Comparison of the electronic structures of imine and hydrazone side-chain functionalities with the aid of 13C and 15N NMR chemical shifts and PM3 calculations. The influence of C=N-substitution on the sensitivity to aromatic substitution.

Benzaldehyde derivatives possessing a C=N double bond in the side-chain of the aromatic ring exhibit a reverse dependence of the (13)C NMR chemical shifts of the C=N carbon on the benzylidenic substituents X. Thus, electron-withdrawing substituents cause shielding (shift is reduced), while electron-donating ones cause deshielding. The origin of this phenomenon, which is in contrast with the idea of the generalized electronic effect, is extensively studied here by comparing the behavior of sets of benzaldehyde derivatives bearing various substitutents Y on the C=N nitrogen (Y-N=CH-C(6)H(4)-X). The effects of substituents X on the C=N unit change when Y is varied. Combination of the influences of the substituents X and Y gives a sensitive balance between the different resonance structures of the compounds. Our graphical treatment, where the rho(I) and rho(R) values observed for substituent X are plotted against the sigma(p)(+) value of substituent Y, is a novel use of Hammett-type substituent parameters. The justification of this method and our conclusions could be verified, for instance, by the fair correlation between the rho(I) or rho(R) values and the atomic charges of the imine carbon of the unsubstitued phenyl derivatives as well as by the correlations of the relevant bond orders and/or bond lengths both with the substituent parameters and with the atomic charges.

Condensation of triformylmethane with guanosine.

Guanosine has been reacted with triformylmethane (TFM) in refluxing pyridine. Four different products, 4-7, were isolated by preparative RP-HPLC, and characterized by 1H and 13C NMR and UV spectroscopy and mass spectrometry. One of the products. the cyclic 1:1 adduct 4, is a stable cyclic carbinolamine formed probably by cyclization of the expected aminomethylene derivative 3. Compound 4 then undergoes reversible dehydration to the fully conjugated adduct 5. The appearance of the additional adducts, 6 and 7, suggests that TFM is prone to transformations resulting in the formation of methylenemalonaldehyde (9) and 1,1,3,3-tetraformylpropane (11).

Occupational exposures and cancers of the endometrium and cervix uteri in Finland.

BACKGROUND: Endometrial cancer incidence rates are low in Asia and Africa and high in North America and Northern Europe. Cervical cancer is often the most common female cancer in developing countries, and infection with human papillomavirus (HPV) is its main risk factor. However, other factors, such as occupational exposures may modify the HPV-related risk. We conducted an exploratory register-linkage study in Finland to assess the role of occupational exposures on incidence rates of cancers of the endometrium and cervix uteri. METHODS: Occupational risk factors for endometrial and cervical cancers were explored in a 25-year follow-up of female workers born 1906-1945 (N = 413,877) identified through the Population Census of Finland of 1970. Job titles in census records were converted to exposures of 31 occupational agents through a job-exposure matrix. Poisson regression models estimated relative risks (RR) for each agent, standardized for birth cohort, follow-up period, and socio-economic status. For each agent, the product of level and probability of exposure was calculated and subdivided in three categories: zero, low, and medium/high. Adjustment at the job title level was done for the turnover rate (endometrial and cervical cancers), mean parity, and age at first birth (endometrial cancer). RESULTS: Endometrial cancer (2,833 cases) was associated with exposure to animal dust (RR 1.2, low level, 174 cases) and sedentary work (RR 1.3, high level, 145 cases). Cervical cancer (1,101 cases) was associated with exposure to aliphatic and alicyclic (RR 1.3, low level, 91 cases), aromatic (RR 1.2, low level, 318 cases; RR 1.4, high level, 41 cases), and chlorinated hydrocarbon solvents (RR 1.3, low level, 50 cases), silica dust (RR 1.2, low level, 251 cases), and wood dust (RR 1.2, low level, 249 cases). CONCLUSIONS: This study suggests that occupational exposures may be associated with increased risk of endometrial and cervical cancers.

Reduced oxidized low-density lipoprotein after weight reduction in obese premenopausal women.

BACKGROUND: Several studies support the hypothesis that oxidation of low-density lipoprotein (LDL) promotes atherogenesis. Obesity is one of the risk factors of atherosclerosis, but it is not known whether obesity is related to LDL oxidation. OBJECTIVE AND DESIGN: We investigated the effect of weight reduction and subsequent weight maintenance program on LDL oxidation in 77 obese premenopausal women (BMI 29-46 kg/m(2)). Another group of seven obese women served as a control group. Oxidized LDL was measured as baseline concentration of conjugated dienes in LDL lipids (ox-LDL). The weight reduction was performed in 12 weeks, using a very-low-energy diet. RESULTS: The mean weight loss was 13 kg (92 vs 79 kg). During weight reduction, the concentration of LDL cholesterol decreased by 11%, the concentration of ox-LDL decreased by 40%, and the ratio of ox-LDL to LDL by 33%. The concentration of LDL antioxidant capacity (LDL-TRAP) decreased by 8%, but the decrease was caused by the decrease in LDL. The concentration of LDL, ox-LDL or LDL-TRAP did not change in the control group. The weight reduction correlated with the decrease of ox-LDL. During the subsequent 9 month weight maintenance programme, the concentrations of serum LDL (10%), ox-LDL (11%), LDL-TRAP (29%), and the ratio of LDL-TRAP to LDL (21%) decreased. CONCLUSION: This study strengthens the evidence that the risk of atherogenesis is influenced favourably by weight reduction in obese women. This risk reduction is associated with a reduced oxidation of LDL.

Substituent influences on the stability of the ring and chain tautomers in 1,3-O,N-heterocyclic systems: characterization by 13C NMR chemical shifts, PM3 charge densities, and isodesmic reactions.

Substituent effects on the stabilities of the ring and chain forms in a tautomeric equilibrium of five series of 2-phenyloxazolidines or -perhydro-1,3-oxazines possessing nine different substitutions at the phenyl moiety have been studied with the aid of 13C NMR spectroscopy and PM3 charge density and energy calculations. Reaction energies of the isodesmic reactions, obtained from the calculated energies of formation, show that electron-donating substituents stabilize both the chain and ring tautomers but the effect is stronger on the stability of the chain form than on that of the ring form. The 13C chemical shift changes induced by the phenyl substituents (SCS) were analyzed by several different single and dual substituent parameter approaches. The best correlations were obtained by equation SCS = rhoFsigmaF + rhoRsigmaR. In all cases the rhoF values and in most cases also the rhoR values were negative at both the C=N and C-2 carbons, indicating a reverse behavior of the electron density. This concept could be verified by the charge density calculations. The 13C chemical shifts of the C=N and C-2 carbons show a normal dependence on the charge density (q(tot)), but the charge density shows a reverse dependence on substitution. Correlation analysis of the 13C chemical shifts, solvent effect (CDCl3 vs DMSO-d6) on the NMR behavior as well as the effect of substituents on the electron densities and on the stabilities of the ring and chain tautomers show that the substituent dependence of the relative stability of the ring and chain tautomers in equilibrium is governed by several different electronic effects. At least intramolecular hydrogen bonding between the imine nitrogen and the hydroxyl group as well as polarization of the C=N bond seem to contribute in the chain form. Stereoelectronic and electrostatic effects are possible to explain the increase in stability of the ring form by electron-donating substituents.

Oxidized LDL and thickness of carotid intima-media are associated with coronary atherosclerosis in middle-aged men: lower levels of oxidized LDL with statin therapy.

We investigated the relation between serum lipids including oxidized LDL and the severity of coronary atherosclerosis. Serum lipids and oxidized LDL was measured in 62 men (33-66 years), who underwent diagnostic coronary angiography and sonography to measure the carotid intima-media thickness. LDL oxidation was found in chemical analyses to be due to conjugated fatty acids in cholesteryl esters and triglycerides. Regression analysis indicated that the carotid intima-media thickness and the ratio of LDL diene conjugation to LDL cholesterol (the ox-LDL:LDL ratio) were the only factors associated independently with the severity of coronary atherosclerosis. The patients with multi-vessel disease who did not use lipid lowering therapy had a 50% thicker carotid intima media (P = 0.030) and a 41% higher ox-LDL:LDL ratio (P = 0.020) than patients with normal vessels. Further, patients with multi-vessel disease on statin therapy had a 24% lower ox-LDL:LDL ratio than the subjects with multi-vessel disease who did not use lipid lowering drugs (P = 0.027), although the concentration of LDL cholesterol did not differ between the groups. This study supports the hypothesis that lipid oxidation plays a role in the development of atherosclerosis.

Stereospecific modulation of GABA(A) receptor function by urocanic acid isomers.

A deamination product of histidine, urocanic acid, accumulates in the skin of mammals as trans-urocanic acid. Ultraviolet (UV) irradition converts it to the cis-isomer that is an important mediator in UV-induced immunosuppression. We have recently shown that urocanic acid interferes with the agonist binding to GABA(A) receptors. We now report that the effects of urocanic acid on binding of a convulsant ligand (t-butylbicyclo[35S]phosphorothionate) to GABA(A) receptors in brain membrane homogenates are dependent on pH of the incubation medium, the agonistic actions being enhanced at the normal pH of the skin (5.5). Using Xenopus laevis oocytes expressing recombinant rat alpha1beta1gamma2S GABA(A) receptors, the low pH potentiated the direct agonistic action of trans-urocanic acid under two-electrode voltage-clamp, whereas cis-urocanic acid retained its low efficacy both at pH 5.5 and 7.4. The results thus indicate clear differences between urocanic acid isomers in functional activity at one putative receptor site of immunosuppression, the GABA(A) receptor, the presence of which in the skin remains to be demonstrated.

Cleavage of the phosphodiester bond of uridylyl-(3',5')-8-carboxymethylaminoadenosine by hydronium, hydroxide and zinc(II) ions: a model study aimed at elucidating the potential of a carboxylate function as an intramolecular catalyst.

Uridylyl-(3',5')-8-carboxymethylaminoadenosine has been synthesised, and its transesterification to uridine 2',3'-cyclic phosphate in the presence and absence of Zn2+ ion has been studied. The results show that a carboxylate function in the vicinity of the phosphodiester bond accelerates the metal ion promoted cleavage but not the metal ion independent reaction. Under acidic conditions, the predominant reaction is the cleavage of the side chain, giving the 8-amino derivative.

Breast cancer and occupational exposures in women in Finland.

BACKGROUND: The etiology of breast cancer is not fully understood. Environmental and occupational exposures may contribute to breast cancer risk. METHODS: We linked 324 job titles from the 1970 census of 892,591 Finnish women with incidence of breast cancer (23,638 cases) during 1971-1995. We converted job titles to 31 chemical and two ergonomic agents through a measurement-based, period-specific, national job-exposure matrix. Poisson regression models were fit to the data, with adjustment for birth cohort, follow-up period, socioeconomic status, mean number of children, mean age at first delivery, and turnover rate. RESULTS: For premenopausal breast cancer, medium/high level of occupational exposure to ionizing radiation was associated with a standardized incidence ratio (SIR) of 1.3 (95% confidence interval (CI) 0.7-2.5; trend P = 0.03). For postmenopausal breast cancer, we found on SIR of 1.2 (1.1-1.3) for low level and 1.4 (1.1-1.8) for medium/high level of ionizing radiation (trend P = 0.001); and an SIR 1.3 (1.1-1.7) for medium/high levels of both asbestos and man-made vitreous fibers. Aromatic hydrocarbon solvents showed a significant trend for a modest excess of postmenopausal breast cancer. CONCLUSIONS: Our study indicates that occupational exposure to ionizing radiation may be associated with an increased risk of female breast cancer. High-quality studies on environmental and occupational etiology of breast cancer are needed for further elucidation of risk factors.

Ovarian cancer and occupational exposures in Finland.

BACKGROUND: No single occupational or environmental agent has been established as causing ovarian cancer, existing studies often being based on ecologic or proportional mortality data in which potential confounders related to reproductive history have not been taken into account. METHODS: This study linked 324 job titles of occupationally active Finnish women (n = 892,591) at 1970 census with incidence of ovarian cancer (Finnish Cancer Registry, 5,072 cases) during 1971-1995 (over 15 million person-years). The job titles were converted into indicators of exposure to 33 agents, using a national job-exposure matrix based on measurements and surveys (FINJEM). Poisson regression analyses were performed with stratification by birth cohort, follow-up period, and socioeconomic status, and adjusted for mean number of children, mean age at first delivery, and turnover rate for each job title. RESULTS: We found indications of elevated risks for aromatic hydrocarbon solvents (standardized incidence ratio 1.3 (95% CI 1.0-1.7), leather dust (1.4; 0.7-2.7), man-made vitreous fibers (1.3; 0.9-1.8), and high levels of asbestos (1.3; 0.9-1.8), and diesel (1.7; 0.7-4.1), and gasoline (1.5; 1.0-2.0) engine exhausts). Previously reported findings for hairdressers and women in the printing industry were supported in our data, but not for women in dry cleaning jobs. CONCLUSIONS: Given the various drawbacks in linkage studies and job-exposure matrices, the excesses found in this study need confirmation in individual-level studies.

Epidemiology of occupational and environmental risk factors related to ovarian cancer.

This paper reviews articles published during 1970-1997 from 48 epidemiologic studies on occupational and environmental risk factors of ovarian cancer. Current evidence is characterized by poorly focused data for occupational and environmental agents, vulnerability to biases, and an almost complete lack of quantitative exposure-response data. The moderate amount of data on nurses, teachers, professionals, dry cleaning employees, women in agriculture, the pharmaceutical industry, pharmacists, waitresses, and cooks show very little, if any, evidence of excess risk. Hairdressers, beauticians, and women employed in the printing industry may be at increased risk, but the data are insufficient for strong conclusions. Some case-referent studies suggest a modest-to-moderate excess in association with genital talc application. Few high-quality studies have been carried out, and no chemical agents have been studied extensively, with the exception of exposure to talc. Ovarian cancer may have occupational and environmental etiologies intertwined with cultural, behavioral, and life-style factors and genetic susceptibility, but current knowledge is insufficient to quantify occupational and environmental etiologies reliably. Well-designed analytic epidemiologic studies with sufficient power are needed.

Environmental risk factors of breast cancer.

Breast cancer is women's most ubiquitous cancer. The role of dietary factors is controversial, but there is limited evidence for such occupational risk factors as employment in the pharmaceutical industry and as a beautician. Ionizing radiation probably increases the risk. Exposure to chlorinated hydrocarbon pesticides, chlorinated solvents, and polychlorinated biphenyls may be risk factors, although the evidence is insufficient. Data on low-frequency electromagnetic fields are inconclusive. Tobacco smoking may be a risk factor, but the effect may depend on N-acetyltransferase 2 genetic polymorphisms. There are yet unidentified determinants, probably environmental, that may act via estrogenic activity or through other mechanisms. The etiology may vary according to the joint estrogen and progesterone receptor status of the tumor. P53 mutation frequency varies considerably in breast cancer populations, which may reflect variation in exogenous exposures. Epidemiology research on breast cancer needs to consider subtypes of the disease, lifetime exposure assessment, host susceptibility, and adjustment for reproductive and menstrual history.

Effects of cis- and trans-urocanic acids on the secretion of interleukin-1 beta and tumour necrosis factor-alpha by human peripheral blood monocytes.

In order to investigate the mechanism of urocanic acid (UCA)-mediated immune modulation, we studied the effect of cis- and trans-UCA on interleukin-1 beta and tumour necrosis factor-alpha production by human peripheral blood monocytes, using immunospecific ELISA techniques. Trans-UCA augmented the interleukin-1 beta production and inhibited tumour necrosis factor-alpha production in a dose-dependent manner, whereas cis-UCA had no effect on the secretion of these cytokines by phorbol myristate acetate or lipopolysaccharide-stimulated monocytes. This is a novel example of trans-UCA mediating a biological effect, a finding earlier reported for cyclic adenosine monophosphate up-regulation in human fibroblasts by Palaszynski and coworkers and for human natural killer cell inhibition by ourselves. Our data suggest an important role for trans-UCA as an immunomodulator in the skin.

The role of histamine-like receptors in immunosuppression of delayed hypersensitivity induced by cis-urocanic acid.

The cis-isomer of urocanic acid (UCA) has been shown previously to mimic the effect of ultraviolet B (UVB) irradiation in suppressing delayed hypersensitivity (DH) responses to virus in a murine model of herpes simplex virus (HSV) infection. Cimetidine, an H2 receptor antagonist, and terfenadine, an H1 receptor antagonist, abrogated the suppression of DH to HSV induced by cis-UCA, leading to the suggestion that histamine-like receptors may be involved in the mechanism of action of cis-UCA on immune responses. In the present study, cis and trans-isomers of 4 UCA analogues (1- and 2-imidazoyl-acrylic acid), and (2- and 3-pyridyl-acrylic acid) were tested for their ability to suppress DH to HSV in infected mice, and only cis-2-pyridyl-acrylic acid was effective. Second, an H2 and H3 agonist were similarly tested: the former was suppressive and the latter had no effect. Third, an H3 receptor antagonist, thioperamide, did not seem to abrogate the suppression of DH induced by cis-UCA. These results substantiate a role for H1 and H2-like receptors, but probably not H3 receptors, in cis-UCA induced immunosuppression.

Effect of psoriasis heliotherapy on epidermal urocanic acid isomer concentrations.

A noninvasive Finn Chamber sampling method and HPLC analysis were used to determine epidermal urocanic acid (UCA) concentrations of psoriasis patients during 4 weeks of heliotherapy on the Spanish Canary Islands and a follow-up period of 8 weeks. During heliotherapy the epidermal cis-UCA concentration increased from a mean initial value of 0.2 nmol/cm2 to a mean final value of 2.9 nmol/cm2. The total UCA concentration decreased during the first week of heliotherapy from an initial value of 5.5 nmol/cm2 to a nadir of 2.0 nmol/cm2. Thereafter, a steady increase was recorded in the total UCA level, with a maximum of 10.2 nmol/cm2 in week 2 of the post-treatment follow-up period. Suberythemal sun exposures caused near-maximal UCA isomerization, and during heliotherapy the cis isomer constituted 63.7-74.3% of the total UCA concentration. Clinical response of psoriasis to heliotherapy, however, seemed to be independent of UCA isomer levels.

A non-invasive chamber sampling technique for HPLC analysis of human epidermal urocanic acid isomers.

A new, non-invasive chamber sampling technique for HPLC analysis of human epidermal urocanic acid isomers is described. Easily processed samples are obtained in a rapid and non-invasive manner, without discomfort to the patient. HPLC data from chamber samples are reproducible, and recorded urocanic acid isomer levels are comparable to those measured in samples taken with tape stripping technique.