Preterm birth and risk factors for chronic disease : Helsinki Study of Very Low Birth Weight Adults

Background: The improved prognosis of early preterm birth has created a generation of surviving very low birth weight (< 1500 g, VLBW) infants whose health risks in adulthood are poorly known. Of every 1000 live-born infants in Finland, about 8 are born at VLBW. Variation in birth weight, even within the normal range, relates to considerable variation in the risk for several common adult disorders, including cardiovascular disease and osteoporosis. Small preterm infants frequently exhibit severe postnatal or prenatal growth retardation, or both. Much reason for concern thus exists, regarding adverse health effects in surviving small preterm infants later lives. We studied young adults, aiming at exploring whether VLBW birth and postnatal events after such a birth are associated with higher levels of risk factors for cardiovascular disease or osteoporosis. Subjects and Methods: A follow-up study for VLBW infants began in 1978; by the end of 1985, 335 VLBW survivors at Helsinki University Central Hospital participated in the follow-up. Their gestational ages ranged from 24 to 35 weeks, mean 29.2 and standard deviation 2.2 weeks. In 2004, we invited for a clinic visit 255 subjects, aged 18 to 27, who still lived in the greater Helsinki area. From the same birth hospitals, we also invited 314 term-born controls of similar age and sex. These two study groups underwent measurements of body size and composition, function of brachial arterial endothelium (flow-mediated dilatation, FMD) and carotid artery intima-media thickness (cIMT) by ultrasound. In addition, we measured plasma lipid concentrations, ambulatory blood pressure, fasting insulin, glucose tolerance and, by dual-energy x-ray densitometry, bone-mineral density. Results: 172 control and 166 VLBW participants underwent lipid measurements and a glucose tolerance test. VLBW adults fasting insulin (adjusted for body mass index) was 12.6% (95% confidence interval, 0.8 to 25.8) higher than that of the controls. The glucose and insulin concentrations 120 minutes after 75 g glucose ingestion showed similar differences (N=332) (I). VLBW adults had 3.9 mmHg (1.3 to 6.4) higher office systolic blood pressure, 3.5 mmHg (1.7 to 5.2) higher office diastolic blood pressure (I), and, when adjusted for body mass index and height, 3.1 mmHg (0.5 to 5.5) higher 24-hour mean systolic blood pressure (N=238) (II). VLBW birth was associated neither with HDL- or total cholesterol nor triglyceride concentrations (N=332) (I), nor was it associated with a low FMD or a high cIMT (N=160) (III). VLBW adults had 0.51-unit (0.28 to 0.75) lower lumbar spine Z scores and 0.56-unit (0.34 to 0.78) lower femoral neck Z scores (N=283). Adjustments for size attenuated the differences, but only partially (IV). Conclusions: These results imply that those born at VLBW, although mostly healthy as young adults, already bear several risk factors for chronic adult disease. The significantly higher fasting insulin level in adults with VLBW suggests increased insulin resistance. The higher blood pressure in young adults born at VLBW may indicate they later are at risk for hypertension, although their unaffected endothelial function may be evidence for some form of protection from cardiovascular disease. Lower bone mineral density around the age of peak bone mass may suggest increased risk for later osteoporotic fractures. Because cardiovascular disease and osteoporosis are frequent, and their prevention is relatively cheap and safe, one should focus on prevention now. When initiated early, preventive measures are likely to have sufficient time to be effective in preventing or postponing the onset of chronic disease.

Preterm birth and risk factors for chronic disease : Helsinki Study of Very Low Birth Weight Adults

Background: The improved prognosis of early preterm birth has created a generation of surviving very low birth weight (PIENEMPI KUIN 1500 g, VLBW) infants whose health risks in adulthood are poorly known. Of every 1000 live-born infants in Finland, about 8 are born at VLBW. Variation in birth weight, even within the normal range, relates to considerable variation in the risk for several common adult disorders, including cardiovascular disease and osteoporosis. Small preterm infants frequently exhibit severe postnatal or prenatal growth retardation, or both. Much reason for concern thus exists, regarding adverse health effects in surviving small preterm infants later lives. We studied young adults, aiming at exploring whether VLBW birth and postnatal events after such a birth are associated with higher levels of risk factors for cardiovascular disease or osteoporosis. Subjects and Methods: A follow-up study for VLBW infants began in 1978; by the end of 1985, 335 VLBW survivors at Helsinki University Central Hospital participated in the follow-up. Their gestational ages ranged from 24 to 35 weeks, mean 29.2 and standard deviation 2.2 weeks. In 2004, we invited for a clinic visit 255 subjects, aged 18 to 27, who still lived in the greater Helsinki area. From the same birth hospitals, we also invited 314 term-born controls of similar age and sex. These two study groups underwent measurements of body size and composition, function of brachial arterial endothelium (flow-mediated dilatation, FMD) and carotid artery intima-media thickness (cIMT) by ultrasound. In addition, we measured plasma lipid concentrations, ambulatory blood pressure, fasting insulin, glucose tolerance and, by dual-energy x-ray densitometry, bone-mineral density. Results: 172 control and 166 VLBW participants underwent lipid measurements and a glucose tolerance test. VLBW adults fasting insulin (adjusted for body mass index) was 12.6% (95% confidence interval, 0.8 to 25.8) higher than that of the controls. The glucose and insulin concentrations 120 minutes after 75 g glucose ingestion showed similar differences (N=332) (I). VLBW adults had 3.9 mmHg (1.3 to 6.4) higher office systolic blood pressure, 3.5 mmHg (1.7 to 5.2) higher office diastolic blood pressure (I), and, when adjusted for body mass index and height, 3.1 mmHg (0.5 to 5.5) higher 24-hour mean systolic blood pressure (N=238) (II). VLBW birth was associated neither with HDL- or total cholesterol nor triglyceride concentrations (N=332) (I), nor was it associated with a low FMD or a high cIMT (N=160) (III). VLBW adults had 0.51-unit (0.28 to 0.75) lower lumbar spine Z scores and 0.56-unit (0.34 to 0.78) lower femoral neck Z scores (N=283). Adjustments for size attenuated the differences, but only partially (IV). Conclusions: These results imply that those born at VLBW, although mostly healthy as young adults, already bear several risk factors for chronic adult disease. The significantly higher fasting insulin level in adults with VLBW suggests increased insulin resistance. The higher blood pressure in young adults born at VLBW may indicate they later are at risk for hypertension, although their unaffected endothelial function may be evidence for some form of protection from cardiovascular disease. Lower bone mineral density around the age of peak bone mass may suggest increased risk for later osteoporotic fractures. Because cardiovascular disease and osteoporosis are frequent, and their prevention is relatively cheap and safe, one should focus on prevention now. When initiated early, preventive measures are likely to have sufficient time to be effective in preventing or postponing the onset of chronic disease.

Estradiol - 17β induces polyaromatic hydrocarbon-inducible cytochrome P-450 in chicken liver

A cDNA clone has been isolated from a chicken liver library prepared against messenger RNA isolated after chronic estradiol-17β treatment. The clone, pP-450 IA - 61, has an insert of 900nt and the sequence shows high homology to CYPIA2 subfamily from four other species. A single injection of estradiol-17β to immature chicken results in a striking induction of mRNA hybridizing to labeled pP-450IA - 61. The probe also hybridizes to mRNA induced by 3 — methylcholanthrene in chicken. These results offer direct proof for the similarity in the mode of action at the transcriptional level of polyaromatic hydrocarbons and estrogenic compounds.

Silva Fennica Vol. 17, 1983.

Julkaistu Silva Fennica Vol. 17(4) -numeron liitteenä.

The identification of 14 alpha,17 beta-dihydroxyandrost-4-en-3-one monohydrate and 14 alpha,17 beta-dihydroxyandrosta-1,4-dien-3-one monohydrate, metabolites of androstenedione in Mucor piriformis

The microorganism Mucor piriformis transforms androst-4-ene-3,17-dione into a major and several minor metabolites. X-ray crystallographic analysis of two of these metabolites was undertaken to determine unambiguously their composition and chirality. Crystals belong to the orthorhombic space-group P2(1)2(1)2(1), with a = 7.199(4) angstrom and a = 6.023(3) angstrom, b = 11.719(3) angstrom and b = 13.455(4) angstrom, c = 20.409(3) angstrom and c = 20.702(4) angstrom for the two title compounds, respectively. The structures have been refined to final R values of 0.060 and 0.040, respectively.

Total synthesis of substituted (±)-6,6-dimethyl-B-norestra-1,3,5(10)-trien-17?-ols and their 9?-isomers

Total syntheses of (±)-1,4-dimethoxy-6,6-dimethyl-B-norestra-1,3,5(10)-trien-17?-ol(11a), (±)-2,3-dimethoxy-6,6-dimethyl-B-norestra-1,3,5(10)-trien-17?-ol (11b), and (±)-3-methoxy-6,6-dimethyl-B-norestra-1,3,5(10)trien-17?-ol (11c), have been carried out starting from 4,7-dimethoxy-3,3-dimethylindan-1-one (1), 5,6-dimethoxy-3,3-dimethylindan-1-one (2), and 4?-methoxy-3-methylbut-2-enophenone (4), respectively. Generally, it is found that the intermediate 6,6-dimethyl-B-norestra-1,3,5(10),8-tetraen-17?-ols (10), on lithium�liquid ammonia reduction, yield a mixture of 8?,9?- and 8?,9?-trienols, (11) and (12) respectively, in the ratio 1 : 1. This is due to the comparable stabilities of these two isomers. However, the reduction carried out in presence of aniline affords a higher percentage of the 8?,9?-trienol (11). The assignment of configurations is made by chemical and 1H n.m.r. analysis. Catalytic hydrogenation of the tetraenols (10) is shown to proceed via initial isomerisation to the corresponding 6,6-dimethyl-B-norestra-1,3,5(10),9(11)-tetraen-17?-ols (26), followed by hydrogenation from the ?-side to give, exclusively, the 8?,9?-trienols (12).

Role of oestradiol-17β in the regulation of synthesis and secretion of human chorionic gonadotrophin by first trimester human placenta

Inhibition of aromatase, a key enzyme in the biosynthesis of oestradiol-17 beta, by the addition of 1,4,6-androstatrien-3,17-dione resulted in a significant increase in the levels of immunoreactive human chorionic gonadotrophin (hCG) in the medium and tissue. This increase was partially reversed by the simultaneous addition of oestradiol-17 beta. These effects on the levels of immunoreactive hCG were also reflected by the increased levels of mRNA specific for the alpha and beta subunits of hCG following the addition of the aromatase inhibitor. However, addition of tamoxifen resulted in a drastic decrease in the levels of both the messages. Based on these results, it is suggested that the synthesis of hCG is negatively modulated by oestradiol-17 beta in the human placenta.

Solvation and axial ligation properties of (2,3,7,8,12,13,17,18-octabromo-5,10,15,20-tetraphenylporphyrinato)zinc(II)

he solvation of (2,3,7,8,12,13,17,18-octabromo-5,10,15,20-tetraphenylporphyrinato)zinc(II)[Zn(obtpp)], in twelve different solvents results in large red shifts of the B and Q bands of the porphyrin accompanied by enhanced absorbance ratios of the Q bands. These observations are ascribed to the destabilisation of the highest occupied molecular orbital a2u of the porphyrin arising from a flow of charge from the axial ligand to the porphyrin ring through the zinc(II) ion. The binding constants of adducts of [Zn(obtpp)] with neutral bases have been found to be an order of magnitude greater than those observed for the corresponding adducts of (5,10,15,20-tetraphenylporphyrinato)-zinc and vary in the order piperidine > imidazole > pyridine > 3-methylpyridine > pyridine-3-carbaldehyde. The enhanced binding constants and large spectral shifts are interpreted in terms of the electrophilicity of [Zn(obtpp)] induced by the electron-withdrawing bromine substituents in the porphyrin core. The structure of [Zn(obtpp)(PrCN)2] has been determined; it reveals six-co-ordinated zinc(II) with two long Zn–N distance [2.51(4), 2.59(3)Å]. The porphyrin is non-planar and displays a saddle-shaped conformation.

Transformation of 16-dehydroprogesterone and 17?-hydroxyprogesterone by Mucor piriformis

Mucor piriformis was used to study the mode of transformation of 16-dehydroprogesterone (I, pregna-4, 16-diene-3, 20-dione) and 17 alpha-hydroxyprogesterone (II, 17 alpha-hydroxypregn-4-ene-3, 20-dione). Biotransformation products formed from I were 14 alpha-hydroxypregna-4, 16-diene-3, 20-dione (Ia), 7 alpha, 14 alpha-dihydroxypregna-4 16-diene-3, 20-dione (Ib), 3 beta, 7 alpha, 14 alpha-trihydroxy-5 alpha-pregn-16-en-20-one (Ic), and 3 alpha, 7 alpha, 14 alpha-trihydroxy-5 alpha-pregn-16-en-20-one (Id). Metabolites Ic and Id appear to be hitherto unknown. Timecourse studies suggested that the transformation is initiated by hydroxylation at the 14 alpha-position (Ia) followed by hydroxylation at the 7 alpha-position (Ib). Microsomes (105,000 g sediment) prepared from 16-dehydroprogesterone-induced cells hydroxylate I to its 14 alpha-hydroxy derivative (Ia) in the presence of NADPH. Incubation of Ia with the organism resulted in the formation of Ib, Ic and Id. Biotransformation products formed from compound II were 17 alpha, 20 alpha-dihydroxypregn-4-en-3-one (IIa), 7 alpha, 17 alpha-dihydroxypregn-4-ene-3, 20-dione (IIb), 6 beta, 17 alpha, 20 alpha-trihydroxypregn-4-en-3-one (IIc) and 11 alpha, 17 alpha, 20 alpha-trihydroxypregn-4-en-3-one (IId). Time-course studies indicated that IIa is the initial product formed, which is further hydroxylated either at the 6 beta or 11 alpha position. Incubation of IIa with the organism resulted in the formation of IIc and IId. Reduction of the 4-en-3-one system and 20-keto group has not been observed before in organisms of the order Mucorales. In addition, M. piriformis has been shown to carry out hydroxylation at the C-6, C-7, C-11 and C-14 positions in the steroid molecules tested.

Systematic crystallographic investigation of hydrogen-bonded networks involving monohydrogen tartrate-amine complexes: Potential materials for nonlinear optics

Crystal structures of six binary salts involving aromatic amines as cations and hydrogen tartrates as anions are presented. The materials are 2,6-xylidinium-L-monohydrogen tartrate monohydrate, C12H18O6.5N, P22(1)2(1), a = 7.283(2) Angstrom, b = 17.030(2) Angstrom, c = 22.196(2) Angstrom, Z = 8; 2,6-xylidinium-D-dibenzoyl monohydrogen tartrate, C26H25O8N, P2(1), a = 7.906(1) Angstrom, b = 24.757(1) Angstrom, c = 13.166(1) Angstrom, beta = 105.01(1)degrees, Z = 4; 2,3-xylidinium-D-dibenzoyl monohydrogen tartrate monohydrate, C26H26O8.5N, P2(1), a = 7.837(1) Angstrom, b = 24.488(1) Angstrom, c = 13.763(1) Angstrom, beta = 105.69(1)degrees, Z = 4; 2-toluidinium-D-dibenzoyl monohydrogen tartrate, C25H23O8N, P2(1)2(1)2(1), a = 13.553(2) Angstrom, b = 15.869(3) Angstrom, c = 22.123(2) Angstrom, Z = 8; 3-toluidinium-D-dibenzoyl monohydrogen tartrate (1:1), C25H23O8N, P1, a = 7.916(3) Angstrom, b = 11.467(6) Angstrom, c = 14.203(8) Angstrom, alpha = 96.44(4)degrees, beta = 98.20(5)degrees, = 110.55(5)degrees, Z = 2; 3-toluidinium-D-dibenzoyl tartrate dihydrate (1:2), C32H36O10N, P1, a = 7.828(3) Angstrom, b = 8.233(1) Angstrom, c = 24.888(8) Angstrom, alpha = 93.98 degrees, beta = 94.58(3)degrees, = 89.99(2)degrees, Z = 2. An analysis of the hydrogen-bonding schemes in terms of crystal packing, stoichiometric variations, and substitutional variations in these materials provides insights to design hydrogen-bonded networks directed toward the engineering of crystalline nonlinear optical materials.

Structure of 9[alpha],19-dihydroxy-4-androstene-3,17-dione

C19H26O4, M(r) = 318.41, orthorhombic, P2(1)2(1)2(1), a = 10.591 (1), b = 11.133 (1), c = 13.657 (2) angstrom, V = 1610.29 angstrom 3, Z = 4, D(m) (flotation in KI) = 1.301, D(x) = 1.313 g cm-3, Mo K-alpha, lambda = 0.7107 angstrom, mu = 0.85 cm-1, F(000) = 688, T = 293 K, R = 0.057 for 1253 significant reflections. The A ring is disordered with atoms C(2) and O(19) occupying two possible sites. The molecules are held together by a hydrogen bond [O(9)...O(17) = 2.89 angstrom].

The effect of malathion, an organophosphate, on the plasma FSH, 17 beta-estradiol and progesterone concentrations and acetylcholinesterase activity and conception in dairy cattle

The effect of malathion on jugular plasma concentrations of follicle-stimulating hormone (FSH), estradiol (E2), progesterone (P4) and acetylcholinesterase (AchE) on conception in dairy cattle during a cloprostenol (prostaglandin F2-alpha analogue, PG)-induced estrus was studied. Malathion (1 mg/kg, intraruminally) given at the onset of estrus (48 h after PG) did not alter the plasma FSH or E2 concentrations but significantly (P < 0.05) inhibited plasma P4 concentration. The mean P4 concentration in the malathion-treated group on days 8 and 12 were 0.8 +/- 0.4 and 1.0 +/- 0.5 ng/ml, as compared to 2.6 +/- 0.0 and 2.4 +/- 0.3 ng/ml in the control group. There was a nonsignificant (P > 0.05) inhibition of plasma AchE activity in malathion-treated cattle. Conception was 16.6% in malathion-treated cows and 50% in controls. Inhibition of progesterone secretion and poor conception occurred after the single intraruminal dose of malathion at the onset of estrus.

Synthesis based on cyclohexadienes. Part 17. Total synthesis of the sesquiterpenes of Eremophila georgei diels

The first stereoselective total synthesis of the novel sesquiterpenes 1 and 2 is described. The preparation of the key intermediate 27 involved a rearrangement of a bicyclo[3.2.1] octane framework to an isomeric bicyclo[3.2.1]octane skeleton via a bicyclo[2.2.2]octane derivative.

Regulation of progesterone biosynthesis in the human placenta by estradiol 17 beta and progesterone

Ex vivo addition of estradiol 17 beta to first trimester or term human placental minces caused a significant increase in the quantity of progesterone produced. Addition of an aromatase inhibitor, CGS 16949 A or the estrogen receptor antagonist, ICI 182780, significantly inhibited progesterone production confirming the role of estradiol 17 beta in the regulation of progesterone synthesis in human placenta. RU 486 and ZK 98299, which are antagonists of progesterone receptor, significantly modulated progesterone synthesis in the human placenta but exhibited paradoxical effects on the first trimester and term placenta We conclude that progesterone synthesis in the human placenta is regulated by estradiol 17 beta and progesterone. This is the first report providing evidence for autoregulation of progesterone synthesis in the human placenta.