Dietary determinants of lipoproteins, total cholesterol, viscosity, fibrinogen, and blood pressure.

High-density lipoprotein cholesterol, low-density lipoprotein cholesterol, total cholesterol, viscosity, fibrinogen, and blood pressure were determined in 117 men aged 44 to 60 yr selected from the general population who also completed 7-day weighed dietary records. Associations between these measurements and a number of dietary factors were assessed by multiple regression analysis, allowing where necessary for the effects of age, body mass index, and smoking habit. High-density lipoprotein cholesterol was associated positively with both alcohol and fish consumption and negatively with saturated fat intake. High-density lipoprotein cholesterol expressed as a percentage of total cholesterol was associated negatively with the percentage of energy from fat and positively with fish consumption. Low-density lipoprotein cholesterol was associated positively with the percentage of energy from fat and negatively with fish consumption. Fibrinogen and systolic blood pressure were inversely related to cereal fiber intake.

5-Amino-1-(chloromethyl)-1,2-dihydro-3H-benz[e]indoles: relationships between structure and cytotoxicity for analogues bearing different DNA minor groove binding subunits.

A series of 5-amino-seco-CBI compounds, designed for use as effectors for prodrugs, were prepared to study structure-activity relationships for the cytotoxicity of side chain analogues. Compounds were prepared by coupling 1-(chloromethyl)-5-nitro-1, 2-dihydro-3H-benz[e]indole to appropriate carboxylic acids, followed by nitro group reduction, or by coupling suitable 5-amino-protected indolines to alpha,beta-unsaturated acids, followed by deblocking. These AT-specific DNA alkylating agents were evaluated for cytotoxicity in a series of tumor cell lines (AA8, UV4, EMT6, SKOV3). For those analogues bearing an indolecarbonyl side chain, the 5'-methoxy derivative was the most cytotoxic (IC(50) 1.3 nM in AA8 cells, 4 h exposure), comparable to that of the parent CBI-TMI (5', 6',7'-trimethoxyindole) derivative (IC(50) 0.46 nM in the above assay). A subset of solubilized derivatives bearing O(CH(2))(2)NMe(2) substituents were about 10-fold less potent. For compounds containing an acryloyl linker in the side chain, the 4'-methoxycinnamoyl derivative proved the most cytotoxic (IC(50) 0. 09 nM in the above assay). A number of these 5-amino-seco-CBI-TMI analogues (including the solubilized compounds) are of interest both as cytotoxins and as components of amine-based prodrugs designed for tumor-specific activation.

Synthesis of 1-substituted 3-(chloromethyl)-6-aminoindoline (6-amino-seco-CI) DNA minor groove alkylating agents and structure-activity relationships for their cytotoxicity.

A series of racemic 6-amino-seco-cyclopropylindole (seco-CI) compounds was prepared by coupling 1-(tert-butyloxycarbonyl)-3-(chloromethyl)-6-nitroindoline with appropriate acids, followed by nitro group reduction, and evaluated for cytotoxicity in AA8, UV4, EMT6, and SKOV3 cell lines. These compounds are of interest due to their close structural relationship to known AT-specific alkylating agents and cytotoxins and also for the possible construction of stable amine-based prodrugs designed for tumor-specific release. Variations included indole or furan side chains with different substituents, sulfonamide or carboxamide linkers, extension of the minor groove binding side chain to two subunits, and the use of a pyrroylacryloyl unit previously reported to give extremely potent analogues. The parent compound, with a trimethoxyindole side chain, was a moderately potent cytotoxin (IC50 = 0.34 microM in AA8 cells, 4 h exposure). A single 5-methoxy group on the indole minor groove binding unit was sufficient to maintain potency, and a series of dimethylaminoethoxy-substituted analogues retained the cytotoxicity of the parent compound, while providing increased aqueous solubility.

Synthesis and biological evaluation of prostaglandin-F alkylphosphinic acid derivatives as bone anabolic agents for the treatment of osteoporosis.

A series of novel C(1) alkylphosphinic acid analogues of the prostaglandin-F family have been evaluated at the eight human prostaglandin receptors for potential use in the treatment of osteoporosis. Using molecular modeling as a tool for structure-based drug design, we have discovered that the phosphinic acid moiety (P(O)(OH)R) behaves as an isostere for the C(1) carboxylic acid in the human prostaglandin FP binding assay in vitro and possesses enhanced hFP receptor selectivity when compared to the parent carboxylic acid. When evaluated in vivo, the methyl phosphinic acid analogue (4b) produced a bone anabolic response in rats, returning bone mineral volume (BMV) [corrected], to intact levels in the distal femur in the ovariectomized rat (OVX) model. These results suggest that prostaglandins of this class may be useful agents in the treatment of diseases associated with bone loss.

First total synthesis of (+/-)-stemonamide and (+/-)-isostemonamide.

[structure: see text] The total synthesis of the tetracyclic alkaloids stemonamide (1) and isostemonamide (2) is presented. The key step is the reaction between a silyloxyfuran and an N-acyliminium ion. The second quaternary center is created by an intramolecular aldol spirocyclization. After 1,4-addition of an appropriate side chain, the methyl and double bond are installed by Mannich reaction. The seven-membered ring is closed by intramolecular nucleophilic displacement.

Determinants of plasma lipoproteins and coagulation factors in men from Caerphilly, South Wales.

Dietary, social, and constitutional determinants of plasma concentrations of some major risk factors for ischaemic heart disease were investigated in a cross sectional study among 711 men from the general population aged 30-69. For high density lipoprotein cholesterol (HDL-C) six variables were significantly associated with plasma concentrations, and these variables explained 12.6% of the variance. For low density lipoprotein cholesterol (LDL-C), total cholesterol (T-C), and triglyceride 8.4%, 7.5%, and 18.5% of the variance was explained by significantly associated variables. Fibrinogen concentrations determined chemically were significantly associated with age, smoking habit, body mass index, alcohol consumption, and intake of cereal fibre (24.2% variance). These data provide some encouragement for the possibility of dietary intervention to influence plasma concentrations of major risk factors for ischaemic heart disease in men.

Determinants of high density lipoprotein and total cholesterol in women.

An epidemiological study was carried out among a random sample of women aged 18 to 69 years to examine possible determinants of plasma high density lipoprotein and total cholesterol (HDL-C and T-C). In a multiple regression analysis consumption of alcohol, fatty fish, and parental longevity showed positive associations with HDL-C, which were statistically significant. Smoking habit, sucrose consumption, and a family history of ischaemic heart disease showed significantly negative associations. In contrast, T-C was associated significantly only with age and Quetelet's index of body mass. Five variables having significant associations with HDL-C explained only 8% of the total variance; in the case of T-C 17% of the variance was explained by age and body mass.

Factors associated with urinary incontinence in women.

Possible aetiological factors for urinary incontinence were examined in a prevalence study among a random sample of 1000 women aged 18 and over. Infective factors were not markedly associated with incontinence but mechanical factors such as parity and obesity were. No association was found, however, between a history of perineal damage at childbirth and incontinence. Women with incontinence had on average a higher score for a 'neuroticism' trait elicited by questionnaire than women without the disorder.

The prognostic significance of weight and of vitamin C status in the elderly.

Eight hundred and thirty elderly subjects who were seen in a nutritional survey were followed up after eight years. A marked decline of body weight with age, which had been evident in the original cross-sectional data, appeared to be due to a loss of weight in individuals rather than to any survival advantages of less obese persons. Indeed, over the age of 70 years the survivors tended to have been heavier when originally seen than those who died, suggesting that an above-average weight is a favourable prognostic factor in old age. There was a tendency for the women who died to have had lower ascorbic-acid levels than those who survived, but this was not obviously related to any one cause of death. Although it is possible that a poor vitamin C status increases mortality, the associations reported are probably due to the fact that elderly persons who are biologically younger than their contemporaries tend in consequence to be heavier and to have higher ascorbic acid levels and lower mortality rates than others of their chronological age.

The nutritional status of the elderly.

Data are presented relating to the nutritional status of over 1500 elderly subjects seen in three community surveys. There was s decline in weight, arm circumference and skinfold thickness, and to a lesser extent in Quetelet's index (weight + height2), with advancing age. Haemoglobin levels declined with age in one area but not in the others, probably due to differences in nutritional state. Plasma protein and albumin concentrations showed no decline with age and were similar to values reported from younger subjects. Men who ate alone tended to have a poorer vitamin C and thiamine status than men whose meals were cooked or shared by another person, but no such difference was found among women; indeed, women eating alone had significantly higher leucocyte ascorbic acid levels.

The relationship between plasma ascorbate and lipid concentrations in fasting men.

A study was undertaken to investigate the relationship between vitamin C status and plasma lipid concentrations in 97 fasting men. Plasma ascorbate was found to be negatively associated with total cholesterol and positively associated with both high-density lipoprotein (HDL) cholesterol concentration and the HDL/total cholesterol ratio (P less than 0.05 in each case). There was no association between ascorbate and triglyceride levels. In view of the relevance of HDL cholesterol to ischaemic heart disease these associations may have some clinical importance, although they were all rather weak.

A short dietary questionnaire for use in an epidemiological survey: comparison with weighed dietary records.

Nutrient data from a short dietary questionnaire designed for self-administration in epidemiological studies of ischaemic heart disease were compared with those from 7-day weighed dietary records obtained 2 to 6 weeks later in a sample of 119 men from the general population. For the major nutrients correlation coefficients of between 0.27 (total carbohydrate) and 0.75 (alcohol) were obtained all of which were statistically significant. In the case of alcohol over 90 per cent of the weekly intake was consumed outside the home in standard measures. In the case of other nutrients improvement in the precision of the questionnaire estimates may be obtained by direct estimates of portion sizes.

Cytotoxicity and DNA interaction of the enantiomers of 6-amino-3-(chloromethyl)-1-[(5,6,7-trimethoxyindol-2-yl)carbonyl]indo- line (amino-seco-CI-TMI).

The enantiomers of the previously reported racemic 6-amino-3-(chloromethyl)-1-[(5,6,7-trimethoxyindol-2-yl)carbonyl] indoline (amino-seco-CI-TMI) were prepared via resolution of a precursor by chiral HPLC. The only detectable product isolated from reaction of the racemic compound with calf thymus DNA, followed by thermal cleavage, was shown by mass spectrometry and two-dimensional NMR spectroscopy to be the adenine N3 adduct. Polyacrylamide gel electrophoresis assays with the racemate and with each enantiomer also showed adenine to be the only site of alkylation. While the racemic amino compound exhibited sequence selectivity identical to that of the previously characterized phenol analogue, the enantiomers exhibited distinctly different sequence selectivities, allowing the (+) enantiomer to be assigned the "natural" S configuration. The (+)-(S) enantiomer is 3-fold more cytotoxic than the (-)-(R) enantiomer (IC(50) values of 240 and 700 nM, respectively, in AA8 cells, after exposure for 4 h).

Quinolone signaling in the cell-to-cell communication system of Pseudomonas aeruginosa.

Numerous species of bacteria use an elegant regulatory mechanism known as quorum sensing to control the expression of specific genes in a cell-density dependent manner. In Gram-negative bacteria, quorum sensing systems function through a cell-to-cell signal molecule (autoinducer) that consists of a homoserine lactone with a fatty acid side chain. Such is the case in the opportunistic human pathogen Pseudomonas aeruginosa, which contains two quorum sensing systems (las and rhl) that operate via the autoinducers, N-(3-oxododecanoyl)-L-homoserine lactone and N-butyryl-L-homoserine lactone. The study of these signal molecules has shown that they bind to and activate transcriptional activator proteins that specifically induce numerous P. aeruginosa virulence genes. We report here that P. aeruginosa produces another signal molecule, 2-heptyl-3-hydroxy-4-quinolone, which has been designated as the Pseudomonas quinolone signal. It was found that this unique cell-to-cell signal controlled the expression of lasB, which encodes for the major virulence factor, LasB elastase. We also show that the synthesis and bioactivity of Pseudomonas quinolone signal were mediated by the P. aeruginosa las and rhl quorum sensing systems, respectively. The demonstration that 2-heptyl-3-hydroxy-4-quinolone can function as an intercellular signal sheds light on the role of secondary metabolites and shows that P. aeruginosa cell-to-cell signaling is not restricted to acyl-homoserine lactones.