bluuebunny/crossref_metadata_2025 huggingface dataset:
Reflections on and alternatives to WHO's fairness of financial contribution index
Authors: Wagstaff Adam
Published: August 2002

In its 2000 World Health Report (WHR), the World Health Organization argues that a key dimension of a health system's performance is the fairness of its financing system. This paper provides a critical assessment of the index of fairness of financial contribution (FFC) proposed in the WHR. It shows that the index cannot discriminate between health financing systems that are regressive and those that are progressive, and cannot discriminate between horizontal inequity on the one hand, and progressivity and regressivity on the other. The paper compares the WHO index to an alternative and more illuminating approach developed in the income redistribution literature in the early 1990s and used in the late 1990s to study the fairness of various OECD countries' health financing systems. It ends with an illustrative empirical comparison of the two approaches using data on out‐of‐pocket payments for health services in Vietnam for two years – 1993 and 1998. This analysis is of some interest in its own right, given the large share of health spending from out‐of‐pocket payments in Vietnam, and the changes in fees and drug prices over the 1990s. Copyright © 2002 John Wiley & Sons, Ltd.
Glomus jugulare tumor: Tumor control and complications after stereotactic radiosurgery
Authors: Foote Robert L. , Pollock Bruce E. , Gorman Deborah A. , Schomberg Paula J. , Stafford Scott L. , Link Michael J. , Kline Robert W. , Strome Scott E. , Kasperbauer Jan L. , Olsen Kerry D.
Published: August 2002

Background

We evaluated toxicity and long‐term efficacy of stereotactic radiosurgery in patients with symptomatic or progressive glomus jugulare tumors.

Methods

Twenty‐five consecutive patients (age, 30–88 years; 17 women, 8 men) who underwent stereotactic radiosurgery with the Leksell Gamma Knife (dose, 12–18 Gy) were prospectively followed. MRI and clinical examinations were performed at 6 months and 1, 2, and 3 years, and then every 2 years.

Results

None of the tumors increased in size, 17 were stable, and 8 decreased (median imaging follow‐up, 35 months; range, 10–113 months). Symptoms subsided in 15 patients (60%); vertigo occurred in 1, but balance improved with vestibular training (median clinical follow‐up, 37 months; range, 11–118 months). No other new or progressive neuropathy of cranial nerves V–XII developed.

Conclusions

Stereotactic radiosurgery can achieve excellent tumor control with low risk of morbidity in the treatment of glomus jugulare tumors. The lower cranial nerves can safely tolerate a radiosurgical dose of 12 to 18 Gy. © 2002 Wiley Periodicals, Inc. Head Neck 24: 332–339, 2002; DOI 10.1002/hed.10005
Temporospatial expression of HSP72 and c‐JUN, and DNA fragmentation in goat hippocampus after global cerebral ischemia
Authors: Torregrosa Germán , Barberá María D. , Ortí Marta , Centeno José M. , Salom Juan B. , Justicia Carles , Planas Anna M. , Alborch Enrique
Published: August 2002

The role of gene induction (expression of HSP72 and c‐JUN proteins) and delayed ischemic cell death (in situ labeling of DNA fragmentation) have been investigated in the goat hippocampus after transient global cerebral ischemia. The animals were subjected to 20‐min ischemia (bilateral occlusion of the external carotid arteries plus bilateral jugular vein compression) and allowed to reperfuse for 2 h, and then 1, 3, and 7 days. Histological signs of cell loss were not found in the hippocampus at 2 h, 1 day, or 3 days of reperfusion. However, such an ischemic insult produced extensive, selective, and delayed degeneration in the hippocampus, as 68% of the neurons in CA1 had died at 7 days, but cell loss was not detected in CA3 and dentate gyrus fields. Concomitantly, a high percentage of TUNEL‐positive CA1 neurons (60 ± 9%, mean ± SEM) was seen at 7 days, but not at the earlier time points. Mild induction of HSP72 was detected in the goat hippocampus after ischemia. The maximum percentage of HSP72‐positive neurons (10–15%) was shown at 3 days of reperfusion and was concentrated mainly in the CA3 field, subiculum, and hilus, rather than in the CA1 field, whereas HSP72 expression was hardly detected at 7 days. At this later time point, scattered induction of nuclear c‐JUN was found in a few neurons. The results show that: 1) postischemic delayed neuronal death selectively affects the CA1 field in the goat hippocampus, a phenomenon which seems to take longer to develop than in previously reported rodent models; and 2) postischemic expression of c‐JUN does not appear to be related to cell death or survival, while the inability of most CA1 neurons to express HSP72 could contribute to neuronal death. Hippocampus 2001;11:146–156. © 2001 Wiley‐Liss, Inc.
Computational model of carbachol‐induced delta, theta, and gamma oscillations in the hippocampus
Authors: Tiesinga Paul H.E. , Fellous Jean‐Marc , José Jorge V. , Sejnowski Terrence J.
Published: August 2002

Field potential recordings from the rat hippocampus in vivo contain distinct frequency bands of activity, including δ (0.5–2 Hz), θ (4–12 Hz), and γ (30–80 Hz), that are correlated with the behavioral state of the animal. The cholinergic agonist carbachol (CCH) induces oscillations in the δ (CCH‐δ), θ (CCH‐θ), and γ (CCH‐γ) frequency ranges in the hippocampal slice preparation, eliciting asynchronous CCH‐θ, synchronous CCH‐δ, and synchronous CCH‐θ with increasing CCH concentration (Fellous and Sejnowski, Hippocampus 2000;10:187–197).

In a network model of area CA3, the time scale for CCH‐δ corresponded to the decay constant of the gating variable of the calcium‐dependent potassium (K‐AHP) current, that of CCH‐θ to an intrinsic subthreshold membrane potential oscillation of the pyramidal cells, and that of CCH‐γ to the decay constant of GABAergic inhibitory synaptic potentials onto the pyramidal cells. In model simulations, the known physiological effects of carbachol on the muscarinic and K‐AHP currents, and on the strengths of excitatory postsynaptic potentials, reproduced transitions from asynchronous CCH‐θ to CCH‐δ and from CCH‐δ to synchronous CCH‐θ. The simulations also exhibited the interspersed CCH‐γ/CCH‐δ and CCH‐γ/CCH‐θ that were observed in experiments. The model, in addition, predicted an oscillatory state with all three frequency bands present, which has not yet been observed experimentally. Hippocampus 2001;11:251–274. © 2001 Wiley‐Liss, Inc.
Learning deficits in aged rats related to decrease in extracellular volume and loss of diffusion anisotropy in hippocampus
Authors: Syková E. , Mazel T. , Hasenöhrl R.U. , Harvey A.R. , Šimonová Z. , Mulders W.H.A.M. , Huston J.P.
Published: August 2002

The extracellular space (ECS) is the microenvironment of the nerve cells and an important communication channel, allowing for long‐distance extrasynaptic communication between cells. Changes in ECS size, geometry, and composition have been reported in diverse (patho)physiological states, including aging. In the present study, real‐time tetramethylammonium (TMA+) iontophoresis was used to quantify ECS diffusion parameters in different brain regions of adult and behaviorally characterized aged rats. Prior to ECS diffusion measurement, superior and inferior learners were selected from a large group of aged rats, according to their performance in the open‐field water maze. The main finding was that the degree of impaired maze performance of old rats correlates, firstly, with decrease in ECS volume, loss of diffusion anisotropy in hippocampus, and degree of astrogliosis, and secondly, with disorganization of the astrocytic processes and reduction of hippocampal ECS matrix molecules. Importantly, no significant differences were found in the density of neurons in any region of the hippocampus or dentate gyrus. The alterations in hippocampal diffusion parameters evident in aged animals with severe learning deficits could account for the learning impairment, due to their effects on extrasynaptic volume transmission and/or on the “cross‐talk” between synapses, which has been suggested to be involved in neural processes associated with learning and memory formation. Hippocampus 2002;12:269–279. © 2002 Wiley‐Liss, Inc.
Role of Bcl‐2 family of proteins in malignancy
Authors: Baliga Belinda C. , Kumar Sharad
Published: August 2002

B cell lymphoma gene‐2 (Bcl‐2) is the prototypic member of a growing family of proteins that play evolutionarily conserved, key regulatory roles in apoptosis. The Bcl‐2 family members are characterized by the presence of one or more Bcl‐2 homology domains and are comprised of both the prosurvival and proapoptotic proteins. Bcl‐2 itself is a prosurvival member of the family and its aberrant expression has been linked to a variety of different cancers, including several hematological malignancies. Although the exact mechanism of action of Bcl‐2 family of proteins in regulating apoptosis is still a matter of some debate, these proteins appear to act upstream of caspase activation. Many recent studies have shown the therapeutic potential of targeting Bcl‐2 family members for the treatment of cancer. This article summarizes what is currently known about Bcl‐2‐like proteins and how the evolving understanding of the biology of these proteins is paving way for the development of novel cancer therapeutics. Copyright © 2001 John Wiley & Sons, Ltd.
Private medical services in acute‐care hospitals in Israel
Authors: Shirom Arie
Published: August 2002

The objective of this study was to assess the proposed introduction of out‐of‐pocket funded inpatient and outpatient services (abbreviated as PMS) into government acute‐care hospitals in Israel. This issue of public–private mix in not‐for‐profit hospitals is discussed in terms of the experience with PMS gained in selected advanced market economies. Then, the major contours of the Israeli system of health care, and the gradual evolving of patient‐financed medical services within government acute‐care hospitals in Israel, is described. The experience gained in the few public hospitals in Jerusalem that have been operating PMS is assessed critically. The concluding part reviews the advantages and disadvantages of these developments in public and government acute‐care hospitals in Israel. It is concluded that PMS in public hospitals in Israel represents a policy aimed primarily at benefiting a select group of senior physicians in those hospitals. Copyright © 2001 John Wiley & Sons, Ltd.
Thermal design of a closed cabinet with a heat exchanger for inner air cooling
Authors: Kobayashi Takashi , Nakamura Mitsunori , Ogushi Tetsuro , Iwamaru Akifumi , Fujii Masao
Published: August 2002

This paper describes a thermal design and simulation method of a closed cabinet with a heat exchanger for inner air cooling. In the controller system that we used for this research, the cabinet is equipped to be outdoors, and the cabinet is sealed to prevent the introduction of dust. Because this system dissipated 630 W in total, it suffered from a problem that the inner air temperature of the cabinet was raised over 30 K. Thus, we installed a heat pipe and heat exchanger in the cabinet, and we also changed the air flow path to realize the best performance of heat exchange according to the results from thermal and fluid simulations using a macroscopic model of heat exchanger to reduce the computational load. We found that the inner air temperature rise was reduced below 15 K, and the measured results were in good agreement with the simulation. © 2001 Scripta Technica, Heat Trans Asian Res, 30(4): 267–279, 2001
Natural convection heat transfer in the open space between two horizontal circular planes with different temperatures
Authors: Tokanai Hideki , Kuriyama Masafumi , Harada Eiji , Konno Hirotaka
Published: August 2002

A vertical cylinder maintained at room temperature is located right above a horizontal circular heated plane to constitute a narrow air space between the plane and the cylinder bottom surface. Natural convection heat transfer in the space is experimentally investigated.

Average heat transfer coefficients of the heated plane are presented with the variation of space distance and Rayleigh number, and are compared with the predictions of the correlation equations which have been proposed for the space between two infinite parallel plates.

Visualized flow patterns above the heated plane are also shown. The relation between the flow pattern and the heat transfer coefficient is discussed to clarify the mechanism of heat transfer in the narrow space. As a result, a heat transfer correlation is proposed, which is applicable over a wide range of space distances. © 2001 Scripta Technica, Heat Trans Asian Res, 30(6): 521–531, 2001
The Pharmacokinetics of the THC in fat and brain: Resulting functional responses to marihuana smoking: G. Nahas, Volume 16 Issue 3, April 2001, pages 247–255.
Authors: Nahas G.
Published: August 2002

The original article to which this Erratum refers was published in Human Psychopharmacology: Clinical and Experimental 16 (3) 2001, 247–255.
Reproduction of temporal scaling by a rectangular pulses rainfall model
Authors: Olsson Jonas , Burlando Paolo
Published: August 2002

The presence of scaling statistical properties in temporal rainfall has been well established in many empirical investigations during the latest decade. These properties have more and more come to be regarded as a fundamental feature of the rainfall process. How to best use the scaling properties for applied modelling remains to be assessed, however, particularly in the case of continuous rainfall time‐series. One therefore is forced to use conventional time‐series modelling, e.g. based on point process theory, which does not explicitly take scaling into account. In light of this, there is a need to investigate the degree to which point‐process models are able to ‘unintentionally’ reproduce the empirical scaling properties. In the present study, four 25‐year series of 20‐min rainfall intensities observed in Arno River basin, Italy, were investigated. A Neyman–Scott rectangular pulses (NSRP) model was fitted to these series, so enabling the generation of synthetic time‐series suitable for investigation. A multifractal scaling behaviour was found to characterize the raw data within a range of time‐scales between approximately 20 min and 1 week. The main features of this behaviour were surprisingly well reproduced in the simulated data, although some differences were observed, particularly at small scales below the typical duration of a rain cell. This suggests the possibility of a combined use of the NSRP model and a scaling approach, in order to extend the NSRP range of applicability for simulation purposes. Copyright © 2002 John Wiley & Sons, Ltd.
TCL‐1, MTCP‐1 and TML‐1 gene expression profile in non‐leukemic clonal proliferations associated with ataxia‐telangiectasia
Authors: Chun Helen H. , Castellví‐Bel Sergi , Wang Zhijun , Nagourney Robert A. , Plaeger Susan , Becker‐Catania Sara G. , Naeim Faramarz , Sparkes Robert S. , Gatti Richard A.
Published: August 2002

We analyzed the role of 4 genes, TCL‐1, MTCP‐1, TML‐1 and ATM, in the early pathogenesis of T cell leukemia, with particular interest in the characteristics of long‐standing non‐leukemic clonal proliferations in ataxia‐telangiectasia (A‐T) patients. Five patients were studied: 4 patients had A‐T (2 of whom had non‐leukemic clonal proliferations [ATCP]), 1 had B cell lymphoma and 1 had T‐ALL; a fifth patient with T‐PLL did not have A‐T. We measured the levels of expression for TCL‐1, MTCP‐1 and TML‐1. TCL‐1, not expressed in unstimulated mature T cells, was upregulated in the peripheral blood leukocytes (PBL) of the 2 A‐T patients with ATCP. It was also expressed in the malignant cells of the A‐T patient with B cell lymphoma and the T‐PLL cells of the patient without A‐T. In the same cells, MTCP‐1 type A was expressed equally in all 5 patients, as well as in the controls; MTCP‐1 type B transcripts were not observed. TML‐1, also not expressed in unstimulated T cells, was expressed in the PBL of one A‐T patient with ATCP and in the leukemic cells of the non‐A‐T T‐PLL patient. These expression patterns were compared to cellular immunophenotypes. The non‐leukemic clonal T cell populations had the characteristics of immature T cells. We conclude that TCL‐1 and TML‐1 play a role in cell proliferation and survival but are not pivotal genes in the progression to malignancy, even when the ATM gene is mutated. Additional genetic alterations must occur to initiate tumorigenesis. © 2001 Wiley‐Liss, Inc.
N‐3 and N‐6 fatty acids in breast adipose tissue and relative risk of breast cancer in a case‐control study in Tours, France
Authors: Maillard Virginie , Bougnoux Philippe , Ferrari Pietro , Jourdan Marie‐Lise , Pinault Michelle , Lavillonnière Flore , Body Gilles , Le Floch Olivier , Chajès Véronique
Published: August 2002

Experimental studies have indicated that n‐3 fatty acids, including alpha‐linolenic acid (18:3 n‐3) and long‐chain n‐3 polyunsaturated fatty acids inhibit mammary tumor growth and metastasis. Earlier epidemiological studies have given inconclusive results about a potential protective effect of dietary n‐3 polyunsaturated fatty acids on breast cancer risk, possibly because of methodological issues inherent to nutritional epidemiology. To evaluate the hypothesis that n‐3 fatty acids protect against breast cancer, we examined the fatty acid composition in adipose tissue from 241 patients with invasive, nonmetastatic breast carcinoma and from 88 patients with benign breast disease, in a case‐control study in Tours, central France. Fatty acid composition in breast adipose tissue was used as a qualitative biomarker of past dietary intake of fatty acids. Biopsies of adipose tissue were obtained at the time of surgery. Individual fatty acids were measured as a percentage of total fatty acids, using capillary gas chromatography. Unconditional logistic regression modeling was used to obtain odds ratio estimates while adjusting for age, height, menopausal status and body mass index. We found inverse associations between breast cancer‐risk and n‐3 fatty acid levels in breast adipose tissue. Women in the highest tertile of alpha‐linolenic acid (18:3 n‐3) had an odds ratio of 0.39 (95% confidence intervals [CI] = 0.19–0.78) compared to women in the lowest tertile (trendp= 0.01). In a similar way, women in the highest tertile of docosahexaenoic acid (22:6 n‐3) had an odds ratio of 0.31 (95% CI = 0.13‐0.75) compared to women in the lowest tertile (trendp= 0.016). Women in the highest tertile of the long‐chain n‐3/total n‐6 ratio had an odds ratio of 0.33 (95% confidence interval = 0.17–0.66) compared to women in the lowest tertile (trendp= 0.0002). In conclusion, our data based on fatty acids levels in breast adipose tissue suggest a protective effect of n‐3 fatty acids on breast cancer risk and support the hypothesis that the balance between n‐3 and n‐6 fatty acids plays a role in breast cancer. © 2001 Wiley‐Liss, Inc.
Serologic response to human oncogenic papillomavirus types 16, 18, 31, 33, 39, 58 and 59 virus‐like particles in colombian women with invasive cervical cancer
Authors: Combita Alba‐Lucia , Bravo Maria‐Mercedes , Touzé Antoine , Orozco Oscar , Coursaget Pierre
Published: August 2002

The serologic response against virus‐like particles (VLP) from 7 high risk genital papillomaviruses was investigated by ELISA in 147 Colombian women with invasive cervical cancer and 147 age‐matched cytologically normal and HPV‐DNA negative women. Anti‐VLP antibodies were detected in 82% of the invasive cervical cancer patients and in 56% of the controls. Detection of antibodies against multiple HPV types is the rule and the presence of high antibody titers was associated with higher survival of cancer patients. Higher anti‐VLP seroprevalence was observed in younger cancer patients. In those followed serologically for 1 year, antibodies generally remained at the same level. However, in some patients an increase or decrease in antibody levels occurred simultaneously for multiple HPV types, suggesting cross‐reactivity between the HPV types investigated. Investigation of seroreactivity between 8 high risk HPVs suggested that there is some cross‐reactivity between phylogeneticaly‐related types such as 16, 31, 33 and 58; and 18, 45 and 59. In conclusion, our results confirmed (i) the high rate of HPV infections in Colombia, both in patients with cervical cancer and in the general population, and the particularly high rate of infections due to HPV 31 and 58; and (ii) the validity of anti‐VLPs as a marker of present or past HPV infection. The simultaneous appearance or disappearance of antibodies against multiple HPV VLPs suggests that the antibodies detected by ELISA are not always type specific. © 2001 Wiley‐Liss, Inc.
Neurotrophin receptor p75NTR suppresses growth and nerve growth factor‐mediated metastasis of human prostate cancer cells
Authors: Krygier Scott , Djakiew Daniel
Published: August 2002

The loss of tumor‐ and/or metastasis‐suppressor gene function contributes to the transformation of human prostate epithelial cells to a malignant pathology. Such a putative tumor‐suppressor and metastasis‐suppressor gene(s) has been mapped to the region of 17q21, which coincidentally is in the vicinity of the human gene locus for the neurotrophin receptor p75NTR. The p75NTR is expressed in normal human prostate epithelial cells and exhibits an inverse association of p75NTR expression with the malignant progression of the prostate, consistent with a pathologic role of the p75NTR as a putative tumor and metastasis suppressor. Utilizing stable transfectants of the TSU‐pr1 and PC‐3 human prostate tumor cell lines that exhibit a rank order (dose‐dependent) increase in p75NTR protein expression, we investigated the effects of the p75NTR in combination with its predominant ligand, nerve growth factor (NGF), on tumor cell growth. A rank order (dose‐dependent) increase in p75NTR expression was found to suppress the growth of prostate tumors in severe combined immunodeficient (SCID) mice. Treatment of these tumors with NGF stimulated both proliferation as indicated by PCNA expression and apoptosis as indicated by TUNEL assay, the net result of which was no change in the overall growth of the tumors. However, NGF was found to increase the formation of satellite tumors, both contiguous and noncontiguous with respect to the primary tumor mass, indicating dose‐dependent induction of metastasis. Significantly, the formation of satellite tumors was suppressed by the expression of p75NTR. This suggests that p75NTR is a tumor suppressor of growth and a metastasis suppressor of NGF‐stimulated migration of human prostate tumor cells. © 2001 Wiley‐Liss, Inc.
A breast cancer screening programme operating in a liberal health care system: The Luxembourg Mammography Programme, 1992–1997
Authors: Autier Philippe , Shannoun Ferid , Scharpantgen Astrid , Lux Christiane , Back Carlo , Severi Gianluca , Steil Simone , Hansen‐Koenig Danielle
Published: August 2002

The national breast cancer screening programme in Luxembourg, the Mammography Programme (MP), was launched in 1992. Its primary goal was to set up an organised breast cancer screening with biennial invitation‐reinvitation of women 50–64 years, 2‐view mammography, technical quality assurance, double‐reading procedures and close monitoring of performance. In 1994, the decision was taken by health authorities to only reimburse screening mammograms done within the MP. We evaluated the performance of 3 screening rounds that took place in 1992–1997. In 1992, 4,815 women had opportunistic screening and 4,790 attended the MP. In 1997, 861 women had opportunistic screening and 8,603 attended the MP. In 1997, the participation rate in the MP reached 50%. The referral rate in the MP was 10% for initial screening and 5% for subsequent screening. Echographic examinations accounted for 71% of referrals. Per 1,000 screened women, biopsy and cancer rates were 18.0 and 8.0 for initial screening and 10.3 and 5.8 for subsequent screening. Twenty‐one percent of the breast cancers diagnosed in screened women were interval cancers. The age‐adjusted proportion of tumours >20 mm was 56.1% before 1992, 45.1% for women not (yet) screened by the MP, 27.0% for interval cancers, 26.6% for initial screening and 12.0% for subsequent screenings. Tumour size distribution was similar to that observed in the Dutch Breast Cancer Screening Programme, 1990–1993, except that in the latter programme, no difference was observed between initial and subsequent screening. The Luxembourg experience shows that in a liberal health care system, a policy of organising the screening process by reimbursing only those mammograms done within the context of the organised screening programme can drastically reduce opportunistic screening. Further efforts in the Mammography Programme will aim at increasing participation and look at ways to decrease referrals to echography. © 2001 Wiley‐Liss, Inc.
Interphase FISH assays for the detection of translocations with breakpoints in immunoglobulin light chain loci
Authors: Martín‐Subero José I. , Harder Lana , Gesk Stefan , Schlegelberger Brigitte , Grote Werner , Martinez‐Climent José A. , Dyer Martin J.S. , Novo Francisco J. , Calasanz María J. , Siebert Reiner
Published: August 2002

Many B‐cell malignancies bear chromosomal translocations juxtaposing immunoglobulin (IG) genes with oncogenes, resulting in deregulated expression of the latter. Translocations affecting the IG heavy chain (IGH) locus in chromosomal region 14q32 are most prevalent. However, variant translocations involving the IG kappa (IGK) locus in 2p12 or the IG lambda (IGL) locus in 22q11 occur recurrently in B‐cell neoplasias. No routine methods for the detection of all breakpoints involving IG light chain loci independently of the translocation partner have been described. For this reason, we have designed 2 novel interphase fluorescence in situ hybridization (FISH) assays using differentially labeled probes flanking the IGK and IGL locus, respectively. Based on extensive control studies, the diagnostic thresholds for the detection of breakpoints were set at 0.3% for IGK and 1.4% for IGL. Fifteen cases of B‐cell malignancies with cytogenetically detectable chromosomal abnormalities in 2p11‐14 were investigated with the FISH assay for IGK. Breakpoints affecting the IGK locus were detected in 7 cases including all 4 variant Burkitt's translocations t(2;8)(p12;q24) and a variant BCL2‐associated translocation t(2;18)(p12;q21). Other translocation partners were chromosome bands 7q21 and 16q24. Ten cases with abnormalities in 22q11‐12 were investigated with the FISH assay for IGL. Breakpoints in the IGL locus were diagnosed in 7 cases including both variant Burkitt's translocations t(8;22)(q24;q11) and a t(3;22)(q27;q11) involving the BCL6 locus. Other translocation partners were 2p13‐14, 4q13 and 16p12. Our results show that these FISH assays provide flexible, simple and reliable tools in the diagnosis and characterization of genetic changes in B‐cell malignancies. © 2002 Wiley‐Liss, Inc.
Incidence and mortality of testicular and prostatic cancers in relation to world dietary practices
Authors: Ganmaa Davaasambuu , Li Xiang‐Ming , Wang Jing , Qin Li‐Qiang , Wang Pei‐Yu , Sato Akio
Published: August 2002

The incidence and mortality rates of testicular and prostatic cancers in 42 countries were correlated with the dietary practices in these countries using the cancer rates (1988–92) provided by the International Agency for Research on Cancer (IARC) and the food supply data (1961–90) provided by the Food and Agriculture Organization (FAO). Among the food items we examined, cheese was most closely correlated with the incidence of testicular cancer at ages 20–39, followed by animal fats and milk. The correlation coefficient (r) was highest (r = 0.804) when calculated for cheese consumed during the period 1961–65 (maternal or prepubertal consumption). Stepwise‐multiple‐regression analysis revealed that milk + cheese (1961–65) made a significant contribution to the incidence of testicular cancer (standardized regression coefficient [R] = 0.654). Concerning prostatic cancer, milk (1961–90) was most closely correlated (r = 0.711) with its incidence, followed by meat and coffee. Stepwise‐multiple‐regression analysis identified milk + cheese as a factor contributing to the incidence of prostatic cancer (R = 0.525). The food that was most closely correlated with the mortality rate of prostatic cancer was milk (r = 0.766), followed by coffee, cheese and animal fats. Stepwise‐multiple‐regression analysis revealed that milk + cheese was a factor contributing to mortality from prostatic cancer (R = 0.580). The results of our study suggest a role of milk and dairy products in the development and growth of testicular and prostatic cancers. The close correlation between cheese and testicular cancer and between milk and prostatic cancer suggests that further mechanistic studies should be undertaken concerning the development of male genital organ cancers. © 2001 Wiley‐Liss, Inc.
Anti‐viral cytotoxic T cells inhibit the growth of cancer cells with antibody targeted hla class I/peptide complexes in scid mice
Authors: Savage Philip , Cowburn Pam , Clayton Aled , Man Stephen , Lawson Tom , Ogg Graham , Lemoine Nick , McMichael Andrew , Epenetos Agamemnon
Published: August 2002

A number of experimental antibody mediated cancer therapies aim to redirect cytotoxic T cells (CTLs) of non‐tumour specificity to cancer cells. It has been previously demonstrated that cancer cells targeted with recombinant HLA‐class I/viral peptide complexes via antibody delivery systems can be killed by virus specific CTLs. This novel therapeutic system has been developed with a simple pre‐clinical model using the recombinant anti‐CD20 B9E9 scFvSA fusion protein to target HLA–A2/peptide complexes to CD20 +ve Daudi lymphoma cells. In vitro data confirmed that, although binding of the B9E9 scFvSA fusion protein alone to Daudi cells had no effect on their growth, effective CTL mediated killing of Daudi cells could be achieved by targeting with B9E9 sfvScSA and recombinant HLA‐A2/MI complexes at dilutions as low as 100 pg/ml. In contrast the free HLA‐A2/MI complexes only significantly inhibited CTL activity at concentrations in excess of 100 ng/ml. The in vivo tumour protection assays in SCID mice demonstrated that only 1 of the 4 mice that received anti‐HLA‐A2/M1 CTLs and Daudi cells targeted with the B9E9 scFvSA fusion protein and HLA‐A2/M1 complexes developed a tumour. In contrast in the control mice that received CTL and native Daudi cells all 4 developed tumours, as did all 4 that received targeted Daudi cells but no CTLs. Similar results were obtained in a parallel experiment using Daudi cells targeted with B9E9 scFvSA and HLA‐A2/BMLF1 complexes and a CTL line to HLA‐A2/BMLF1. The demonstration of in vivo activity for targeted HLA class I/peptide complexes combined with anti‐viral T cells, supports the further clinical development of the system where it may be combined with autologous CTLs produced by vaccination or ex vivo expansion. © 2002 Wiley‐Liss, Inc.
Urokinase receptor‐associated protein (UPARAP) is expressed in connection with malignant as well as benign lesions of the human breast and occurs in specific populations of stromal cells
Authors: Nielsen Boye Schnack , Rank Fritz , Engelholm Lars H. , Holm Arne , Danø Keld , Behrendt Niels
Published: August 2002

The urokinase‐type plasminogen activator (uPA) and the uPA receptor (uPAR) are key components in the plasminogen activation system, serving to promote specific events of extracellular matrix degradation in connection with tissue remodeling and cancer invasion. We recently described a new uPAR‐associated protein (uPARAP), an internalization receptor that interacts with the pro‐uPA:uPAR complex. In our study, we generated a specific polyclonal peptide antibody against human uPARAP and used it for the localization of uPARAP in different breast lesions. The affinity‐purified antibodies specifically recognized uPARAP in Western blotting and gave a strong signal in immunohistochemistry. The immunohistochemic localization pattern was found to be identical to that of uPARAP mRNA as determined in parallel by in situ hybridization. uPARAP expression was then studied in both benign and malignant breast lesions. Whereas the normal breast tissue was uPARAP‐negative, all benign lesions and ductal carcinoma in situ lesions showed immunoreactivity in fibroblast‐like cells and myoepithelial cells associated with the lesion. In invasive carcinoma, uPARAP immunoreactivity was limited to tumor‐associated mesenchymal cells. Double immunofluorescence analysis of invasive ductal carcinoma using antibodies against specific cell markers showed that uPARAP was localized in myofibroblasts and macrophages. No malignant cells, no endothelial cells and no vascular smooth muscle cells showed uPARAP immunoreactivity. We conclude that expression of uPARAP is associated with the abnormal breast and that expression appears in myofibroblasts, macrophages and myoepithelium. We suggest that uPARAP is involved in the clearance of the uPA:uPAR complex as well as other possible ligands during benign and malignant tissue remodeling. © 2002 Wiley‐Liss, Inc.
Testing mouse mammary tumor virus superantigen as adjuvant in cytotoxic T‐lymphocyte responses against a melanoma tumor antigen
Authors: Wirth Susanne , Bille Frédéric , Koenig Sylvain , Wehrli Nathalie , Miconnet Isabelle , Lévy Frédéric , Diggelmann Heidi , Romero Pedro , Acha‐Orbea Hans
Published: August 2002

Cytotoxic T cells represent a powerful strategy for antitumor treatment. Depending on the route of injection, an important role for CD4 T cell–mediated help was observed in the induction of this response. For this reason, we investigated whether induction of a CTL response to the HLA‐A2–restricted immunodominant peptide melanoma antigen Melan‐A was improved by using rVVs expressing the CTL‐defined epitope alone or in combination with an SAg. In the latter case, the few infected dendritic cells simultaneously presented an SAg and an antigen, i.e., peptide. Here, we show that the anti‐Melan‐A response was efficiently induced but not significantly improved by coexpression of the SAg. © 2002 Wiley‐Liss, Inc.
Antibody‐guided enzyme therapy of cancer producing cyanide results in necrosis of targeted cells
Authors: Kousparou Christina A. , Epenetos Agamemnon A. , Deonarain Mahendra P.
Published: August 2002

A number of enzyme/prodrug activation approaches for the treatment of cancer have been reported to date with varying success. We describe progress in the development of a system based on a β‐glucosidase enzyme in combination with a naturally occurring “prodrug,” the sugar linamarin, which releases the cytotoxin cyanide. A recombinant fusion protein, composed of an scFv (MFE‐23) reactive against carcinoembryonic antigen (CEA) and a plant‐derived β‐glucosidase (linamarase), was produced and its cytotoxic potential was investigated. The fusion protein was expressed in a supersecretory mutant strain of Saccharomyces cerevisiae and purified by affinity chromatography. Extensive functional in vitro characterisation of the fusion protein showed that it retained antigen binding activity but that its catalytic activity was impaired, a problem not related to its fusion with the scFv. Nevertheless, we demonstrated complete tumour cell killing at doses of prodrug that are completely nontoxic to nontargeted cells. Preliminary in vivo characterisation showed that extensive glycosylation of the fusion protein caused its rapid clearance through the hepatic route. Aggregational properties also led to poor pharmacokinetics. Furthermore, we present some data analysing the mode of cell death resulting from exposure to this system. Enzymic catalysis of the substrate generates cyanide, a metabolic poison that asphyxiates cells and leads them to a necrotic‐like cell death. This system has been called antibody‐guided enzyme nitrile therapy (AGENT). © 2002 Wiley‐Liss, Inc.
Grand multiparity and incidence of endometrial cancer: A population‐based study in Finland
Authors: Hinkula Marianne , Pukkala Eero , Kyyrönen Pentti , Kauppila Antti
Published: August 2002

The hormonal background of endometrial cancer is insufficiently characterised. We investigated the significance of parity, age at first birth, intensity between births, length of time from the first to the last birth and length of delivery‐free premenopausal period in a cohort of grand multiparous (GM) women, i.e., women with at least 5 births. Data of the Population Register of Finland (86,978 GM‐women) and the population‐based Finnish Cancer Registry were combined. Standardised incidence ratios (SIRs) were calculated by dividing the number of observed cancer cases by the expected number based on the national incidence rates. Multivariate relative risks (RRs) were estimated by Poisson regression analysis. The SIR for endometrial cancer among GM‐women was low [419 cases; SIR=0.57, 95% confidence interval (CI) 0.52–0.63]. The RR of endometrial cancer was 0.58 (95% CI 0.34–0.97) among women giving their first birth at an age of more than 30 years compared to women with first birth before the age of 20. In ages 50+ (94% of endometrial cancer cases), the RR for women with at least 8 births was 0.63 (95% CI 0.44–0.92) compared to those with 5 births, and those with a birth period of 20+ years had RR=0.57 (95% CI 0.34–0.96) compared to those with a period of <10 years, while prolonged average intensity between births showed only a small protective effect. The RR of endometrial cancer also correlated with the length of premenopausal delivery‐free period (RR = 0.61, 95% CI 0.44–0.86) for women with a short (<10 years) period compared to women with a long (>15 years) period. Our findings, that a large number of births, old age at first birth, a long birth period and a short premenopausal delivery‐free period reduced the risk of postmenopausal endometrial cancer of GM‐women, emphasise the protective role of progesterone and the stimulatory role of estradiol in the hormonal background of this disease. © 2002 Wiley‐Liss, Inc.
Kinetics of the early recruitment of leukocyte subsets at the sites of tumor cells in the lungs: Natural killer (NK) cells rapidly attract monocytes but not lymphocytes in the surveillance of micrometastasis
Authors: Shingu Kiyoshi , Helfritz Andreas , Kuhlmann Susanne , Zielinska‐Skowronek Margot , Jacobs Roland , Schmidt Reinhold E. , Pabst Reinhard , von Hörsten Stephan
Published: August 2002

Early host defense mechanisms play a critical role for the outcome of metastatic disease but most of the initial steps of such responses against tumor cells are still unknown. Here, the specificity and kinetics of leukocyte subsets in response to intravenous inoculation of vital dye labeled Fischer 344 rat syngeneic MADB106 tumor cells were monitored in lungs in situ by immunohistochemistry and image analysis over a time‐period of 6 hr. In comparison with sham injections, tumor cell inoculation induces a dynamic sequence of rapidly increasing granulocyte (+40% at 5 min), NK and T cell (+60% at 15 min) as well as monocyte (+100% at 30 min) numbers in lung tissue. Already within the first minutes frequent colocalizations of granulocytes and NK cells with tumor targets were found in situ. Within the first hour NK cells selectively kill tumor targets, because depletion of NK cells in vivo drastically increases both the number of MADB106 cells retained in lungs and the emerging numbers of lung tumor colonies. In addition, the tumor‐cell‐induced increase of monocytes strictly depends on the presence of NK cells because NK‐depletion completely abrogates the time specific response of monocytes. Under NK depleted conditions the tumor‐induced recruitment of CD4+ T cells is more pronounced suggesting a compensatory mechanism. In contrast, B cell numbers progressively decrease within hours after cell inoculation. These findings demonstrate that NK and T cells mediate the initial steps in the surveillance of lung metastasis. NK cells rapidly kill tumor cells and subsequently recruit monocytes in vivo. © 2002 Wiley‐Liss, Inc.
Telomerase activity and hTERT mRNA expression can be heterogeneous and does not correlate with telomere length in soft tissue sarcomas
Authors: Yan Pu , Benhattar Jean , Coindre Jean‐Michel , Guillou Louis
Published: August 2002

In a previous study, we showed that telomerase activity (TA) and human telomerase reverse transcriptase (hTERT) mRNA expression were undetectable in benign mesenchymal lesions and low‐grade soft tissue sarcomas (STSs), but detectable in about 50% of intermediate‐/high‐grade STSs. We wondered if this lack of TA or hTERT mRNA expression could be related to the tumor sample examined and if there was a relationship between the former 2 parameters and telomere length. Two separate tumor samples from 37 STSs were examined for telomerase activity, using the telomerase repeat amplification protocol (TRAP) assay and for hTERT mRNA expression, using RT‐PCR. Telomere length was determined in each tumor sample, using the terminal restriction fragments (TRF) technique. Significant variations in telomere length, TA and hTERT mRNA expression between 2 samples of the same tumor were observed in 27%, 11% and 27% of STSs, respectively. Telomere length did not correlate with TA or hTERT mRNA expression. Despite great intratumoral heterogeneity in telomere length, short and long telomeres were more often seen in the low/intermediate‐grade and high‐grade STS categories, respectively. Few STSs that showed a TRF pattern suggestive of alternative lengthening of telomeres (ALT) may contain ALT subpopulations. © 2002 Wiley‐Liss, Inc.
Cheng W, Chan KH, Chen H, Luo R, Ng SP, Luk W, Zheng B, Ji M, Liang M, Sham JST, Wang DK, Y Zong Y, Ng MH. Assessing the risk of nasopharyngeal carcinoma on the basis of EBV antibody spectrum. International Journal of Cancer 2002;97(4): 489–492.
Authors: Cheng W , Chan KH , Chen H , Luo R , Ng SP , Luk W , Zheng B , Ji M , Liang M , Sham JST , Wang DK , Zong Y , Ng MH
Published: August 2002

The original article to which this Erratum refers was published in International Journal of Cancer; 2002; 97(4) 489–492.
Cell type‐ and promoter‐dependent modulation of the Wnt signaling pathway by sodium butyrate
Authors: Bordonaro Michael , Lazarova Darina L. , Augenlicht Leonard H. , Sartorelli Alan C.
Published: August 2002

The Wnt signaling pathway modulates the transcription of genes linked to proliferation, differentiation and tumor progression. β‐Catenin‐Tcf (BCT)‐dependent Wnt signaling is influenced by the short‐chain fatty acid sodium butyrate, which induces growth arrest and/or maturation of colonic carcinoma cells. We have compared the effects of sodium butyrate on BCT‐dependent signaling in 2 colon carcinoma cell lines that differ in their physiologic response to butyrate, with SW620 cells responding to butyrate by undergoing terminal differentiation and apoptosis, and HCT‐116 cells undergoing reversible growth arrest, but no significant apoptotic cell death. Furthermore, these colon carcinoma cell lines differ in their mechanism of Wnt pathway activation, with adenomatous polyposis coli (APC) mutant SW620 cells having high levels of BCT complexes and APC wild‐type HCT‐116 cells having mutant β‐catenin, low levels of BCT complexes and correspondingly higher levels of free Tcf. We have demonstrated that in SW620 cells, butyrate downregulates BCT‐dependent expression of the Tcf‐TK, matrilysin and cyclin D1 promoters, whereas in HCT‐116 cells, butyrate upregulates expression of these promoters. Cotransfection with expression vectors that interfere with the Wnt pathway suggests that butyrate enhances BCT complex‐DNA binding. Butyrate reduces the expression of Tcf4 in HCT‐116 cells, consistent with the induction by butyrate of Tcf‐repressible promoters in these cells. These findings indicate that sodium butyrate modulates the Wnt pathway in SW620 and HCT‐116 cells in a different manner and that these differences have consequences for promoter activity that may influence the physiologic response to butyrate. © 2002 Wiley‐Liss, Inc.
Pegylated liposomal tumor necrosis factor‐α results in reduced toxicity and synergistic antitumor activity after systemic administration in combination with liposomal doxorubicin (Doxil®) in soft tissue sarcoma‐bearing rats
Authors: ten Hagen Timo L.M. , Seynhaeve Ann L.B. , van Tiel Sandra T. , Ruiter Dirk J. , Eggermont Alexander M.M.
Published: August 2002

Previously we reported that encapsulation of tumor necrosis factor‐α (TNF) in pegylated (STEALTH®) liposomes (TNF‐PEGL) dramatically improved circulation times of the protein and augmented accumulation in tumor tissue. We and others have demonstrated enhanced antitumor activity of doxorubicin or melphalan by free TNF when used in high doses in an isolated limb perfusion setting. In the present study the antitumor activity of TNF‐PEGL was studied in combination with liposomal chemotherapy. BN rats with subcutaneous BN175 sarcomas (8–12 mm diameter) received no treatment or pegylated liposomal doxorubicin (Doxil®) alone or in combination with various doses of TNF‐PEGL (15–200 μg/kg). The evaluated endpoints were tumor response and toxicity of the treatment regimens. Here we demonstrate that TNF‐PEGL at a dose of 15 μg/kg markedly augments the antitumor activity of liposomal doxorubicin, without resulting in the increased toxic side effects observed with free TNF at doses resulting in a similar enhancement of the antitumor effects. Even at a TNF dose of 200 μg/kg TNF, repeated administration of TNF‐PEGL did not result in severe weight loss or cause diarrhea. Repeated dosing of free TNF at this dose resulted in severe, life‐threatening weight loss and occurrence of diarrhea in all animals. These results indicate that pegylated liposomal encapsulation may be effective in systemic application of TNF for combined treatment with liposomal chemotherapy of advanced solid tumors. © 2002 Wiley‐Liss, Inc.
Event study concerning international bond price effects of credit rating actions
Authors: Steiner Manfred , Heinke Volker G.
Published: August 2002

The influence of credit ratings on eurobond prices has been neglected for a long time. It is questionable whether non‐US investors relate their investment decisions on US ratings and whether ratings from US agencies are relevant information sources for international capital markets. This paper examines daily excess eurobond returns associated with announcements of watchlistings and rating changes by Standard & Poor's and Moody's. Significant bond price reactions are observed for announcements of downgradings and negative watchlistings while upgradings and positive watchlistings do not cause announcement effects. Distinct from the results on national capital markets the international evidence shows that besides actual yield level and issuer type the issuer nationality is a key factor that determines the intensity of price reactions after downgrades. The price reaction is also significantly stronger for downgrades into speculative grade. This indicates, that the announcement effects can in part be explained by price pressure effects due to regulatory constraints rather than original information content of rating changes. Copyright © 2001 John Wiley & Sons, Ltd.
Developing countries' borrowing in the international financial market with an uncertain credit ceiling?
Authors: Isgut Alberto E.
Published: August 2002

In the sovereign debt literature of the 1980s, countries formulated optimal borrowing plans subject to a credit ceiling imposed by their lenders. This paper analyzes the case where the credit ceiling is not known with certainty. The baseline deterministic model shows that consumption, investment and the current account deficit depend positively on the credit ceiling, implying more optimistic expectations about the country's future access to external financing led to larger current account deficits today. An extension of the model shows that when the country recognizes the uncertainty about future access to borrowing, optimal current account deficits are more moderate. Copyright © 2001 John Wiley & Sons, Ltd.