bluuebunny/crossref_metadata_2025 huggingface dataset:
A Note on One‐Sided Tests with Multiple Endpoints
Authors: Perlman Michael D. , Wu Lang
Published: March 2004

Summary.  Testing problems with multivariate one‐sided alternative hypotheses are common in clinical trials with multiple endpoints. In the case of comparing two treatments, treatment 1 is often preferred if it is superior for at least one of the endpoints and not biologically inferior for the remaining endpoints. Bloch et al. (2001, Biometrics57, 1039–1047) propose an intersection–union test (IUT) for this testing problem, but their test does not utilize the appropriate multivariate one‐sided test. In this note we modify their test by an alternative IUT that does utilize the appropriate one‐sided test. Empirical and graphical evidence show that the proposed test is more appropriate for this testing problem.
Optimal Estimator for the Survival Distribution and Related Quantities for Treatment Policies in Two‐Stage Randomization Designs in Clinical Trials
Authors: Wahed Abdus S. , Tsiatis Anastasios A.
Published: March 2004

Summary.  Two‐stage designs, where patients are initially randomized to an induction therapy and then depending upon their response and consent, are randomized to a maintenance therapy, are common in cancer and other clinical trials. The goal is to compare different combinations of primary and maintenance therapies to find the combination that is most beneficial. In practice, the analysis is usually conducted in two separate stages which does not directly address the major objective of finding the best combination. Recently Lunceford, Davidian, and Tsiatis (2002, Biometrics58, 48–57) introduced ad hoc estimators for the survival distribution and mean restricted survival time under different treatment policies. These estimators are consistent but not efficient, and do not include information from auxiliary covariates. In this article we derive estimators that are easy to compute and are more efficient than previous estimators. We also show how to improve efficiency further by taking into account additional information from auxiliary variables. Large sample properties of these estimators are derived and comparisons with other estimators are made using simulation. We apply our estimators to a leukemia clinical trial data set that motivated this study.
A Bound for Publication Bias Based on the Fraction of Unpublished Studies
Authors: Copas John , Jackson Dan
Published: March 2004

Summary.  Publication bias in meta‐analysis is usually modeled in terms of an accept/reject selection procedure in which the selected studies are the “published” studies and the rejected studies are the “unpublished” studies. One possible selection mechanism is to suppose that only studies that report an estimated treatment effect exceeding (or falling short of) some threshold are accepted. We show that, with appropriate choice of thresholds, this attains the maximum bias among all selection mechanisms in which the probability of selection increases with study size. It is impossible to estimate the selection mechanism from the observed studies alone: this result leads to a “worst‐case” sensitivity analysis for publication bias, which is remarkably easy to implement in practice. The method is illustrated using data on the effectiveness of prophylactic corticosteroids.
Estimation of Fish Abundance Indices Based on Scientific Research Trawl Surveys
Authors: Chen Jiahua , Thompson Mary E. , Wu Changbao
Published: March 2004

Summary.  The fish abundance index over an ocean region is defined here to be the integral of expected catch per unit effort (CPUE), approximated by the sum of expected CPUE over grid squares. When trawl surveys are done within grid squares selected according to a probability sampling design, several other sources of variation such as the fish population dynamics and the catching process are also involved. In such situations model‐assisted methods for estimating abundance, assessed under both design and model perspectives, have some advantages over purely design‐based methods such as the Horvitz–Thompson (HT) estimator or purely model‐based prediction approaches. This article develops model‐assisted empirical likelihood (EL) methods via loglinear regression and nonparametric smoothing. The methods are applied to grid surveys of the Grand Bank region carried out annually by Fishery Products International from 1996 through 2002. The HT and EL methods produce similar point estimates of abundance indices. Simulation results, however, indicate that the EL estimator under local linear smoothing is associated with smaller standard errors.
Multivariate Multilevel Nonlinear Mixed Effects Models for Timber Yield Predictions
Authors: Hall Daniel B. , Clutter Michael
Published: March 2004

Summary. Nonlinear mixed effects models have become important tools for growth and yield modeling in forestry. To date, applications have concentrated on modeling single growth variables such as tree height or bole volume. Here, we propose multivariate multilevel nonlinear mixed effects models for describing several plot‐level timber quantity characteristics simultaneously. We describe how such models can be used to produce future predictions of timber volume (yield). The class of models and methods of estimation and prediction are developed and then illustrated on data from a University of Georgia study of the effects of various site preparation methods on the growth of slash pine (Pinus elliottiiEngelm.).
A New Method for Dealing with Measurement Error in Explanatory Variables of Regression Models
Authors: Freedman Laurence S. , Fainberg Vitaly , Kipnis Victor , Midthune Douglas , Carroll Raymond J.
Published: March 2004

Summary.  We introduce a new method, moment reconstruction, of correcting for measurement error in covariates in regression models. The central idea is similar to regression calibration in that the values of the covariates that are measured with error are replaced by “adjusted” values. In regression calibration the adjusted value is the expectation of the true value conditional on the measured value. In moment reconstruction the adjusted value is the variance‐preserving empirical Bayes estimate of the true value conditional on the outcome variable. The adjusted values thereby have the same first two moments and the same covariance with the outcome variable as the unobserved “true” covariate values. We show that moment reconstruction is equivalent to regression calibration in the case of linear regression, but leads to different results for logistic regression. For case–control studies with logistic regression and covariates that are normally distributed within cases and controls, we show that the resulting estimates of the regression coefficients are consistent. In simulations we demonstrate that for logistic regression, moment reconstruction carries less bias than regression calibration, and for case–control studies is superior in mean‐square error to the standard regression calibration approach. Finally, we give an example of the use of moment reconstruction in linear discriminant analysis and a nonstandard problem where we wish to adjust a classification tree for measurement error in the explanatory variables.
Generalized Linear Mixed Models with Varying Coefficients for Longitudinal Data
Authors: Zhang Daowen
Published: March 2004

Summary.  The routinely assumed parametric functional form in the linear predictor of a generalized linear mixed model for longitudinal data may be too restrictive to represent true underlying covariate effects. We relax this assumption by representing these covariate effects by smooth but otherwise arbitrary functions of time, with random effects used to model the correlation induced by among‐subject and within‐subject variation. Due to the usually intractable integration involved in evaluating the quasi‐likelihood function, the double penalized quasi‐likelihood (DPQL) approach of Lin and Zhang (1999, Journal of the Royal Statistical Society, Series B61, 381–400) is used to estimate the varying coefficients and the variance components simultaneously by representing a nonparametric function by a linear combination of fixed effects and random effects. A scaled chi‐squared test based on the mixed model representation of the proposed model is developed to test whether an underlying varying coefficient is a polynomial of certain degree. We evaluate the performance of the procedures through simulation studies and illustrate their application with Indonesian children infectious disease data.
Conditional Estimation for Generalized Linear Models When Covariates Are Subject‐Specific Parameters in a Mixed Model for Longitudinal Measurements
Authors: Li Erning , Zhang Daowen , Davidian Marie
Published: March 2004

Summary.  The relationship between a primary endpoint and features of longitudinal profiles of a continuous response is often of interest, and a relevant framework is that of a generalized linear model with covariates that are subject‐specific random effects in a linear mixed model for the longitudinal measurements. Naive implementation by imputing subject‐specific effects from individual regression fits yields biased inference, and several methods for reducing this bias have been proposed. These require a parametric (normality) assumption on the random effects, which may be unrealistic. Adapting a strategy of Stefanski and Carroll (1987, Biometrika74, 703–716), we propose estimators for the generalized linear model parameters that require no assumptions on the random effects and yield consistent inference regardless of the true distribution. The methods are illustrated via simulation and by application to a study of bone mineral density in women transitioning to menopause.
Reaching American Families: Making Diversity Real in Family Life Education*
Authors: Wiley Angela R. , Ebata Aaron
Published: March 2004

The American population is constantly evolving, as are its needs for family life education. We discuss how family life educators can address issues of diversity in developing and conducting programs for families. Domains for change are suggested in which educators can incorporate cultural competence in their daily work. Four general strategies are presented for extending programming to more audiences. Interwoven throughout are specific examples and recommendations for use by family life educators. We end with a diversity agenda for the future.
Improving the Lives of Children in Foster Care: The Impact of Supervised Visitation*
Authors: McWey Lenore M. , Mullis Ann K.
Published: March 2004

Our purpose was to test a model explaining the quality of attachment of 123 children in foster care receiving supervised visitation with their biological parents. The results indicated that for families in which reunification is a goal, children who have more consistent and frequent contact with their biological parents have stronger attachments than children who have less contact. In addition, relationships between attachment and indicators of adjustment were examined. Children with higher levels of attachment had fewer behavioral problems, were less likely to take psychiatric medication, and were less likely to be termed “developmentally delayed” than were children with negative levels of attachment. Implications of these findings for case workers and other family service providers are discussed.
Interpreting Outcomes: Using Focus Groups in Evaluation Research*
Authors: Ansay Sylvia J. , Perkins Daniel F. , Nelson Colonel John
Published: March 2004

Although focus groups continue to gain popularity in marketing and social science research, their use in program evaluation has been limited. Here we demonstrate how focus groups can benefit evaluators, program staff, policy makers and administrators by providing an in‐depth understanding of program effectiveness from the perspective of participants as stakeholders in program outcomes. Using data from the Youth Action Program, a prevention program funded by the United States Air Force for military dependent adolescents at risk, our methodology included a narrative approach to data analysis, combining theme analysis with a systematic interpretive approach centering on how group members experienced the program within the contexts of their daily lives. We show that the parents benefited from the program beyond youth outcomes, and this was useful information for program improvement and expansion.
Fiscal Federalism in Australia
Authors: McLean Iain
Published: March 2004

Australia displays high vertical fiscal imbalance (VFI) for historical and constitutional reasons. It also attempts to achieve the highest degree of horizontal fiscal equalization (HFE) to be found in any democratic federation. The Commonwealth Grants Commission (CGC), a non‐partisan body at arm's length from politicians, oversees the regime. A recent report claims that equity, efficiency and transparency would all improve if the regime were abolished. Such a change is politically unachievable, but it raises interesting issues in public finance and public administration, which carry over to other federations and union states.

An economically efficient system would: minimize perverse incentives, especially incentives to seek rent; encourage states to grow; discourage suboptimal location decisions; minimize transaction costs. An equitable system would maximize equity between relevantly similar individuals. Aspects of the Australian system that should be copied include the non‐partisan agency and the target of HFE between component parts of the country. Aspects that should be discussed and perhaps copied include the very extensive equalization, including the feature of equalizing away the effects of grants for special purposes. Aspects that should probably not be copied include the cumbersome formulae and some of the perverse methods of calculating for ‘needs’. All abbreviations and acronyms are spelt out in the Appendix on page 37.
The Effects of ‘High Commitment’ HRM Practices on Employee Attitude: The Views of Public Sector Workers
Authors: Gould‐Williams Julian
Published: March 2004

Although there is a growing body of evidence demonstrating positive effects of ‘high commitment’ HRM practices on organizational performance, there is less evidence evaluating their effects on individual workers, especially within the public sector. Therefore the implications of applying ‘high commitment’ practices in the public sector needs to be considered. This paper seeks to address this gap by reporting the results of a staff survey and follow‐up interviews conducted on a cross‐section of  local government employees. The results showed that eight of the ten ‘high commitment’ practices had significant effects on worker attitudes. The results are discussed in light of HRM theory together with the implications for public sector managers.
New Labour's modernization in the public sector: a neo‐Durkheimian approach and the case of mental health services
Authors: 6 Perri , Peck Edward
Published: March 2004

Five accounts of New Labour's style of public management reform can be identified in the recent academic literature. Although each has merits, none is wholly convincing. After a discussion of their scope and limits, this article offers a distinctive account, grounded in wider social theory, which also synthesizes the most valuable elements in the five mainstream accounts. The article then uses the case of New Labour's reforms of the mental health system to support this account, showing how it exemplifies each of the 15 major strands of reform activity that have together been the hallmark of what in practice New Labour has meant by ‘modernization’. This provides the basis for a critique of the limits and dangers of the New Labour style.
Collaborating for Mental Health Services in Wales: A Process Evaluation
Authors: Jones Norah , Thomas Paul , Rudd Les
Published: March 2004

The need for inter‐agency collaboration between managers of mental health services has long been recognized, as has the difficulty of achieving and maintaining such relationships. Hudson et al. (1999) have developed a model for collaboration in the public sector and the current research has tested the model against attempts to achieve and maintain inter‐agency collaboration between mental health managers in Wales. We find Hudson's model a useful analytical framework but our evidence suggests that it needs to be amended by giving greater emphasis to the importance of ‘uninterrupted . . . opportunities for interaction’ between key managers. Forthcoming changes to NHS structures in Wales (for example, the abolition of Health Authorities and the conversion of Local Health Groups into Local Health Boards) will not necessarily facilitate collaboration if the Local Health Boards are given the role of planning and commissioning mental health services without having the necessary ‘critical mass’ of knowledge, expertise and dedicated staff capacity for planning and commissioning mental health services.
The Future of Public Administration in Denmark: Projections, Prospects and High Hopes
Authors: Jensen Lotte , Nørgaard Asbjørn Sonne , Sørensen Eva
Published: March 2004

Public Administration research in Denmark has a relatively short history. It was first initiated in the 1970s and was developed from public law. However, from an initial homogeneity it has become increasingly pluralistic in its approach due to three factors: a strong orientation towards the study of institutional reform in the public sector, inspiration from the international literature and the specific institutional set up of the academic community that divides it into separate schools. It is possible to distinguish three trends in today's Danish Public Administration research. These trends are inspired by historical institutionalism, rational choice institutionalism and sociological institutionalism, respectively. What is needed in the future is an increased dialogue between these trends. The purpose of the dialogue should not be to reach for a new homogeneity but to increase the critical debate among different schools in order to increase the general quality of public administration research in Denmark.
Governing by Looking Back: Historical Analogies and Crisis Management
Authors: Brändström Annika , Bynander Fredrik , Hart Paul ’t
Published: March 2004

This article offers a conceptual framework that broadens and enhances our understanding of the role of ‘history’ in contemporary governance and the attempts by policy‐makers to ‘manage’ critical issues. Building upon the literature on historical analogies in policy‐making, we distinguish three dimensions that clarify how the past may emerge in and affect the current deliberations, choices and rhetoric of policy‐makers. We apply this in a comparative examination of two cases of crisis management where historical analogies played an important part: the Swedish response to (alleged) submarine intrusions in 1982, and the European Union sanctions against Austria in 1999. We induce from the case comparison new concepts and hypotheses for understanding the role of historical analogies in public policy‐making and crisis management.
Grubs and Grasshoppers: Challenge‐Based Recreation and the Collective Efficacy of Families with At‐Risk Youth*
Authors: Sara Wells Mary , Widmer Mark A. , Kelly McCoy J.
Published: March 2004

This study examined the influence of challenge‐based recreation on the collective efficacy of families with at‐risk adolescents. Thirty‐four families participated in one of three experimental groups and a control group. Collective family recreation efficacy and conflict resolution efficacy increased for families in all three recreation contexts. These findings support the theory that collective efficacy in one domain may generalize to other domains of family life.
Internal and External Adaptation in Army Families: Lessons from Operations Desert Shield and Desert Storm
Authors: Pittman Joe F. , Kerpelman Jennifer L. , McFadyen Jennifer M.
Published: March 2004

This study examined 1,064 Army families reunited after a member's deployment for Operation Desert Shield and Operation Desert Storm. Postdeployment outcomes were conceptualized in terms of the “fit” between the family and the demands of Army life, especially the stress of deployment. A structural model was used to test the hypothesized effects of deployment‐period family coping, use of family support services, and perceptions of the unit culture on family outcomes. Especially salient in the findings were the effects of unit culture, which mediated the effects of family support services on outcomes. Moderating effects were noted in the model for service member's rank, as well as spouse's ethnicity and parental status. Implications for policy and practice are addressed.
Is Income Inequality a Determinant of Population Health? Part 1. A Systematic Review
Authors: LYNCH JOHN , SMITH GEORGE DAVEY , HARPER SAM , HILLEMEIER MARIANNE , ROSS NANCY , KAPLAN GEORGE A. , WOLFSON MICHAEL
Published: March 2004

This article reviews 98 aggregate and multilevel studies examining the associations between income inequality and health. Overall, there seems to be little support for the idea that income inequality is a major, generalizable determinant of population health differences within or between rich countries. Income inequality may, however, directly influence some health outcomes, such as homicide in some contexts. The strongest evidence for direct health effects is among states in the United States, but even that is somewhat mixed. Despite little support for a direct effect of income inequality on health per se, reducing income inequality by raising the incomes of the most disadvantaged will improve their health, help reduce health inequalities, and generally improve population health.
Genetic Modification of Preimplantation Embryos: Toward Adequate Human Research Policies
Authors: DRESSER REBECCA
Published: March 2004

Citing advances in transgenic animal research and setbacks in human trials of somatic cell genetic interventions, some scientists and others want to begin planning for research involving the genetic modification of human embryos. Because this form of genetic modification could affect later‐born children and their offspring, the protection of human subjects should be a priority in decisions about whether to proceed with such research. Yet because of gaps in existing federal policies, embryo modification proposals might not receive adequate scientific and ethical scrutiny. This article describes current policy shortcomings and recommends policy actions designed to ensure that the investigational genetic modification of embryos meets accepted standards for research on human subjects.
The influence of alcohol oral intake on the effects of 35% CO2challenge. A study in healthy volunteers
Authors: Cosci Fiammetta , Schruers Koen , Faravelli Carlo , Griez Eric
Published: March 2004

Objective:

Alcohol use disorders and panic disorder co-occur at a rate that exceeds chance significantly. The underlying mechanism of alcoholism associated with anxiety has rarely been examined using experimental methodologies. The present study in healthy volunteers tested whether alcohol consumption reduces anxiety associated with a panic-challenge procedure (35% CO2challenge).

Methods:

The study design was placebo-controlled, double-blind, randomized. Eight healthy volunteers were enrolled; all subjects had an alcohol and a placebo oral intake according to a crossover design. After each consumption the subjects underwent the 35% CO2challenge and a series of anxiety symptom assessments.

Results:

After the alcohol intake, the subjects presented a significant reduction in the anxiety state associated with the challenge procedure. The Panic Symptom List score is significantly lower after alcohol intake (P =0.032), as compared with the placebo, and the Visual Analogue Anxiety Scale shows a trend to be lower after alcohol intake (P =0.111).

Conclusions:

Moderate doses of alcohol acutely decrease the response to a 35% CO2challenge in healthy volunteers. These results lend support to the pharmacological anxiolytic effect of alcohol and suggest that this property may reinforce the drinking behaviour among those with high levels of anxiety.
The genetics of panic disorder: state of the art
Authors: van West Dirk , Claes Stephan
Published: March 2004

Panic disorder (PD) is a highly prevalent, debilitating disorder. The heritability of the disease has been estimated by twin studies to be between 30 and 60%. The vulnerability for PD overlaps with an increased risk of bipolar disorder in some families. Classical genetic methods such as linkage analysis and association studies have not yet identified genetic risk factors beyond doubt. However, two independent studies confirm linkage of a specific syndrome characterized by PD, bladder problems, severe headaches, mitral valve prolapse and thyroid dysfunction to genetic markers on chromosome 13q. Association studies, although showing divergent results, give some support to a causative role for the genes encoding for monoamine oxidase A (MAO-A), cholecystokinin (CCK) and catechol-O-methyltransferase (COMT). Finally, a somatic duplication of a 19-Mb region on chromosome 15 has been associated with PD, but this intriguing finding awaits confirmation.
The role of serotonin in panic: evidence from tryptophan depletion studies
Authors: Pyle A. C. , Argyropoulos S. V. , Nutt D. J.
Published: March 2004

There has been growing interest in the role of serotonin (5-hydroxytryptamine, 5-HT) in anxiety, including pathological states such as panic disorder. The technique of tryptophan depletion (TD), which causes an acute, temporary and reversible reduction in brain 5-HT levels, is a useful minimally invasive paradigm to aid the research of the role of 5-HT in various disorders. This review discusses the evidence supporting the hypothesis that 5-HT function is of importance in the neurobiology of panic disorder and considers in more detail how our understanding has been influenced by work using the technique of TD. Possible avenues for future research are also discussed.
New insights in cognitive behavioural therapy as treatment of panic disorder: a brief overview
Authors: Luermans J. R. L. M. , De Cort K. , Schruers K. , Griez E.
Published: March 2004

Cognitive behavioural therapy (CBT) has been proved to be very effective in the treatment of panic disorder. In this article we attempt to give a brief representation of more recent insights and techniques in the field of cognitive behavioural therapy in the treatment of panic disorder.
Amplified expression of dominant‐negative transforming growth factor‐beta type II receptor inhibits collagen type I production via reduced Smad‐3 activity
Authors: HERNANDEZ‐CAÑAVERAL IVAN , GONZÁLEZ JAIME , LÓPEZ‐CASILLAS FERNANDO , ARMENDARIZ‐BORUNDA JUAN
Published: March 2004

Background and Aim:  As a pleiotropic protein, transforming growth factor (TGF)‐β induces its effects by binding to its Ser/Thr kinase receptor type II and then recruiting and activating receptor type I, which is phosphorylated and activates Smads that transduce the signal to the nucleus.

Methods:  In this work, the authors blocked TGF‐β1 signal transduction pathway via delivery of a dominant‐negative receptor‐II (ΔCyTbRII)‐cDNA lacking Ser/Thr kinase intracytoplasmic domain activity. Thus, Cos‐1 and hepatic stellate cells were cotransfected with pCMV5‐ΔCyTbRII and pAdTrack‐green fluorescent protein using lipofectamine.

Results:  Fluorescence microscopy demonstrated an average 10% transfection efficiency. Radiolabeled 125I‐TGF‐β was bound mostly by cell membrane‐expressed truncated receptor‐II rather than wild‐type receptor type II. Electrophoretic mobility shift assays were performed using consensus Smad‐2 and ‐3 sequences rendering a three‐fold decrease in DNA‐binding activity, reflecting a down‐activation in Smad complexes in pCMV5‐ΔCyTbRII‐transfected cells, but not in mock‐transfected cells. The identity of these transcriptional factors was confirmed using irrelevant double‐stranded oligonucleotides and specific antibodies to compete for DNA binding. Also, collagen I mRNA expression showed a five‐fold decrease, which was reflected at the protein level as a diminished collagen type I production in pCMV5‐ΔCyTbRII‐transfected Cos‐1 cells as measured by [3H]proline incorporation and sodium dodecyl sulfate–polyacrylamide gel electrophoresis.

Conclusion:  Thus, this could be a useful strategy to downregulate or prevent exacerbated synthesis and deposition of extracellular matrix in a given fibrotic process.
Treatment of murine hepatocellular carcinoma using genetically modified cells to express interleukin‐12
Authors: PERON JEAN‐MARIE , COUDERC BETTINA , ROCHAIX PHILIPPE , DOUIN‐ECHINARD VICTORINE , ASNACIOS AMANI , SOUQUE ANNY , VOIGT JEAN‐JACQUES , BUSCAIL LOUIS , VINEL JEAN‐PIERRE , FAVRE GILLES
Published: March 2004

Background and Aim:  The majority of patients cannot benefit from the conventional curative treatments that are currently used for hepatocellular carcinoma (HCC), which remains a world health problem. Interleukin (IL)‐12 is one of the most potent anti‐tumor cytokines. The aim of the present study was to examine the anti‐tumor effect and toxicity of intrahepatic delivery of IL‐12 using an ex vivo gene therapy approach in a murine model of HCC.

Methods:  Syngenic fibroblasts or MM45T‐Li HCC tumor cells were genetically modified in vitro to express IL‐12 using a polycistronic TFG murine IL‐12 retroviral vector (TFGmIL‐12) coding for both p35 and p40 murine IL‐12 subunits. Hepatocellular carcinoma was generated using direct intrahepatic inoculation of the tumor cell line into the left liver lobe of BALB/c mice.

Results:  Direct liver expression of IL‐12 by the injected genetically modified tumor cells induced a marked inhibition of tumor growth. This effect was associated with an early infiltration of macrophages, and lymphocytes forming numerous intralobular foci. There was no significant liver toxicity, as shown by normal biochemical liver tests. At a later time, the intralobular foci were rare and consisted mainly of CD4+ T cells, while CD8+ T cells were present in the lobule. Intrahepatic expression of IL‐12 did not modify circulating or splenic B lymphocytes or natural killer (NK) cells. The inhibition of tumor growth was maintained in nude mice even when depleted in NK cells. Importantly, in a second model, treatment of established day 7 liver tumors in BALB/c mice using direct intra‐tumor injection of syngenic fibroblasts that were genetically modified to express IL‐12 significantly reduced tumor size.

Conclusion:  In conclusion, these data provide evidence that experimental HCC can be efficiently and safely treated using ex vivo IL‐12 gene therapy, which seems promising for future clinical studies.
Leptin levels in the acute stage of ulcerative colitis
Authors: TUZUN AHMET , UYGUN AHMET , YESILOVA ZEKI , OZEL A MELIH , ERDIL AHMET , YAMAN HALIL , BAGCI SAIT , GULSEN MUSTAFA , KARAEREN NECMETTIN , DAGALP KEMAL
Published: March 2004

Background and Aims:  Leptin, a recently discovered protein, acts as a hormonal feedback signal in regulating adipose tissue mass via hypothalamic mechanisms. Inflammatory bowel disease is often associated with anorexia and weight loss. The aim of the present study was to investigate serum leptin levels during the time course of the acute phase of ulcerative colitis (UC) and to evaluate whether leptin leads to anorexia and bodyweight loss in these patients.

Methods:  Serum leptin levels of 29 male patients with acute UC and 17 healthy controls with similar age, sex and body mass index (BMI) were measured. Erythrocyte sedimentation rate (ESR), BMI, serum albumin and C‐reactive protein concentrations, and white blood cell counts were determined.

Results:  A significant increase in serum leptin levels was found in patients with acute UC when compared with controls (5.89 ± 2.06 ng/mL and 3.64 ± 1.69 ng/mL, respectively; p = 0.001). There was no correlation between leptin levels and BMI.

Conclusions:  Our findings in the acute stage of UC suggest that increased serum leptin levels may contribute to anorexia and weight loss. However, an inappropriate increase in leptin levels is independent of body mass in acute UC, and we believe that other factors may be involved in inflammation‐induced increases in leptin levels.
Assessment of clinical impact of endoscopic ultrasound on esophageal cancer
Authors: HAREWOOD GAVIN C , KUMAR K SHIVA
Published: March 2004

Background and Aim: Endoscopic ultrasound (EUS) with fine needle aspiration (FNA) is the most accurate imaging modality for locoregional staging of esophageal cancer. It remains unclear whether this technology impacts on the outcome of patients with this malignancy. The aim of the present study was to assess the impact of EUS FNA by comparing the clinical outcomes of patients with esophageal cancer before and after the introduction of this staging modality in our institution.

Methods: Outcomes of patients with de novo non‐metastatic esophageal cancer seen in 1998 without EUS FNA evaluation (non‐EUS control group) were compared to patients evaluated in 2000 with EUS FNA (EUS group).

Results: Outcomes of 60 (non‐EUS control group) and 107 (EUS group) patients with non‐metastatic esophageal cancer were compared. Preoperative neoadjuvant therapy was administered to 35 patients in the EUS group, all of whom had advanced disease. Cox proportional hazards demonstrated EUS FNA to be associated with reduced recurrence risk (hazard ratio [HR]: 0.63; 95% confidence interval [CI]: 0.43–0.87),P = 0.004, and reduced mortality (HR: 0.66; 95% CI: 0.47–0.90),P = 0.008.

Conclusions: The EUS staging of esophageal cancer leads to appropriate use of preoperative neoadjuvant therapy in patients with advanced disease. Use of EUS is associated with a recurrence‐free survival advantage and overall survival advantage in patients, thus supporting its routine use in esophageal cancer staging.
p16INK4A Gene alterations are not a prognostic indicator for survival in patients with hepatocellular carcinoma undergoing curative hepatectomy
Authors: ANZOLA MONICA , CUEVAS NEREA , LOPEZ‐MARTINEZ MONICA , DE PANCORBO MARIAN MARTINEZ , BURGOS JUAN JOSE
Published: March 2004

Background and Aim:  Hepatocellular carcinoma (HCC) is a common malignancy worldwide that is highly associated with chronic hepatitis B or C infection and cirrhosis. The tumor suppressor gene p16INK4A is an important component of the cell cycle and inactivation of the gene has been found in a variety of human cancers. The present study was performed to determine genetic and epigenetic alterations in the p16INK4A tumor suppressor gene and the effect of these on HCC progression.

Methods:  The status of p16INK4A was evaluated in 117 HCC tumoral nodules and 110 corresponding peritumoral tissues by loss of heterozigosity (LOH) at the 9p21–22 region, homozygous deletions, single‐strand conformation polymorphism–polymerase chain reaction (PCR) mutational analysis and methylation specific PCR.

Results:  The most frequent inactivation mechanism was hypermethylation of the promoter region, which was found in 63.2% of the tumor samples and in 28.2% of the peritumoral samples. Loss of heterozygosity at the 9p21 region was detected in 27.3% and 10% of tumor and peritumoral tissues, respectively. Homozygous deletions and mutations were less common events in hepatocarcinogenesis. The authors found 5.9% of the tumor cases with exon 2 homozygous deletions and 8.6% with mutations. Two polymorphisms were detected, one at codon 148 (GCG → ACG, Ala → Thr) in three cases and the other in exon 3 at 540 bp (34.2% of the samples). No association was found between inactivation of p16INK4A and clinicopathological characteristics or prognosis.

Conclusion:  p16

INK4A
is altered frequently and early in HCC, being the predominant mechanism of inactivation promoter hypermethylation. The present results suggest that the p16INK4A gene plays an important role in the pathogenesis of HCC.
Responses of human clasp and sling fibers to neuromimetics
Authors: TIAN ZI‐QIANG , LIU JUN‐FENG , WANG GUI‐YING , LI BAO‐QING , WANG FU‐SHUN , WANG QI‐ZHANG , CAO FU‐MIN , ZHANG YUE‐FENG
Published: March 2004

Background and Aims:  It has previously been demonstrated that clasp and sling fibers at the human gastroesophageal junction respond differently to acetylcholine (Ach). The present study was undertaken to investigate the differences between the physiological and pharmacological properties of the two types of muscle fiber.

Methods:  Recordings were made of the isometric tension of human sling and clasp fibers in response to Ach, dopamine (DA), phenylephrine (Phe), and isoprenaline (Iso). These specimens were obtained from 18 patients who were operated on for esophageal cancer.

Results:  Both Ach and Phe increased the tension of the two types of muscle; the values in the Ach group being 3–4‐fold greater than those in the Phe group, while Iso decreased the tension of both types of muscle strip. The tension of the sling fibers was reduced by DA at lower concentration, and then increased gradually as the concentration was increased. In contrast, the tension of the clasp fibers did not obviously change when the concentration of DA was lower, but a slow elevation of tension was seen with the increase in DA concentration.

Conclusions:  The sensitivities and maximum responses to each agent differed between the clasp fibers and sling fibers. This suggests that the two kinds of fiber have different roles in establishing tension in the lower esophageal sphincter, with implications for the medical and surgical treatment of disorders in this region.
Role of transfusion‐transmitted virus in acute viral hepatitis and fulminant hepatic failure of unknown etiology
Authors: DAS KUNAL , KAR P , GUPTA RK , DAS BC
Published: March 2004

Background and Aim:  The role of the newly described transfusion‐transmitted virus (TTV), a circular single‐stranded DNA virus, has been investigated in acute liver disease, comprising 36 patients with acute viral hepatitis (AVH) and 25 with fulminant hepatic failure (FHF), including 50 volunteer blood donors as controls.

Methods:  Detection of  TTV DNA sequences was carried out by polymerase chain reaction (PCR) using primers derived from the UTR(A) region of the TTV genome. The clinical course and biochemical profile when infected with TTV alone or coinfected with other classical hepatotropic viruses were analyzed. All patients were first evaluated for liver function profile and for the presence of various hepatotropic viruses using serological tests and PCR in serologically negative patients.

Results:  Transfusion‐transmitted virus DNA was detected in 80.6% (29/36) of the AVH cases and in 76% (19/25) of the FHF cases, which were significantly higher levels (P < 0.05) than the 52% (26/50) observed in volunteer blood donors. No significant difference in symptoms, clinical course, liver function and risk factor profile between TTV‐positive and TTV‐negative patients could be observed in both AVH and FHF patients. TTV was found to coexist with both parenterally and non‐parenterally transmitted hepatotropic viruses in similar frequency in both AVH and FHF patients. Further, there was no significant difference in the mortality rates between TTV‐positive and TTV‐negative FHF patients. Also, there was no difference between patients coinfected by TTV and other hepatotropic viruses and those with TTV infection alone.

Conclusion:  Thus, it appears that TTV, although it exists in a very high frequency in the Indian population, appears to have no significant etiological role in AVH and FHF.
Evaluation of the 13C‐triolein breath test for fat malabsorption in adult patients with cystic fibrosis
Authors: RITZ MARC A , FRASER ROBERT J , DI MATTEO ADDOLORATA C , GREVILLE HUGH , BUTLER ROSS , CMIELEWSKI PATRICIA , DAVIDSON GEOFF
Published: March 2004

Background and Aims: A simple non‐invasive test not requiring the use of radioactive isotopes is required to assess fat malabsorption in adult cystic fibrosis (CF) patients. Breath tests using substrates labeled with 13C meet these conditions. The 14C‐triolein breath test is sensitive and specific for measuring fat malabsorption, but involves radiation exposure. The aim of this study was to examine the utility of a test using a 13C label and to determine whether pancreatic replacement therapy would return the test to the values of a normal control group.

Methods: 13CO2 recovery was assessed after an overnight fast in six adult patients with CF, both with and without pancreatic enzyme replacement therapy (PERT) in the usual dose for a light snack, in a randomized order, on different days. Studies were also performed in eight healthy volunteers after oral ingestion. Subjects drank 50 mL of a liquid meal mixed with 200 µL 13C‐triolein and breath samples were collected by blowing through a straw into collection tubes every 30 min for 6 h. The effect of gastric emptying was assessed by comparison of oral ingestion with intraduodenal infusion. Intra‐individual variability was assessed in nine volunteers by repeating the breath test after drinking the test meal on a separate day.

Results: Compared with healthy subjects there was virtually no recovery of 13CO2 in CF patients without PERT. The median (interquartile range) cumulative percentage dose recovery (cPDR) at 6 h was 3% (0–8) in CF patients compared with 28% (22–41) in healthy controls (P < 0.01). Fat absorption was normalized (37%) (36–43) after ingestion of PERT. Gastric emptying delayed the peak in 13CO2 recovery, but there was no difference in the cPDR at 6 h. There was no difference in recovery between days 1 and 2.

Conclusions: The 13C‐triolein breath test is a simple and reproducible method to measure fat malabsorption. The test provides a screening technique for fat malabsorption in adult CF patients and may be useful for monitoring the lowest effective dose of PERT.
Biliary excretion of azelnidipine, a calcium antagonist, in rats
Authors: HANAWA NAOKO , SANO NAOYO , TAKIKAWA HAJIME
Published: March 2004

Background and Aims:  Azelnidipine (CS‐905) is a novel dihydropyridine calcium antagonist that is known to be excreted in feces. To examine the mechanism of biliary excretion of azelnidipine, the authors studied its biliary excretion in Eisai hyperbilirubinuria rats (EHBR), multidrug resistance protein (Mrp)2‐deficient rats, and the effect of cholephilic compounds on the biliary excretion of azelnidipine in rats.

Methods:  Radiolabeled azelnidipine was intravenously administered to EHBR and control rats, and the biliary excretion of radiolabeled metabolites was studied. Furthermore, the effect of sulfobromophthalein, taurocholate and vinblastine on the biliary excretion of azelnidipine metabolites was also studied in control rats.

Results:  The biliary excretion of azelnidipine metabolites was delayed in EHBR. The biliary excretion of azelnidipine metabolites was inhibited by sulfobromophthalein and vinblastine, but was not inhibited by taurocholate or phenothiazine pretreatment.

Conclusion:  These findings suggest that the metabolites of azelnidipine are excreted into the bile partly by Mrp2 and P‐glycoprotein.
Comparison of image quality between electronic and mechanical radial scanning echoendoscopes in pancreatic diseases
Authors: NIWA KATSUSHI , HIROOKA YOSHIKI , NIWA YASUMASA , ITOH AKIHIRO , OHMIYA NAOKI , HASHIMOTO SENJU , ISHIKAWA HIDEKI , OKADA NAOTO , ITOH TERUTOMO , GOTO HIDEMI
Published: March 2004

Background and Aim: It is common knowledge that endoscopic ultrasonography (EUS) can accurately diagnose pancreatic diseases. Echoendoscopes for EUS are roughly classified into two categories, the mechanical radial scanning echoendoscope (MR‐ES) and the electronic linear array echoendoscope, both of which have their merits and demerits. In 2000, a newly designed echoendoscope, the electronic radial scanning echoendoscope (ER‐ES), appeared. The aim of the present study was to compare B‐mode image quality between the ER‐ES and the MR‐ES in pancreatic diseases.

Methods: Patients with pancreatic diseases (30 cystic diseases and 22 solid diseases) underwent EUS with both ER‐ES and MR‐ES. The B‐mode images obtained using both echoendoscopes were graded using a scoring system and statistically analyzed. The assessed point for cystic lesions was the existence of mechanical‐noise‐like ring‐like artifacts derived using multiple reflections (‘ring‐down’), grating robe and so on, and that for solid lesions was the scale of penetration. The authors compared maneuverability, endurance and endoscopic images between the two types of echoendoscopes.

Results: The ER‐ES had a significantly higher score than the MR‐ES (P < 0.05) in the analysis of both cystic and solid diseases. There was no apparent difference as to maneuverability, endurance and endoscopic images.

Conclusion: Ultrasound images acquired by ER‐ES appear better compared with those acquired by MR‐ES.
Characteristics of antepartum and intrapartum eclampsia in the National Maternal and Child Health Center in Cambodia
Authors: Koum Kanal , Hy Soryaphea , Tiv Say , Sieng Tharith , Obara Hiromi , Matsui Mitsuaki , Fujita Noriko
Published: March 2004

Aim:  To measure maternal and perinatal outcome and analyze risk factors for antepartum and intrapartum eclampsia, which is one of main causes of high maternal mortality at the top referral hospital in the Kingdom of Cambodia.

Methods:  A hospital‐based retrospective study of 164 antepartum and intrapartum eclampsia cases out of 20 449 deliveries.

Results:  Overall case–fatality rate was 12%. Rate of stillbirth and low birth weight were 20% and 44%, respectively. Eighty percent of the cases presented signs of severe pre‐eclampsia and 27% of the patients who gave birth received cesarean section. Living outside the capital city, teenage pregnancy and twin pregnancy are more frequently associated with eclampsia.

Conclusion:  Antepartum and intrapartum eclampsia is associated with severe pre‐eclampsia and with poor maternal and perinatal outcome. Recommendations to reduce the burden of eclampsia are promoting and improving quality of antenatal care and health education especially in the third trimester; increasing access to high‐quality essential obstetric care; improving the service delivery in rural areas; and monitoring the progress by hospital data.
Significance of endometrial polyps detected hysteroscopically in eumenorrheic infertile women
Authors: Shokeir Tarek A. , Shalan Hesham M. , El‐Shafei Mohamed M.
Published: March 2004

Aim:  To determine if the incidence of small endometrial polyps detected hysteroscopically in an infertile eumenorrheic population differed from that in an apparently fertile eumenorrheic population. Evidence was sought to determine whether removal of such lesions would enhance reproductive performance.

Methods:  In a prospective study, 266 consecutive infertile women had undergone complete fertility evaluation. None of the women had experienced any change in their menstrual cycle. They were divided into two groups; 235 infertile patients (group 1) and 31 requesting a reversal of a previous tubal sterilization (group 2). All patients were examined by simultaneous combined laparoscopy and hysteroscopy as part of their routine infertility evaluation. When endometrial polyps were noted they were removed by hysteroscopy and histopathologically examined. Patients in whom the only apparent finding was endometrial polyps were followed up to determine their reproductive outcomes subsequent to removal of the polyps.

Results:  Of the 224 uterine cavities successfully visualized in the infertile group, 134 were judged to be normal (60%) and 90 were abnormal (40%). Endometrial polyps were noted in 35 patients of group 1 and in one patient of group 2 (P < 0.01). Most polyps were located in the region of the utero‐tubal junction and proved to be functional. A 50% pregnancy rate was achieved by hysteroscopic polypectomy. Fertility‐related factors in women whose only apparent finding was endometrial polyps before and after hysteroscopy were comparable.

Conclusion:  Diagnostic hysteroscopy should be used routinely in the work‐up of infertile woman, even in the presence of eumenorrhea. Persistent functional endometrial polyps, even if small, are likely to impair fertility in this select patient group. Removal of such lesions may improve subsequent reproductive performance.