bluuebunny/crossref_metadata_2025 huggingface dataset:
Significance of Tilt Table Testing in Patients with Suspected Arrhythmic Syncope and Negative Electrophysiologic Study
Authors: GARCÍA‐CIVERA ROBERTO , RUIZ‐GRANELL RICARDO , MORELL‐CABEDO SALVADOR , SANJUAN‐MAÑEZ RAFAEL , FERRERO ANGEL , MARTÍNEZ‐BROTONS ANGEL , ROSELLÓ ARACELI , BOTELLA SEGISMUNDO , LLACER ANGEL
Published: August 2005

Background: The diagnostic significance of a tilt table test (TTT) in patients with a suspected arrhythmic etiology for syncope and negative electrophysiologic study (EPS) has not been previously assessed comparing the TTT results with the findings of prolonged monitoring using an implantable loop recorder (ILR). We sought to assess the diagnostic yielding of TTT in patients with suspected arrhythmic syncope and negative EPS.

Methods and Results: In 81 patients with suspected arrhythmic etiology for syncope and negative EPS, TTT was performed and an ILR implanted regardless the results of TTT. TTT was positive in 38 patients. During follow‐up, syncope or presyncope recurred in 32 patients (39.5%). No differences were found in recurrence rates in patients with positive and negative TTT (31.5% vs 46.5%, P = ns). According to rhythm registered during ILR activation, mechanisms of syncopal events were classified as: arrhythmic (atrioventricular [AV] block and ventricular tachycardia; n = 18), neurally mediated (sinus bradycardia and sinus pause; n = 9), and indeterminate (normal sinus rhythm; n = 5). There was no statistical association between the results of TTT and the mechanism of syncope.

Conclusions: In patients with a suspected arrhythmic etiology for syncope and a negative EPS, TTT is of little value to predict the mechanism of syncope and the ILR implantation seems to be a useful and safe diagnostic strategy.
Recording Techniques for Clinical Electrophysiology
Authors: STEVENSON WILLIAM G. , SOEJIMA KYOKO
Published: August 2005

The precise techniques employed in the electrophysiology laboratory influence the nature of the electrograms that are recorded during mapping procedures. Unipolar recordings that are minimally filtered can be useful for mapping focal arrhythmia sources, but have substantial far‐field signal that can obscure low‐amplitude signals of interest in abnormal regions. Bipolar recordings are standard in most laboratories because rejection of far‐field signal facilitates identification of local potentials in abnormal areas, but the signal of interest can be beneath either recording electrode and far‐field signals do occur. Simultaneously obtained unipolar recordings are a useful adjunct to bipolar recordings in some situations. High pass filtering and digital sampling also influence electrogram characteristics. High pass filtering of unipolar recordings can be useful to reduce far‐field components, but limits inferences from electrogram morphology.
The Performance of Mixture Models in Heterogeneous Closed Population Capture–Recapture
Authors: Pledger Shirley
Published: August 2005

Summary Dorazio and Royle (2003, Biometrics59, 351–364) investigated the behavior of three mixture models for closed population capture–recapture analysis in the presence of individual heterogeneity of capture probability. Their simulations were from the beta‐binomial distribution, with analyses from the beta‐binomial, the logit‐normal, and the finite mixture (latent class) models. In this response, simulations from many different distributions give a broader picture of the relative value of the beta‐binomial and the finite mixture models, and provide some preliminary insights into the situations in which these models are useful.
On the Effect of Misclassification on Bias of Perfectly Measured Covariates in Regression
Authors: Buonaccorsi John P. , Laake Petter , Veierød Marit B.
Published: August 2005

Summary This note clarifies under what conditions a naive analysis using a misclassified predictor will induce bias for the regression coefficients of other perfectly measured predictors in the model. An apparent discrepancy between some previous results and a result for measurement error of a continuous variable in linear regression is resolved. We show that similar to the linear setting, misclassification (even when not related to the other predictors) induces bias in the coefficients of the perfectly measured predictors, unless the misclassified variable and the perfectly measured predictors are independent. Conditional and asymptotic biases are discussed in the case of linear regression, and explored numerically for an example relating birth weight to the weight and smoking status of the mother.
Simultaneous Group Sequential Analysis of Rank‐Based and Weighted Kaplan–Meier Tests for Paired Censored Survival Data
Authors: Andrei Adin‐Cristian , Murray Susan
Published: August 2005

Summary This research sequentially monitors paired survival differences using a new class of nonparametric tests based on functionals of standardized paired weighted log‐rank (PWLR) and standardized paired weighted Kaplan–Meier (PWKM) tests. During a trial, these tests may alternately assume the role of the more extreme statistic. By monitoring PEMAX, the maximum between the absolute values of the standardized PWLR and PWKM, one combines advantages of rank‐based (RB) and non‐RB paired testing paradigms. Simulations show that monitoring treatment differences using PEMAX maintains type I error and is nearly as powerful as using the more advantageous of the two tests in proportional hazards (PH) as well as non‐PH situations. Hence, PEMAX preserves power more robustly than individually monitored PWLR and PWKM, while maintaining a reasonably simple approach to design and analysis of results. An example from the Early Treatment Diabetic Retinopathy Study (ETDRS) is given.
Missing Covariates in Longitudinal Data with Informative Dropouts: Bias Analysis and Inference
Authors: Roy Jason , Lin Xihong
Published: August 2005

SummaryWe consider estimation in generalized linear mixed models (GLMM) for longitudinal data with informative dropouts. At the time a unit drops out, time‐varying covariates are often unobserved in addition to the missing outcome. However, existing informative dropout models typically require covariates to be completely observed. This assumption is not realistic in the presence of time‐varying covariates. In this article, we first study the asymptotic bias that would result from applying existing methods, where missing time‐varying covariates are handled using naive approaches, which include: (1) using only baseline values; (2) carrying forward the last observation; and (3) assuming the missing data are ignorable. Our asymptotic bias analysis shows that these naive approaches yield inconsistent estimators of model parameters. We next propose a selection/transition model that allows covariates to be missing in addition to the outcome variable at the time of dropout. The EM algorithm is used for inference in the proposed model. Data from a longitudinal study of human immunodeficiency virus (HIV)–infected women are used to illustrate the methodology.
A Semiparametric Mixture Model for Analyzing Clustered Competing Risks Data
Authors: Naskar Malay , Das Kalyan , Ibrahim Joseph G.
Published: August 2005

Summary A very general class of multivariate life distributions is considered for analyzing failure time clustered data that are subject to censoring and multiple modes of failure. Conditional on cluster‐specific quantities, the joint distribution of the failure time and event indicator can be expressed as a mixture of the distribution of time to failure due to a certain type (or specific cause), and the failure type distribution. We assume here the marginal probabilities of various failure types are logistic functions of some covariates. The cluster‐specific quantities are subject to some unknown distribution that causes frailty. The unknown frailty distribution is modeled nonparametrically using a Dirichlet process. In such a semiparametric setup, a hybrid method of estimation is proposed based on the i.i.d. Weighted Chinese Restaurant algorithm that helps us generate observations from the predictive distribution of the frailty. The Monte Carlo ECM algorithm plays a vital role for obtaining the estimates of the parameters that assess the extent of the effects of the causal factors for failures of a certain type. A simulation study is conducted to study the consistency of our methodology. The proposed methodology is used to analyze a real data set on HIV infection of a cohort of female prostitutes in Senegal.
A Longitudinal Measurement Error Model with a Semicontinuous Covariate
Authors: Li Liang , Shao Jun , Palta Mari
Published: August 2005

Summary Covariate measurement error in regression is typically assumed to act in an additive or multiplicative manner on the true covariate value. However, such an assumption does not hold for the measurement error of sleep‐disordered breathing (SDB) in the Wisconsin Sleep Cohort Study (WSCS). The true covariate is the severity of SDB, and the observed surrogate is the number of breathing pauses per unit time of sleep, which has a nonnegative semicontinuous distribution with a point mass at zero. We propose a latent variable measurement error model for the error structure in this situation and implement it in a linear mixed model. The estimation procedure is similar to regression calibration but involves a distributional assumption for the latent variable. Modeling and model‐fitting strategies are explored and illustrated through an example from the WSCS.
Semiparametric Methods for Mapping Quantitative Trait Loci with Censored Data
Authors: Diao Guoqing , Lin D. Y.
Published: August 2005

SummaryStatistical methods for the detection of genes influencing quantitative traits with the aid of genetic markers are well developed for normally distributed, fully observed phenotypes. Many experiments are concerned with failure‐time phenotypes, which have skewed distributions and which are usually subject to censoring because of random loss to follow‐up, failures from competing causes, or limited duration of the experiment. In this article, we develop semiparametric statistical methods for mapping quantitative trait loci (QTLs) based on censored failure‐time phenotypes. We formulate the effects of the QTL genotype on the failure time through theCox(1972,Journal of the Royal Statistical Society, Series B34,187–220) proportional hazards model and derive efficient likelihood‐based inference procedures. In addition, we show how to assess statistical significance when searching several regions or the entire genome for QTLs. Extensive simulation studies demonstrate that the proposed methods perform well in practical situations. Applications to two animal studies are provided.
Assessing the Skill of Yes/No Predictions
Authors: Briggs William , Ruppert David
Published: August 2005

Summary Should healthy, middle‐aged women receive precautionary mammograms? Should trauma surgeons use the popular TRISS score to predict the likelihood of patient survival? These are examples of questions confronting us when we decide whether to use a yes/no prediction. In order to trust a prediction we must show that it is more valuable than would be our best guess of the future in the absence of the prediction. Calculating value means identifying our loss should the prediction err and examining the past performance of the prediction with respect to that loss. A statistical test to do this is developed. Predictions that pass this test are said to have skill. Only skillful predictions should be used. Graphical and numerical methods to identify skill will be demonstrated. The usefulness of mammograms is explored.
Capture–Recapture Studies Using Radio Telemetry with Premature Radio‐Tag Failure
Authors: Cowen Laura , Schwarz Carl J.
Published: August 2005

Summary Radio tags, because of their high detectability, are often used in capture–recapture studies. A key assumption is that radio tags do not cease functioning during the study. Radio‐tag failure before the end of a study can lead to underestimates of survival rates. We develop a model to incorporate secondary radio‐tag failure data. This model was applied to chinook smolts (Oncorhynchus tshawytscha) on the Columbia River, Washington. Estimates of fish survival from this model were much larger than those from the standard Cormack–Jolly–Seber analysis.
Quantitative Risk Assessment for Multivariate Continuous Outcomes with Application to Neurotoxicology: The Bivariate Case
Authors: Yu Zi‐Fan , Catalano Paul J.
Published: August 2005

Summary The neurotoxic effects of chemical agents are often investigated in controlled studies on rodents, with multiple binary and continuous endpoints routinely collected. One goal is to conduct quantitative risk assessment to determine safe dose levels. Such studies face two major challenges for continuous outcomes. First, characterizing risk and defining a benchmark dose are difficult. Usually associated with an adverse binary event, risk is clearly definable in quantal settings as presence or absence of an event; finding a similar probability scale for continuous outcomes is less clear. Often, an adverse event is defined for continuous outcomes as any value below a specified cutoff level in a distribution assumed normal or log normal. Second, while continuous outcomes are traditionally analyzed separately for such studies, recent literature advocates also using multiple outcomes to assess risk. We propose a method for modeling and quantitative risk assessment for bivariate continuous outcomes that address both difficulties by extending existing percentile regression methods. The model is likelihood based; it allows separate dose–response models for each outcome while accounting for the bivariate correlation and overall characterization of risk. The approach to estimation of a benchmark dose is analogous to that for quantal data without the need to specify arbitrary cutoff values. We illustrate our methods with data from a neurotoxicity study of triethyl tin exposure in rats.
Models for Estimating Bayes Factors with Applications to Phylogeny and Tests of Monophyly
Authors: Suchard Marc A. , Weiss Robert E. , Sinsheimer Janet S.
Published: August 2005

SummaryBayes factors comparing two or more competing hypotheses are often estimated by constructing a Markov chain Monte Carlo (MCMC) sampler to explore the joint space of the hypotheses. To obtain efficient Bayes factor estimates,Carlin and Chib(1995,Journal of the Royal Statistical Society, Series B57,473–484) suggest adjusting the prior odds of the competing hypotheses so that the posterior odds are approximately one, then estimating the Bayes factor by simple division. A byproduct is that one often produces several independent MCMC chains, only one of which is actually used for estimation. We extend this approach to incorporate output from multiple chains by proposing three statistical models. The first assumes independent sampler draws and models the hypothesis indicator function using logistic regression for various choices of the prior odds. The two more complex models relax the independence assumption by allowing for higher‐lag dependence within the MCMC output. These models allow us to estimate the uncertainty in our Bayes factor calculation and to fully use several different MCMC chains even when the prior odds of the hypotheses vary from chain to chain. We apply these methods to calculate Bayes factors for tests of monophyly in two phylogenetic examples. The first example explores the relationship of an unknown pathogen to a set of known pathogens. Identification of the unknown's monophyletic relationship may affect antibiotic choice in a clinical setting. The second example focuses on HIV recombination detection. For potential clinical application, these types of analyses must be completed as efficiently as possible.
Retrospective Analysis of Sequential Dose‐Finding Designs
Authors: O'Quigley John
Published: August 2005

Summary The continual reassessment method (CRM) is a dose‐finding design using a dynamic sequential updating scheme. In common with other dynamic schemes the method estimates a current dose level corresponding to some target percentile for experimentation. The estimate is based on all included subjects. This continual reevaluation is made possible by the use of a simple model. As it stands, neither the CRM, nor any of the other dynamic schemes, allow for the correct estimation of some target percentile, based on retrospective data apart from the exceptional situation in which the simplified model exactly generates the observations. In this article we focus on the very specific issue of retrospective analysis of data generated by some arbitrary mechanism and subsequently analyzed via the continual reassessment method. We show how this can be done consistently. The proposed methodology is not restricted to that particular design and is applicable to any sequential updating scheme in which dose levels are associated with percentiles via model inversion.
Propensity Score Matching with Time‐Dependent Covariates
Authors: Lu Bo
Published: August 2005

SummaryIn observational studies with a time‐dependent treatment and time‐dependent covariates, it is desirable to balance the distribution of the covariates at every time point. A time‐dependent propensity score based on the Cox proportional hazards model is proposed and used in risk set matching. Matching on this propensity score is shown to achieve a balanced distribution of the covariates in both treated and control groups. Optimal matching with various designs is conducted and compared in a study of a surgical treatment, cystoscopy and hydrodistention, given in response to a chronic bladder disease, interstitial cystitis. Simulation studies also suggest that the statistical analysis after matching outperforms the analysis without matching in terms of both point and interval estimations.
Robust Tests for Treatment Effects Based on Censored Recurrent Event Data Observed over Multiple Periods
Authors: Cook Richard J. , Wei Wei , Yi Grace Y.
Published: August 2005

SummaryWe derive semiparametric methods for estimating and testing treatment effects when censored recurrent event data are available over multiple periods. These methods are based on estimating functions motivated by a working “mixed‐Poisson” assumption under which conditioning can eliminate subject‐specific random effects. Robust pseudoscore test statistics are obtained via “sandwich” variance estimation. The relative efficiency of conditional versus marginal analyses is assessed analytically under a mixed time‐homogeneous Poisson model. The robustness and empirical power of the semiparametric approach are assessed through simulation. Adaptations to handle recurrent events arising in crossover trials are described and these methods are applied to data from a two‐period crossover trial of patients with bronchial asthma.
Cardiovascular risk factors and events in glaucoma patients with peripapillary focal arteriolar narrowing
Authors: Lam Andrew , Bunya Vatinee Y. , Piltz‐Seymour Jody R.
Published: September 2005

Purpose:  To evaluate cardiovascular risk factors and events in glaucoma patients with and without peripapillary focal arteriolar narrowing of retinal vessels.

Methods:  We examined the fundus photographs of 325 consecutive glaucoma patients for evidence of focal arteriolar narrowing of retinal vessels adjacent to the optic disc. Cases and controls were matched for age, race, sex and mean deviation on Humphrey visual field. Medical information regarding cardiovascular risk factors and events was collected from patients' primary care physicians, and this information was confirmed by questionnaires sent to the patients themselves.

Results:  A total of 58 pairs of cases and controls were matched. The prevalence of hypertension and diabetes was exactly equal in both groups, 65.5% and 27.6%, respectively. Similarly, the prevalences of myocardial infarction, cardiac surgery, angioplasty, family history of heart disease and smoking were nearly identical in both groups. There was no significant difference in the prevalence of strokes or transient ischaemic attacks. The prevalence of hypercholesterolemia and mortality was greater in the case group (mean differences of 8.6, p = 0.42 and 5.2, p = 0.25, respectively), however, these differences were not statistically significant.

Conclusion:  There is no significant relationship between peripapillary focal arteriolar narrowing of retinal vessels and cardiovascular risk factors or events in patients with glaucoma. Proximal narrowing does not appear to be a marker of systemic vascular disease.
Early insight predicts depression and attempted suicide after 4 years in first‐episode schizophrenia and schizophreniform disorder
Authors: Crumlish N. , Whitty P. , Kamali M. , Clarke M. , Browne S. , McTigue O. , Lane A. , Kinsella A. , Larkin C. , O'Callaghan E.
Published: August 2005

Objective:  To map the development of insight in the 4 years after presentation with first‐episode schizophrenia and schizophreniform disorder and to determine the effects of evolving insight on depression and the likelihood of attempted suicide.

Method:  We assessed 101 individuals at presentation, 6 months and 4 years. We measured insight, including recognition of mental illness, recognition of need for treatment and ability to relabel psychotic symptoms. We measured depression and recorded all suicide attempts.

Results:  Insight improved with time. Recognition of mental illness at 6 months predicted depression and attempted suicide at 4 years.

Conclusion:  Six months after presentation, the greater the acknowledgement by people that they had a mental illness, the more depressed they were at 4 years and the greater the likelihood that they would attempt suicide by 4 years. This may have implications for disclosure of diagnosis.
Maintenance antipsychotic medication patterns in outpatient schizophrenia patients: a naturalistic cohort study
Authors: Burns T. , Christova L. , Cooper S. , Harrison G. , McKendrick J. , Laugharne R. , Obuaya T. , McCreadie R. , O'Brien S. , Perrington S. , Stephenson D.
Published: August 2005

Objective:  Newer antipsychotics are increasingly used in schizophrenia maintenance. The UK change has been slow with little known on switching patterns. We aimed to investigate antipsychotic prescribing patterns in schizophrenia patients.

Method:  A naturalistic six‐site cohort sample of 600 patients were interviewed by researchers at 6‐monthly intervals for 2 years to record their clinical and social functioning; use of services and medication for the preceding 6 months was obtained by structured extraction from clinical case notes.

Results:  Alterations in antipsychotic medication were frequent in this group, mainly during periods of inpatient care. Atypical prescribing increased steadily, though slowly, across the period. Polypharmacy was less than anticipated.

Conclusion:  Inpatient care remains the main forum for switching of antipsychotics. The UK maintains a slow shift to atypical antipsychotics.
A soybean Kunitz trypsin inhibitor reduces tumor necrosis factor‐α production in ultraviolet‐exposed primary human keratinocytes
Authors: Kobayashi Hiroshi , Yoshida Ryuji , Kanada Yasufumi , Fukuda Yoichi , Yagyu Tatsuo , Inagaki Kiyokazu , Kondo Toshiharu , Kurita Noriyuki , Yamada Yoshihiko , Sado Toshiyuki , Kitanaka Takashi , Suzuki Mika , Kanayama Naohiro , Terao Toshihiko
Published: September 2005

Background:  Cytokines are produced as a consequence of photo‐damaged DNA and oxidative stress in ultraviolet (UV)‐exposed keratinocytes. A soybean Kunitz trypsin inhibitor (KTI) down‐regulates the expression of proinflammatory cytokines such as tumor necrosis factor‐α (TNF‐α) in tumor cells and inflammatory cells.

Aim:  The effect of KTI on TNF‐α production in UV‐exposed primary human keratinocytes was analyzed.

Results:  We show (i) UV induced up‐regulation of TNF‐α mRNA and protein expression in keratinocytes; (ii) cells treated with KTI before UV irradiation showed a significantly lower accumulation of TNF‐α protein in a dose‐dependent manner and a reduced UV‐induced up‐regulation of TNF‐α mRNA expression; (iii) KTI inhibited the induction of TNF‐α target molecules interleukin‐1β (IL‐1β) and IL‐6 proteins; (iv) UV irradiation transiently activated c‐Jun N‐terminal kinase (JNK) and Akt signaling but only weakly activated extracellular signal‐regulated kinase (ERK) and p38; (v) KTI specifically inhibited UV‐induced activation of ERK, JNK, and p38, but not Akt; (vi) treatment of cells with SP600125, a pharmacological inhibitor of JNK, predominantly suppressed UV‐induced up‐regulation of TNF‐α expression; and (vii) KTI did not enhance suppression of UV‐induced JNK phosphorylation by SP600125.

Conclusions:  KTI specifically inhibited UV‐induced up‐regulation of cytokine expression predominantly through suppression of JNK signaling pathway.
Incidence rates for oral leukoplakia and lichen planus in a Japanese population
Authors: Nagao Toru , Ikeda Noriaki , Fukano Hideo , Hashimoto Shuji , Shimozato Kazuo , Warnakulasuriya Saman
Published: September 2005

Background:  Data on the incidence rates of potentially malignant diseases of the oral cavity in different populations is meagre. This is the first study to report on the age‐specific incidence of oral leukoplakia and oral lichen planus from an industrialized country.

Methods:  Annual screening for oral cancer and pre‐cancer was undertaken in Municipal Health Centres in Tokoname city, Japan from 1995 to 1998. A total of 9536 volunteers aged 40–95 years participated in this programme. A cohort of 6340 (67%) subjects attended annual mouth examinations following a negative screen result at entry, allowing 13 072 person‐years of observations. Some associated risk factors (tobacco and alcohol misuse) and health‐related variables were also evaluated.

Results:  Over a 4‐year follow‐up period, 18 new oral leukoplakias (all homogenous; 11 idiopathic and seven tobacco‐associated) and 24 oral lichen planus (22 reticular, one erythematous and one ulcerative) were detected at screening and confirmed by re‐examination at specialist units. The age‐adjusted incidence rate for leukoplakia was 409.2 (95% CI: 90.6–727.9) in male and 70.0 (95% CI: 17.9–121.8) in female per 100 000 person‐years observations. For lichen planus, the corresponding rates were 59.7 (95% CI: 7.4–112.1) and 188.0 (95% CI: 96.0–280.1). The age‐adjusted incidence rate for tobacco‐associated leukoplakia in males was almost 12 times compared with female (560.3 vs. 45.2 per 100 000). Age‐specific incidence rates for oral leukoplakia varied by age groups. New oral leukoplakias were more prevalent on gingival/alveolar ridge (33.3%) than in other oral sites, and lichen planus at buccal site (33.3%). Prevalence of smoking habits among those positive for leukoplakia (38.9%) was higher compared with the screen‐negatives (26.4%) but these differences did not reach statistical significance (P = 0.232). Regular drinking was not related to occurrence of either oral leukoplakia or oral lichen planus. In cases with diabetes mellitus, relative risk for oral lichen planus adjusted by logistic regression was 6.4 (95% CI: 2.4–17.6), suggesting an association.

Conclusions:  The reported incidence rates for oral leukoplakia in this Japanese population are somewhat higher to those reported from India, the risk habits of the two groups being markedly different. The reported rates for oral leukoplakia and lichen planus allow estimation of service needs in specialist oral medicine clinics and for the training of primary care dentists. A high incidence of idiopathic leukoplakia found in this study raises challenges to the strategy of screening high‐risk populations aimed at conserving resources.
Detection of mitochondria‐mediated apoptosis signaling molecules in ameloblastomas
Authors: Kumamoto Hiroyuki , Ooya Kiyoshi
Published: September 2005

Background:  To investigate the roles of the apoptosis signaling pathway mediated by mitochondria in oncogenesis and cytodifferentiation of odontogenic tumors, expression of pathway signaling molecules was analyzed in ameloblastomas as well as in tooth germs.

Methods:  Tissue specimens of 12 tooth germs, 41 benign ameloblastomas, and five malignant ameloblastomas were examined by reverse transcriptase polymerase chain reaction (RT‐PCR) and immunohistochemistry to determine the expression of cytochrome c, apoptotic protease‐activating factor‐1 (APAF‐1), caspase‐9, and apoptosis‐inducing factor (AIF).

Results:  The mRNA expression of APAF‐1, caspase‐9, and AIF was detected in all samples of normal and neoplastic odontogenic tissues. Immunohistochemical reactivity for cytochrome c, APAF‐1, caspase‐9, and AIF was detected in both normal and neoplastic odontogenic tissues. Expression of cytochrome c and AIF was evident in odontogenic epithelial cells neighboring the basement membrane, and APAF‐1 and caspase‐9 were detected in most odontogenic epithelial cells. Immunoreactivity for cytochrome c in tooth germs was slightly weaker than that in benign and malignant ameloblastomas. Keratinizing cells in acanthomatous ameloblastomas and granular cells in granular cell ameloblastomas showed a decrease or loss of immunoreactivity for these mitochondria‐mediated apoptosis signaling molecules. Expression of AIF was obviously low in ameloblastic carcinomas.

Conclusion:  Expression of cytochrome c, APAF‐1, caspase‐9, and AIF in tooth germs and ameloblastomas suggests that the mitochondria‐mediated apoptotic pathway has a role in apoptotic cell death of normal and neoplastic odontogenic epithelium. Expression of these mitochondrial apoptosis signaling molecules might be involved in oncogenesis, cytodifferentiation, and malignant transformation of odontogenic epithelium.
Peripheral odontogenic tumor: a clinicopathologic study of 30 cases. General features and hamartomatous lesions
Authors: Ide F. , Obara K. , Mishima K. , Saito I. , Horie N. , Shimoyama T. , Kusama K.
Published: September 2005

Background:  Peripheral odontogenic tumors (POT), either neoplastic or hamartomatous, are rare. This study briefly summarizes the general features of POT and selectively reviews the histomorphologic spectrum of under‐recognized hamartomatous lesions that we have designated peripheral odontogenic hamartomas (POH) in order to shed more light into the pathogenesis of POT.

Methods:  Archival material accessioned at our institutions between 1970 and 2004 was systematically searched to identify examples of POT/POH.

Results:  Among 39 660 biopsies, we retrieved 25 cases of ‘classical’ POT and five cases of ‘unique’ POH. Odontogenic fibroma and ameloblastoma were by far the most common. Of POH, two purely epithelial lesions showed multiple strands of basaloid rests [odontogenic gingival epithelial hamartoma (OGEH)] and a conglomerate of polyhedral epithelium, ghost cells and concentric calcifications (calcifying epithelial odontogenic tumor‐like hamartoma), respectively. OGEH and peripheral squamous odontogenic tumor (PSOT) deserve to be a related entity. In two types of mixed POH, ectomesenchymal elements appeared juxtaposed to the squamous lining (gingival cyst‐like organoid hamartoma) and ghost cells aggregated in the enamel organ of a microdont (peripheral odontoma). None of POH exhibited continuity with the surface epithelium.

Conclusion:  On the basis of this relatively limited series of cases, POH, to conceptualize a unified histogenetic source, are speculated to arise from the soft‐tissue remnants of dental lamina. Gingival rests of Serres seem to retain the ability to pursue epithelial–ectomesenchymal interactions that are necessary leading to odontoma formation.
The NH2‐Terminal Transmembrane and Lumenal Domains of LGP85 are Needed for the Formation of Enlarged Endosomes/Lysosomes
Authors: Kuronita Toshio , Hatano Toshiyuki , Furuyama Atsuko , Hirota Yuko , Masuyama Naoko , Saftig Paul , Himeno Masaru , Fujita Hideaki , Tanaka Yoshitaka
Published: September 2005

LGP85 is a lysosomal membrane protein possessing a type III topology and is also known as a member of the CD36 superfamily of proteins, such as CD36 and the scavenger‐receptor BI (SR‐BI). We have recently demonstrated that overexpression of LGP85 in various mammalian cell lines causes the enlargement of endosomal/lysosomal compartments (ELCs). Using chimeras and deletion mutants, we show here that the lumenal region of LGP85 is necessary, but not sufficient, for the development of ELCs. Effective formation of enlarged ELC was largely dependent on the presence of a preceding NH2‐terminal transmembrane segment. Analyses of deletion mutants within the lumenal domain further revealed a requirement of the NH2‐terminal transmembrane proximal lumenal region, with high sequence similarity with SR‐BI for the enlargement of ELC. These results suggest that an interaction of the NH2‐terminal transmembrane proximal lumenal domain of LGP85 with the inner leaflet of endosomal/lysosomal membranes through the connection with the transmembrane domain is an essential determinant for the regulation of endosomal/lysosomal membrane traffic. Interestingly, although the NH2‐terminal transmembrane domain itself was not sufficient for the enlargement of ELCs, it appeared to be required for direct targeting of LGP85 from the trans‐Golgi network to late endosomes/lysosomes. Taken together, these results indicate the involvement of distinct domain of LGP85 in the targeting to, and biogenesis and maintenance of, ELC.
Nuclear Actin‐Binding Proteins as Modulators of Gene Transcription
Authors: Gettemans Jan , Van Impe Katrien , Delanote Veerle , Hubert Thomas , Vandekerckhove Joël , De Corte Veerle
Published: September 2005

Dynamic transformations in the organization of the cellular microfilament system are the driving force behind fundamental biological processes such as cellular motility, cytokinesis, wound healing and secretion. Eukaryotic cells express a plethora of actin‐binding proteins (ABPs) allowing cells to control the organization of the actin cytoskeleton in a flexible manner. These structural proteins were, not surprisingly, originally described as (major) constituents of the cytoplasm. However, in recent years, there has been a steady flow of reports detailing not only translocation of ABPs into and out of the nucleus but also describing their role in the nuclear compartment. This review focuses on recent developments pertaining to nucleocytoplasmic transport of ABPs, including their mode of translocation and nuclear function. In particular, evidence that structurally and functionally unrelated cytoplasmic ABPs regulate transcription activation by various nuclear (steroid hormone) receptors is steadily accruing. Furthermore, the recent finding that actin is a necessary component of the RNA polymerase II‐containing preinitiation complex opens up new opportunities for nuclear ABPs in gene transcription regulation.
Serum Matrix Metalloproteinase and Tissue Inhibitor of Metalloproteinase Concentrations in Infertile Women Achieved Pregnancy Following IVF‐ET
Authors: Shibahara Hiroaki , Suzuki Tatsuya , Ayustawati  , Kikuchi Kumiko , Hirano Yuki , Suzuki Mitsuaki
Published: August 2005

Problem

Matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) play important roles throughout various stages of pregnancy, including embryo implantation, trophoblastic invasion, placentation in early gestation, and cervical dilatation in later gestation, and feto‐maternal membrane lysis. It would be beneficial if assessment of serum concentrations of MMP and TIMP could predict successful implantation following in vitro fertilization‐embryo transfer (IVF‐ET). This study was performed to compare serum MMP and TIMP concentrations between patients with and without the establishment of pregnancy following ET.

Method of study

Ten patients who conceived and 10 patients who did not after IVF‐ET were entered in the present study. Only intra‐uterine single pregnancies with uneventful courses to term were included in the study subjects. Blood samples were obtained at 7, 14 and 21 days after oocyte retrieval. Serum concentrations of MMP‐1, MMP‐2, MMP‐3, and TIMP‐1 were measured using enzyme‐linked immunosorbent assay. These variables were compared with estradiol (E2), progesterone (P4), and βhCG levels in the patients’ sera. Clinical pregnancies were diagnosed only when fetal heartbeat was visualized on ultrasound.

Results

There were no significant differences in serum MMP concentrations between the pregnant group and the non‐pregnant group. However, serum TIMP‐1 concentrations on Days 14 and 21 in the pregnant group were significantly higher than those in non‐pregnant group [Day 14: 223.1 ± 11.9 versus 177.5 ± 20.6 ng/mL (P = 0.004); Day 21: 215.4 ± 27.8 versus 181.5 ± 27.4 ng/mL (P = 0.03)]. Serum TIMP‐1 concentrations were also correlated with serum E2 and P4 levels (P < 0.0001), but not with those of the MMPs. None of MMP nor TIMP‐1 were correlated with serum βhCG level.

Conclusions

It was demonstrated that the patients who successfully conceived after IVF‐ET showed significantly higher levels of TIMP‐1 at 14 and 21 days after IVF‐ET, but not at day 7; further work will be required to determine if serum TIMP‐1 can be used to improve prediction of pregnancy outcome in these patients.
Concentration of Adiponectin in Peritoneal Fluid is Decreased in Women with Endometriosis
Authors: Takemura Yuri , Osuga Yutaka , Harada Miyuki , Hirata Tetsuya , Koga Kaori , Yoshino Osamu , Hirota Yasushi , Morimoto Chieko , Yano Tetsu , Taketani Yuji
Published: August 2005

Problem

Adiponectin is a novel adipocytokine of extreme importance for the metabolism. Recent studies have indicated that adiponectin suppresses inflammation, angiogenesis, and fibrosis, which are central pathogenic factors for endometriosis. We addressed the possibility that adiponectin is implicated in endometriosis.

Method of study

We measured concentrations of adiponectin in peritoneal fluid (PF) of women with (n = 54) or without (n = 26) endometriosis using specific enzyme‐linked immunosorbent assay.

Results

Adiponectin concentrations in PF of women with endometriosis were significantly lower than those of women without endometriosis. With respect to the stages of the disease, the concentrations of adiponectin in women with stage III/IV endometriosis were significantly lower compared to those in women without endometriosis and with stage I/II endometriosis. Body mass index were comparable among the groups.

Conclusions

These findings imply that adiponectin may be an anti‐endometriotic factor, possibly due to its anti‐inflammatory, anti‐angiogenic, and anti‐fibrotic properties.
Immunity, Inflammation and Infection in Post‐partum Breast and Formula Feeders
Authors: Groer Maureen Wimberly , Davis Mitzi W. , Smith Kathlene , Casey Karyn , Kramer Valerie , Bukovsky Eva
Published: August 2005

Problem

Little is known about immunological recovery in post‐partum women and if lactational status affects immunocompetence. Many physiological changes occur, such as uterine involution and recovery of non‐pregnant immune status. These changes may also affect susceptibility to disease.

Method

The study compared immune and inflammatory activation markers (serum cytokines, Epstein Barr viral antibody titer, neopterin, c‐reactive protein (CRP), lymphocyte subset percentages, ex vivo cytokine production, lymphocyte proliferation, salivary Immunoglubulin A (sIgA) in exclusively breastfeeding (EB) and exclusively formula feeding (EF) women at 4–6 weeks post‐partum, and control (C) women.

Results

EBs had higher ratios of interferon‐γ (IFN‐γ)/interleukin‐10 (IL‐10) than EFs, and post‐partums were higher than Cs. Both IFN‐γ and IL‐10 were significantly higher in post‐partums compared to controls. Post‐partums also had higher proinflammatory cytokines, CRP and neopterin, salivary IgA and fewer infection symptoms. There were also differences in lymphocyte subsets.

Conclusions

The post‐partum period is oriented towards heightened and activated innate and specific immune defenses, with breastfeeding providing a boost in these phenomena.
Immunological Characterization of Superantigen‐induced Intrauterine Fetal and Newborn Death
Authors: Takei Eriko , Tamauchi Hidekazu , Maruyama Hiroko , Nakanishi Kuniaki , Ishikawa Masakazu , Unno Nobuya , Habu Sonoko
Published: August 2005

Problem

The present study characterizes the immunological responses induced by superantigen and the underlying pathological mechanism using T‐cell receptor‐transgenic mice (TCR‐Tg) to enable the ligand toxic shock syndrome toxin‐1 (TSST‐1) to induce a cytokine storm.

Method of study

Three kinds of pregnant mice which could respond to TSST‐1 at various levels were injected with TSST‐1 on gestation day 17.5 and then the incidence of fetal/newborn death, production of cytokines including serum interleukin‐2 (IL‐2) and the histological status of the placenta were examined on day 18.5.

Results

The incidence of fetal/newborn death and the concentrations of cytokines such as IL‐2 were higher in TCR‐Tg mother than those in other strains of mice. Pathological examinations revealed that the placenta was congestive and apoptotic in TCR‐Tg mice.

Conclusions

Superantigen injection into pregnant mice appears to increase the incidence of fetal/newborn death through an IL‐2‐dependent immunological pathway.
Family Businesses and Interfirm Cooperation
Authors: Roessl Dietmar
Published: September 2005

The objective of this article is to formulate hypotheses as to cooperation tendencies and capabilities in family businesses. As a first step, the circumstances under which inter-company cooperation arrangements originate are presented on the basis of an analysis of the relevant literature. Then, these circumstances are compared to cooperation-related characteristics of family businesses, thus identifying factors that hinder or encourage cooperation. This leads to the hypothesis that family businesses tend to be less willing to enter into cooperation arrangements as many characteristics of family businesses have a hindering effect on cooperation.
An Institutional Theory View of the Family Business
Authors: Leaptrott John
Published: September 2005

This article discusses the organizational forces common to the family business from the perspective of institutional theory. Both “old” and “new” institutionalism add useful perspectives for the analysis of family businesses. “Old” institutionalism encourages the study of structural change as a result of environmental pressures. “New” institutionalism focuses on the symbolic nature of organizations. Propositions regarding elements of these theories of institutional theory in a family business context are offered. Parallels between institutional theory and family systems theory are discussed.
Entrepreneurship and Family Business in a Hostile Environment: The Case of Lithuania
Authors: Dyer W. Gibb , Panicheva Mortensen Svetlana
Published: September 2005

This article compares the survival strategies used by the founders of family and nonfamily businesses in the hostile economic environment of Lithuania. In this exploratory study, six firms were studied in depth: three family firms and three nonfamily firms. These firms were in that sector of the Lithuanian economy designated as “light industry.” The major strategies used by founders to keep their firms viable include (1) developing social capital to gain favor with local authorities and important customers and suppliers and (2) using family networks to gain access to human and financial capital. The family businesses appeared to be more successful than the nonfamily enterprises. Moreover, the ability to draw on family resources seemed to be the predominant reason for their modest success.
Calcium signalling by nicotinic acid adenine dinucleotide phosphate (NAADP)
Authors: Yamasaki Michiko , Churchill Grant C. , Galione Antony
Published: September 2005

Nicotinic acid adenine dinucleotide phosphate (NAADP) is a recently described Ca2+ mobilizing messenger, and probably the most potent. We briefly review its unique properties as a Ca2+ mobilizing agent. We present arguments for its action in targeting acidic calcium stores rather than the endoplasmic reticulum. Finally, we discuss possible biosynthetic pathways for NAADP in cells and candidates for its target Ca2+ release channel, which has eluded identification so far.
Control of the coagulation system by serpins
Authors: Pike Robert N. , Buckle Ashley M. , le Bonniec Bernard F. , Church Frank C.
Published: September 2005

Members of the serine protease inhibitor (serpin) superfamily play important roles in the inhibition of serine proteases involved in complex systems. This is evident in the regulation of coagulation serine proteases, especially the central enzyme in this system, thrombin. This review focuses on three serpins which are known to be key players in the regulation of thrombin: antithrombin and heparin cofactor II, which inhibit thrombin in its procoagulant role, and protein C inhibitor, which primarily inhibits the thrombin/thrombomodulin complex, where thrombin plays an anticoagulant role. Several structures have been published in the past few years which have given great insight into the mechanism of action of these serpins and have significantly added to a wealth of biochemical and biophysical studies carried out previously. A major feature of these serpins is that they are under the control of glycosaminoglycans, which play a key role in accelerating and localizing their action. While further work is clearly required to understand the mechanism of action of the glycosaminoglycans, the biological mechanisms whereby cognate glycosaminoglycans for each serpin come into contact with the inhibitors also requires much further work in this important field.
The influence of cold shock proteins on transcription and translation studied in cell‐free model systems
Authors: Hofweber Roland , Horn Gudrun , Langmann Thomas , Balbach Jochen , Kremer Werner , Schmitz Gerd , Kalbitzer Hans R.
Published: September 2005

Cold shock proteins (CSPs) form a family of highly conserved bacterial proteins capable of single‐stranded nucleic acid binding. They are suggested to act as RNA chaperones during cold shock inhibiting the formation of RNA secondary structures, which are unfavourable for transcription and translation. To test this commonly accepted theory, isolated CSPs from a mesophilic, thermophilic and a hyperthermophilic bacterium (Bacillus subtilis, Bacillus caldolyticus and Thermotoga maritima) were studied in an Escherichia coli based cell free expression system on their capability of enhancing protein expression by reduction of mRNA secondary structures. The E. coli based expression of chloramphenicol acetyltransferase and of H‐Ras served as model systems. We observed a concentration‐dependent suppression of transcription and translation by the different CSPs which makes the considered addition of CSPs for enhancing the protein expression in in vitro translation systems obsolete. Protein expression was completely inhibited at CSP concentrations present under cold shock conditions. The CSP concentrations necessary for 50% inhibition were lowest (140 µm) for the protein of the hyperthermophilic and increased when the thermophilic (215 µm) or even the mesophilic protein (451 µm) was used. Isolated in vitro transcription under the influence of CSPs showed that the transcriptory effect is independent from the rest of the cell. It could be shown in a control experiment that the inhibition of protein expression can be removed by addition of hepta‐2’‐desoxy‐thymidylate (dT7); a heptanucleotide that competitively binds to CSP. The data are in line with a hypothesis that CSPs act on bulk protein expression not as RNA chaperones but inhibit their transcription and translation by rather unspecific nucleic acid binding.