
OBJECTIVE: Our purpose was to evaluate whether intratumoral blood flow velocity measured by transvaginal Doppler ultrasonography would afford better discrimination between benign and malignant adnexal tumors. STUDY DESIGN: One hundred two patients with adnexal tumors (72 benign, 30 malignant) were studied with transvaginal B-mode, color, and pulsed Doppler ultrasonography before surgery. RESULTS: Sixty-five benign tumors (90.3%) had abnormal morphologic features suggesting malignancy, and blood flow was detected in 29 (40.3%). The peak systolic velocity was 13.1 +/- 9.1 cm/sec and the resistance index was 0.563 +/- 0.177. All malignant tumors had abnormal morphologic features and blood flow was detectable in all cases. The peak systolic velocity was 23.9 +/- 11.5 cm/sec and the resistance index was 0.488 +/- 0.118. When 16 cm/sec was considered as the cutoff value of peak systolic velocity, the sensitivity and specificity of peak systolic velocity in detecting malignant adnexal tumors were 83.3% and 91.6%, respectively. The sensitivity and specificity of the resistance index (cutoff value 0.72) was 93.3% and 68.1%, respectively. There was no significant difference in sensitivity between peak systolic velocity and resistance index. The specificity of the peak systolic velocity was significantly higher than that of the resistance index (p < 0.05). Moreover, the sensitivity of the peak systolic velocity did not significantly differ from that with transvaginal ultrasonography diagnosis (86.7%), and the specificity of the peak systolic velocity was significantly higher than that of transvaginal ultrasonography (69.4%). CONCLUSION: These results suggest that peak systolic velocity obtained from intratumoral abnormal morphologic features provides a superior means for differentiating malignant from benign adnexal tumors.
Effect of dehydroepiandrosterone sulfate on uterine artery flow velocity waveforms in term pregnancy.
OBJECTIVE: To investigate the interrelation between estrogen synthesis by the fetoplacental unit and uteroplacental hemodynamics in term pregnancy. METHODS: Transvaginal color Doppler flow imaging and pulsed Doppler ultrasonographic assessments were made on ten normal full-term pregnant women before and 3, 5, 10, 30, and 60 minutes after the administration of a 200-mg intravenous dose of dehydroepiandrosterone sulfate (DHAS) in 20 mL of 5% dextrose. Ten normal full-term pregnant women received 20 mL of 5% dextrose as controls. The pulsatility index (PI) values for the uterine artery, heart rate, and mean arterial pressure were recorded. Plasma estradiol (E2) was measured before and 10 minutes after the infusion. RESULTS: In the DHAS group, uterine artery PI decreased from baseline by 26% (P < .05) after 5 minutes, and the mean reduction was 36% (P < .05) after 10 minutes and 15% (P < .05) after 30 minutes. The PI returned to the baseline value 60 minutes later. In the control group, there was no change in uterine artery PI. No change was found in heart rate or mean arterial blood pressure in the control or DHAS groups. The mean plasma E2 increased from 22.3 +/- 6.6 to 56.2 +/- 24.1 ng/mL (P < .05) 10 minutes after the infusion in DHAS subjects, whereas there was no significant change in plasma E2 in the controls. CONCLUSION: Dehydroepiandrosterone sulfate induces a significant decrease in the uterine artery PI, which suggests a possible decrease in uterine vascular impedance in term pregnancy.
Behavioral characteristics of SART-stressed mice in the forced swim test and drug action.
SART-stressed (repeated cold-stressed) mice exhibited shortened immobility time in forced swimming tests, and a time-dependent increase in the duration of immobility time of stressed mice was less compared to unstressed mice. These changes were blocked by diazepam and alprazolam without influence on the immobility time of unstressed mice. The shortening of immobility time caused by SART stress was inhibited by repeated pretreatment with imipramine and mianserin, but not by a single dose. In contrast, neither single nor repeated administrations of lithium carbonate had effect on the immobility time of SART-stressed mice. The SART stress technique may be a potential model to investigate the relationship between stress and depression with complex symptoms like excessive emotion- and anxiety-related depression.
Interleukin 1 alpha-induced expression of manganous superoxide dismutase reduces myocardial reperfusion injury in the rat.
We investigated the effects of pretreatment with interleukin (IL)-1 alpha on the expression of manganous (Mn) superoxide dismutase (SOD) mRNA and reperfusion-induced arrhythmias and the size of myocardial infarct in rats. Male Wistar rats received 10 mg intraperitoneal injections of human recombinant IL-1 alpha. Their hearts were thereafter isolated at 6, 12, 24, 36 h. A Northern analysis showed that Mn-SOD mRNA was mainly expressed in the heart and slightly in kidney, but not in any other organs. The expression of Mn-SOD mRNA peaked at 6 h after the injection of IL-1 alpha. The Mn-SOD protein content was most increased 12 h after injection. In the isolated heart model, the rats were pretreated with IL-1 alpha 24 h earlier and their hearts were perfused by the Langendorff method. After 20 min of ischemia which was induced by a ligation of a coronary artery, reperfusion-induced arrhythmias were observed. There were no significant differences in the incidence of ventricular arrhythmias between the IL-1 alpha pretreated and the untreated hearts. IL-1 alpha pretreatment significantly reduced the mean duration of the ventricular arrhythmias and also delayed the onset of arrhythmias. The effect of IL-1 alpha pretreatment was also investigated in a 30-min model of ischemia followed by a 3-min reperfusion in anesthetized rats. The infarct size expressed as a percentage of the area at risk was significantly reduced in the IL-1 alpha pretreated hearts compared with the untreated hearts. The left ventricular systolic pressure increased significantly in rat hearts pretreated with IL-1 alpha. Our results therefore showed that the pretreatment with IL-1 alpha induced the overexpression of Mn-SOD mRNA in the rat hearts and also suggested that pretreatment with IL-1 alpha 24 h before ischemia reduced the risk of ischemia-reperfusion injury.
Changes in blood velocities of fetal circulation in association with fetal heart rate abnormalities: effect of sublingual administration of nifedipine.
Nifedipine has been used to treat hypertension in pregnancy, and does not influence fetal or uteroplacental circulations in patients with preeclampsia. A 29-year-old multi-gravid woman presented at 32 weeks' gestation with significant elevation of her blood pressure. After sublingual administration of nifedipine, the blood pressure decreased from 208/122 to 136/96 mm Hg at 30 minutes. In her growth-retarded fetus with abnormal flow velocity waveforms, pulsatility index values for middle cerebral artery and umbilical artery did not change; however, peak systolic velocities, end-diastolic velocities, and time-averaged mean peak velocities for these arteries became significantly elevated. Simultaneously, severe variable decelerations and late decelerations occurred. The adverse effect of nifedipine on fetal circulation might occur in a growth-retarded fetus with abnormal flow velocity waveforms.
Effect of dehydroepiandrosterone sulfate on ophthalmic artery flow velocity waveforms in full-term pregnant women.
The possible effects of dehydroepiandrosterone sulfate on orbital circulation in 14 term pregnant women were examined by color Doppler flow mapping and pulsed Doppler ultrasound assessments of ophthalmic artery blood flow velocities before and 3 minutes after the intravenous drug injection. Blood pressure, heart rate, peak systolic velocity, end-diastolic velocity, time-averaged mean peak velocity, and pulsatility index were studied. Dehydroepiandrosterone sulfate injected intravenously had little effect on blood pressure, heart rate, and peak systolic velocity, increasing (p < 0.02) the mean end-diastolic velocity from 3.7 +/- 1.7 to 4.9 +/- 2.0 cm/s (mean +/- SD) and the mean time-averaged mean peak velocity (p < 0.02) from 9.8 +/- 3.2 to 12.1 +/- 3.9 cm/s (mean +/- SD). The mean pulsatility index decreased simultaneously (p < 0.02) from 2.75 +/- 0.79 to 2.29 +/- 0.58 (mean +/- SD). Dehydroepiandrosterone sulfate vasodilates the ophthalmic artery, increasing blood flows in term pregnant women, and similar changes might occur in other cerebral vessels. It seems that this vasodilative effect of dehydroepiandrosterone sulfate is expected for treatment of preeclampsia.
Mathematical modeling of fetal organ growth using the Rossavik growth model: IV. Lung.
Growth of the fetal lung has been monitored by left lung area (LLA), right lung area (RLA), and total lung area (TLA) from 14 to 41 weeks menstrual age in 116 normal Japanese fetuses. Growth of the fetal heart and chest has also been monitored by heart area (HA) and chest area (CA), respectively. Growth curves for these parameters have been determined by using a Rossavik growth model [p = c(t)k+s(t)]. R2 values of 95.3%, 90.3%, 89.0%, 88.7%, and 92.1% were obtained for CA, HA, LLA, RLA, and TLA, respectively. Variability analysis indicated a progressive increase in variability with fetal age for these five parameters. Variability data were used with the growth curve models to determine standard curves for these parameters. These standard curves provide a superior means for evaluating the normal fetal lung growth in the fetus and for identifying pulmonary hypoplasia in utero.
Effect of maternal hyperglycemia on fetal regional circulation in appropriate for gestational age and small for gestational age fetuses.
The effect of maternal hyperglycemia on fetal regional circulation in appropriate for gestational age and small for gestational age fetuses was evaluated. Color Doppler flow imaging and pulsed Doppler ultrasonographic assessments were made on 15 appropriate for gestational age and 19 small for gestational age fetuses, ranging from 33 to 40 weeks' gestation before, 60 minutes, and 120 minutes after a maternal 75 g glucose load. The pulsatility index (PI) was calculated for middle cerebral artery, descending aorta, splenic artery, renal artery, femoral artery, and umbilical artery. Simultaneously, maternal plasma glucose concentration was measured. Baseline PI value (1.50 +/- 0.31) for middle cerebral artery in small for gestational age fetuses was significantly lower than that (1.89 +/- 0.37) in appropriate for gestational age fetuses (p < 0.05); however, there were no significant differences in baseline PI values for other arteries in both groups. In appropriate for gestational age fetuses, the mean PI decreased from 1.89 +/- 0.37 to 1.47 +/- 0.33 at 60 minutes, and to 1.55 +/- 0.32 at 120 minutes (p < 0.05), but no changes were found in the other arteries. In small for gestational age fetuses, there was no significant change in PI value for each artery before and after maternal glucose load. Maternal hyperglycemia induces a significant decrease in cerebrovascular resistance in appropriate for gestational age fetuses but not in small for gestational age fetuses. These results provide a foundation for evaluating the effect of maternal hyperglycemia on fetal regional circulation.
Chorangiosis and chorangioma in three cohorts of placentas from Nepal, Tibet, and Japan.
It has been reported that both chorangiosis and chorangioma are increased in placentas at high altitudes. In this study, 1.14% of 2448 Japanese placentas obtained at 30-300 m had chorangiosis or chorangioma, compared with 3.24% of the Nepalese placentas (1300-3000 m) and 9.09% of the Tibetan samples (3800-4200 m). The incidence of both pathologies was significantly higher in the Himalayan groups than those of the Japanese group (P < 0.05). Obstetric complications of the 28 Japanese placentas with chorangiosis and chorangioma included Caesarean section 16 (57.1%), abruptio placentae 2 (7.14%), intrauterine growth retardation 3 (10.7%), intrauterine fetal death 4 (14.2%) and placenta praevia 4 (14.2%). Four infants (14.2%) had Apgar scores ranging from 0 to 3. Among 48 Himalayan placentas with chorangiosis and chorangioma, incidence of marked subchorionic fibrin was significantly higher (25%) than in the Japanese group (3.57%) (P < 0.05). The incidence of abnormal insertion of the cord was significantly higher (14.2%) in the Japanese group than in the Himalayan group (5%) (P < 0.05). There was no significant difference in the frequencies of intervillous thrombosis and infarction between the two groups. These findings suggest that the incidence of pathological change such as chorangiosis and chorangioma may be increased in placentas at Himalayan altitudes.
Effective absorption of nitrogen dioxide with soda lime.
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Absorption of nitrogen dioxide and nitric oxide by soda lime.
Inhaled nitric oxide (NO) is used for the treatment of pulmonary hypertension as a selective pulmonary vasodilator. However, NO is oxidized rapidly to the more toxic nitrogen dioxide (NO2). Elimination of NO2 from inspired gas is essential for safe clinical use NO. We therefore investigated the efficacy of soda lime in absorbing NO2 from NO2-containing gases. Commercially available soda limes (Soda sorb and Wako lime-A), were exposed to the following six gas mixtures containing NO and NO2 in a hypoxic carrier gas for 20 min: No. 1: NO 40 ppm; No. 2: NO 35 ppm and NO2 5 ppm; No. 3: NO 30 ppm and NO2 10 ppm; No. 4: NO 20 ppm and NO2 20 ppm; No. 5: NO 10 ppm and NO2 30 ppm; and No. 6: NO2 40 ppm. Both types of soda lime completely absorbed the NO2 in all samples when it was present (Nos 2-6). NO concentration in these gas mixtures was reduced by an amount equal to the NO2 absorbed by soda lime. NO was absorbed minimally when NO2 was not present in the mixture. Nitrite was detected from the Wako lime-A granules exposed to the test gas by the chemical analysis. These findings suggest that soda lime completely absorbs NO2 by chemical neutralization, but NO is absorbed as simultaneously absorbed NO2 only where NO and NO2 coexist. Therefore, we conclude that soda lime is useful for NO2 absorption during NO inhalation therapy but NO monitoring from a point distal to the soda lime is required for precise control of inspired NO concentration.