Mothers' symptoms of anxiety and depression and the development of child temperament: A genetically informative, longitudinal investigation.

Background: Child temperament traits and mothers' emotional symptoms relating to anxiety and depression may drive changes in one another, leading to their 'co-development' across time. Alternatively, links between mother and child traits may be attributable to shared genetic propensities. We explored longitudinal associations between mothers' emotional symptoms and child temperament traits and adjusted for genetic effects shared across generations. Methods: This study is based on the Norwegian Mother, Father and Child Cohort Study (MoBa). Mothers (n = 34,060) reported on their symptoms of anxiety and depression, and temperament among offspring (n = 42,526), at child ages 1.5, 3 and 5 years. Structural equation models parameterised developmental change in traits, and an extended family design adjusted for genetic effects. Results: We found individual differences in stable trait scores and rate of change for all study variables. Longitudinal stability in mothers' emotional symptoms was associated with longitudinal stability in offspring emotionality (r = 0.143), shyness (r = 0.031), and sociability (r = -0.015). Longitudinal change in mothers' symptoms showed very small or negligible correlations with longitudinal change in child temperament. Both genetic and environmental influences explained the stable longitudinal association between mothers' symptoms and child emotionality. Conclusions: The studied associations between mother and child traits across time appeared to be due to stable, trait-like factors, involving genetic and environmental influence, rather than their co-development. Findings contribute knowledge on how emotional symptoms develop in families across time, and the methods with which we can explore such development.

Analysis of resveratrol as a lung cancer chemopreventive agent in A/J mice exposed to benzo[a]pyrene.

Resveratrol inhibits PAH bioactivation through reduced expression of the CYP1A1 and CYP1B1 genes in human bronchial epithelial cells. Ad libitum access to a diet containing resveratrol showed no effect on benzo[a]pyrene-induced lung tumorigenesis in A/J mice. Also, resveratrol did not change CYP1A1 and CYP1B1 gene expression or benzo[a]pyrene protein adduct levels in the lung tissue. The lack of chemopreventive activity may have been caused by insufficient concentrations or nonreactive forms of resveratrol in the lungs.

Growth of human lung adenocarcinoma in nude mice is influenced by various types of dietary fat and vitamin E.

Studies have shown effects of dietary lipids on carcinogenesis and tumour progression. Different mechanisms for the inhibitory effect of n-3 fatty acids (FA) have been proposed. The inhibition of the growth of subcutaneously transplanted A427 lung adenocarcinoma cells in athymic nude mice may occur due to an increased level of lipid peroxidation products and is the object of this study. The nude mice were fed diets supplemented with corn oil (CO), olive oil (OO) or K85, a mixture of ethyl esters of n-3 FAs, mainly eicosapentaenoic acid (EPA, 20:5, n-3) and docosahexaenoic acid (DHA, 22:6, n-3). Tumours of the n-3 FA group showed reduced growth. Peroxidation products measured by the thiobarbituric acid reactive substances (TBARS) test showed higher levels in tumours from n-3 FA fed mice than in the other diet groups. The growth inhibitory effects and the elevated level of TBARS in the n-3 FA diet group were counteracted by vitamin E supplement in the diet. Cu/Zn-superoxide dismutase (SOD) activity in liver did not differ greatly among the diet groups. The Ki-67 labelling index (LI), indicating cell proliferation rate was significantly lower in the K85 diet group compared to the other diet groups.

Fertility in mice after prenatal exposure to benzo[a]pyrene and inorganic lead.

Experimental evidence suggests that inorganic lead and benzo[a]pyrene (BaP) suppress the development of primordial oocytes during fetal life. We examined the single and combined effects of prenatal exposure to BaP and moderate doses of lead. The fertility and ovarian morphology of F1 female NMRI mice in four treatment groups (nine mice per group) were investigated: control; lead (F0 given 1 g PbCl2/L in drinking water until mating); BaP (10 mg/kg body weight daily by oral intubation on days 7-16 of F0 pregnancy); and combined lead and BaP. F1 groups exposed prenatally to BaP either alone or in combination with inorganic lead showed markedly reduced fertility with few ovarian follicles compared to controls, whereas the group exposed to lead only had measures comparable to the controls. Mice exposed to both lead and BaP had a significantly longer gestation period (days to litter) compared to mice exposed only to BaP, lead, or controls. There is a nonsignificant indication that the compounds together further reduce number of offspring, number of litters, and litter size. These results suggest that lead and BaP have synergistic effects on impairment of fertility. The possibility of synergism may be of human relevance as inorganic lead and BaP are ubiquitous environmental pollutants.

Effects of n-3 fatty acids during neoplastic progression and comparison of in vitro and in vivo sensitivity of two human tumour cell lines.

Several studies have shown that dietary lipid exerts an effect on carcinogenesis. We report here that progression to malignancy in vitro is associated with changes in the response to fatty acids (FAs). Tumorigenic (THKE) cells were more sensitive to the n-3 FAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) than immortalised (IHKE) cells. The growth of THKE cells was inhibited 25% more than the growth of IHKE cells at 80 microM EPA (P < 0.01) and 35% more at 40 microM DHA (P < 0.001). Furthermore, the results indicate that there is a wide cell type variation in the response to FAs. We found that the in vitro inhibition by FAs correlated with the reduction in the growth rate of the tumour in nude mice fed K85 (55% EPA and 30% DHA). A significant difference in tumour latency was observed for the A427 cell tumour groups (10 days, P < 0.05). Tumours in the animals fed n-3 FA exhibited significantly higher levels of EPA and DHA; the level of arachidonic acid (ARA) was significantly lower in THKE tumours and the level of linoleic acid (LA) was significantly lower in A427 tumours than in controls fed corn oil. The higher sensitivity of the A427 cell line was not explained by higher uptake of EPA/DHA.

Decline in FEV1 and airflow limitation related to occupational exposures in men of an urban community.

The purpose of this survey was to evaluate the effects of smoking and occupational exposures on the decline in forced expiratory volume in one second (FEV1), and the presence of airflow limitation (FEV1 x100/forced vital capacity (FVC) being < 65) at follow-up. A random sample of 1,933 men aged 22-54 years in Bergen, Norway, were invited into the survey. Smoking habits and measurements of FEV1 were recorded at the initial survey in 1965-1970 (n = 1,591) and at follow-up in 1988-1990 (n = 951). Past or present self-reported occupational exposures to eleven airborne agents (dusts, gases, vapours and fumes) and measurements of FVC were recorded at follow-up only. The decline in FEV1 was associated (p < 0.001) with age, body height and smoking. Smoking cessation reduced the decline to the level of lifetime nonsmokers. Accelerated decline in FEV1 was observed in subjects exposed to sulphur dioxide gas and to metal fumes. The adjusted decline in FEV1 increased progressively in subjects exposed to increasing numbers of occupational agents (test for trend: p < 0.01). Airflow limitation was observed in 9.5% at follow-up, and increased with age and cigarette consumption. In this community follow-up survey in men, smoking and occupational exposures to sulphur dioxide gas, metal fumes and the numbers of specific agents were found to be important predictors for accelerated decline in FEV1.

Effect modification by inorganic lead in the dominant lethal assay.

Experimental evidence suggests that inorganic lead may modify mutagenic events. We examined the modifying effect of lead on mutagenic events in late spermatogenesis in the dominant lethal assay. Twelve NMRI male mice were given lead chloride in the drinking water and 12 male mice received tap water without lead chloride. Cyclophosphamide (120 mg/kg b.w., i.p.) was given to six males in the lead treatment group and six males in the tap water group 1 week before mating. This resulted in four treatment groups: control, lead, cyclophosphamide, and lead plus cyclophosphamide. Cyclophosphamide given to the males (with or without lead treatment) reduced the numbers of live implants in mated females. The most prominent effect of cyclophosphamide was an increase of resorbed implants. Females mated to lead exposed male mice showed a nonsignificantly lower frequency of resorptions compared to controls. The results give no support to the hypothesis that inorganic lead may influence the mutagenicity of cyclophosphamide in the dominant lethal test.

Pharmacokinetics and metabolism of a leukotriene D4/E4-antagonist (2-[3'-(2"-quinolylmethoxy)phenylamino]benzoic acid) in rat, dog,guinea pig and man.

1. The absorption, distribution, metabolism and excretion of 2-[3'-(2"-quinolyl-methoxy)phenylamino]benzoic acid (QMPB), a novel leukotriene D4/E4 antagonist, were investigated in rat, dog, guinea pig and man. 2. The oral absorption of the potassium salt of QMPB was rapid and almost complete (90%) in rats, and about 50% in dogs. In man, high oral bioavailability was indicated. Absorption in dogs of the zwitterion form was only 7%. 3. The distribution of 3H-QMPB was examined in rats and guinea pigs. Whole-body autoradiography in rats showed that radioactivity was concentrated predominantly in the liver, bile and intestinal lumen, after both oral and i.v. administration. 4. A major metabolite was identified as the O-ester beta-glucuronide of QMPB. 5. Renal excretion in rat, dog and man was very low. In rat, almost complete biliary excretion of QMPB as the glucuronide conjugate was demonstrated. 6. Pronounced enterohepatic circulation of QMPB was demonstrated in rats, and the plasma concentration curves and the negligible renal excretion in dog and man also indicate enterohepatic circulation in these species.

Plasma lipids, lipoproteins, and fecal excretion of neutral sterols and bile acids in rats fed various high fat diets or a low fat/high sucrose diet.

The effect of feeding various diets on plasma lipids and lipoproteins and on fecal excretion of neutral sterols and bile acids was studied in rats fed for 7 wk diets containing 42% of energy as either coconut oil (CO), sunflower seed oil (SO), fish body oil (FBO), cod liver oil (CLO), or a low fat/high sucrose diet (SU). Triacylglycerols (TG) in whole plasma and VLDL + LDL were lower in rats fed high amounts of polyunsaturated fatty acids (PUFA) than in those fed the CO diet. Plasma HDL2 components in FBO and CLO groups were generally lower than in the other groups. Percentages of liver and heart linoleic and arachidonic acid were higher in the SO group, but lower in groups fed marine oils, than in the CO group. There was a high relative amount of eicosapentaenoic and docosahexaenoic acid in liver and heart of rats fed marine oils. Fecal excretion of bile acids was lower in the PUFA groups than in the CO group, whereas the sum of neutral sterols was similar in all groups. Plasma HDL2 (and VLDL + LDL) correlated positively, but HDL3 negatively, with fecal bile acid excretion. Accordingly, increased bile acid excretion does not seem to account for hypolipemia following intake of PUFA diets.

Hypercholesterolaemia, hypotriacylglycerolaemia and increased lipoprotein lipase activity following orchidectomy in rats.

Plasma lipoproteins, faecal cholesterol excretion, and activities of lecithin: cholesterol acyltransferase (LCAT) hepatic lipase (HL), and lipoprotein lipase (LPL) were determined in castrated rats, in rats treated with testosterone propionate after castration, and in sham-operated controls. Compared to control rats, whole-plasma total cholesterol (TC) rose, and triacylglycerols (TG) fell in castrated rats, but were normalized by androgen substitution. VLDL components tended to be reduced, whereas HDL2 components rose following castration. In general, testosterone substitution normalized the alterations induced by castration. Adipose tissue LPL was higher in castrated rats than in control rats, whereas activities of HL and LCAT were not significantly affected by the treatments. Hepatic cholesterol concentration, and faecal excretion of cholesterol and bile acids were not significantly altered by the treatments. Considering all 3 groups together, there was a significant positive correlation between the concentration of plasma cholesterol and cholesterol in liver, between plasma HDL2-cholesteryl esters and hepatic cholesterol, and also between HL and faecal cholesterol excretion. The results suggest that short term castration of rats causes increased levels of lipoprotein lipase and thereby brings about a lowering of VLDL and an increased concentration of LDL and HDL2. These effects are reflected in hypotriacylglycerolaemia and hypercholesterolaemia.

Pharmacokinetics and distribution of the new antihypertensive agent pinacidil in rat, dog and man.

1. The antihypertensive agent pinacidil was rapidly, and almost completely, absorbed following oral administration of 0.5 mg/kg of the [14C]pinacidil monohydrate to rats and dogs. The half-life was about 1 and 2 h in the two species, respectively. A bioavailability of 80% of unchanged pinacidil in the rat suggests a first-pass effect in this species. 2. After oral and intravenous administration of [14C]pinacidil about 85% of the radioactivity was recovered in the urine and 15% in the faeces in rats and dogs; 80-90% was excreted during the first 24 h. Autoradiographic studies in the rat showed similar distributions after oral and intravenous administration. 3. An oral dose of 5 or 10 mg pinacidil monohydrate was rapidly absorbed in healthy volunteers and had a pharmacokinetic profile very similar to that found in rats and dogs. Concomitant food ingestion did not change the bioavailability of the drug.

Metabolism of the new antihypertensive agent pinacidil in rat, dog and man.

1. The antihypertensive agent pinacidil is eliminated from the body mainly by biotransformation in the liver, followed principally by renal excretion of the metabolites. 2. The metabolism and elimination of pinacidil is similar in rat, dog and man, and is independent of the route of administration. 3. After an oral dose, the 24 h urinary excretion of unchanged pinacidil is 13, 4, and 5% in rat, dog and man, respectively. Faecal excretion in the rat and dog is 2 and 4%. 4. In rat, dog and man the main biotransformation product is the pyridine-N-oxide of pinacidil. Following oral administration of pinacidil, 40, 54 and 54%, respectively, is excreted in the urine as the N-oxide during the first 24 h, and less than 1% in the faeces in rat and dog. 5. Three unidentified minor metabolites were found in plasma, urine and faeces in rat and dog. 6. The major metabolite, the pyridine-N-oxide of pinacidil, has an anti-hypertensive potency about a quarter of that of pinacidil. In animals and human volunteers with normal kidney function, however, the plasma concn. of the N-oxide are always lower than those of the parent compound, so that the metabolite contributes little to the antihypertensive effect of pinacidil.

Reduced urine kallikrein excretion and antikaliuresis by chlorazanil in rats.

In normal conscious female Sprague-Dawley rats chlorazanil (3 mg/kg intraperitoneally) reduced urine kallikrein excretion by approximately 80%. Thus, urine kininogenase activity decreased from 54 +/- 5 U/kg/3 hrs to 10 +/- 2 U/kg/3 hrs and urine TAMe-esterase activity decreased from 34 +/- 1.5 mEU/kg/3 hrs to 7.4 +/- 1.0 mEU/kg/3 hrs. In addition kidney kallikrein content decreased by approximately 50% from 0.76 +/- 0.03 U/kidney to 0.40 +/- 0.07 U/kidney at three hours post treatment. Chlorazanil (3 mg/kg intraperitoneally) increased urine sodium excretion from 0.48 +/- 0.04 mmol/kg/3 hrs to 2.48 +/- 0.98 mmol/kg/3 hrs and decreased the potassium excretion from 1.06 +/- 0.45 mmol/kg/3 hrs to 0.29 +/- 0.09 mmol/kg/3 hrs. Comparable antikaliuretic doses of amiloride (5 mg/kg intraperitoneally) or triamterene (10 mg/kg orally) did not change urine kallikrein excretion It is suggested that chlorazanil inhibits kidney kallikrein synthesis perhaps by an innate antimineralocorticoid-like effect.

Enhancement of urinary prostaglandin excretion by chlorazanil in rats. Effects of indomethacin.

In conscious unloaded Sprague-Dawley female rats chlorazanil (10 mg/kg orally) markedly increased urinary prostaglandin E2-excretion from 51 +/- 9 to 813 +/- 112 ng/kg/6 hrs. Urinary flow rate increased from 12.8 +/- 0.6 to 42.0 +/- 1.4 ml/kg/6 hrs and urinary sodium excretion from 0.96 +/- 0.12 to 3.86 +/- 0.33 mmol/kg/6 hrs Urinary potassium excretion was unchanged. Indomethacin pretreatment (5 mg/kg orally) greatly induced the effect of chlorazanil on urinary prostaglandin E2-excretion. In addition indomethacin modified the excretory effects of chlorazanil, thus the enhancement of urinary flow rate was attenuated, the potassium excretion decreased, while sodium excretion tended to be potentiated. In non-pretreated condition chlorazanil variably affected urinary kallikrein excretion (TAMe-esterase activity) from 108 +/- 6 to 92 +/- 33 mEU/kg/6 hrs. After indomethacin pretreatment chlorazanil invariably reduced urine enzyme excretion from 111 +/- 6 to 32 +/- 4 mEU/kg/6 hrs.

Plasma lipid and lipoprotein responses of rats to starch and sucrose diets with and without brewer's yeast.

The effect of starch and sucrose diets, with and without brewer's yeast, on plasma total cholesterol and triglyceride concentration and on the lipoprotein distribution in plasma was studied in male rats. The rats were fed a cereal based stock diet, a starch or a sucrose diet, plus or minus brewer's yeast, for 4 weeks. The plasma cholesterol concentration increased to similar levels in rats fed the starch or the sucrose diets but remained unchanged in rats fed the stock diet. The plasma triglyceride level increased in rats fed stock diet, but was unchanged in those fed starch or sucrose diets. Brewer's yeast did not modify the cholesterol value in any of the three groups but reduced the triglyceride level in rats fed the stock and the starch diets. In rats fed the starch diet there was a reduction in the relative amount of prebeta lipoproteins, but no significant alterations in the beta, prealpha and alpha fractions, as compared with rats fed stock diet. Rats fed the sucrose diet had lower prebeta, beta and alpha lipoprotein percentages and a much higher prealpha percentage than rats fed the stock diet. Brewer's yeast had no consistent effects on the lipoprotein distribution. The results support the contention that there might be a dissociation between dietary effects on the plasma lipid level and on the lipoprotein distribution.

The effects on urinary kinin excretion of oral salt and water loads in dogs.

Ten dogs received 1 l of 37 degrees C tap water by stomach tube. Urine flow rate increased from 17 +/- 6 ml in the control hour to 285 +/- 25 ml in the second hour following the water intake. The diuresis was paralleled by increased urine kinin excretion from 23 +/- 9 ng/h to 94 +/- 17 ng/h. Urine kallikrein and urine sodium excretions remained unmodified. In seven dogs urine sodium excretion was increased from 0.87 +/- 0.22 mmol/h to 14.9 +/- 1.9 mmol/h by intragastric administration of 2% NaCl. Urine flow moderately increased from 15.1 +/- 2.5 ml/h to 64.3 +/- 15.0 ml/h. Urine kinin excretion was unchanged. The results suggest a relationship between high rates of urine flow and urinary kinin excretion.

Prostaglandins, a link between renal hydro- and hemodynamic in dogs.

An increase of the intrarenal pressure to 40 mmHg induced by ureteral constriction or by kidney compression is shown to be followed by increased renal blood flow in anesthetized dogs. This hyperemia is probably the result of enhanced intrarenal prostaglandin activity since it is followed by increased urinary prostaglandin E excretion and is abolished by indomethacin pretreatment. The increase of renal blood flow seems to be due to dilation of the afferent arteriole in order to maintain the filtration pressure. The glomerular filtration rate is thus severely depressed in indomethacin pretreated dogs. Urine and electrolyte excretion is comparably redcued during elevated intrarenal pressure in non-pretreated and in indomethacin pretreated dogs, which suggests that factors other than glomerular filtration rate are involved. Urine osmolarity is positively correlated with renal blood flow, and urine osmolarity increases during elevated intrarenal pressure in non pretreated dogs, whilst urine osmolarity remains unchanged in dogs pretreated with indomethacin.