Effect of maternal age on incidences of apoptotic and proliferative cells in trophoblasts of full-term human placenta.

Advanced maternal age is known to be a risk factor for various kinds of obstetric complications, including placental dysfunction. As a first step towards determining the maternal age-related changes in placental, as well as trophoblastic function, we examined the incidences of apoptotic and proliferative cells in trophoblasts of placentae from women of various ages using the TUNEL method and immunohistochemistry for Ki-67 antigen. Tissue sections were collected from the placentae of healthy mothers with normal delivery of healthy babies so that the placental cell kinetics maintaining normal pregnancy and delivery could be studied. The TUNEL-positive cells of the placenta were syncytiotrophoblasts with clustering of nuclei and the TUNEL-positive index of these cells varied from 0.28-1.2%. This index revealed a significant inverse correlation with maternal age. In contrast, the Ki-67-positive index of mononuclear trophoblasts of the placenta ranged between 1.2-2.8% and showed a positive correlation with maternal age. Many of the apoptotic cells of placental villi expressed the pro-apoptotic Bak protein, but were negative for expression of the anti-apoptotic Bcl-2 protein. These results suggest that trophoblasts have higher proliferative activity in older mothers, with a normal process of pregnancy and delivery. The Bcl-2 family proteins could be important for the regulation of trophoblastic apoptosis, although the cellular and molecular mechanisms mediating maternal age-related changes of the placenta remain to be determined.

Dopaminergic activity and endorenal dopamine synthesis in non-insulin dependent diabetes mellitus.

In the present study we tried to clarify the differences of the cardiovascular and renal responses to feeding in relation to the peripheral dopamine system. In control subjects (C), ingestion of protein (100 g) induced an increase in Ccr accompanied by an increase in tubular sodium excretion (FENa+). Patients with non-insulin dependent diabetic (NIDDM), a protein-induced increase in Ccr was comparable to that in C, while FEN+ did not change following protein. Since an increase in urinary 3,4-dihydroxyphenylacetic acid was blunted in NIDDM, an impaired natriuretic response to high protein may be results from an insufficient synthesis of renal dopamine. Plasma dopamine and its metabolites in NIDDM following protein tended to be greater than in C. Protein induced a greater decrease in blood pressure (BP) in NIDDM, but no increase in pulse rate was observed. An ordinary diet containing 10 g of protein also induced a decrease in BP. A reflex tachycardia was observed in C and normotensive NIDDM but not in hypertensive one. In normotensive NIDDM, plasma dopamine and norepinephrine increased after the diet, while in hypertensive NIDDM there were no increases in catecholamines. From these results it is suggested that the relatively elevated peripheral dopaminergic activity and the blunted dopamine synthesis in the kidney may be responsible for the abnormal cardiovascular and renal responses to feeding in patients with NIDDM.

[The role of beta 2-adrenoceptor on the pathogenesis of insulin resistance in essential hypertension].

The role of beta 2-adrenoceptor on the pathogenesis of insulin resistance in essential hypertension (EH) was explored. After the measurement of blood pressure in 15 EH patients and 8 control subjects, EH patients were divided into two groups by the elevation of plasma NE (delta NE) 5 min after standing: 7 normoadrenergic EH (delta NE < 140 pg/ml) and 8 hyperadrenergic EH (delta NE > or = 140 pg/ml). On the morning after a 12-h overnight fast, regular insulin (0.1 U/kg) was injected intravenously, and glucose disappearance rate (GDR) was measured and used as an index of insulin sensitivity. On the following day, the test was reinvestigated following the administration of mabuterol, a beta 2 agonist. Plasma growth hormone (GH), cortisol, norepinephrine (NE) and epinephrine (Epi) were measured before and after the mabuterol administration. Although there were no significant differences of basal GDR among these three groups, mabuterol induced a considerable decrease in GDR in EH patients but not in control subjects. There was no significant difference in the decrease of GDR between normo- and hyperadrenergic EH. The decrease in GDR tended to correlate with the mean blood pressure at rest in EH but not in normal subjects. Plasma glucose and serum insulin in EH patients were increased more than in normal subjects. Plasma GH, cortisol and Epi were not elevated by mabuterol, but plasma NE increased in each group, significantly in hyperadrenergic EH. There was no correlationship between the increase in plasma NE and the decrease in GDR after mabuterol.(ABSTRACT TRUNCATED AT 250 WORDS)

[A case of insulinoma with frequent hypoglycemic attacks not showing evident hyperinsulinemia].

Confirmation of inappropriate hyperinsulinemia is an indispensable requisite for the diagnosis of insulinoma. We report here a case of insulinoma without evident hyperinsulinemia at an early stage. The patient, a 49-year-old woman, had been admitted to our hospital for the evaluation of frequent hypoglycemic attacks. At that time, plasma immunoreactive insulin (IRI) after an overnight fast ranged from 7 to 16 microU/ml. The ratio of IRI/fasting blood sugar (FBS) (Fajans index; normal range, below 0.3) was always between 0.13 and 0.28 even at hypoglycemic states. In addition, because computed tomography and arteriography of the abdomen failed to settle the diagnosis of insulinoma, the patient was discharged and followed up at our outpatient clinic for 2 years. She was admitted to our hospital at 51 years of age for the re-evaluation of hypoglycemic attacks. Laboratory examinations revealed high fasting plasma levels of IRI ranging from 20 to 29 microU/ml. Fajans index also increased to 0.47-0.89. Celiac arteriography was able to confirm the existence of insulinoma. We suggest that insulinoma should be considered in the presence of unexplained hypoglycemic attacks even when there is no evident hyperinsulinemia.

Prognosis of patients with medically treated aortic dissections.

The purpose of this study is to evaluate the long-term results of medical treatment for a dissecting aorta and to detect the risk factors that determine the prognosis of medically treated patients. During the past 10 years, 228 patients with aortic dissections were admitted to our hospital and affiliated hospitals. One hundred thirty-four patients, including 60 with proximal type (Stanford, type A) and 74 with peripheral type (Stanford, type B) dissections, were treated by medical means alone. The survival rates of medically treated patients with type A dissections at 24 hours, 2 weeks, and 5 and 10 years after the onset of the disease were 72, 43, 34, and 28%, respectively, and the survival rates in type B dissections were 100, 92, 76, and 56%, respectively. The risk factors that determine poor prognosis in the acute phase of dissections were type A dissection and serious complications (rupture of the aorta, shock, cerebral accident, myocardial infarction, severe aortic regurgitation, renal failure, mesenteric infarction, and arterial occlusion in the extremities). The risk factors in the chronic phase were serious complications, excluding shock and rupture in the acute phase, the large diameter of the dissecting aorta, and increasing age. These results show that emergency surgical intervention is indicated in the patients with acute type A dissections and in those who had acute type B dissections with these serious complications. Medical treatment may be tentatively recommended for the patients with uncomplicated type B dissections until the operative death rate in these patients becomes less than presently identified.

[Release of endothelin from isolated perfused human umbilical vein. I: Effect of ionomycin].

Endothelin-like immunoreactivity (ET-LI) was directly measured in the perfusate from the isolated human umbilical vein perfused with Krebs-Ringer solution. The identity of the immunoreactive peptide was confirmed as ET-1 by high-performance liquid chromatography. The rate of release of ET-LI was 86.7 +/- 25.9 (SE) fmol during the first perfusion period of 30 min, and it remained stable at least for 4 hours. Calcium ionophore ionomycin, added to the perfusion medium (10(-7)-10(-6) M), stimulated the ET-LI release in a dose-dependent fashion; it increased the rate of release by 29.1% and 143.4% over the control at the concentrations of 10(-7) and 10(-6) M, respectively. These results taken together with previous observations of synthesis of ET in cultured vascular endothelium provide direct evidence for local generation and subsequent release of ET from vascular beds of human beings.

Clinical importance of coronary calcification detected by CT.

Coronary calcifications appear in advanced atheromatous lesions therefore fluoroscopy is useful for the detection of the atherosclerotic coronary artery disease (Aldrich et al., 1979). However, the detection of coronary calcification by fluoroscopy is difficult in the case of obesity or thick chest wall and also impaired by the background structures including bone and other intrathoracic calcifications. X-ray CT is more advantageous than fluoroscopy in the detection of coronary calcification. It can eliminate the interference from background structures and clearly demonstrates calcified sites of the coronary artery. Therefore, we investigated the clinical usefulness in the detection of coronary calcification with X-ray CT.

Coronary artery calcification detected by CT: clinical significance and angiographic correlates.

Cardiac computed tomography (CT) to detect coronary calcification was performed on 161 patients undergoing coronary angiography for proven or suspected coronary artery disease. Among 108 patients in whom coronary calcifications was identified, 90% had significant coronary stenosis angiographically (greater than 75% stenosis), and 80% of 121 patients with significant coronary stenosis showed calcification by CT. The relationship between the calcification site and the significance in stenosis of each vessel was determined. Calcification was present in 133 arteries among 205 stenotic coronary arteries (sensitivity = 65%) as compared with 59 of 439 entire arteries with normal coronary angiograms (specificity = 87%). In the younger age group the sensitivity of calcification for stenosis of each coronary artery was lower and the specificity and predictive value were generally higher than those in the elderly group. These results demonstrate that CT is a valuable procedure for detecting coronary arterial disease, since this examination is easy to conduct, noninvasive, and widely applicable for screening a large population.

[Diagnosis of myocardial infarction by CT: the study of an initial filling defect and late enhancement of the infarcted myocardium after injection of contrast material].

Several animal experimental studies have shown that the enhanced CT gives the direct evidence of acute myocardial infarction characterized by an initial filling defect and late enhancement in the site of the damaged myocardium. Therefore, we studied experimentally and clinically the diagnostic value of these CT findings in detecting and quantitating recent and remote myocardial infarctions. Sixteen mongrel dogs with anterior myocardial infarction were subjected to the present study. The cardiac infarction within one month after coronary arterial ligation was visualized as a filling defect by early CT scan after intravenous injection of contrast material. The delayed scan after the injection showed late enhancement of the infarcted area in both acute and chronic phases. Post mortem histologic studies confirmed that the area of filling defect coincided with the necrotic myocardium and late enhancement coincided with the totally infarcted myocardium including healed scar. The total infarct size measured from CT images was closely correlated with histo-pathological infarct volume (r = 0.96). In the clinical study, the enhanced CT was performed on 112 patients with myocardial infarction and 12 patients with angina pectoris. The filling defect and late enhancement of the infarcted myocardium in the antero-septal or apical wall were detected as clearly as in the animal experiment; the former was found in 85% of the patients with recent infarction, and the latter was detected in about a half of the patients with both recent and remote infarctions. However, these CT findings were not clearly recognized in the patients with infero-posterior infarction, subendocardial infarction or angina pectoris. These results indicate the usefulness of CT in the noninvasive diagnosis and a follow-up study of myocardial infarction.

[Evaluation of constrictive pericarditis by computed tomography].

Since extensive studies of constrictive pericarditis by CT have not been reported, we performed a plain and contrast enhanced CT on 4 patients of constrictive pericarditis diagnosed by cardiac catheterization or echocardiography and confirmed at the time of surgical operation. The CT findings were as follows: The normal pericardium was smooth, could be visualized in the right and anterior regions of the heart, and was approximately or less 2 mm in thickness. On the other hand, the pericardium in constrictive pericarditis was irregularly thickened, was visualized even in the left and posterior regions of the heart, and was more than 2 mm in thickness. The mean CT value of the pericardium in constrictive pericarditis was significantly increased as compared with that of the normal pericardium. The contrast enhanced CT image revealed a marked dilatation of superior and inferior caval veins (SVC and IVC) even in the cases with normal size of each cardiac chamber. The ECG gated CT performed on one case demonstrated the impaired ventricular expansion. After pericardiectomy, the ventricular chambers showed a tendency to dilate, and the dimension of the SVC and IVC were reduced. Thus, CT is thought to be a useful noninvasive technique in evaluating the thickness of the pericardium, its pathology and the degree of dilatation in each cardiac chamber or the vena cavae.

[Positron computed tomography for the assessment of myocardial infarction].

Positron computed tomography (PCT) was performed on 2 normal subjects and 3 patients with myocardial infarction. The PCT device "Positologica-II" developed at the National Institute of Radiological Science Japan was used in this study (Fig. 1). This is a whole body positron CT consisting of 3 detector rings that provide 5 sliced images simultaneously. The radiopharmaceutical 13N-ammonia (13NH3) synthesized by the cyclotron at the institute was used as an indicator of myocardial blood flow. Immediately after the intravenous administration of 13NH3, five serial 1-min PCT scans were performed with 3 additional scans that provided 15 static images spaced 6 mm apart. Cardiac blood pool images were obtained from the first scan. A patient with extensive anterior myocardial infarction revealed an outward bulging of the blood pool compatible with aneurysmal formation (Fig. 2). Three additional late scans provided high quality cross-sectional images of the distribution of 13N in the left ventricular myocardium. Although 13N distribution in myocardium was uniform in normal subjects (Figs. 3 & 4), the patients with myocardial infarction revealed defects in the accumulation of 13N at the sites corresponding to the infarction (Figs. 5, 6, 7 & 8). The conclusions are as follows: (1) serial PCT scans with 13NH3 provide cardiac blood pool images, and (2) myocardial 13N tissue concentration seems to reflect myocardial blood flow.

[Diagnostic value of CT in congenital disorders of the great vessels].

Computed tomographic (CT) studies of the cardiovascular system were performed on 850 cases at our institute during the last five years. The aorta was clearly demonstrated by CT from the aortic root to the bifurcation of the iliac artery, and in most cases the main aortic branches including the coronary, brachiocephalic, common carotid, subclavian, celiac, superior mesenteric, renal and iliac arteries were satisfactorily evaluated (Fig. 1-3). Therefore CT renders us encouraging to detect the abnormality of these arteries. This paper described the CT findings of congenital anomalies of the great vessels in 14 patients with 16 anomalies including two cases of l-corrected transposition of the great vessels, two of double aortic arch, one of aneurysm of the sinus of Valsalva, six of patent ductus arteriosus (PDA) and five of right-sided descending aorta, two of which had double aortic arch aforementioned and the remaining three had dextrocardia. The diagnosis of these abnormalities except for PDA were made only by CT. For instance, l-corrected transposition of the great vessels was diagnosed easily by observing the side-to-side relationship of the great vessels, the aorta is situated to the left and anterior to the pulmonary artery. In the case of double aortic arch, not only the left and right aortic arch, but also the degree of narrowing as well as compression of the trachea and esophagus were well evaluated. The diagnosis of aneurysm of the sinus of Valsalva was made by the characteristically marked dilatation of the aorta at the level of sinus of Valsalva on CT. Only in one case of PDA, the ductus connecting the descending aorta to the left pulmonary artery was demonstrated by CT. Plain CT was well tolerable, but enhanced CT was much more informative to detect cardiovascular abnormalities, and moreover, dynamic CT was rewarding in the detailed evaluation of blood flow in the cardiovascular system.

[Pharmacokinetics study on gentamicin intravenous drip infusion in children].

Pharmacokinetics of gentamicin in children after intravenous infusion over 60 minutes were compared with that after intramuscular injection. 1. Mean measured peak serum levels after intravenous infusion of 2.5 mg/kg and intramuscular injection of 2.0 mg/kg were 6.1 micrograms/ml at termination of infusion and 6.5 micrograms/ml at 30 or 60 minutes after injection, respectively. Older children showed higher serum levels. 2. There was no difference in serum half-life between both modes of administration. 3. The AUC after intravenous infusion was slightly larger than that after intramuscular injection. 4. It was suggested that the efficacy and safety of the treatment by intravenous infusion in children are comparable to that by the intramuscular injection, and optimum single dose is 1.5--2.5 mg/kg.

[Assessment of an intracardiac mural thrombus by contrast enhanced computed tomography].

The usefulness of computed tomography (CT) in the diagnosis of an intracardiac mural thrombus was examined by comparing with two-dimensional echocardiography (2-DE), left ventricular cineangiography (LVG), and operative findings. The following results were obtained: 1) Left atrial thrombi: Among 43 cases of valvular disease with mitral stenosis, left atrial thrombi were noted in 10 cases (13 regions) by CT. Out of these 13 regions, 2-DE detected six regions (Fig. 2). Among 11 patients who underwent operation, thrombi were present in four (six regions). Of these six regions, thrombus was suspected in one region and another one was undetectable, but detected in the remaining four regions by CT and was in good accord with the operative findings (Table 1). Left atrial thrombi were detected in two of 138 cases of coronary heart disease, and in one of 26 cases of cardiomyopathy by CT. 2) Left ventricular thrombi: Left ventricular thrombi were detected in 26 of 122 cases of myocardial infarction (21%) by CT, and had a particularly high incidence in the cases having a ventricular aneurysm (Fig. 4). Of 81 cases in which 2-DE was performed, left ventricular thrombi were detected in 13 cases by both CT and 2-DE, and were not detected in 59 cases by both methods. In nine cases 2-DE diagnosis was not consistent with CT (Table 2). Of 76 cases in which left ventricular cineangiography was performed, left ventricular thrombi were detected in 12 cases by both CT and LVG, and were not detected in 58 cases by both methods. There were six cases of disaccord between 2-DE and CT (Table 2). In two of five cases of congestive cardiomyopathy, left ventricular thrombi were noted by CT. CT was able to detect thrombi in the left atrial appendage, the left atrial lateral wall (Fig. 6), and the regions near the left ventricular apex, which were difficult to be investigated by 2-DE (Fig. 8). CT was, in particular, superior in depicting the size, location and property of thrombi. In addition, CT was able to depict clearly a small thrombus in the left ventricular apex to the extent of, or better than, left ventriculography. Therefore, contrast enhanced CT is a useful diagnostic method for the detection of intracardiac mural thrombi.

[Measurement of cardiac volume by computed tomography (author's transl)].

Noninvasive cardiac volume measurement by computed tomography (CT) was attempted in this study. It was found that non-gated CT images were very close to the end-diastolic images by ECG-gated CT. Ten to fifteen non-gated scannings were obtained serially from the upper atria to the left diaphragm in 9 normal subjects and 72 patients (6 hypertensives, 7 aortic valvular diseases, 22 mitral valvular diseases, 5 shunt lesions and 33 ischemic heart diseases). To demarcate each chamber, contrast enhancement CT was performed by drip infusion in most cases, but it was done by 4-6 times bolus injections at the level of the left ventricle (LV) to visualize LV lumen in ischemic cardiac patients who had ventriculography. The volume was calculated by summing each slice's volume which was obtained from the area times slice thickness (Fig. 2). The total cardiac volume and the volume of each chamber (LA, RA, RV and LV) were calculated. The interventricular septum and LV wall were included into LV volume. There was a good relationship (r = 0.90) between the total cardiac volume by CT and that by chest X-ray (PA and lateral views) (Fig. 4). Each volume by CT in 9 normal subjects was: 353 +/- 30 ml/m2 in total, RA: 53 +/- 17 ml/m2, LA: 54 +/- 21 ml/m2, RV: 90 +/- 15 ml/m2, and LV: 123 +/- 15 ml/m2 (mean +/- SD), respectively, and an increment of each volume was shown according to the hemodynamic features of various heart diseases: the total volume was increased significantly in valvular disease (Fig. 5), RA and RV volumes in mitral valvular disease with tricuspid regurgitation and ASD (Figs. 6, 7) LA volume in mitral valvular disease and shunt lesion (Fig. 8) and LV volume in aortic valvular disease and mitral regurgitation (Fig. 9). Between the left ventricular lumen volume by Ct and its end-diastolic volume by ventriculography (area-length method), there was a good relationship (r - 0.81) in 17 cases without cardiac aneurysms out of 22 ischemic cardiac patients examined by ventriculography (RAO and LAO views) (Fig. 11). The cardiac CT was found very useful for measurements of cardiac volume, since it is noninvasive and quite simple yet reasonably accurate.