bluuebunny/crossref_metadata_2025 huggingface dataset:
Patterns of circulating hepatitis B virus serum nucleic acids during lamivudine therapy
Authors: Zhang Wei , Hacker Hans Jörg , Tokus Mehmet , Bock Thomas , Schröder Claus H.
Published: July 2003

We examined whether lamivudine treatment, in addition to the rapid decline of HBV serum DNA described in a large number of laboratories, causes changes in composition and amount of discernable circulating viral DNA and RNA. Nucleic acids were extracted from serial serum samples of a patient infected chronically and treated with lamivudine for 14 weeks. Three sequence segments of the HBV genome synthesized successively during replication, X, C, and X‐preC, were analyzed by competitive PCR and RT/PCR. In addition, RNA was examined for differential polyadenylation. Before treatment, identical DNA copy numbers (109/ml) were found in all three segments. C segment DNA displayed the expected rapid decline. X‐preC, a target contiguous only on plus‐strand DNA behaved similarly. In contrast, the X segment DNA copy numbers showed a less pronounced decrease remaining at higher values (107/ml) than the C and X‐preC segment (both about 2 × 105/ml) at the end of therapy. X segment RNA displayed a persisting copy number of about 107/ml, while C and X‐preC RNA decreased to about 105 copies/ml. Polyadenylated HBV RNA, full‐length and truncated, persisted initially at 105 but decreased to 104 to 103 copies/ml at the end of treatment. The major conclusions are the actual numbers of virus particles during lamivudine therapy can only be assessed via X segment DNA, since it is reverse transcribed first, and Lamivudine induced coexistence of DNA and RNA for the C and X segment at similar levels indicates drug‐arrested intermediates of reverse transcribed HBV DNA minus‐strand. Packaged RNA lacks a poly(A) tail whereas polyadenylated RNA is likely not packaged. J. Med. Virol. 71:24–30, 2003. © 2003 Wiley‐Liss, Inc.
Genotyping of herpes simplex virus type 1 strains isolated from ocular materials of patients with herpetic keratitis
Authors: Umene Kenichi , Inoue Tomoyuki , Inoue Yoshitsugu , Shimomura Yoshikazu
Published: July 2003

Herpes simplex virus type 1 (HSV‐1) is the etiological agent of herpetic keratitis. The epithelial form (“epithelial keratitis”) is attributed mainly to destruction of the epithelium through active viral replication within the epithelium. The stromal form (“stromal keratitis”) is associated with immune reactions within the stroma and is the common cause of human blindness. In the present study, 29 HSV‐1 strains isolated from human ocular materials of herpetic keratitis were classified into 14 genotypes on the basis of DNA polymorphisms. Twenty‐one of 29 (72%) strains from eyes examined in the present study were of genotypes that were shown previously to be present in strains from non‐ocular lesions (including genital herpes). Five of nine (56%) strains from eyes related to stromal keratitis were of the F1 genotype, while four of twenty (20%) strains from eyes not related to stromal keratitis were of the F1 genotype. Thus, the proportion of F1 genotype was assumed to be larger in the group of strains related to stromal keratitis than in that not so related, suggesting an association of the F1 genotype with stromal keratitis. A connection of F1 genotype with recurrence was proposed previously; hence, F1 genotype seems to be associated to both stromal keratitis and the recurrence, thereby supporting the relationship between stromal keratitis and recurrence. J. Med. Virol. 71:75–81, 2003. © 2003 Wiley‐Liss, Inc.
Ground state solutions of non‐linear singular Schrödinger equations with lack of compactness
Authors: Mihǎilescu Mihai , Rǎdulescu Vicenţiu
Published: July 2003

We study a class of time‐independent non‐linear Schrödinger‐type equations on the whole space with a repulsive singular potential in the divergence operator and we establish the existence of non‐trivial standing wave solutions for this problem in an appropriate weighted Sobolev space. Such equations have been derived as models of several physical phenomena. Our proofs rely essentially on critical point theory tools combined with the Caffarelli–Kohn–Nirenberg inequality. Copyright © 2003 John Wiley & Sons, Ltd.
On a quadrature algorithm for the piecewise linear wavelet collocation applied to boundary integral equations
Authors: Rathsfeld Andreas , Schneider Reinhold
Published: July 2003

In this paper, we consider a piecewise linear collocation method for the solution of a pseudo‐differential equation of order r=0, −1 over a closed and smooth boundary manifold. The trial space is the space of all continuous and piecewise linear functions defined over a uniform triangular grid and the collocation points are the grid points. For the wavelet basis in the trial space we choose the three‐point hierarchical basis together with a slight modification near the boundary points of the global patches of parametrization. We choose linear combinations of Dirac delta functionals as wavelet basis in the space of test functionals. For the corresponding wavelet algorithm, we show that the parametrization can be approximated by low‐order piecewise polynomial interpolation and that the integrals in the stiffness matrix can be computed by quadrature, where the quadrature rules are composite rules of simple low‐order quadratures. The whole algorithm for the assembling of the matrix requires no more than O(N [logN]3) arithmetic operations, and the error of the collocation approximation, including the compression, the approximative parametrization, and the quadratures, is less than O(N−(2−r)/2). Note that, in contrast to well‐known algorithms by Petersdorff, Schwab, and Schneider, only a finite degree of smoothness is required. In contrast to an algorithm of Ehrich and Rathsfeld, no multiplicative splitting of the kernel function is required. Beside the usual mapping properties of the integral operator in low order Sobolev spaces, estimates of Calderón–Zygmund type are the only assumptions on the kernel function. Copyright © 2003 John Wiley & Sons, Ltd.
An Analysis of Market-Index Certificates of Deposit
Authors: Chen Andrew H. , Kensinger John W.
Published: July 2003

We analyze the new market-index certificates of deposit (MICDs), which pay variable interest pegged to the performance of the Standard and Poor’s (S&P) 500 stock market index. The pricing formulas as well as the equilibrium relationship between the participation percentages for both the call- and put- type MICDs are derived and discussed. From the implicit value of the option component we compute implied standard deviations (ISDs) for the market index, and find inconsistencies in the pricing policies of the recent issuers of MICDs. The terms under which “bear” versions are being offered are particularly unattractive, and offering better terms would create new opportunities for the issuers of MICDs. We also analyze the issuer’s risk exposure, and discuss the natural as well as the dynamic hedging strategies. Journal of Financial Services Research, Vol. 4, No. 2 (July 1990) pp. 93-l 10. (Reprinted with permission of Kluwer Academic Publishers.)
Accrual Equivalent Marginal Tax Rates for Personal Financial Assets
Authors: Glenday Graham , Davies James B.
Published: July 2003

This paper shows that the appropriate approach to calculating accrual equivalent marginal tax rates for nonaccrual taxes on personal financial investments is the relative-reduction-in-the-internal-rate-of-return approach, which equates the present values from the after-tax returns from an investment under an accrual and a nonaccrual tax. Detailed comparisons are made with alternative approaches proposed by Boadway, Bruce, and Mintz (1984) and by King and Fullerton (1984) for the capital gains tax. Both find accrual tax rates that equate the present values of accrual and actual tax revenues. Fundamental problems are found with both alternative approaches. Canadian Journal of Economics, Vol. 23, No. 1 (February 1990) pp. 189-209. (Reprinted with permission of the Journal of Economic Literature.)
Dividends and Taxes
Authors: Chaplinsky Susan , Seyhun H. Nejat
Published: July 2003

This article investigates two aspects of dividend tax avoidance not addressed by prior research. First, it examines the aggregate dividend tax savings provided to individuals through tax-exempt and tax-deferred accumulators. Using the Internal Revenue Service Individual Income Tax Model, it then proceeds to determine whether specific provisions of the Internal Revenue Code, such as the preferential treatment of capital gains, the investment-interest limitation, and the $100 dividend exclusion, affect the individual’s choice of investment income. Finally, it provides a direct estimate of the average marginal tax rate on dividends that takes into account tax-favored accumulators. Journal of Business, Vol. 63, No. 2 (April 1990), pp. 239-260. (Reprinted with permission of the University of Chicago Press.)
Distribution of Pension Benefits on Divorce
Authors: Henszey Benjamin N. , Shapiro Arnold F.
Published: July 2003

The authors were involved in a study of the analytical procedures and assump- tions for the distribution of pension benefits on divorce. The purpose of the study was (1) to review the positions that the courts have taken; (2) to organize them within an analytical framework; and (3) to identify and articulate the unresolved issues which impede the court’s ability to render economically unbiased decisions. This article presents the findings of that study. The Journal of Risk and Insurance, Vol. LVIII, No. 3 (September 1991), pp. 480-496. (Reprinted with permission of ne Journal of Risk and Insurance.)
Differential Information and Timing Ability
Authors: Elton E.J. , Gruber M.J.
Published: July 2003

This paper discusses performance evaluation when the analyst has access to the composition of the portfolio. In the United States, master trustees and custodi- ans have this information. With this assumption, the paper derives techniques for evaluating superior performance. The techniques, unlike conventional measures, can detect superior performance even when the manager is attempting to market time. Journal of Banking and Finance, Vol. 15, No. 1 (February 1991), pp. 117-131. (Reprinted with permission of the Journal of Economic Literature.)
Why Investors Value Multinationality
Authors: Merck Randall , Yeung Bernard
Published: July 2003

We examine the value of multinationality to investors as reflected in firms’ q ratios. The positive impact of research and development and advertising spending on a firm’s q is enhanced by multinationality, but multinationality itself has no significant impact. This supports the internalization theory’s prediction that intan- gible assets are necessary to justify direct foreign investment and, thus, a recent strand of trade literature that assumes multinational firms have intangible assets with public good properties. Our results do not support the hypothesis that investors value multinational firms as a means of diversifying their portfolios internationally. Journal ofBusiness, Vol. 64, No. 2 (April 1991), pp. 165-87. (Reprinted with permission of the University of Chicago.)
Retrospective Capital Gains Taxation
Authors: Auerbach Alan J.
Published: July 2003

This paper presents a new approach to the taxation of capital gains that eliminates the deferral advantage of realization-based systems, along with the lock- in effect and tax-arbitrage possibilities associated with this deferral advantage. The new method still taxes capital gains only upon realization but, effectively by charg- ing interest on past gains when realization finally occurs, eliminates the incentive to defer such realization. Unlike a similar scheme suggested previously by Vickrey, the present method does not require knowledge of the potentially unobservable pattern of gains over time. It thus is applicable to a very broad range of capital assets. The American EconomicReview, Vol. 81, No. 1(March 1991), pp. 167-178. (Reprinted with permission of the American Economic Association.)
Uninsured Idiosyncratic Risk and Aggregate Saving,
Authors: Aiyagari S. Rao
Published: July 2003

A qualitative and quantitative analysis of the standard growth model modified to include p~caution~ saving motives and liquidity constr~nts is presented. The impact on the aggregate saving rate, the importance of asset trading to individuals, and the relative inequality of wealth and income distributions are addressed. Results suggest that the contribution of uninsured idiosyncratic risk to aggregate saving is quite modest, at least for moderate and empirically plausible values of risk aversion, variability, and persistence in earnings. However, for sufficiently high variabitity and persistence in earnings, theaggregate saving rate could be higher by as much as 7 to 14 percentage points. In addition, in contrast to representative agent models, it turns out that access to asset markets is quite important in enabling customers to smooth out earnings fluctuations. Quarterly Journal of Economics, August 1994, 109(3): 659-684. (Reprinted with permission of AEWInform, Copyright UMI.)
Incentives, Insurance, and the Variability of Consumption and Leisure
Authors: Phelan Christopher
Published: July 2003

This paper considers to what extent dynamic incentive models such as Green (1987), Phelan and Townsend (199 l), and Atkeson and Lucas (1992) can quantitatively explain why some individuals consume (or work) more than others and why a typical individual’s consumption (or leisure) varies over time. A simple repeated agency model is shown to be able to better match several population moments concerning life-cycle labor supply and consumption variation than the same model without incentive constraints. On the other hand, I show for the standard stylized models of repeated agency, incentive-induced variability is an insufficient explanation of the variability in the data. Journal of Economic Dynamics and Control, May/July 1994, 18(3/4): 581-599. (Reprinted with permission of North-Holland Publishing Company.)
Baby Boom, Population Aging, and Capital Markets
Authors: Bakshi Gurdip S. , Chen Zhiwu
Published: July 2003

This article tests how demographic changes affect capital markets. The life-cycle investment hypothesis states that at an early stage an investor allocates more wealth in housing and then switches to financial assets at a later stage. Consequently, the stock market should rise but the housing market should decline with the average age, a prediction supported in the post-1945 period. The second hypothesis that an investor’s risk aversion increases with age is tested by estimating the resulting Euler equation and supported in the post 1945 period. A rise in average age is found to predict a rise in risk premiums. Journal ofBusiness, 1994,67(2): 165-202. (Reprinted with permission of the Journaf of Business.)
Risk Incentive Problems and Foreign Currency Bonds
Authors: Schnabel Jacques A. , Roumi Ebrahim
Published: July 2003

This paper examines the incentives of stockholders to expropriate bondholder wealth by changing the probability distribution of the firm’s assets in a corporation with foreign currency denominated debt outstanding. It is shown that foreign currency bonds attenuate the incentives of stockholders to engage in this wealth expropriation by increasing the volatility of corporate assets. However, foreign currency bonds provide the stockholders with new scope for engaging in this wealth expropriation by altering the correlation between the exchange rate on the foreign currency and the value of corporate assets. Journal of Economics and Business, August 1994,46(3): 167-175. (Reprinted with permission of the Journal of Economics and Business.)
International Diversification of Investment Portfolios
Authors: Eun Cheol S. , Resnick Bruce G.
Published: July 2003

The gains from international diversification of investment portfolios from the Japanese as well as the U.S. perspectives are analysed. The major findings are detailed. First, the potential gains from international, as opposed to purely domestic, diversification are much greater for U.S. investors than for Japanese investors. For U.S. investors, the gains accrue not so much in terms of lower risk as in terms of higher return, and the opposite holds for Japanese investors. Second, using various ex ante international investment strategies de- signed to control parameter uncertainty, U.S. investors can realize substantial gains from international diversification in out-of-sample periods. Japanese investors, however, can gain relatively little. Third hedging exchange risk generally allows U.S., but not Japanese, investors to benefit more from international diversification. Management Science, January 1994,40(l): 140-161. (Reprinted with permission of ABI/Inform, Copyright UMI.)
Monocyte Chemoattractant Protein‐1 (CCL2) in Inflammatory Disease and Adaptive Immunity: Therapeutic Opportunities and Controversies
Authors: DALY CHRISTINE , ROLLINS BARRETT J.
Published: July 2003

Monocyte chemoattractant protein (MCP)‐1 (CCL2) specifically attracts monocytes and memory T cells. Its expression occurs in a variety of diseases characterized by mononuclear cell infiltration, and there is substantial biological and genetic evidence for its essential role in atherosclerosis and multiple sclerosis. Despite intensive screening, there are as yet no small‐molecule antagonists of the receptor of MCP‐1/CCL2, CCR2. However, biological agents, including antibodies and inhibitory peptides, have been developed and may be useful for these indications. Recent evidence from genetically modified mice indicates that MCP‐1 and CCR2 have unanticipated effects on T helper (Th) cell development. However, unlike the identical phenotypes of MCP‐1/CCL2−/− and CCR2−/− mice in inflammatory diseases, the phenotypes of these mice are disparate in adaptive immunity: MCP‐1 stimulates Th2 polarization, whereas CCR2 activation stimulates Th1 polarization. This presents both a challenge and an opportunity for targeting the MCP‐1/CCL2/CCR2 axis in disease.
Chemokines in Lymphocyte Trafficking and Intestinal Immunity
Authors: KUNKEL ERIC J. , CAMPBELL DANIEL J. , BUTCHER EUGENE C.
Published: July 2003

Lymphocyte migration through gut‐associated lymphoid tissues (GALT) and into intestinal effector sites is critical to intestinal immune system function and homeostasis. Chemokines contribute to lymphocyte trafficking by triggering integrin activation and firm arrest in the vasculature and mediating chemotactic localization within tissues. Several chemokines have been identified that are expressed in the GALT and/or the intestines themselves (TECK/CCL25, MEC/CCL28, and MIP‐3α/CCL20) and play a role in intestinal lymphocyte localization, including unification of intestinal and other mucosa‐associated effector sites; segmental specialization of the intestines; and subset selective localization to the intestines. This review examines the role of these chemokines (and their receptors CCR9, CCR10, and CCR6, respectively) in lymphocyte homing to the GALT, in the induction and differentiation of intestinal effector and memory lymphocytes, and in the homeostatic and inflammatory localization of lymphocytes to the intestines.
Shaping Up Adaptive Immunity: The Impact of CCR7 and CXCR5 on Lymphocyte Trafficking
Authors: MÜLLER GERD , LIPP MARTIN
Published: July 2003

The effective onset of adaptive immune responses requires that naïve antigen‐specific lymphocytes, being inherently rare throughout the body, rapidly encounter foreign antigens. This problem has been elegantly solved in evolution by inventing secondary lymphoid tissues as intersections in the migratory pathway of antigen‐presenting dendritic cells and antigen‐specific lymphocytes. Chemokines play a central role in guiding cell movements in the course of immune responses and in lymphoid system homeostasis. In particular, the chemokine receptors CCR7 and CXCR5 are key molecules for the entry of lymphocytes and dendritic cells into secondary lymphoid organs and their homing to T‐cell and B‐cell zones therein. CCR7 and CXCR5 are differentially expressed on the cell surface of lymphocytes and dendritic cells depending on the stage of cellular differentiation and activation, thus allowing these cells to change their homing capacity and prospective traffic routes.
Role of Chemokines in Angiogenesis: CXCL12/SDF‐1 and CXCR4 Interaction, a Key Regulator of Endothelial Cell Responses
Authors: SALCEDO ROSALBA , OPPENHEIM JOOST J.
Published: July 2003

Chemokines are small proteins that act as cell attractants via the activation of G protein‐coupled receptors. Chemokines play an important role in several pathophysiological processes such as inflammation and immunity. Many proinflammatory chemokines also support the development of vascular blood supply at the site of inflammation. Similarly, tumor‐generated chemokines can contribute to tumor growth by promoting angiogenesis. Recently, significant advances have been made in understanding the contribution of chemokines to the angiogenesis process. This review will discuss first the evidence supporting the direct contribution of different chemokine subfamily members, including CC, CXC, and CX3C chemokines, as positive or negative regulators of the angiogenesis process based on the expression of their cognate receptors on endothelial cells. Additionally, the relationship between classic angiogenic factors and chemokine receptor expression on endothelial cells, and the implications of chemokine production by cancer cells will be analyzed with particular emphasis on the CXCL12/stromal‐cell derived factor‐1 interaction with CXCR4.
L‐Selectin: An Emerging Player in Chemokine Function
Authors: KHAN ADIL I. , KUBES PAUL
Published: July 2003

The emigration of leukocytes across the blood‐endothelium barrier and their subsequent transmigration through the interstitium is a complex process that is vital for maintaining the efficiency of the body's innate and adaptive immunity. The chemokines, a family of low‐molecular‐weight chemoattractant cytokines, are well recognized to be key players in this process. However, recent investigations have highlighted an important role played by the selectin family of adhesion molecules in enhancing chemokine functions. This review summarizes the in vitro and in vivo studies that support this growing notion. It discusses chemotaxis in the context of the phosphoinositide 3‐kinase and p38 mitogen‐activated protein kinase pathways, and their relation to several chemoattractants (i.e., interleukin‐8, leukotriene‐B4, formyl‐methionyl‐leucyl‐phenylalanine, keratinocyte‐derived cytokine, and macrophage inflammatory protein‐2), the possible role played by L‐selectin, and finally how chemotaxis can be altered in different inflammatory settings, such as lipopolysaccharide‐mediated endotoxemia or chronic vasculitis.
Lack of pharmacokinetic interaction between retigabine and phenobarbitone at steady‐state in healthy subjects
Authors: Ferron Geraldine M. , Patat Alain , Parks Virginia , Rolan Paul , Troy Steven M.
Published: July 2003

Aims  To evaluate potential pharmacokinetic interactions between phenobarbitone and retigabine, a new antiepileptic drug.

Methods
 Fifteen healthy men received 200 mg of retigabine on day 1. On days 4–32, phenobarbitone 90 mg was administered at 22.00 h. On days 26–32, increasing doses of retigabine were given to achieve a final dose of 200 mg every 8 h on day 32. The pharmacokinetics of retigabine were determined on days 1 and 32, and those for phenobarbitone on days 25 and 31.

Results  After administration of a single 200 mg dose, retigabine was rapidly absorbed and eliminated with a mean terminal half‐life of 6.7 h, a mean AUC of 3936 ng ml−1 h and a mean apparent clearance of 0.76 l h−1 kg−1. Similar exposure to the partially active acetylated metabolite (AWD21‐360) of retigabine was observed. After administration of phenobarbitone dosed to steady‐state, the pharmacokinetics of retigabine at steady‐state were similar (AUC of 4433 ng ml−1 h and t1/2 of 8.5 h) to those of retigabine alone. The AUC of phenobarbitone was 298 mg l−1 h when administered alone and 311 mg ml−1 h after retigabine administration. The geometric mean ratios and 90% confidence intervals of the AUC were 1.11 (0.97, 1.28) for retigabine, 1.01 (0.88, 1.06) for AWD21‐360 and 1.04 (0.96, 1.11) for phenobarbitone. Individual and combined treatments were generally well tolerated. One subject was withdrawn from the study on day 10 due to severe abdominal pain. Headache was the most commonly reported adverse event. No clinically relevant changes were observed in the electrocardiograms, vital signs or laboratory measurements.

Conclusions  There was no pharmacokinetic interaction between retigabine and phenobarbitone in healthy subjects. No dosage adjustment is likely to be necessary when retigabine and phenobarbitone are coadministered to patients.
Effects of fluticasone vs. fluticasone/salmeterol on airway calibre and airway hyperresponsiveness in mild persistent asthma
Authors: Currie Graeme P. , Stenback Suvi , Lipworth Brian J.
Published: July 2003

Aims  Inhaled corticosteroids alone or in combination with long acting β2‐agonists are indicated for use in mild persistent asthmatics. We set out to evaluate effects on airway hyperresponsiveness (AHR) and airway calibre using hydrofluoroalkane fluticasone/salmeterol (FP/SM) vs. double the dose of fluticasone alone (FP).

Methods  Fourteen mild persistent asthmatics completed a randomized double‐blind crossover study with 1‐week run‐in and washout periods prior to treatments. Subjects received 3 weeks of FP 250 µg or FP 125 µg/SM 25 µg as 1 puff twice daily. Methacholine PD20 and lung function were measured after both baseline and treatment periods.

Results  There were no significant differences in baseline values prior to randomized treatments. Compared with pooled baseline, FP/SM and FP conferred improvements (P < 0.05) on methacholine PD20: 2.5 (95% confidence interval 1.7, 3.2) and 1.6 (0.8–2.3) doubling dose improvements, respectively; between FP/SM vs. FP there was a 0.9 (0.4, 1.4) doubling dose difference (P < 0.05). For forced expiratory volume in 1 s (FEV1), forced mid‐expiratory flow (FEF25−75) and morning peak expiratory flow (PEF), FP/SM but not FP conferred improvements (P < 0.05) compared with pooled baseline, with FP/SM being greater than FP (P < 0.05): differences in FEV1 of 7.2% (3.8, 10.6) predicted, FEF25−75 of 11.2% (6.3, 16.1) predicted, and morning PEF of 17 L min−1(1–32).

Conclusions  FP/SM conferred improvements on AHR and airway calibre, while twice the dose of FP improved only AHR in patients with mild asthma. The differential effects of FP/SM and FP suggest separate but complementary actions of the two moieties on airway inflammation and smooth muscle stabilization. This may explain the beneficial effects of combination inhalers on exacerbations.
Pharmacokinetics of cathinone, cathine and norephedrine after the chewing of khat leaves
Authors: Toennes Stefan W. , Harder Sebastian , Schramm Markus , Niess Constanze , Kauert Gerold F.
Published: July 2003

Aim  The stimulating herbal drug khat is habitually used in East Africa and the Arabian peninsula but is also imported into other countries. The aim was to study the pharmacokinetics of its alkaloids cathinone, cathine and norephedrine.

Methods  Four volunteers chewed khat leaves in an amount equivalent to one‐quarter of that used in a typical khat session. Blood samples were collected up to 80 h and the alkaloids were assayed using gas chromatography‐mass spectrometry. The data were evaluated using computerized pharmacokinetic compartmental analysis.

Results  The plasma concentration‐time data for the alkaloids could be described using a two‐compartment model with two‐segment absorption. The mucosa of the oral cavity is considered to be the first absorption segment, where the major proportion of the alkaloids is absorbed (mean ± SD 59 ± 21% for cathinone and 84 ± 6% for cathine). The extraction of the alkaloids from the leaves by chewing was very effective with only 9.1 ± 4.2% remaining as a residue. Cathinone was eliminated from the central compartment with a mean half‐life of 1.5 ± 0.8 h. The half‐life of cathine was 5.2 ± 3.4 h. The metabolism of cathinone to norephedrine had a substantial influence on its plasma concentration profile. Psychophysical functions were essentially unaffected by the chewing of khat.

Conclusions  The pharmacokinetics of khat alkaloids in humans explain why chewing is the preferred form of khat ingestion. Subjects absorbed a mean dose of 45 mg of cathinone, and did not suffer any severe adverse reactions.
Angiotensin II dose–effect curves and Schild regression plots for characterization of different angiotensin II AT1 receptor antagonists in clinical pharmacology
Authors: Belz Gustav G.
Published: July 2003

The ‘Schild regression’ method is based on the principle of assessing the rightward shift of agonist dose–effect curves in the presence of different doses/concentrations of the respective receptor antagonist and presenting their relationship in a double log plot (i.e. the ‘Schild plot’). The original method was developed to quantitatively characterize antagonistic drugs in experimental pharmacology. The method was adopted for evaluation of various AT1 antagonists in humans utilizing (human) angiotensin II as the agonist. Angiotensin II (Ang II) in continuous intravenous dose‐incremental administration resulted in a clearly dose‐dependent increase in blood pressure. All AT1 antagonists tested after oral administration yielded concentration‐dependent rightward shifts of those Ang II dose–effect curves that were quantified as dose ratio (DR). DR minus 1 (DR−1) enabled the assessment of antagonist time kinetics in humans and a quantitatively precise determination of the half‐life of antagonism in vivo. Schild plots allowed for assessment of apparent Ki doses indicative of a twofold rightward shift of the Ang II effect, thus providing the means for a rational comparison of the pharmacological potency of many of these compounds, where the Ki doses obtained at 24 h after administration were in the range of ‘therapeutic’ doses. Schild plots of a variety of substances showed linear relations independent of whether the blockade was deemed surmountable or not. It is therefore assumed that this property does not play a role at clinical doses/concentrations. Slopes slightly below 1 in the Schild plots of all tested antagonists point to a second ‘counterregulatory’ vasodilatory mechanism of action of Ang II which becomes apparent with AT1 blockade in conditions of high doses/concentrations of Ang II. Concentration vs. effect relationships indicate that if assessed at the same degree of direct vascular antagonism, other effects, such as increase in plasma renin activity, may be present to a varying degree with different antagonists. Thus for irbesartan, the potency to stimulate renin release was found to be at least twice that of candesartan. These observations should stimulate further research into the relevance of these dynamic differences between the various compounds. Thus, methodologies relying on fundamental principles of experimental pharmacology can provide the clinical pharmacologist with powerful tools to measure accurately degree of antagonism and time kinetics and to investigate the nature of receptor antagonism in humans.
The child's – or the state's – best interests? An examination of the ways immigration officials work with unaccompanied asylum seeking minors in Norway
Authors: Engebrigtsen Ada
Published: July 2003

This article questions the way in which Norwegian immigration officials apply the principle of the child's best interests in cases concerning family reunion for unaccompanied asylum seeking minors in Norway. It is claimed that the official definition of child migrants and the interpretation of what is in their best interest does not take the child's background and circumstances into account with sufficient detail and sensitivity. This paper further discusses the bureaucratic procedures that turn an individual child with individual interests into a judicial and generalized prototype that appears to have the same interests as the immigration authorities. Thus the combination of a culture‐blind and context‐free consideration of an abstract child's best interests primarily serves to justify increasing restriction of family reunion for child migrants, and thereby serves the state's best interest at the cost of the individual child.
Unsettling the ‘social’ in social work: responses to asylum seeking children in Ireland
Authors: Christie Alastair
Published: July 2003

The ‘social’ context in which social work is located is becoming increasingly unsettled by emerging patterns of mobility. Mobility is constrained for many social work service users who are trapped within disadvantaged areas, while for others it has become a forced necessity to cross national boundaries and inhabit uncertain status in their nations of destination. This article explores the responses of the social work profession to children seeking asylum in the Republic of Ireland. These children's complex needs, produced by the conditions of mobility they have encountered and by the conditions of arrival/settlement in Ireland, force social work practice to be orientated beyond the boundaries of the national welfare state. In order to explore the varied responses of the social work profession in the Republic of Ireland to asylum seeking children, three different groups of children are considered: children seeking asylum who have been separated from their parents; children who are seeking asylum with their parent(s)/family; and young Irish citizens whose asylum seeking parents are in danger of being deported. It argues that the provision of appropriate services for these children requires the development of post‐national forms of social work practice.
A multicentre, randomized, double‐blind, placebo‐controlled, 1‐year study of bupropion SR for smoking cessation
Authors: Tønnesen P. , Tonstad S. , Hjalmarson A. , Lebargy F. , Van Spiegel P. I. , Hider A. , Sweet R. , Townsend J.
Published: July 2003

Abstract.  Tønnesen P, Tonstad S, Hjalmarson A, Lebargy F, van Spiegel PI, Hider A, Sweet R, Townsend J (Gentofte University Hospital, Gentofte, Denmark; Clinic for Preventive Medicine, Ullevål University Hospital, Oslo, Norway; Smoking Cessation Clinic, Sahlgrenska University Hospital, Gothenburg, Sweden; Hospital Maison Blanche, Reims Cedex, France; Slotervaart Hospital, Amsterdam, The Netherlands; and GlaxoSmithKline Research and Development, Greenford, Middlesex, UK). A multicentre, randomized, double‐blind, placebo‐controlled, 1‐year study of bupropion SR for smoking cessation. J Intern Med 2003; 254: 184–192.

Background.  Bupropion sustained release (bupropion SR) has been shown to increase smoking cessation success rates in the US studies.

Objective.  To determine whether bupropion SR, in combination with counselling, is effective for smoking cessation in a multi‐country study.

Methods.  This randomized, double‐blind, placebo‐controlled trial enrolled 707 smokers. A total of 527 received bupropion SR 300 mg daily for 7 weeks and 180 received placebo. A total of 11 clinic visits and 10 telephone contacts were scheduled, during the course of 1 year. Seven‐week and 12‐month abstinence rates were the study outcomes.

Results.  Both continuous and weekly point prevalence smoking abstinence rates were significantly higher in the bupropion SR group compared with placebo. The continuous abstinence rate from weeks 4 to 7 was 46% in the bupropion SR group compared with 23% in the placebo group [odds ratio (OR) = 2.82; 95% confidence interval (CI) 1.89–4.28; P < 0.001). At month 12, the continuous abstinence rates were 21% for the bupropion SR group and 11% for the placebo group (OR = 2.19; 95% CI 1.29–3.86, P = 0.002). For most nicotine‐withdrawal symptoms small changes were measured. Adverse events were higher for the bupropion SR group compared with placebo (insomnia 24% vs. 15%; dry mouth 13% vs. 5%).

Conclusion. Bupropion SR in combination with counselling increased the abstinence rate compared with placebo, and was well tolerated.
Changes in mitogen‐activated protein kinase activity occur in the maize pulvinus in response to gravistimulation and are important for the bending response
Authors: CLORE A. M. , TURNER W. S. , MORSE A. M. , WHETTEN R. W.
Published: July 2003

The maize (Zea mays L.) pulvinus was used as a model system to study the signalling events that lead to differential growth in response to gravistimulation in plants. The pulvinus functions to return tipped plants to vertical via differential elongation of the cells on its lower side. By performing immunokinase assays using total soluble protein extracts and an antibody against mammalian ERK1, a mitogen‐activated protein kinase (MAPK)‐like activity was assayed in pulvini halves harvested at various time points after tipping. We detected a reproducible alternation of higher levels of activity occurring between the upper and lower halves of the pulvinus between 75 and 180 min after tipping, with a sustained increase in the upper half occurring at the end of the time‐course. This timing roughly corresponds to the presentation time for maize (i.e. the amount of time that the plant needs to be tipped before it is committed to bend), which occurs between 2 and 4 h. Treatment of maize stem explants with an inhibitor of MAPK activation, U0126, led to a reduction in the activity of this kinase, as well as an almost 65% reduction in bending as measured at 20 h. Rinsing out of the inhibitor resulted in recovery of both bending and kinase activity. It is possible that changes in MAPK activity in the gravistimulated pulvinus are part of a signalling cascade that may help to distinguish between minor perturbations in plant orientation and more significant and long‐term changes, and may also help to determine the direction of bending.
Whole‐tree water transport scales with sapwood capacitance in tropical forest canopy trees
Authors: MEINZER F. C. , JAMES S. A. , GOLDSTEIN G. , WOODRUFF D.
Published: July 2003

The present study examines the manner in which several whole‐tree water transport properties scale with species‐specific variation in sapwood water storage capacity. The hypothesis that constraints on relationships between sapwood capacitance and other water relations characteristics lead to predictable scaling relationships between intrinsic capacitance and whole‐tree behaviour was investigated. Samples of sapwood from four tropical forest canopy tree species selected to represent a range of wood density, tree size and architecture, and taxonomic diversity were used to generate moisture release curves in thermocouple psychrometer chambers, from which species‐specific values of sapwood capacitance were calculated. Sapwood capacitance was then used to scale several whole‐tree water transport properties determined from measurements of upper branch and basal sap flow, branch water potential, and axial and radial movement of deuterated water (D2O) injected into the base of the trunk as a tracer. Sapwood capacitance ranged from 83 to 416 kg m−3 MPa−1 among the four species studied and was strongly correlated with minimum branch water potential, soil‐to‐branch hydraulic conductance, daily utilization of stored water, and axial and radial movement of D2O. The species‐independent scaling of several whole‐tree water transport properties with sapwood capacitance indicated that substantial convergence in plant function at multiple levels of biological organization was revealed by a simple variable related to a biophysical property of water transport tissue.
The lower cell density of leaf parenchyma in the Arabidopsis thaliana mutant lcd1‐1 is associated with increased sensitivity to ozone and virulent Pseudomonas syringae
Authors: Barth Carina , Conklin Patricia L.
Published: July 2003

Under optimal growth conditions (120 µmol photons m−2 sec−1 photosynthetically active radiation (PAR), 16‐h photoperiod), the recessive ozone‐sensitive Arabidopsis thaliana L. Heynh. mutant lcd1‐1 exhibits a pale phenotype compared to the wild type. Confocal and multiphoton microscopy revealed that the paleness of lcd1‐1 is because of a lower cell density in the leaf palisade parenchyma, resulting in decreased chlorophyll content. When exposed to ozone, lcd1‐1 leaves become paler and contain an increased amount of the lipid peroxidation product malondialdehyde compared to the wild type, suggesting that lcd1‐1 suffers from elevated levels of reactive oxygen species (ROS) generated in the apoplast. Infection of leaves with virulent Pseudomonas syringae reveals higher bacterial growth as well as lower pathogenesis‐related protein 1 (PR‐1) and PR‐5 expression in lcd1‐1 than in the wild type. When the wild type and lcd1‐1 are exposed to short‐term high‐light stress, leaves do not bleach in lcd1‐1 and potential activities of photosystems I (PSI) and II (PSII) decrease to a similar extent in both the genotypes, indicating that the photosynthetic apparatus is not affected by lcd1‐1 mutation. The LCD1 gene, found to contain a nonsense mutation in the mutant, has been identified. It is located at the bottom of chromosome 2 of the Arabidopsis genome. However, the function of the protein encoded by LCD1 is not yet known. We hypothesize that LCD1 plays a role in normal leaf development, and that the increased sensitivity to ozone and virulent P. syringae is a secondary effect that presumably results from the lower‐cell‐density phenotype in lcd1‐1.
Gene trapping of the Arabidopsis genome with a firefly luciferase reporter
Authors: Yamamoto Yoshiharu Y. , Tsuhara Yumi , Gohda Kazuhito , Suzuki Kumiko , Matsui Minami
Published: July 2003

Experiments with gene‐trap vectors containing the firefly luciferase (LUC) reporter genes were carried out with the aim of analyzing functions of the Arabidopsis genome. Studies with protein fusion‐type trap vectors as well as an internal ribosome entry site (IRES)‐assisted non‐fusion‐type vector revealed that both types of vectors were suitable for gene trapping in Arabidopsis, although there were some differences in trapping efficiencies. The established trap lines were subjected to analyses for light responses, demonstrating the powerful and unique applications of a LUC‐trapping system. A systematic survey of the insertion sites of the T‐DNAs in LUC‐expressing lines revealed 12–41% gene‐trapping efficiencies depending on the vector. We demonstrate that the LUC‐trapping system provides a unique system with which to monitor temporal expression of plant genes.
Photodiagnostic techniques for the endoscopic detection of premalignant gastrointestinal lesions
Authors: DaCosta Ralph S. , Wilson Brian C. , Marcon Norman E.
Published: July 2003

Considerable attention is given to the clinical diagnosis of gastrointestinal (GI) malignancies as they remain the second leading cause of cancer‐associated deaths in developed countries. Detection and intervention at an early stage of preneoplastic development significantly improve patient survival. High‐risk assessment of asymptomatic patients is currently performed by strict endoscopic surveillance biopsy protocols aimed at early detection of dysplasia and malignancy. However, poor sensitivity associated with frequent surveillance programs incorporating conventional screening tools, such as white light endoscopy and multiple random biopsy, is a significant limitation. Recent advances in biomedical optics are illuminating new ways to detect premalignant lesions of the GI tract with endoscopy. The present review presents a summary report on the newest developments in modern GI endoscopy, which are based on novel optical endoscopic techniques: fluorescence endoscopic imaging and spectroscopy, Raman spectroscopy, light scattering spectroscopy, optical coherence tomography, chromoendoscopy, confocal fluorescence endoscopy and immunofluorescence endoscopy. Relying on the interaction of light with tissue, these ‘state‐of‐the‐art’ techniques potentially offer an improved strategy for diagnosis of early mucosal lesions by facilitating targeted excisional biopsies. Furthermore, the prospects of real‐time ‘optical biopsy’ and improved staging of lesions may significantly enhance the endoscopist's ability to detect subtle preneoplastic mucosal changes and lead to curative endoscopic ablation of these lesions. Such advancements within this specialty will be rewarded in the long term with improved patient survival and quality of life.
Laparoscopic ablation therapy for hepatocellular carcinoma. Clinical significance of a newly developed laparoscopic sector ultrasonic probe
Authors: Noguchi Osamu , Izumi Namiki , Inoue Kazunari , Nishimura Yuki , Ueda Ken , Tsuchiya Kaoru , Hamano Kosei , Itakura Jun , Asahina Yasuhiro , Uchihara Masakatsu , Miyake Shozo
Published: July 2003

Background:  Although a laparoscopic approach for local ablation plays an important role in treating hepatocellular carcinoma (HCC) near the liver surface, precise targeting ablation has been difficult using a conventional linear ultrasonic probe. We have recently developed a sector ultrasonic probe with a guiding tract for precisely targeting tumors.

Methods:  Since 1996, 349 HCC cases have been treated with either microwave or radiofrequency ablation. A percutaneous approach was selected in 298 cases, and a laparoscopic approach was selected in 51 cases. The laparoscopic approach was selected in the cases in which serious complications due to the tumors being located on the surface or protruding from the liver, or adjacent to the gallbladder or intestine made it difficult to treat percutaneously. In the latest 21 cases, the sector ultrasonic probe was used.

Results:  All the cases were safely and successfully treated by laparoscopic ablation with an exception by an extensive HCC case with portal vein tumor thrombus. Survival after the treatment by laparoscopic ablation was 95.2% in 1 year, and 82.4% in 3 years. The tumor stage was a significant prognostic factor (P < 0.0001). There was no local recurrence within 6 months of treatment in the successfully treated cases. The use of the sector probe widened indications for the laparoscopic approach for treating HCC.

Conclusion:  Laparoscopic ablation can result in a satisfactory outcome in difficult‐to‐treat cases by the percutaneous approach. The newly developed sector ultrasonic probe has allowed us more therapeutic choices in the treatment of HCC.
Evaluation of the type V pit pattern in the lesions of colonic Tis and T1 cancer
Authors: Tamura Satoru , Yokoyama Yuichi , Ookawauchi Kohji , Onishi Tomoko , Onishi Saburo , Miyazaki Jun‐ichi
Published: July 2003

Background:  The usefulness of magnifying videoendoscopic pit pattern diagnosis has been recognized in the differential diagnosis of colonic neoplasms. Also, the correspondence between lesions with a type V pit pattern and cancer has been emphasized. We evaluated the relationship between the type V pit pattern and carcinoma in situ or subdivided submucosal invading carcinomas.

Methods:   During the period from May 1997 to December 2001, a total of 8696 colonoscopies were performed and 6672 colorectal lesions were detected. Colorectal lesions (47.7%; 3181/6672) were examined by videoendoscopic magnification. The type V pit pattern was divided into two groups: VI and VN. The submucosal extensions of cancers were classified as sm1, sm2 and sm3 according to the vertical level of invasion. All Tis (n = 57) and operated T1 carcinomas (n = 69) with the type V pit pattern were selected for this study.

Results:  Cancer invasion with the type VI pit pattern was limited up to sm2, and the type VN pit pattern was closely related to sm3 extension in protruded type (P = 0.0005). The frequency of the appearance of the type VI pit pattern decreased and that of the type VN pit pattern increased as the invasion extended deeper into the submucosal layer in superficial‐type cancers (P < 0.0001).

Conclusions:   Superficial type cancers well reflected the submucosal infiltrating cancer glands when their surface structure had a type VN pit pattern. In contrast, only 20% of sm2 cancers presented a type VN pit pattern among the protruded types.