The effect of vasoactive intestinal polypeptide (VIP) on forskolin stimulated adenylate cyclase in the caudate-putamen of the rat

Summary Vasoactive intestinal polypeptide (VIP) was incubated in an adenylate cyclase assay with a particulate fraction of caudate-putamen (CP) tissue of the rat in order to examine the effect of the peptide on forskolin-activated adenylate cyclase in vitro. Forskolin induced an enhancement of cyclic AMP formation that was mediated by an effect on catalytic subunit and stimulatory guanine nucleotide regulatory protein (N_s). In our preparation, VIP did not influence basal adenylate cyclase activity or the stimulation by dopamine and sodium fluoride but, in the absence of guanylylimidodiphosphate (guanosine 5-(,y-imido)-triphosphate) VIP inhibited the forskolin-stimulation of the enzyme in a noncompetitive manner. Met-encephalin, acting on a D-2 receptor-coupled putative inhibitory guanine nucleotide regulatory protein (N_i), inhibited the adenylate cyclase activity stimulated by forskolin to a slightly greater extent than VIP. When assayed together, these inhibition effects were additive, implying that the peptide receptors are not identical. The N_i — antagonist, MnCl₂ completely blocked the inhibition of met-encephalin but had no significant effect on VIP-induced inhibition. In addition, pertussis toxin did not influence the effect of VIP on forskolin-stimulation in contrast to cholera toxin which did antagonize the VIP effect via the stimulatory guanine nucleotide regulatory protein (N_s). Furthermore, specific D-1 and D-2 dopaminergic receptor antagonists (+)-flupentixol and spiperone had no effect on VIP-modulated forskolin-stimulated adenylate cyclase activity. These results suggest that the neuromodulatory effect of VIP is mediated by a N_s distinct from those involved in several adenylate cyclase pools sensitive to stimulation by dopamine and VIP in the rat striatum.     

Pharmacokinetics and pharmacodynamics of lanoteplase (n-PA)

In acute myocardial infarction rapid, complete, and sustained reperfusion of the infarct-related coronary artery is the most important therapeutic principle. Lanoteplase or n-PA, a third-generation plasminogen activator consisting of a deletion and point mutant of tissue-type plasminogen activator (t-PA), is a promising agent to approach this therapeutic goal. The molecule exhibits an increased plasma half-life allowing single-bolus administration. In this article, after characterizing the n-PA molecule, the currently available pharmacokinetic and pharmacodynamic data including the results of the InTIME study are reviewed.     

Chromosomal rearrangement segregating with adrenoleukodystrophy: associated changes in color vision.

A patient from a large kindred with adrenoleukodystrophy showed profound disturbance of color ordering, color matching, increment thresholds, and luminosity. Except for color matching, his performance was similar to blue-cone "monochromacy," an X chromosome-linked recessive retinal dystrophy in which color vision is dichromatic, mediated by the visual pigments of rods and short-wave-sensitive cones. Color matching, however, indicated that an abnormal rudimentary visual pigment was also present. This may reflect the presence of a recombinant visual pigment protein or altered regulation of residual pigment genes, due to DNA changes--deletion of the long-wave pigment gene and reorganized sequences 5' to the pigment gene cluster--that segregate with the metabolic defect in this kindred.     

Occupational mortality of women aged 15-59 years at death in England and Wales.

STUDY OBJECTIVE--The aim was to analyse occupational mortality differences among women using follow up data from a large nationally representative sample. DESIGN--Occupational information was obtained from the 1971 census records of women in the Longitudinal Study carried out by the Office of Population Censuses and Surveys (OPCS) and related to their subsequent mortality in the period between the 1971 and 1981 censuses. SETTING--In the Longitudinal Study, census, vital statistics, and other OPCS records are linked for a 1% sample of the population of England and Wales. The women studied in this paper were drawn from the 513,071 persons in the 1971 census who were included in the Longitudinal Study and whose entries were traced at the National Health Service Central Register by 1977. PARTICIPANTS--The analysis was based on 77,081 women aged 15-59 years in the Longitudinal Study for whom occupational information was collected in the 1971 census (99% of whom were in paid employment in the week before the census). There were 1553 deaths among these women in the follow up period analysed here. MEASUREMENTS AND MAIN RESULTS--Numbers of deaths in each occupational group at census were compared to those expected on the basis of age specific death rates among all women in the study. "Professional, technical workers, and artists" had significantly low mortality while "Engineering and allied trades workers nec" had significantly high mortality. Among the latter, cancer mortality of electrical production process workers was extremely high. A number of other cause specific associations (which appear to confirm proportionate Decennial Supplement analyses) were suggested by the data; examples include high levels of mortality from ischaemic heart disease among cooks, lung cancer and respiratory disease among charwomen and cleaners, and accidents, poisonings, and violence among several groups of professional and technical workers. CONCLUSIONS--By using prospective follow up from the census, occupational differences in mortality can be identified among women in paid employment. As follow up of this study continues, numbers of deaths available for analysis will increase, allowing increasingly comprehensive analyses to be undertaken.     

Hemin enhances the in vitro growth of primitive erythroid progenitor cells

Since exogenous hemin has been shown to exert a variety of stimulatory effects on erythroid cells, including the augmentation of hemoglobin synthesis, we determined its effect on early stages of erythroid development by employing clonal cells assays. The addition of hemin at a concentration of 2 X 10(-4) M to cultures of normal murine marrow substantially increased the observed number of primitive BFU-E, which was in contrast to its lack of an effect on more mature erythroid colony-forming cells. This cell-specific enhancement of primitive BFU-E resulted in marrow frequencies equivalent to or exceeding those reported in the presence of "burst-promoting activity." In the presence of hemin, the number of BFU-E was also observed to be linearly related to the number of cells plated at very low plating densities, and the cell titration curve was observed to extrapolate to the origin. The evidence suggests that hemin may be a primary growth regulator of early developmental stages of erythroid progenitor cells.     

Assessment of the mutagenicity of dichloroacetic acid in lacI transgenic B6C3F1 mouse liver

Dichloroacetic acid (DCA) is a chlorination byproduct found in finished drinking water. When administered in drinking water this chemical has been shown to produce hepatocellular adenomas and carcinomas in B6C3F1 mice over the animal's lifetime. In this study, we investigated whether mutant frequencies were increased in mouse liver using treatment protocols that yielded significant tumor induction. DCA was administered continuously at either 1.0 or 3.5 g/l in drinking water to male transgenic B6C3F1 mice harboring the bacterial lacI gene. Groups of five or six animals were killed at 4, 10 or 60 weeks and livers removed. At both 4 and 10 weeks of treatment, there was no significant difference in mutant frequency between the treated and control animals at either dose level. At 60 weeks, mice treated with 1.0 g/l DCA showed a 1.3-fold increase in mutant frequency over concurrent controls (P = 0.05). Mice treated with 3.5 g/l DCA for 60 weeks had a 2.3-fold increase in mutant frequency over the concurrent controls (P = 0.002). The mutation spectrum recovered from mice treated with 3.5 g/l DCA for 60 weeks contained G:C-->A:T transitions (32.79%) and G:C-->T:A transversions (21.31%). In contrast, G:C-->A:T transitions comprised 53.19% of the recovered mutants among control animals. Although only 19.15% of mutations among the controls were at T:A sites, 32.79% of the mutations from DCA-treated animals were at T:A sites. This is consistent with the previous observation that the proportion of mutations at T:A sites in codon 61 of the H-ras gene was increased in DCA-induced liver tumors in B6C3F1 mice. The present study demonstrates DCA-associated mutagenicity in the mouse liver under conditions in which DCA produces hepatic tumors.      

Fatty acid balance studies in term infants fed formula milk containing long-chain polyunsaturated fatty acids

Long-chain polyunsaturated fatty acids (LCP) are thought to be required for optimal nervous system development in the newborn. A commercial milk formula containing LCP (Aptamil-LCP) with a fatty acid profile closely resembling breast milk, has recently been introduced for term infants. The absorption of fatty acids in term infants was examined in a double-blind randomized controlled trial comparing Aptamil-LCP ( n = 20) and standard Aptamil ( n = 20). Formula-fed newborn infants were studied from birth for 14 d. Fat balances (3 d) were performed from d 10. A 3-d stool collection was performed from d 10 in a parallel breastfed group ( n = 21). Plasma samples were taken on d 6. Median fat excretion (mg kg⁻¹) was 897.1, 615.0 and 355.2 with Aptamil, Aptamil-LCP and breastfeeding, respectively. The median total fat absorption coefficient in Aptamil-LCP-fed infants was higher than in those fed standard Aptamil ( p < 0:01). These findings were accounted for by differences in the excretion and absorption of long-chain saturated fatty acids (C14:0, C16:0 and C18:0). Higher fat excretion was associated with bulkier and firmer stools. Only trace amounts of LCP were detected in the stools of all groups. This accounted for less than 4% of dietary intake in Aptamil-LCP-fed infants. No differences in the utilization of LCP from Aptamil-LCP and breast milk feeding were apparent. Plasma phospholipid fatty acid composition data reflected differences in dietary LCP intake. Thus, PL LCP levels were highest in the breastfed infants and lowest in the Aptamil-fed infants, with values for the Aptamil-LCP-fed group falling in between.