Influence of the methyl group in isoprene epoxides on reactivity compared to butadiene epoxides: Biological significance.

Reactions of the epoxides of 1,3-butadiene and isoprene (2-methyl-1,3-butadiene) with oxygen, nitrogen and sulfur nucleophiles have been compared to enable a better molecular understanding of the relative human toxicities of these epoxides. Hydrolysis of rac.-ethenyloxirane in (O)water gave 77% (2-O)but-3-ene-1,2-diol and 23% (1-O)but-3-ene-1,2-diol.

Modeling the formation and reactions of benzene metabolites.

One or more of the muconaldehyde isomers is a putative product of benzene metabolism. As muconaldehydes are highly reactive dienals and potentially mutagenic they might be relevant to the carcinogenicity of benzene. Muconaldehydes may be derived through the action of a cytochrome P450 mono-oxygenase on benzene oxide-oxepin, which are established metabolites of benzene.

Immunoreactivity for the GABAA receptor alpha1 subunit, somatostatin and Connexin36 distinguishes axoaxonic, basket, and bistratified interneurons of the rat hippocampus.

Parvalbumin (PV)-expressing interneurons synchronize cortical neurons through gamma-aminobutyric acidergic (GABAergic) synapses. Three types of PV-containing interneurons populate stratum pyramidale of the hippocampal CA1 area: basket cells targeting somata and proximal dendrites, axoaxonic cells innervating axon initial segments, and bistratified cells targeting the dendrites of pyramidal cells. We tested whether this axonal specialization is accompanied by a differential expression of molecules involved in neuronal signaling.

Evidence for the formation of Michael adducts from reactions of (E,E)-muconaldehyde with glutathione and other thiols.

Glutathione induces the rapid isomerization of (Z,Z)-muconaldehyde to (E,E)-muconaldehyde via (E,Z)-muconaldehyde, probably via reversible Michael addition of the thiol to one of the enal moieties of the muconaldehyde. Reactions of (E,E)-muconaldehyde with glutathione (in the presence and absence of equine glutathione S-transferase), phenylmethanethiol, N-acetyl-l-cysteine, and N-acetyl-l-cysteine methyl ester were investigated using mass spectrometric techniques. In each case, evidence was obtained for the formation of Michael adducts, e.

Reactions of benzene oxide with thiols including glutathione.

S-Phenylmercapturic acid is a minor metabolite of benzene used as a biomarker for human benzene exposures. The reaction of intracellular glutathione with benzene oxide-oxepin, the initial metabolite of benzene, is presumed to give 1-(S-glutathionyl)-cyclohexa-3,5-dien-2-ol, which undergoes dehydration to S-phenylglutathione, the precursor of S-phenylmercapturic acid. To validate the proposed route to S-phenylglutathione, reactions of benzene oxide-oxepin with glutathione and other sulfur nucleophiles have been studied.

2,6-diarylaminotetrahydropyrans from reactions of glutaraldehyde with anilines: models for biomolecule cross-linking.

Glutaraldehyde reacts with weakly nucleophilic anilines, e.g., 3-fluoro-4-nitroaniline, which are models for amino groups in DNA, to give meso-2,6-disubstituted tetrahydropyrans, e.

Modulation of brain stem monoamines and gamma-aminobutyric acid by NK1 receptors in rats.

To understand the role of substance P in stress, anxiety and depression, we have investigated in rats the relationship between NK1 receptors and monoamines or GABA, and between substance P and serotonin (5-HT) in brain stem neurons by immunohistochemical double-staining techniques. In the periaqueductal gray and dorsal raphe nucleus, there was no colocalization between NK1 and 5-HT or between NK1 and tyrosine hydroxylase (a marker for adrenaline and dopamine neurons). However, many GABA-positive neurons (> 50%) were NK1 positive, and some substance P-positive neurons were 5-HT positive as well.

Trapping of benzene oxide-oxepin and methyl-substituted derivatives with 4-phenyl- and 4-pentafluorophenyl-1,2,4-triazoline-3,5-dione.

4-Phenyl-1,2,4-triazoline-3,5-dione and its pentafluoro analogue are efficient reagents for trapping arene oxides, e.g. benzene oxide-oxepin, affording crystalline adducts that can be quantitatively analysed by HPLC and MS techniques.

Resistance-modifying agents. 8. Inhibition of O(6)-alkylguanine-DNA alkyltransferase by O(6)-alkenyl-, O(6)-cycloalkenyl-, and O(6)-(2-oxoalkyl)guanines and potentiation of temozolomide cytotoxicity in vitro by O(6)-(1-cyclopentenylmethyl)guanine.

A series of O(6)-allyl- and O(6)-(2-oxoalkyl)guanines were synthesized and evaluated, in comparison with the corresponding O(6)-alkylguanines, as potential inhibitors of the DNA-repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT). Simple O(6)-alkyl- and O(6)-cycloalkylguanines were weak AGT inactivators compared with O(6)-allylguanine (IC(50) = 8.5 +/- 0.

Dimethyldioxirane converts benzene oxide/oxepin into (Z,Z)-muconaldehyde and sym-oxepin oxide: modeling the metabolism of benzene and its photooxidative degradation.

Oxidation of 7-oxabicyclo[4.1.0]hepta-2,4-diene (benzene oxide)/oxepin with dimethyldioxirane (DMDO) gave mainly (Z,Z)-muconaldehyde, with complete diastereoselectivity.

Chemistry of muconaldehydes of possible relevance to the toxicology of benzene.

(Z,Z)-Muconaldehyde reacted with primary amines to give N-substituted-2(2'-oxoethyl)-pyrroles, which were reduced to N-substituted-2-(2'-hydroxyethyl)-pyrroles by sodium borohydride. The pyrrole-forming reaction is exhibited by valine and its methyl ester, and is being developed with terminal valine in hemoglobin as a means of dose monitoring (Z,Z)-muconaldehyde, a putative metabolite of benzene. Reactions in aqueous solution between (Z,Z)-muconaldehyde and adenosine, deoxyadenosine, guanosine, or deoxyguanosine leading to pyrrole-containing adducts are described.

Studies on the molecular toxicology of buta-1,3-diene and isoprene epoxides.

Reactions of ethenyloxirane with amino (RNH2) and thiol (R'SH) nucleophiles occur by an SN2 mechanism involving competing ring cleavage at C-2 and C-3. In contrast, 2-ethenyl-2-methyloxirane reacts with amino (RNH2) and thiolate (R'S-) nucleophiles in methanol by regioselective SN2 attack at C-3 ("neo-pentyl" position). However, in pure water or methanol SN1 reaction occurs mainly at C-2.

Mechanisms of formation of adducts from reactions of glycidaldehyde with 2'-deoxyguanosine and/or guanosine.

Convenient synthesis of rac-glycidaldehyde from rac-but-3-ene-1,2-diol and (R)-glycidaldehyde from D-mannitol are described. (R)-Glycidaldehyde (1) reacts with guanosine in water (pH 4-11, faster reaction at higher pH) to give initially 6(S)-hydroxy-7(S)-(hydroxymethyl)-3-(beta-D-ribofuranosyl)-5,6,7- trihydroimidazo[1,2-alpha]purin-9(3H)-one (7a) and 6(S),7(R)-dihydroxy-3-(beta-D-ribofuranosyl)-5,6,7,8- tetrahydropyrimido[1,2- alpha]purin-10(3H)-one (8a). The former decomposes to 7-(hydroxymethyl)-5,9-dihydro-9-oxo-3-(beta-D-ribofuranosyl)imidazo[1,2- alpha]purine (3a), 5,9-dihydro-9-oxo-3-(beta-D-ribofuranosyl)imidazo[1,2-alpha]purine (5a, 1,N2-ethenoguanosine), and formaldehyde, while the latter adduct is relatively stable.

The achievement of isoeffective bronchial mucosal dose during endobronchial brachytherapy.

Purpose: The use of endobronchial brachytherapy in the treatment of lung cancer is increasing due to the more widespread availability of high dose rate afterloading equipment. The complications include small airway (segmental and small lobar bronchi) fibrosis, stenosis, and obstructive complications in addition to hemorrhage. A progressive reduction in the diameter of the bronchial lumen occurs at each division of the bronchial tree.

Radiotherapy and chemotherapy for inoperable non-small cell lung cancer.

Non-small cell lung cancer is a major cause of mortality and significant morbidity in the UK. The majority of patients are inoperable and the optimum management of these patients requires a multidisciplinary approach involving the cooperation of respiratory physicians, thoracic surgeons and clinical oncologists (radiotherapists). Treatment techniques are constantly being refined and new approaches developed.

Non-uniform dwell times in line source high dose rate brachytherapy: physical and radiobiological considerations.

The ability to vary source dwell times in high dose rate (HDR) brachytherapy allows for the use of non-uniform dwell times along a line source. This may have advantages in the radical treatment of tumours depending on individual tumour geometry. This study investigates the potential improvements in local tumour control relative to adjacent normal tissue isoeffects when intratumour source dwell times are increased along the central portion of a line source (technique A) in radiotherapy schedules which include a relatively small component of HDR brachytherapy.

A mathematical model of intraluminal and intracavitary brachytherapy.

The adaptation of the linear-quadratic model to allow for the effect of tumour regression and clonogen repopulation between initial teletherapy and subsequent brachytherapy has been extended to include the geometrical conditions encountered in intraluminal and intracavitary brachytherapy. For a radiation line source placed at the centre of a lumen or cavity, regression of any endoluminal tumour towards its mural origin will not result in any change in the minimum brachytherapy-tumour dose with time. In contrast, regression of transmural tumour will cause a potentially advantageous increase in the minimum brachytherapy-tumour dose with time.

Effect of overall time when radiotherapy includes teletherapy and brachytherapy: a mathematical model.

By expanding the linear quadratic equations to allow for the interval of time between teletherapy and brachytherapy in a model which assumes continual exponential tumour regression following teletherapy, the loge cell kill resulting from brachytherapy is found to depend on radiosensitivity, tumour regression rate (lambda) and tumour clonogen doubling time (Tp). When lambda is relatively small the precise timing of brachytherapy following teletherapy is shown to influence the tumour cure probabilities. The model predicts a reduction in tumour control if brachytherapy is delayed when lambda values are small and Tp values are short, but when Tp values are long, deferral of brachytherapy may be advantageous.

Differential free-radical activity after successful and unsuccessful thrombolytic reperfusion in acute myocardial infarction.

Background: Free-radical generation after successful thrombolysis in acute myocardial infarction may jeopardize ischaemic but viable myocardium, thus limiting the optimal benefits of reperfusion.

Methods: Circulating free-radical activity was assessed in 25 consecutive patients with acute myocardial infarction. Those who successfully reperfused (Group A) were compared with those who did not (Group B).

Reactions of muconaldehyde isomers with nucleophiles including tri-O-acetylguanosine: formation of 1,2-disubstituted pyrroles from reactions of the (Z,Z)-isomer with primary amines.

(Z,Z)-Muconaldehyde reacts with primary amines, including valine and lysine (epsilon-amino), to afford N-substituted-2-(oxoethyl)pyrroles, which were reduced with sodium borohydride to the more stable N-substituted-2-(hydroxyethyl)pyrroles. The formation of the pyrrole aldehydes was performed in a variety of solvents including aqueous methanol. With tri-O-acetylguanosine, the putative pyrrole aldehyde derived from reaction at NH2 condenses with N-1 (guanine component) to afford a bicyclic adduct: 4,5-dihydro-5-hydroxy-10-beta-D-tri-O- acetylribosylpyrrolo[1',2':3,4]pyrimido[1,2-a]purin-7(10H)-one (5a).

Accuracy of diagnostic coding of hospital admissions for cryptogenic fibrosing alveolitis.

To determine the accuracy of diagnostic coding of cryptogenic fibrosing alveolitis, the case notes of 166 admissions to four hospitals were reviewed. These consisted of all admissions that had been coded as "idiopathic fibrosing alveolitis" (ICD code 516.3: 97 admissions) or as "postinflammatory pulmonary fibrosis" (ICD code 515.