bluuebunny/crossref_metadata_2025 huggingface dataset:
Asymmetry of Long‐latency Auditory Evoked Potentials in LGI1‐related Autosomal Dominant Lateral Temporal Lobe Epilepsy
Authors: Brodtkorb Eylert , Steinlein Ortrud K. , Sand Trond
Published: September 2005

Summary:  Purpose: To investigate auditory processing with cortical long‐latency auditory evoked potentials (AEPs) in patients with autosomal dominant lateral temporal lobe epilepsy (ADTLE).

Methods: Eight patients with LGI1‐related ADTLE belonging to a family with predominantly aphasic seizures were studied. Sixty‐five individuals without epilepsy served as controls. AEPs (N1‐P2 amplitudes) to binaural tones were recorded over the left and the right hemispheres. Brainstem auditory evoked potentials (BAEPs) to monaural rarefaction clicks also were analyzed. Group differences were statistically assessed with Student's t test and repeated‐measures analysis of variance.

Results: Left N1‐P2 AEP amplitudes were moderately reduced in ADTLE patients (p = 0.005). No group differences in BAEP were found, indicating unaffected cochlear system and auditory brainstem pathways.

Conclusions: A moderate, but highly significant reduction in N1‐P2 AEP amplitudes over the left hemisphere was demonstrated in patients with ADTLE. This finding corresponds to the cardinal symptom of aphasia in this family, and also to the generally prevailing left‐sided EEG abnormalities in this condition. The background for this electrophysiologic lateralization in LGI1‐related epilepsy is unknown. It may be related to a specific function of LGI1 in the dominant hemisphere.
Late‐onset and Slow‐progressing Lafora Disease in Four Siblings with EPM2B Mutation
Authors: Baykan Betul , Striano Pasquale , Gianotti Stefania , Bebek Nerses , Gennaro Elena , Gurses Candan , Zara Federico
Published: September 2005

Summary:  We report a family with four brothers affected by Lafora disease (LD). Mean age at onset was 19.5 years (range, 17–21). In all cases, the initial obvious symptoms were diffuse myoclonus and occasional generalized tonic–clonic seizures (GTCSs), followed by cognitive difficulties. Severity of myoclonus, seizure diaries, and neurologic and neuropsychological status were finally evaluated in March 2005. The duration of follow‐up was >10 years for three subjects. Daily living activities and social interaction were preserved in all cases and, overall, the progression of the disease was slow. Genetic study revealed the homozygous mutation D146N in the EPM2B gene. We suggest that this mutation may be associated with a less severe LD phenotype.
Anti‐HPA‐9bw (Maxa) fetomaternal alloimmunization, a clinically severe neonatal thrombocytopenia: difficulties in diagnosis and therapy and report on eight families
Authors: Kaplan Cécile , Porcelijn Leendert , Vanlieferinghen Philippe , Julien Eric , Bianchi Frederic , Martageix Corinne , Bertrand Gerald , Jallu Vincent
Published: October 2005

BACKGROUND:Fetal or neonatal alloimmune thrombocytopenia (FMAIT) results from a maternal alloimmunization against fetal platelet (PLT) antigens. In Caucasian persons, HPA‐1a is the most frequently implicated antigen. During the past few years, FMAIT has been reported associated with rare or private antigens.

STUDY DESIGN AND METHODS:Since the first documented case of FMAIT due to anti‐HPA‐9bw (Maxa), no additional cases have been reported. Here a retrospective analysis is presented of the cases referred to our laboratories in recent years. The diagnosis was performed by genotyping and identification of the maternal alloantibody by the monoclonal antibody–specific immobilization of PLT antigens (MAIPA) technique.

RESULTS:Parental genotyping showed HPA‐9bw (Maxa) mismatch as the sole antigenic incompatibility in seven of eight families. Because the father was found to be HPA‐9bw (Maxa) heterozygous in all the cases, the infant or fetus was genotyped to ascertain the diagnosis. The maternal alloantibody was identified in the MAIPA technique. These data strongly suggest, however, that recognition of the HPA‐9bw (Maxa) epitope is not uniform. The neonatal thrombocytopenia was severe in most cases with bleeding. The outcome was good in all the cases but one.

CONCLUSION:This analysis confirms that anti‐HPA‐9bw (Maxa) FMAIT is not uncommon and was found to be approximately 2 percent of our confirmed FMAIT cases. It is a clinically severe syndrome that requires prompt diagnosis, albeit difficult, and maternal PLT transfusion therapy. Laboratory investigation of a suspected FMAIT case should be carried out in a specialist laboratory well‐experienced in optimal testing. Appropriate management and antenatal therapy should be considered for successive pregnancies to prevent fetal bleeding.
Demonstrable parasitemia among Connecticut blood donors with antibodies to Babesia microti
Authors: Leiby David A. , Chung Amy P.S. , Gill Jennifer E. , Houghton Raymond L. , Persing David H. , Badon Stanley , Cable Ritchard G.
Published: October 2005

BACKGROUND: Reports of transfusion‐transmitted Babesia microti have risen steadily during the past several years, reflecting a concurrent increase in US cases of human babesiosis. Although several studies have measured B. microti antibodies in blood donors, little is known about associated parasitemia and the inherent risk of transmitting the parasite by transfusion.

STUDY DESIGN AND METHODS: Donations from blood donors located in Babesia‐endemic and nonendemic areas of Connecticut were tested for B. microti antibodies from July through September. Subsequently, an additional blood sample was collected from selected seropositive donors and tested by nested polymerase chain reaction (PCR) for B. microti nucleic acids.

RESULTS: A total of 3490 donations, 1745 each from endemic and nonendemic areas, were tested for B. microti antibodies; 30 (0.9%) were confirmed as positive and seroprevalence rates peaked in July. Significantly more seropositive donations were from endemic areas (24, 1.4%) than nonendemic areas (6, 0.3%). Ten (53%) of 19 seropositive donors subsequently tested by PCR were positive.

CONCLUSION: B. microti seroprevalence was highest in those areas of Connecticut where the parasite is endemic. More than half of seropositive donors tested had demonstrable parasitemia, indicating that many are at risk for transmitting B. microti by blood transfusion. Three donors were identified as parasitemic in October, suggesting that donors may be at risk for transmitting the parasite outside of the peak period of community‐acquired infection.
What Is a Life Worth? Robustness of VSL Values from Contingent Valuation Surveys
Authors: Alberini Anna
Published: September 2005

The value of a statistical life (VSL) is a key input for estimating the benefits of policies that save lives. Several recent studies have obtained estimates of the VSL from contingent valuation surveys, i.e., by asking people to say how much they would pay to reduce their risk of dying. This article examines statistical factors that may influence the estimates of the VSL obtained from such surveys. We examine the importance of distributional assumptions, the choice of the welfare statistics of interest, the procedure for computing them, outliers, undesirable response effects, and internal validity of the willingness‐to‐pay (WTP) responses. We illustrate the importance of these factors using dichotomous‐choice and open‐ended WTP data from four recent contingent valuation surveys.
Estimating the Health Impacts of Tobacco Harm Reduction Policies: A Simulation Modeling Approach
Authors: Ahmad Sajjad , Billimek John
Published: September 2005

With adult smoking prevalence rates declining too slowly to reach national objectives, opinion leaders are considering policies to improve tobacco‐related outcomes by regulating the composition of cigarettes to be (1) less harmful and/or (2) less addictive. Because harm reduction efforts may actually encourage higher cigarette consumption by promoting a safer image, and addictiveness reduction may increase the harmfulness of cigarettes by encouraging compensatory smoking behaviors, policymakers must consider the tradeoffs between these two approaches when proposing legislation to control cigarette content. To estimate health impacts, we developed a dynamic computer model simulating changes in the age‐ and gender‐specific smoking behaviors of the U.S. population over time. Secondary data for model parameters were obtained from publicly available sources. Population health impacts were measured as change in smoking prevalence and the change in cumulative quality‐adjusted life‐years (QALYs) in the U.S. population over 75 years. According to the risk‐use threshold matrix generated by the simulation, modifying cigarettes to reduce their harmfulness and/or addictiveness could result in important gains to the nation's health. Addictiveness reduction efforts producing a 60% improvement in smoking behavior change probabilities would produce a net gain in population health at every plausible level of increase of smoking‐related harm that was modeled. A 40% reduction in smoking‐related harm would produce a net QALY gain at every level of behavior change considered. This research should prove useful to policymakers as they contemplate giving the FDA the authority to regulate the composition of cigarettes.
An Interagency Comparison of Screening‐Level Risk Assessment Approaches
Authors: Jones‐Otazo Heather A. , Diamond Miriam L. , Richardson G. Mark
Published: September 2005

Approaches to risk assessment have been shown to vary among regulatory agencies and across jurisdictional boundaries according to the different assumptions and justifications used. Approaches to screening‐level risk assessment from six international agencies were applied to an urban case study focusing on benzo[a]pyrene (B[a]P) exposure and compared in order to provide insight into the differences between agency methods, assumptions, and justifications. Exposure estimates ranged four‐fold, with most of the dose stemming from exposure to animal products (8–73%) and plant products (24–88%). Total cancer risk across agencies varied by two orders of magnitude, with exposure to air and plant and animal products contributing most to total cancer risk, while the air contribution showed the greatest variability (1–99%). Variability in cancer risk of 100‐fold was attributed to choices of toxicological reference values (TRVs), either based on a combination of epidemiological and animal data, or on animal data. The contribution and importance of the urban exposure pathway for cancer risk varied according to the TRV and, ultimately, according to differences in risk assessment assumptions and guidance. While all agency risk assessment methods are predicated on science, the study results suggest that the largest impact on the differential assessment of risk by international agencies comes from policy and judgment, rather than science.
A Numerical Solution to the Nonhomogeneous Two‐Stage MVK Model of Cancer
Authors: Crump Kenny S. , Subramaniam Ravi P. , Van Landingham Cynthia B.
Published: September 2005

In this article, we describe a straightforward method for solving the probability of at least one malignant cell by time t, and the associated hazard function, in the general (i.e., nonhomogeneous) two‐stage Moolgavkar‐Venzon‐Knudson (MVK) model of cancer. The method consists of solving four coupled ordinary differential equations derived from the Kolmogorov backward equations for this process. The relationship of this method to previously proposed solutions is discussed.
Avoiding Microbubbles Formation During Radiofrequency Left Atrial Ablation Versus Continuous Microbubbles Formation and Standard Radiofrequency Ablation Protocols: Comparison of Energy Profiles and Chronic Lesion Characteristics
Authors: OH SEIL , KILICASLAN FETHI , ZHANG YOUHUA , WAZNI OUSSAMA , MAZGALEV TODOR N. , NATALE ANDREA , MARROUCHE NASSIR F.
Published: September 2005

Background: Radiofrequency (RF) energy parameters and chronic lesion characteristics associated with the microbubbles formation have not been yet fully elucidated.

Objectives: The objective of this study was to compare the energy profiles and chronic lesion characteristics associated with RF ablation of the pulmonary vein antrum using three different ablation protocols: (1) avoiding microbubbles; (2) continuous microbubble formation; (3) temperature‐guided ablation.

Methods: A 4‐mm tip ablation catheter was used for creating RF ablation lesions in 15 adult mongrel dogs. All ablation lesions were created at the posterior aspect of the PV antrum in each animal. Avoiding microbubbles (group 1, n = 5 dogs, 23 lesions), continuous microbubble formation (group 2, n = 5 dogs, 22 lesions), and temperature‐guided (group 3, n = 5 dogs, 19 lesions, target temperature 60°C/power limit 50 W) ablation lesions were analyzed.

Results: Group 1 showed significantly lower power (19 ± 8.6 W), lower temperature (50 ± 4.8°C), higher efficiency‐of‐heating index (2.9 ± 0.8°C/W), and lower impedance (109 ± 24.4 Ω) than groups 2 (38 ± 8.4 W; 63 ± 10°C; 1.8 ± 0.8°C/W; 148 ± 34.4 Ω) and 3 (44 ± 12 W; 57 ± 2.4°C; 1.4 ± 0.5°C/W; 139 ± 23.1 Ω) (P < 0.001 vs groups 2 and 3). During ablation, no significant events were detected in group 1, but 11 cases of audible pop, 11 cases of catheter tip charring, and 1 case of fatal myocardial perforation were observed in groups 2 and 3. Transmural lesions were more frequently created in group 1.

Conclusion: RF energy delivery applying “avoiding microbubbles” protocol seems to be associated with higher degree of safety and efficacy when compared to temperature‐guided and continuous microbubble‐formation ablation protocols.
Catheter Ablation of Long‐Lasting Persistent Atrial Fibrillation: Critical Structures for Termination
Authors: HAÏSSAGUERRE MICHEL , SANDERS PRASHANTHAN , HOCINI MÉLÈZE , TAKAHASHI YOSHIHIDE , ROTTER MARTIN , SACHER FREDERIC , ROSTOCK THOMAS , HSU LI‐FERN , BORDACHAR PIERRE , REUTER SYLVAIN , ROUDAUT RAYMOND , CLÉMENTY JACQUES , JAÏS PIERRE
Published: September 2005

Background: The relative contributions of different atrial regions to the maintenance of persistent atrial fibrillation (AF) are not known.

Methods: Sixty patients (53 ± 9 years) undergoing catheter ablation of persistent AF (17 ± 27 months) were studied. Ablation was performed in a randomized sequence at different left atrial (LA) regions and comprised isolation of the pulmonary veins (PV), isolation of other thoracic veins, and atrial tissue ablation targeting all regions with rapid or heterogeneous activation or guided by activation mapping. Finally, linear ablation at the roof and mitral isthmus was performed if sinus rhythm was not restored after addressing the above‐mentioned areas. The impact of ablation was evaluated by the effect on the fibrillatory cycle length in the coronary sinus and appendages at each step. Activation mapping and entrainment maneuvers were used to define the mechanisms and locations of intermediate focal or macroreentrant atrial tachycardias.

Results: AF terminated in 52 patients (87%), directly to sinus rhythm in 7 or via the ablation of 1–6 intermediate atrial tachycardias (total 87) in 45 patients. This conversion was preceded by prolongation of fibrillatory cycle length by 39 ± 9 msec, with the greatest magnitude occurring during ablation at the anterior LA, coronary sinus and PV‐LA junction. Thirty‐eight atrial tachycardias were focal (originating dominantly from these same sites), while 49 were macroreentrant (involving the mitral or cavotricuspid isthmus or LA roof). Patients without AF termination displayed shorter fibrillatory cycles at baseline: 130 ± 14 vs 156 ± 23 msec; P = 0.002.

Conclusion: Termination of persistent AF can be achieved in 87% of patients by catheter ablation. Ablation of the structures annexed to the left atrium—the left atrial appendage, coronary sinus, and PVs—have the greatest impact on the prolongation of AF cycle length, the conversion of AF to atrial tachycardia, and the termination of focal atrial tachycardias.
A Geometric Approach to Comparing Treatments for Rapidly Fatal Diseases
Authors: Thall Peter F. , Wooten Leiko H. , Shpall Elizabeth J.
Published: September 2005

Summary In therapy of rapidly fatal diseases, early treatment efficacy often is characterized by an event, “response,” which is observed relatively quickly. Since the risk of death decreases at the time of response, it is desirable not only to achieve a response, but to do so as rapidly as possible. We propose a Bayesian method for comparing treatments in this setting based on a competing risks model for response and death without response. Treatment effect is characterized by a two‐dimensional parameter consisting of the probability of response within a specified time and the mean time to response. Several target parameter pairs are elicited from the physician so that, for a reference covariate vector, all elicited pairs embody the same improvement in treatment efficacy compared to a fixed standard. A curve is fit to the elicited pairs and used to determine a two‐dimensional parameter set in which a new treatment is considered superior to the standard. Posterior probabilities of this set are used to construct rules for the treatment comparison and safety monitoring. The method is illustrated by a randomized trial comparing two cord blood transplantation methods.
Assessing Isotropy for Spatial Point Processes
Authors: Guan Yongtao , Sherman Michael , Calvin James A.
Published: September 2005

SummaryA common assumption while analyzing spatial point processes is direction invariance, i.e., isotropy. In this article, we propose a formal nonparametric approach to test for isotropy based on the asymptotic joint normality of the sample second‐order intensity function. We derive anL2consistent subsampling estimator for the asymptotic covariance matrix of the sample second‐order intensity function and use this to construct a test statistic with a χ2limiting distribution. We demonstrate the efficacy of the approach through simulation studies and an application to a desert plant data set, where our approach confirms suspected directional effects in the spatial distribution of the desert plant species.
Semiparametric Models for Missing Covariate and Response Data in Regression Models
Authors: Chen Qingxia , Ibrahim Joseph G.
Published: September 2005

SummaryWe consider a class of semiparametric models for the covariate distribution and missing data mechanism for missing covariate and/or response data for general classes of regression models including generalized linear models and generalized linear mixed models. Ignorable and nonignorable missing covariate and/or response data are considered. The proposed semiparametric model can be viewed as a sensitivity analysis for model misspecification of the missing covariate distribution and/or missing data mechanism. The semiparametric model consists of a generalized additive model (GAM) for the covariate distribution and/or missing data mechanism. Penalized regression splines are used to express the GAMs as a generalized linear mixed effects model, in which the variance of the corresponding random effects provides an intuitive index for choosing between the semiparametric and parametric model. Maximum likelihood estimates are then obtained via the EM algorithm. Simulations are given to demonstrate the methodology, and a real data set from a melanoma cancer clinical trial is analyzed using the proposed methods.
Site Occupancy Models with Heterogeneous Detection Probabilities
Authors: Royle J. Andrew
Published: September 2005

Summary Models for estimating the probability of occurrence of a species in the presence of imperfect detection are important in many ecological disciplines. In these “site occupancy” models, the possibility of heterogeneity in detection probabilities among sites must be considered because variation in abundance (and other factors) among sampled sites induces variation in detection probability (p). In this article, I develop occurrence probability models that allow for heterogeneous detection probabilities by considering several common classes of mixture distributions for p. For any mixing distribution, the likelihood has the general form of a zero‐inflated binomial mixture for which inference based upon integrated likelihood is straightforward. A recent paper by Link (2003, Biometrics59, 1123–1130) demonstrates that in closed population models used for estimating population size, different classes of mixture distributions are indistinguishable from data, yet can produce very different inferences about population size. I demonstrate that this problem can also arise in models for estimating site occupancy in the presence of heterogeneous detection probabilities. The implications of this are discussed in the context of an application to avian survey data and the development of animal monitoring programs.
Synthesis and Characterization of Thin Ferroelectric PbZr0.52Ti0.48O3 Fibrils
Authors: Ram S. , Mandal T. K.
Published: September 2005

Thin fibrils (usually 20–100 nm in diameter) of ferroelectric PbZr0.52Ti0.48O3 have a preferred nucleation and growth in the [001] direction in small particles. X‐ray diffraction with the X‐ray beam facing the fibril surfaces, which lie along the [001] direction, thus involves reflections of manifested intensity from (100) and (010) planes. No reflection occurs from the perpendicular planes to the [001] fibrils. A transmission electron micrograph with the corresponding electron diffraction from fibrils confers the results of the preferred growth. The fibrils have a modified orthorhombic crystal structure of lattice parameters a=0.4038 nm, b=0.4017 nm, and c=04148 nm, with an enhanced 8.033 g/cm3 density over 8.006 g/cm3 in the usual tetragonal structure of a=0.4036 nm and c=04146 nm. Surface anisotropy in a fibril that imposes (and drives) a shear stress over growing crystallites (within the fibril) along the [001] surface favors this specific crystal structure in them according to the precursor structure. A single‐phase sample is obtained in 2 h by heating of an amorphous template of precursor (of the metal cations with a polymer of polyvinyl alcohol and sucrose) at 500°–800°C in air.
Wollastonite from Hydrothermally Synthesized Calcium Hydrometasilicate Obtained from Various Modifications of Silica
Authors: Grigoryan K. , Harutyunyan G. , Grigoryan G.
Published: September 2005

A hydrothermally CaO–SiO2–H2O system was investigated at 150°–200°C, 2.5 h (CaO:SiO2=0.95) using various modifications of SiO2 in the presence of a mineralizer. Synthetic (stabilized) γ‐tridymite is the most reactive among SiO2 modifications. In the reaction mixture, the optimal concentration of the mineralizer (KOH) is 2% (versus the solid phase). The binding degree of CaO with SiO2 practically is 100% at 150°C. It is impossible to synthesize CSH free of C2SH on the basis of β‐cristobalite and β‐quartz under the investigation conditions without the use of mineralizer. The calorimetric effects as well as heat of de‐hydration of hydrosilicates were determined during their transformation into wollastonite. The entropy change at the peaks has been calculated.
Trivariate, Stereological Length–Radius–Orientation Unfolding Derived and Applied to Alumina–Silicon Carbide Whisker Composites
Authors: Mebane David S. , Gokhale Arun M. , Gerhardt Rosario A.
Published: September 2005

A new method of simultaneously unfolding lengths, radii, and orientations of chopped fibers or whiskers embedded in composites with an axis of symmetry is presented. The technique makes use of previously derived stereological results for the unfolding of lengths and radii of chopped fibers that are randomly oriented. An equation relating the trivariate size–shape–orientation distribution to the orientation of elliptical sections appearing on a vertical plane is derived. The procedure is demonstrated on an alumina–silicon carbide whisker composite material. A functional form for the distribution of whiskers in hot pressed ceramic matrix composites is proposed.
In Situ Crystallization of Highly Oriented Silicalite Films on Porous Zircon Supports
Authors: Falamaki Cavus , Afarani Mahdi Shafiee , Aghaie Alireza
Published: September 2005

The growth of silicalite zeolite layers by in situ crystallization on zircon porous supports has been investigated. Because of lower solubility in the mother liquor with respect to alumina substrates, zeolite weight gain with time is enhanced. Using the batch formulation 4.1 Na2O:50 SiO2:691 H2O:TPABr it was not possible to grow zeolite layers in an oriented fashion in the temperature range of 140°–180°C. It was observed that, unlike alumina substrates, porous zircon supports have a high affinity for oriented deposition of silicalite seeds (highly oriented 200/020 planes) by the dip‐coating process. This phenomenon is a strong function of slip pH and concentration. Seed layers are prone to heavy mass losses during the hydrothermal process. A “fixation” process has been applied for the first time to fix the latter by reacting surface Zr–OH and Si–OH groups by condensation reactions between the support and the seed and among the seeds themselves. Such a fixed seed layer undergoes mostly crystal growth with minimal nucleation during the hydrothermal step, resulting in a dense highly oriented zeolite layer.
Toughening of SiC with Ti3SiC2 Particles
Authors: Mogilevsky P. , Mah Tai‐Il , Parthasarathy T. A. , Cooke C. M.
Published: September 2005

Composites in the SiC–TiC–Ti3SiC2 system were synthesized using reactive hot pressing at 1600°C. The results indicate that addition of Ti3SiC2 to SiC leads to improved fracture toughness. In addition, high microhardness can be retained if TiC is added to the material. The best combination of properties obtained in this study is KIc=8.3 MPa·m1/2 and Hv=17.6 GPa. The composition can be tailored in situ using the decomposition of Ti3SiC2. Ti3SiC2 decomposed rapidly at temperatures above 1800°C, but the decomposition could be conducted in a controlled manner at 1750°C. This can be used for synthesis of fully dense composites with improved properties by first consolidating to full density a softer Ti3SiC2‐rich initial composition, and then using controlled decomposition of Ti3SiC2 to achieve the desired combination of microhardness and fracture toughness.
Viscosity of Electrostatically Stabilized Dispersions of Monodispersed, Bimodal, and Trimodal Silica Particles
Authors: Zaman A. A. , Dutcher C. S.
Published: September 2005

Effect of particle size and polydispersity on the viscosity and maximum packing fraction of aqueous colloidal dispersions has been studied. For dispersions of mono‐sized particles, the results indicate that there is a linear relationship between the log(η) (viscosity) and particle size at a fixed shear rate and volume fraction of solids. However, there is a particle diameter at which there is a decrease in the dependency of viscosity on particle size as the slope of the linear plots of log(η) versus particle diameter changes to a smaller value. Preliminary calculations indicate that this particle size may correspond to a separation distance at which electrostatic energy as compared with the thermal energy of the particles can be ignored. In the case of bimodal dispersions, the viscosity is affected by both absolute size and the ratio of the two sizes. The effect of particle size ratio on the viscosity was investigated using bimodal dispersions of the same size coarse particles, but fines of different sizes. There is a critical volume ratio below which bimodal dispersions of larger size ratios show lower viscosities than systems of smaller size ratios. Above this volume ratio of the two sizes, the trend becomes reversed and the fines will have a dominant effect on the viscosity behavior of the bimodal system. Statistically designed experiments were carried out using trimodal mixtures of monodispersed silica particles and it was shown that tridispersed suspensions demonstrate similar behavior as bidispersed suspensions, with a minimum in viscosity observed as a function of particle volume ratio.
Splenectomy for adult chronic idiopathic thrombocytopenic purpura: experience from a single center in China
Authors: Wang Tingting , Xu Maoqiang , Ji Linxiang , Han Zhong Chao , Yang Renchi
Published: September 2005

Abstract:  Objectives: The aim of this study was to explore the results of Chinese chronic idiopathic thrombocytopenic purpura (ITP) patients who underwent splenectomy (SE). Subjects and methods: Data of 149 chronic ITP patients were retrospectively analyzed. Relapse‐free survival was estimated by Kaplan–Meier analysis. Differences between responders and non‐responders were evaluated using the chi‐square. Results: The immediate response rate was 82.6% and the sustained response rate was 63.1%. Twenty‐nine patients (19.5%) relapsed during follow‐up. The 5‐year actuarial relapse‐free survival was about 75%. The overall morbidity was 26.1% and mortality was 2.7%. Patients with higher postsplenectomy peak platelet count, shorter time from diagnosis to SE and previous response to IVIG therapy were more likely to have sustained response to SE. Conclusion: SE is potentially a useful therapy to provide long‐term control of disease in adults with chronic ITP and is associated with low morbidity and mortality. Postsplenectomy peak platelet count, time from diagnosis to SE and previous response to intravenous immune globulin therapy appear predictive for response to SE.
Aging of red blood cells and impaired erythropoiesis following prolonged administration of dichloromethylene diphosphonate containing liposomes in rats
Authors: Giuliani Anna Lisa , Graldi Giuseppe , Veronesi Massimo , Unis Lorenza , Previato Antonio , Lorenzini Franco , Gandini Gloria , Bergamini Carlo , Vanara Franco , Wiener Edith , Wickramasinghe Sunitha N. , Berti Gilberto
Published: September 2005

Abstract:  Objectives: To investigate whether macrophage‐depleted rats may serve as a model for studying red blood cell (RBC) aging. Methods: Rats were macrophage‐depleted by 4 weekly injections of dichloromethylene diphosphonate‐containing liposomes (Cl2MDP‐CL). The macrophage content of spleens and bone marrows (BMs) was investigated by immunohistochemistry and light microscopy and by flow cytometry, respectively, after staining with macrophage‐specific monoclonal antibodies. In addition, the ultrastructure of residual BM macrophages and their ability to phagocytose zymosan was studied. BM was also studied for apoptosis (by the TUNEL reaction) and for erythroid progenitor cell content. Furthermore, RBC indices, morphology, life span (by 51Cr labeling) and aging features (MCV, density, 4.1a/4.1b membrane protein ratio, anti‐spectrin IgG binding, microvesiculation) were investigated. Serum TNF‐α, iron, total iron‐binding capacity (TIBC) and ferritin were also determined. Results: Prolonged treatment with Cl2MDP‐CL caused an almost complete depletion of macrophages in the spleen and a 58% reduction of those in the BM; the residual BM macrophages were activated as judged by their ultrastructure and phagocytic capacity in vitro. These alterations were accompanied by an increase in RBC life span and age‐related RBC changes, as well as by mild anemia associated with a reduced reticulocyte count, reduced BM erythroid progenitors, increased numbers of apoptotic cells in the BM, low serum iron, high TIBC and increased serum TNF‐α levels. Conclusions: Rats subjected to prolonged macrophage depletion showed an increased prevalence of senescent RBC in the circulation due to their impaired clearance by macrophages. Hence, these animals provide a model system in which mechanisms of RBC aging can be delineated. They also showed impaired erythropoiesis, presumably related to a reduction in BM macrophages and increased production of proinflammatory cytokines by residual activated marrow macrophages and other cells.
Improvement of thrombocytopenia with disappearance of HCV RNA in patients treated by interferon‐α therapy: possible etiology of HCV‐associated immune thrombocytopenia
Authors: Iga Daijiro , Tomimatsu Masahiko , Endo Hitoshi , Ohkawa Shin‐Ichiro , Yamada Osamu
Published: September 2005

Abstract:  We evaluated the relationship between the severity of thrombocytopenia and the serum hepatitis C virus (HCV) RNA level to investigate the mechanism of thrombocytopenia in patients with HCV infection. Patients who had chronic hepatitis without splenomegaly were divided into two groups according to the platelet count, which were 18 patients with a platelet count ≤150 × 109/L and 22 patients with a platelet count >150 × 109/L. HCV RNA, platelet‐associated immunoglobulin G (PAIgG), rheumatoid factor (RF), and other immunological parameters were measured and correlations were investigated. Patients in the low platelet group had higher levels of PAIgG, Th1 cells, thrombopoietin (TPO), and RF than those in the normal platelet group (textitP < 0.05). Twenty‐two patients completed 6 months of IFN therapy and were followed for more than 1 yr afterwards. Twelve patients who responded to IFN therapy with clearance of HCV showed an increase of the platelet count, whereas the 10 patients who did not respond to IFN showed a decrease of the platelet count. The improvement of thrombocytopenia after interferon therapy suggests a contribution of HCV infection to this condition.
Acquired thrombotic thrombocytopenic purpura as the presenting symptom of systemic lupus erythematosus. Successful treatment with plasma exchange and immunosuppression – report of two cases
Authors: Starck M. , Abedinpour F. , Dendorfer U. , Wagner‐Czekalla J. , Pachmann M. , Mann J. F. , Nerl C.
Published: September 2005

Abstract:  Thrombotic thrombocytopenic purpura (TTP) is a rare but life‐threatening syndrome characterized by platelet aggregation causing occlusive microangiopathy. It has been described as a complication in systemic lupus erythematosus (SLE). Recent research indicated that genetic or autoantibody‐induced deficiency of the metalloprotease ADAMTS13 plays a key role in the pathogenesis of TTP. Here we report two uncommon cases of TTP as the first presenting symptom of SLE. Both patients were treated with combined plasma exchange and immunosuppressive therapy, and recovered completely. Although TTP and SLE have several clinical findings in common, and both disorders may coexist more frequently than we currently assume, features of one disease should not mislead to reject the alternative disorder.
Protein Z levels and central retinal vein or artery occlusion
Authors: Koren‐Michowitz Maya , Eting Eva , Rahimi‐Levene Naomi , Garach‐Jehoshua Osnat , Volcheck Yulia , Kornberg Abraham
Published: September 2005

Abstract:  Objectives: Central retinal vein occlusion (CRVO) and central retinal artery occlusion (CRAO) are common disorders associated with risk factors for atherosclerosis. Protein Z is a cofactor for the inactivation of activated factor X (Xa) by the protein Z dependent protease inhibitor. Protein Z deficiency was recently linked to increased risk of arterial thrombosis. We investigated whether CRVO and CRAO are associated with low protein Z levels. Patients and methods: Patients with CRVO, CRAO or recurrent branch retinal vein occlusion were recruited to the study. Protein Z level, lupus anticoagulant (LAC), anticardiolipin antibodies (ACA) and activated protein C resistance (APCR) were determined in plasma from patients (n = 36) and healthy controls (n = 42). Results: Thirty patients in the study group had traditional risk factors for retinal vessel occlusion and six patients had none. There was no significant difference in protein Z levels between the whole study group patients and controls (1995 ± 810 vs. 2010 ± 603 ng/mL, P = 0.922). However, patients with no risk factors for retinal vessel occlusion had significantly lower protein Z levels than controls (1379 ± 682 vs. 2010 ± 603 ng/mL, P = 0.022). Positive LAC was found in six patients and one control subject (P = 0.04). There were three patients and one control subject with abnormal APCR (P = 0.3) and none with positive ACA. Low protein Z level (lower than fifth percentile of control) was not associated with the presence of LAC or APCR. Conclusion: Low protein Z level may be another risk factor for retinal vessel occlusion in patients without traditional risk factors for these disorders.
Thalidomide plus dexamethasone is an effective salvage regimen for myeloma patients relapsing after autologous transplant
Authors: Palumbo Antonio , Falco Patrizia , Ambrosini Maria Teresa , Petrucci Maria Teresa , Musto Pellegrino , Caravita Tommaso , Pregno Patrizia , Bertola Alessandra , Cavallo Federica , Ciccone Giovannino , Boccadoro Mario
Published: September 2005

Abstract:  Objectives: High‐dose therapy followed by autologous transplant (AT) is the effective induction treatment for newly diagnosed multiple myeloma (MM) patients. The best salvage therapy has not been defined; treatment options include thalidomide plus dexamethasone (TD), AT and conventional chemotherapy (CC). The aim of the study was to define the best treatment option for patients relapsing after AT. Patients and Methods: We compared the outcome of 90 MM patients treated at diagnosis with AT and then salvaged with TD (43 patients), AT (28 patients) or CC (19 patients). The major prognostic factors, the median times between diagnosis and start of salvage treatment and the progression‐free survival (PFS) from diagnosis were similar among the three groups. Results: The response rate was higher after salvage AT and after TD, and lower after CC (P < 0.001). TD significantly prolonged PFS from first relapse (P < 0.0001). Median PFS was 20.3 months after TD, 9 months after AT, and 4.5 months after CC. Overall survival (OS) from first relapse was significantly improved by TD (median OS 55.5 months) but not by AT (15 months) or CC (27.5 months) (P = 0.008). Multivariate analysis indicated that TD and age were the only independent risk factors associated with improved outcome. Conclusion: TD improved PFS and OS in myeloma patients relapsing after AT.
Apoptosis and expression of anti‐ and pro‐apoptotic proteins in peripheral blood mononuclear cells of Fanconi anaemia patients: a study of 73 cases
Authors: Baruque Graça A. , Bitencourt Marco A. , Pasquini Ricardo , Castelo‐Branco Morgana T. L. , Llerena Juan C. , Rumjanek Vivian M.
Published: September 2005

Abstract:  Fanconi anaemia (FA) is a rare genetic disease whose patients have a high predisposition to haematological abnormalities and cancer. Fas expression levels in peripheral blood lymphocytes samples of 73 FA patients were measured to verify if alterations in Fas expression could lead to predisposition/resistance to spontaneous or PHA induced apoptosis, as well as, to reflect some haematological features of this disease. The anti‐ and pro‐apoptotic proteins Bcl‐2 and Bax were also evaluated. FA patients samples could be divided into three different groups based on Fas expression: 20 samples had low, 32 normal and 21 increased Fas levels when compared to 41 control samples. No correlation was found between Fas and Bcl‐2 expression but a good association was obtained with Bax, in the subgroup with increased Fas expression. The best correlation was seen between Bax expression and apoptosis. Out of the 15 samples with high Bax expression, 11 underwent apoptosis whereas only one out of seven samples with low levels of Bax displayed increased induced apoptosis. Most patients with normal haematological features expressed Fas within normal levels. It is difficult to establish, however, if Fas‐expression is involved in the cause or is a consequence of the effects observed.
Evidence from the stop‐EGFP mouse supports a niche‐sharing model of epidermal proliferative units
Authors: Ro Simon , Rannala Bruce
Published: September 2005

Abstract:  The classical model of epidermal proliferative units (EPUs) postulates that each EPU is composed of a single column of corneocytes plus epidermal cells directly below the column and is maintained by a single stem cell within the unit. Using the stop‐enhanced green fluorescent protein (stop‐EGFP) transgenic mouse system, we previously showed epidermal stem cell clonal lineages could produce multiple adjacent corneocytes (i.e. epidermal cells belonging to multiple adjacent EPUs), contradicting the classical EPU model. One possible problem with our earlier study was that N‐ethyl‐N‐nitrosourea (ENU) was used to generate mutations for clonal analysis. This could alter the normal environment of the epidermal tissue and might lead to an artificial expansion of stem cell clonal lineages. In this study, we replicate our earlier findings using untreated stop‐EGFP mice and relying on spontaneous mutations to generate clonal cell lineages. We propose an alternative to the classical EPU model to explain the dynamic nature of epidermal proliferation. Our niche‐sharing model of EPUs allows epidermal cells to horizontally migrate among EPUs, so that multiple stem cells cooperatively maintain a larger proliferative compartment.
Immunocytochemical demonstration of day/night changes of clock gene protein levels in the murine adrenal gland: differences between melatonin‐proficient (C3H) and melatonin‐deficient (C57BL) mice
Authors: Torres‐Farfan Claudia , Serón‐Ferré María , Dinet Virginie , Korf Horst‐Werner
Published: September 2005

Abstract:  The circadian system comprises several peripheral oscillators and a central rhythm generator that, in mammals, is located in the suprachiasmatic nucleus of the hypothalamus. Expression of clock genes is a characteristic feature of the central rhythm generator and the peripheral oscillators. With regard to the rhythmic production of glucocorticoids, the adrenal gland can be considered as peripheral oscillator, but little is known about clock gene expression in this tissue. Therefore, the present study investigates the levels of three clock gene proteins PER1, BMAL1 and CRY2 in the murine adrenal cortex and medulla at seven different time points of a 12‐hr light/12‐hr dark cycle. To determine a potential role of melatonin we compared the patterns of clock gene proteins in the adrenal gland of melatonin‐proficient mice (C3H) with those of melatonin‐deficient mice (C57BL). In C3H mice, both, the adrenal cortex and medulla displayed day/night variation in PER1‐, CRY2‐ and BMAL1‐protein levels. PER1 and CRY2 peaked in the middle of the light phase, whereas BMAL1 peaked in the dark phase. This pattern was also observed in the adrenal medulla of C57BL, but in the adrenal cortex of C57BL clock gene protein levels did not change with time and were consistently lower than in C3H mice. These results support the hypothesis that the adrenal gland is a peripheral oscillator and raise the possibility that melatonin may be involved in the control of clock gene protein levels in the adrenal cortex of mice.
Short‐ and long‐term effects of melatonin on myocardial post‐ischemic recovery
Authors: Lochner Amanda , Genade Sonia , Davids Ashraf , Ytrehus Kirsti , Moolman Johan A.
Published: September 2005

Abstract:  Melatonin, the chief secretory product of the pineal gland, has been shown to protect the heart against ischemia–reperfusion injury. This was attributed to its free radical scavenging and broad‐spectrum antioxidant properties. The possibility that melatonin may act via its receptor and intracellular signaling, has not yet been addressed in this regard. In all previous studies, only the acute effects of melatonin on the heart, were evaluated. The aims of the present study were to: (i) compare the acute and long‐term effects of melatonin on infarct size and functional recovery of the ischemic heart, and (ii) evaluate the role of the melatonin receptor in cardioprotection. For evaluation of the short‐term effects of melatonin on contractile recovery and infarct size, the isolated perfused working rat heart was subjected to 20 min global ischemia or 35 min regional ischemia respectively, and melatonin (25–50 μm) administered either before and during reperfusion, or before ischemia or during reperfusion after ischemia. The melatonin receptor was manipulated using luzindole and N‐acetyltryptamine. The long‐term effects of melatonin were evaluated 24 hr after melatonin administration (2.5 or 5.0 mg/kg, i.p.) or after oral administration for 7 days (20 or 40 μg/mL). Infarct size and mechanical recovery during reperfusion of the working heart were used as endpoints. Melatonin (50 μm), when administered either before and during reperfusion after ischemia or during reperfusion only, significantly improved cardiac output and work performance and reduced infarct size compared with untreated controls. Luzindole (5 μm), a melatonin receptor antagonist, abolished these cardioprotective effects. Long‐term administration of melatonin (i.p. or orally for 7 days) caused a significant reduction in infarct size of hearts subjected to 35 min regional ischemia. The cardioprotection persisted for 2–4 days after discontinuation of treatment. In summary, the results obtained suggest that melatonin induces short‐ as well as long‐term protection and that the melatonin receptor is also involved in its cardioprotective actions.
The Steady‐State Distribution of Glycosyltransferases Between the Golgi Apparatus and the Endoplasmic Reticulum is Approximately 90:10
Authors: Rhee Sung Wu , Starr Tregei , Forsten‐Williams Kimberly , Storrie Brian
Published: September 2005

Several lines of evidence support a novel model for Golgi protein residency in which these proteins cycle between the Golgi apparatus and the endoplasmic reticulum (ER). However, to preserve the functional distinction between the two organelles, this pool of ER‐resident Golgi enzymes must be small. We quantified the distribution for two Golgi glycosyltransferases in HeLa cells to test this prediction. We reasoned that best‐practice, quantitative solutions would come from treating images as data arrays rather than pictures. Using deconvolution and computer calculated organellar boundaries, the Golgi fraction for both endogenous β1,4‐galactosyltransferase and UDP‐N‐acetylgalactosamine:polypeptide N‐acetylgalactosaminyltransferase 2 fused with green fluorescent protein (GFP) was 91% by fluorescence microscopy. Immunogold labeling followed by electron microscopy and model analysis yielded a similar value. Values reflect steady‐state conditions, as inclusion of a protein synthesis inhibitor had no effect. These data strongly suggest that the fluorescence of a GFP chimera with an organellar protein can be a valid indicator of protein distribution and more generally that fluorescent microscopy can provide a valid, rapid approach for protein quantification. In conclusion, we find the ER pool of cycling Golgi glycosyltransferases is small and approximately 1/100 the concentration found in the Golgi apparatus.
E‐Cadherin Transport from the trans‐Golgi Network in Tubulovesicular Carriers is Selectively Regulated by Golgin‐97
Authors: Lock John G. , Hammond Luke A. , Houghton Fiona , Gleeson Paul A. , Stow Jennifer L.
Published: September 2005

E‐cadherin is a cell–cell adhesion protein that is trafficked and delivered to the basolateral cell surface. Membrane‐bound carriers for the post‐Golgi exocytosis of E‐cadherin have not been characterized. Green fluorescent protein (GFP)‐tagged E‐cadherin (Ecad‐GFP) is transported from the trans‐Golgi network (TGN) to the recycling endosome on its way to the cell surface in tubulovesicular carriers that resemble TGN tubules labeled by members of the golgin family of tethering proteins. Here, we examine the association of golgins with tubular carriers containing E‐cadherin as cargo. Fluorescent GRIP domains from golgin proteins replicate the membrane binding of the full‐length proteins and were coexpressed with Ecad‐GFP. The GRIP domains of p230/golgin‐245 and golgin‐97 had overlapping but nonidentical distributions on the TGN; both domains were on TGN‐derived tubules but only the golgin‐97 GRIP domain coincided with Ecad‐GFP tubules in live cells. When the Arl1‐binding endogenous golgins, p230/golgin‐245 and golgin‐97 were displaced from Golgi membranes by overexpression of the p230 GRIP domain, trafficking of Ecad‐GFP was inhibited. siRNA knockdown of golgin‐97 also inhibited trafficking of Ecad‐GFP. Thus, the GRIP domains of p230/golgin‐245 and golgin‐97 bind discriminately to distinct membrane subdomains of the TGN. Golgin‐97 is identified as a selective and essential component of the tubulovesicular carriers transporting E‐cadherin out of the TGN.