Peripartum type B aortic dissection in patients with Marfan syndrome who underwent aortic root replacement: a case series study.

OBJECTIVE: To investigate pregnancy outcomes, especially the risk of pregnancy-related aortic dissection (AD), in patients with Marfan syndrome (MFS) after prophylactic aortic root replacement (ARR). DESIGN: Retrospective case series study. SETTING: Tertiary perinatal care centre at a university hospital. POPULATION: Pregnant women fulfilling the revised Ghent nosology (2010) criteria for MFS who were managed at our institute. METHODS: The pregnancy outcomes of all patients with MFS managed at our institute between 1982 and September 2016 were reviewed retrospectively based on medical records. MAIN OUTCOME MEASURES: Obstetrical management and complication including the incidence of AD throughout the peripartum period. RESULTS: Among 22 patients (28 pregnancies) who had been managed as potential MFS or related disorders, 14 (17 pregnancies) fulfilled the revised Ghent nosology (2010) criteria for MFS and were enrolled in this study. Five patients (five pregnancies) had received ARR before conception: three (60%) developed type B aortic dissection [AD(B)] during the peripartum period, compared with only one of 10 patients (12 pregnancies) without ARR (P < 0.05, Chi-square test). CONCLUSIONS: Our study results suggest that MFS patients after prophylactic ARR are still at high risk of AD(B) during the peripartum period. Careful pre-pregnancy counselling and multidisciplinary care throughout the peripartum period are essential for the management of MFS, even after surgical repair of an ascending aortic aneurysm. TWEETABLE ABSTRACT: MFS patients after prophylactic ARR are still at high risk of type B aortic dissection during the peripartum period.

Beta-adrenoceptor blocking agents release catecholamines from rat adrenal medulla.

When small doses of pindolol and propranolol (0.1 mg/kg and 5 mg/kg, respectively) were administered intraperitoneally to conscious normotensive Kyoto Wistar rats, acute hypotension occurred. However, these hypotensive effects diminished when the doses were increased to 5 mg/kg and 20 mg/kg, respectively. Unilateral adrenalectomy had no effect on these hypotensive effects but they were suppressed by bilateral adrenalectomy. Subsequently, marked and lasting hypotensive effects (20-35 mm Hg) were observed. In urethane-anaesthetized rats, intravenous infusions of the blocking agents produced a rise in blood pressure and an increase in the content of epinephrine, norepinephrine and dopamine in adrenal venous blood. These hypertensive actions were not seen in adrenalectomized rats. When rats were given 6-hydroxydopamine (2 micrograms/microliters) bilaterally at the C4 level of the spinal cord 7 days before or 5,7-dihydroxytryptamine (2 micrograms/microliters, after desmethylimipramine, 25 mg/kg i.p.), the catecholamine content of adrenal venous blood and the catecholamine releasing actions of these blocking agents decreased, but were not completely abolished. These results suggest that the lack of hypotensive effects with higher doses of beta-adrenoceptor blocking agents may have been due partly to the direct release of catecholamines from the adrenal medulla and partly to central noradrenergic or serotonergic nerve action.

Subacute and chronic toxicity studies of triethylenetetramine dihydrochloride (TJA-250) by oral administration to F-344 rats.

Triethylenetetramine dihydrochloride (trientine-2HCl, TJA-250), a copper chelating agent used to treat Wilson's disease, was administered orally to male and female F-344 rats for 4 or 8 weeks at dosages of 0, 100, 350 or 1200 mg/kg/day or for 26 weeks at dosages of 50, 175 or 600 mg/kg/day. 4 or 8-week study. Two males receiving 1200 mg/kg/day died during week 8 of treatment. In males receiving 1200 mg/kg/day during weeks 5 to 8 of treatment, body weight gain and food consumption were decreased and hunched posture and thin build were observed. During week 4 or 8 of treatment urinalysis revealed, for males receiving 100 mg/kg/day or animals receiving 350 mg/kg/day or more, increased electrolyte outputs possibly due to the hydrochloride nature of trientine-2HCl, with low plasma alkaline phosphatase activities evident in animals receiving 350 or 1200 mg/kg/day. After 4 and 8 weeks, and during 8 weeks of treatment, high lung weights and bronchiolar epithelium hypertrophy and broncho-alveolar pneumonia were recorded for animals receiving 1200 mg/kg/day, and submucosal acute inflammation within the glandular region of the stomach was recorded for males receiving 350 or 1200 mg/kg/day and in all treated female groups. 26-week study. One male receiving 175 mg/kg/day and three males receiving 600 mg/kg/day died, showing lung changes. The body weight gain of animals receiving 600 mg/kg/day was slightly decreased. Blood chemistry and urinalysis examinations showed changes similar to those indicated in the 4- or 8-week study. The low plasma copper concentrations seen in males receiving 600 mg/kg/day, the slightly low liver copper concentrations found in animals receiving 600 or 175 mg/kg/day and the high urinary copper concentrations found in all treated groups, are attributed to the pharmacological action of trientine-2HCl. Histopathology revealed a dosage-related incidence and severity of focal chronic interstitial pneumonitis accompanied by fibrosis of the alveolar walls in females receiving 175 mg/kg/day or more and all treated male groups, but no significant pathological changes in the stomach. Apart from the histological changes found in the lung, all the above changes were reversible. In conclusion, the NOAEL of trientine-2HCl in this 26-week study was considered to be 50 mg/kg/day for females and less than 50 mg/kg/day for males.

[Age-related changes and sex differences on the serum chemistry values in Sprague-Dawley rats--I. 6-30 weeks of age].

Age-related changes of 27 items in serum chemistry were investigated in Sprague-Dawley rats of both sexes from 6 to 30 weeks of age. The following 12 items were shown as an increase in those values during growth and maturity, i.e., total protein, albumin (female only), glucose, total cholesterol, triglyceride, phospholipid (female only), beta-lipoprotein, cholinesterase (female only), asparate aminotransferase (female only), creatinine, direct-bilirubin and total-bilirubin. However, the following 4 items decreased with aging, i.e., asparate aminotransferase, alkaline phosphatase, creatine phosphokinase and inorganic phosphorus. No age-related changes were found in the values for calcium, sodium and chloride in both sexes and for alanine aminotransferase, cholinesterase and albumin in males. The sex differences were shown in the following 12 items: higher values in males were alkaline phosphatase, creatinephosphokinase, glucose and inorganic phosphorus, and higher values in females were cholinesterase, albumin, phospholipid, non-esterified fatty acid, urea nitrogen, direct-bilirubin, total-bilirubin and serum iron. No sex-related differences were found in the values for calcium, sodium, chloride and total cholesterol.

Drug-oxidizing mono-oxygenase system in liver microsomes of goldfish (Carassius auratus).

The fractionation of the liver of goldfish (Carassius auratus) was studied, and the properties of the microsomal fraction were examined. The microsomal fraction contained cytochrome P-450 and catalyzed the oxidation of aminopyrine, aniline, 7-ethoxycoumarin and benzo(a)pyrene. The oxidation activities were significantly lower than those of rat liver microsomes. The titration of cytochrome P-450 by potassium cyanide indicated the presence of multiple forms of cytochrome P-450 in goldfish liver microsomes. Feeding of goldfish with 3-methylcholanthrene-containing food greatly induced benzo(a)pyrene hydroxylation activity of the liver microsomes. The Soret peak of the carbon monoxide compound of cytochrome P-450 was shifted from 450 to 448 nm.

Effects of prostaglandins and several vasoactive substances on blood pressure, respiration and blood flow by intra-ventricular, intra-arterial and intravenous routes.

Differences by routes of administration of the effects of prostaglandins and vasoactive substances on blood pressure, peripheral blood flow and respiration were investigated. Intravenous prostaglandins evoked respiratory excitation in rabbits, and lowered blood pressure more prominently and longer after intracarotid injection than after the intrajugular administration. The effects of prostaglandins were apparently more conspicuous after vertebral artery than via carotid artery. In rats, 1 microgram/kg i.v. of PGE1 and PGE2 caused a fall of blood pressure but 1 microgram/kg i.v. of PGF2 alpha caused a rise. PGF2 alpha produce a decrease of blood pressure when injected 10 micrograms/kg i.v.. A remarkable elevation of blood pressure occurred in rats following injection into the lateral cerebral ventricle of 0.1 microgram/kg of PGE1 or PGF2 alpha or of the same dose of 5-hydroxytryptamine (5-HT). Intra-arterial injection of PGE1 gave rise to an increase in blood flow of rabbit dorsal skeletal muscle whereas that of PGF2 alpha resulted in blood flows. The above results indicate that the effects of prostaglandins on these parameters essentially vary to slight extents with the species of animals and differ in intensity with routes of administration.

Characteristic alterations in adrenal catecholamine contents in SHR, SHRSP, and WKY during development of hypertension and stroke.

The role of adrenal catecholamines (CAs) was investigated with regard to the etiology of hypertension and cerebral stroke in the spontaneously hypertensive rats-stroke prone (SHRSP). The adrenal CAs in SHRSP were measured by high performance liquid chromatography with an electrochemical detector or by gas-liquid chromatography with an electron capture detector and the findings were compared with those in the spontaneously hypertensive rats (SHR) and Wistar-Kyoto strain (WKY). It has been proposed that the facilitation of peripheral sympathetic norepinephrine (NE) neurons in the young animals may act as a trigger in the development of hypertension in the SHR. This was verified by estimating the adrenal NE contents in both SHRSP and SHR at 4 weeks of age. A deficiency in adrenal dopamine (DA) in 4-week-old SHRSP was also observed. This deficiency may contribute to the facilitation of the adrenal NE cell. SHRSP was clearly distinguished from SHR by comparing the adrenal catecholamine contents of each strain. The contents of all three CAS in SHRSP were similar to those in WKY during the development of hypertension, while the contents of epinephrine and DA in the SHR were much higher than those in the WKY. Only in SHRSP did the contents of all three CAs increase rapidly after the development of hypertension. These rapid increases may be related to stroke.

[Alpha-methyldopa and brain monoamines].

Alpha-methyldopa (alpha-MDP) is a widely used hypotensive agent, and it is considered to act on the central nervous system. In the present study, 6-hydroxydopa (6-OHDP) was injected into spontaneously hypertensive rats in a dose of 50 mg/kg on the 19th and 21st days of gestation. Dopamine contents were not changed, but norepinephrine (NE) decreased at 12 weeks of age. When the effect of alpha-MDP was examined at the age of 30 to 40 weeks, the decrease in blood pressure induced by 300 mg/kg alpha-MDP i.p. was significantly attenuated in the 6-OHDP treated rats. Whenever the hypotensive effects of alpha-MDP were inhibited, production of alpha-methylnorepinephrine (alpha-MNE) was markedly reduced only in the spinal cord. 6-Hydroxydopamine (6-OHDA) was also injected into the spinal cord at the C4 level. Although alpha-MDP lowered blood pressure in both 6-OHDA treated and non-treated control rats, the decreased in 6-OHDA treated rats tended to be less pronounced. The accumulation of alpha-MNE in the caudal area of the spinal cord was markedly reduced. Furthermore, in order to destroy the spinal serotonergic neurons selectively, we used intraspinal 5,7-dihydroxytryptamine (5,7-DHT) in the same manner as 6-OHDA injection. In 5,7-DHT treated rats, the blood pressure was decreased fully. These observations seem sufficient to hypothesize, although not to conclude, that the effect of alpha-MDP on the blood pressure is dependent at least partly on the biotransformation to alpha-MNE in the spinal noradrenergic neurons.

[Combined effect of glucocorticoid and TJ-114 (Tsumura Sairei-to)].

TJ-114 (Tsumura Sairei-to) is a powdered extract made from 12 Chinese herbal drugs. TJ-114 is used against various nephrotic diseases and used as an inhibitory treatment for the side effects of glucocorticoids. We expected that TJ-114 would increase the survival ratio of rats given a high dose of glucocorticoid. Therefore, in this study, we investigated the combined effects of glucocorticoid and TJ-114 in rats. An ointment containing fluocinolone acetonide (FA) was applied on the back of 7-week-old Wistar male rats for various periods. TJ-114 was administered orally at the doses of 0.5, 1.0 or 2.0 g/kg simultaneously. The combination with TJ-114 suppressed the loss of body weight by FA. The survival ratio of the FA group was 50%, but it was 83% for the group treated with FA in combination with 0.5 g/kg TJ-114 and no deaths were observed in the other drug combined group. With a lower dose of FA, we investigated its hematological effects and determined the white blood cell (WBC) count. Although the lymphocytes were decreased by FA, the combination with TJ-114 depressed this decrease of lymphocytes significantly. Furthermore, TJ-114 significantly suppressed the insulin increase elicited by FA. Macroscopic observations showed atrophy and decreases in the weights of the thymus, spleen and adrenal, all being target organs of glucocorticoid. The combination with TJ-114 decreased these effects of FA. Moreover, microscopic examinations revealed that FA induced the degeneration of lymphocytes and lymphocyte depletion in the cortex of the thymus, caused atrophy of the white pulp, decreased the extramedullary hematopoiesis of the spleen, and caused the atrophy of zona fasciculata in the adrenal cortex. The combination with TJ-114 depressed these effects significantly. These results suggest that TJ-114 suppresses the adverse side effects of gucocorticoids.

[Dopamine secretion from the adrenal medulla during hypotension induced by hemorrhage in dogs (author's transl)].

The rate of secretion of dopamine (DA) was investigated along with those of norepinephrine (NE) and epinephrine (E) in the case of hemorrhagic hypotension. Blood samples were collected directly from the adrenal vein and DA, NE and E contents were measured using a gas-liquid chromatograph equipped with an electron-capture detector (GLC-ECD). Under the condition of hemorrhagic hypotension, the rates of secretion of DA, NE and E increased from 0.22, 3.4 and 13.7 ng/kg/min to 10.7, 89.7 and 361.4 ng/kg/min in 90 min, respectively. After reinfusion, the levels of DA, NE and E decreased. The concentration of DA in the femoral artery was 1.0 and 1.5 ng/ml at 70 and 90 min after hemorrhage. In spinal transected preparations, increases in the rates of DA, NE and E secretion did not occur during hemorrhagic hypotension. Thus, the rates of secretion of DA, NE and E varies with the hemodynamic changes, the secretion of DA from the adrenal gland is primarily controlled by the central nervous system, and the pattern of increase in level of DA differs from the patterns in the case of NE and E in hemorrhagic hypotension.

[Effects of gomisin A, a lignan component of Schizandra fruits, on experimental liver injuries and liver microsomal drug-metabolizing enzymes].

Effects of oral administration of gomisin A, one of the components isolated from Schizandra fruits, on liver injuries induced by CCl4, d-galactosamine and dl-ethionine and on liver microsomal drug-metabolizing enzyme activities were investigated. Gomisin A suppressed the increase of serum transaminase activities and the appearances of histological changes such as degeneration and necrosis of hepatocyte, inflammatory cell infiltration and fatty deposition in each type of liver injury. The repeated administration of gomisin A (30 or 100 mg/kg, p.o., daily for 4 days) induced an apparent increase of liver weight in liver-injured and normal rats. Gomisin A decreased serum triglyceride and lipid contents of the liver in biochemical studies. Increases of microsomal cytochrome b5 and P-450, elevations of NADPH cytochrome C reductase, aminopyrine N-demethylase and 7-ethoxycoumarin O-deethylase activities and decrease of 3,4-benzo(a)pyrene hydroxylase activity per cytochrome P-450 were observed after the administration of gomisin A. In addition, gomisin A was found to enhance the incorporation of 14C-phenylalanine into liver protein and to shorten the hexobarbital-induced sleeping time. These changes caused by gomisin A were similar to those by phenobarbital. However, gomisin A is distinctly different from phenobarbital in the finding that phenobarbital lessened the survival ratio of CCl4-intoxicated mice, but gomisin A did not. Our observation suggest that gomisin A shows an antihepatotoxic action by oral application and also has hypolipidemic (mainly triglyceridemic) and liver protein synthesis-facilitating actions and that the enlargement of the liver seen with gomisin A is the adaptive hypertrophy which is due to the induction of drug-metabolizing enzymes.

General pharmacological properties of TJ-9 extract.

The general pharmacological properties of TJ-9 extract were investigated in various experimental animals. TJ-9 extract at 0.3, 1.0 and 3.0g/kg showed no effect on spontaneous locomotor activity, hexobarbital-induced sleeping time, electroshock-, strychnine-, and pentylenetetrazol-induced convulsions, frequency of acetic acid-induced writhing, body temperature, and skeletal muscle coordination in mice. In anesthetized dogs, TJ-9 extract at 0.3, 1.0 and 3.0 g/kg, had no effect on the frequency of respiration, blood pressure, heart rate, and ECG. TJ-9 extract at 10(-4), 10(-5) and 10(-6)g/ml also had no effect on acetylcholine or barium chloride-induced contraction of guinea pig ileum. TJ-9 extract at 10(-4)g/ml, however, increased histamine-induced contractions, and spontaneous motility of the guinea pig ileum. TJ-9 extract at 0.3, 1.0 and 3.0 g/kg had no effect on blood coagulation and platelet aggregation in rats. TJ-9 extract at the lowest dose of 0.3 g/kg inhibited the gastric juice secretion, gastric pH, and gastric acid output, and at 1.0 g/kg inhibited the gastric acidity and bile secretion in rats. TJ-9 extract at 0.3, 1.0, and 3.0 g/kg, however, had no effect on the intestinal transport of charcoal meal in rats. TJ-9 extract at 3.0 g/kg produced a decrease of urine volume, but never decreased the urine electrolytes, Na(+), K(+), and CI concentration. These results suggest that TJ-9 extract exerts anti-ulcer properties by inhibiting the gastric secretion and gastric acid output, but it showed no notable pharmacological effects on the central nervous system, autonomic nervous system or smooth muscle function, respiratory and cardiovascular system, and blood coagulation and fibrinolysis function.