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The title admittedly is imperfect. But if it conveys the idea that, in spite of modern techniques, in medical practice the diagnosis of brain tumor is missed or delayed quite as often as it is promptly made, its purpose is served.At least, this has been true in our practice. In most of the cases reported the diagnosis was either mistaken or was delayed so long as to make survival, when it occurred, of dubious usefulness.In 1954 Horrax1 cited Eisenhardt's 1935 review of Cushing's series of 2,000 patients. Of these, 25% (31% of those who survived surgery) lived from 5 to 28 years. Horrax also refers to Grant's review in 1953 of a group of 1,603 patients with brain tumor, 534 (33.3%) of whom lived for 5 years or more. He concludes that "what may perhaps be said is that roughly 30 to 35% of the patients operated

Dextromethorphan (DXM) is a widely used probe drug for human CYP2D6 activity both in vitro and in vivo. In humans, DXM is metabolized to dextrorphan (DXO), as well as 3-methoxymorphinan (MEM) and 3-hydroxymorphinan (HYM). The formation of MEM has been attributed primarily to CYP3A4, and the use of DXM has been debated as a simultaneous probe for CYP3A4 and CYP2D6 activities. Recently, we found that highly purified CYP2D6 has significant DXM N-demethylase activity in addition to its well known DXM O-demethylase activity. Therefore, we desired to further compare the contribution to DXM metabolism by individual human cDNA-expressed cytochromes P450, including 2C8, 2C9, 2C18, 2C19, 2D6, 2B6, and 3A4. Metabolites were quantified following separation by high-pressure liquid chromatography and apparent Michaelis-Menten constants determined for the appearance of DXO and MEM. Intrinsic clearance values were estimated for each P450 and normalized using the average percentage content and relative activity factor approaches for comparison. Simplified kinetic models (when [S] << K(m), V(max)/K(m) = V(o)/[S]) were used at fixed DXM concentrations of 20 (for DXM N-demethylation) and 0.2 microM (for DXM O-demethylation), as well as 2 microM to mimic plasma DXM concentrations in human extensive metabolizers. The results confirm that CYP2D6 contributes at least 80% to the formation of DXO, and CYP3A4 contributes more than 90% to the formation of MEM. All of our in vitro results are consistent and indicate that DXM as a marker for monitoring both CYP2D6 and CYP3A activities is practical in an average human or human liver microsomal preparation.

The O-demethylation of dextromethorphan to dextrorphan in humans is catalyzed primarily by cytochrome P450 2D6 (CYP2D6). However, contrary to conventional wisdom, preparations of recombinant cytochrome P450 (P450) expressed from CYP2D6*1 cDNA also appear to produce significant amounts of 3-methoxymorphinan, the N-demethylated metabolite of dextromethorphan, when assayed in vitro. We hypothesized that both pathways were intrinsic to 2D6 and here further examine the kinetics of formation using a highly purified preparation of CYP2D6 in a reconstituted lipid system. Purified CYP2D6 protein with a measured molecular weight of 55772.0 (55769.6 Da predicted) was reconstituted into an active, lipid-vesicle environment with purified rat cytochrome P450 reductase before the addition of substrate and NADPH. Reaction kinetics were followed, and apparent Michaelis-Menten constants were determined for the appearance of each metabolite by high-pressure liquid chromatography, using both UV and fluorescence detection. In a 2-min assay, purified 2D6 catalyzed the formation of dextrorphan with an apparent K(m) value of 1.9 +/- 0.2 microM and a V(max) value of 8.5 +/- 0.2 nmol/nmol of P450/min and measured simultaneously the formation of 3-methoxymorphinan with an apparent K(m) value of 5000 +/- 700 microM and V(max) value of 176 +/- 12 nmol (nmol of P450)(-1) min(-1). These results indicate that at least two distinct binding orientations exist for dextromethorphan within the active site of CYP2D6.

We have identified CYP2C19 and CYP3A4 as the principal cytochrome P450s involved in the metabolism of flunitrazepam to its major metabolites desmethylflunitrazepam and 3-hydroxyflunitrazepam. Human CYP2C19 and CYP3A4 mediated the formation of desmethylflunitrazepam with Km values of 11.1 and 108 microM, respectively, and 3-hydroxyflunitrazepam with Km values of 642 and 34.0 microM, respectively. In human liver microsomes (n = 4) formation of both metabolites followed biphasic kinetics. Desmethylflunitrazepam formation was inhibited 31% by S-mephenytoin and 78% by ketoconazole, suggesting involvement of both CYP2C19 and CYP3A4. Formation of 3-hydroxyflunitrazepam was also significantly inhibited by ketoconazole (94%) and S-mephenytoin (18%). In support of these chemical inhibition data, antibodies directed against CYP2C19 and CYP3A4 selectively inhibited formation of desmethylflunitrazepam by 26 and 45%, respectively, while anti-CYP3A4 antibodies reduced 3-hydroxyflunitrazepam formation by 80%. Our data also suggest that CYP1A2, -2B6, -2C8, -2C9, -2D6, and -2E1 are not involved in either of these metabolic pathways. We estimate that the relative contributions of CYP2C19 and CYP3A4 to the formation of desmethylflunitrazepam in vivo are 63 and 37%, respectively, at therapeutic flunitrazepam concentrations (0.03 microM). We conclude that the polymorphic enzyme CYP2C19 importantly mediates flunitrazepam demethylation, which may alter the efficacy and safety of the drug, while CYP3A4 catalyzes the formation of 3-hydroxyflunitrazepam.

Acetaminophen (APAP), a widely used analgesic and antipyretic agent, can cause acute hepatic necrosis in both humans and experimental animals when consumed in large doses. It is generally accepted that N-acetyl-p-benzoquinone imine (NAPQI) is the toxic, reactive intermediate whose formation from APAP is mediated by cytochrome P450. Several forms of P450 in humans, including 2E1, 1A2, 2A6, 3A4, have been shown to catalyze the oxidation of APAP to NAPQI. We now present evidence which demonstrates that human cytochrome P450 2D6 (CYP2D6) is also involved in the bioactivation of APAP. The formation of NAPQI from APAP by cDNA-expressed CYP2D6 was examined. K(m) and V(max) values were 1.76 mM and 3.02 nmol/min/nmol of P450, respectively, such that the efficiency of CYP2D6 in the conversion of APAP to NAPQI is approximately one-third of that of CYP2E1. The contribution of CYP2D6 to the total formation of NAPQI from APAP (1 mM) in human liver was investigated using quinidine (1 microm) as a CYP2D6-specific inhibitor, and varied from 4.5 to 22.4% among 10 livers, with an average at 12.6%. The correlation between the contribution of CYP2D6 to NAPQI formation in human liver microsomes and the CYP2D6 activity probed by the O-demethylation of dextromethorphan was studied, and found to be strong (r(2) = 0.85), and significant (P <.0001). Our findings indicate that CYP2D6, one of the major P450 isoforms in humans and also one of the pharmacogenetically important isoforms, may contribute significantly to the formation of the cytotoxic metabolite NAPQI, especially in CYP2D6 ultra-rapid and extensive metabolizers and at toxic doses of APAP when plasma APAP concentrations reach 2 mM or more.

The Dynamics of European Integration, W. WALLACE (Ed), Frances Pinter London (1990), xi + 308 pp. £37.50 (hbk). ISBN 0 86187 843 4.Britain in the European Community, M. FRANKLIN with M. WILKE, Council on Foreign Relations Press, New York (1991). viii + 133 pp. US$14.95 (pbk). ISBN 0 87609 095 1.Local Economic Development: Public-Private Partnership Initiation in Britain and Germany, R. J. BENNETT and G. KREBS, Belhaven Press, London (1991). xii + 200 pp. £39.50 (hbk). ISBN 1 85293 182 5.Industrial Change and Regional Economic Transformation: The Experience of Western Europe, L. RODWIN and H. SAZANAMI (Eds), Harper Collins Academic, London (1991). xiii + 402 pp. £40.00 (hbk). £15.95 (pbk). ISBN 0 04 445882 7 (hbk). ISBN 0 04 445883 5 (pbk).Industrial Restructuring with Job Security: The Case of European Steel, S. N. HOUSEMAN, Harvard University Press, London (1991). ix + 164 pp. £19.95 (hbk). ISBN 0 674 45175 9.Regional Science: Retrospect and Prospect, D. E. BOYCE, P. NIJKAMP and D. SHEFER (Eds), Springer-Verlag, Heidelberg (1991). viii + 499 pp. DM 148 (hbk). ISBN 3 540 53493 8.Collapsing Space and Time: Geographic Aspects of Communication and Information, S. D. BRUNN and T. R. LEINBACH (Eds), Harper Collins Academic, London (1991). xxvi + 404 pp. £46.00 (hbk). £14.95 (pbk). ISBN 0 04 910119 6 (hbk). ISBN 0 04 910120 X (pbk).The Globalization of High Technology Production: Society, Space and Semiconductors in the Restructuring of the Modern World, J. HENDERSON, Routledge, London (1991). xxiii + 198 pp. £10.99 (pbk). ISBN 0 415 06076 1.The Changing Geography of the United Kingdom, 2nd edition, R. J. JOHNSTON and V. GARDINER (Eds), Routledge, London (1991). xvii + 515 pp. £45.00 (hbk). £14.99 (pbk). ISBN 0 415 03241 5 (hbk). ISBN 0 415 03242 3 (pbk).Dilemmas of Planning Practice: Ethics, Legitimacy and the Validation of Knowledge, H. THOMAS and P. HEALEY, Avebury Technical, Aldershot, Hants. (1991). xiv + 244 pp. No price given. ISBN 1 85628 173 6.A Taste of the Country: A Collection of Calvin Beale's Writings, P. A. MORRISON (Ed), Pennsylvania State University Press, London (1990). vi + 249 pp. £27.10 (hbk). ISBN 0 271 00631 5.

Endometrial proliferation is stimulated by oestradiol. The precise mechanism is poorly understood, but may be mediated by epidermal growth factor (EGF). The aim of the present study was to assess the effects of oestradiol and EGF on glandular and stromal proliferation in human endometrial cell cultures, and to determine the localization of EGF-like immunoreactivity (EGF-IR) using immunocytochemistry in normal and endometriotic tissue. Endometrium was obtained from women undergoing curettage or hysterectomy for benign disease, or laparoscopy for endometriosis. For tissue culture experiments, enriched glandular and stromal cells were prepared by digestion with collagenase and DNAase, and cultured for 4 days with oestradiol or EGF, both alone and in combination. Immunocytochemical studies were performed using sheep primary antibody against EGF, with binding visualized using the unlabelled antibody--enzyme method. In combination, oestradiol and EGF increased mean cell counts from 1.15 +/- 0.06 and 1.36 +/- 0.05 x 10(5)/ml to 1.68 +/- 0.1 (+46%) and 1.94 +/- 0.16 (+43%) x 10(5)/ml, in proliferative and secretory gland preparations respectively (n = 10, P less than 0.01). No effect was seen in stromal cell preparations; however the stimulation in gland preparations was further augmented after the addition of stromal-conditioned medium. EGF-IR was detected in endometrium from normal women, and in normal and ectopic endometrium from women with endometriosis. EGF-IR was seen in glands and stroma and was not related to the phase of the menstrual cycle. EGF may play a role in the oestrogen-stimulated proliferation of normal and endometriotic endometrium.

The role of descriptive measures of map pattern for lattice distributions and point processes and the usefulness of proceeding beyond these measures to the construction of statistical models of the data is discussed. For certain problems of estimation, forecasting, and equilibrium process modelling, it is argued that model building does add to an interpretation of map structure.

Models of spatial structure, spatial interaction, and integrated location-interaction models are reviewed and the nature of their contribution to the geographer's understanding of patterns and change is explored. The main discussion focuses first on spatial structure and then on spatial interaction. Integrated models are explored in relation to six categories employed by Zeeman, the first of these being concerned with pattern, the rest with increasingly complicated aspects of dynamics. The categories are: equilibrium, ‘fast’ dynamics, ‘slow’ dynamics, feedbacks, noise, and diffusion. The argument is illustrated by examples at each stage.

The problems that arise when estimating the unknown parameters of models of spatial interaction are considered. Two models are analysed and the large-lattice theory outlined. The need for a small-lattice theory is discussed, and those aspects of the theory that distinguish it from the large-lattice theory are emphasized. The border-value problem, a central feature of small-lattice estimation theory, is discussed in relation to estimator bias. Properties of the least-squares and maximum-likelihood estimators in small-lattice situations are analysed.