bluuebunny/crossref_metadata_2025 huggingface dataset:
A Case of Monochorionic Twin Pregnancy Complicated with Intrauterine Single Fetal Death with Successful Treatment of Intrauterine Blood Transfusion in the Surviving Fetus
Authors: Nakata Masahiko , Sumie Masahiro , Murata Susumu , Miwa Ichiro , Kusaka Emiko , Sugino Norihiro
Published: September 2006

We report a case of monochorionic twin pregnancy complicated with single fetal demise that received successful treatment of intrauterine transfusion for severe anemia of the surviving fetus. A single fetal demise occurred at 20 weeks of gestation and middle cerebral artery peak systolic velocity (MCA-PSV), a marker for fetal anemia, showed marked elevation in the surviving fetus. Fetal blood sampling was immediately done and severe fetal anemia (hemoglobin = 5.5 g/dl, hematocrit = 16.8%) was confirmed, and then intrauterine transfusion was performed. After transfusion, MCA-PSV rapidly decreased to the normal value and remained within normal range until delivery. A healthy 2,640 g male infant was delivered at 35 weeks of gestation without anemic status and no neurological problem was found at 1-year old. The present report supports that intrauterine rescue transfusion is a useful treatment to prevent the adverse outcome of surviving fetus in monochorionic twin pregnancy complicated with single fetal demise, and monitoring of MCA-PSV is also useful to assess anemic status of the surviving fetus.
Premature Rupture of Membranes at 20 Weeks: Report of a Successful Outcome after Transcervical Application of Fibrin Glue
Authors: Calado Elsa , Ayres-de-Campos Diogo
Published: September 2006

A 30-year-old primigravida was admitted to hospital at 20 weeks of gestation because of premature rupture of membranes and oligohydramnios. The patient was maintained in bed rest and given intravenous ampicillin. Forty-eight hours later, after documenting the absence of infection and maintenance of the oligohydramnios, fibrin glue was applied transcervically under ultrasound control. There was subjective improvement in amniotic fluid volume after treatment, but always within the criteria of oligohydramnios. Fibrin glue application was repeated twice due to reported increase in fluid loss and diminished amniotic fluid volume on ultrasound. Amoxicillin per os was started at 23 weeks, and clavulanic acid was added at 26 weeks due to the isolation of an Escherichia coli on cervical-vaginal cultures. No signs of infection ensued until 34 weeks, when an axillary temperature of 39.5°C was detected together with a non-reassuring cardiotocographic pattern, the latter leading to the performance of an urgent cesarean section. The newborn had an Apgar score of 9/10/10, umbilical artery pH of 7.32, and no external deformities. He showed no signs of lung hypoplasia and required no oxygen supplementation. Oropharyngeal and blood cultures revealed an E. coli infection and antibiotic treatment was started. No further complications occurred and he was discharged home on the 8th day of life. At 12 months, the child reveals a normal development. The mother had a mild and short-lasting wound infection and was discharged on the 8th postoperative day.
Beckwith-Wiedemann Syndrome Presenting with an Elevated Triple Screen in the Second Trimester of Pregnancy
Authors: Aagaard-Tillery Kjersti M. , Buchbinder Alan , Boente Mathew P. , Ramin Kirk D.
Published: September 2006

Background: Beckwith-Wiedemann syndrome (BWS) is a distinct clinical syndrome with unique features, generally diagnosed postnatally. Case: A 26-year-old patient, gravida 4, para 3-0-0-3, was noted to have an abnormal maternal serum screen. Amniocentesis with imaging studies were remarkable only for a two-vessel umbilical cord and prominent maternal ovaries. The patient developed HELLP syndrome at 28 weeks and delivered a viable female infant with distinct clinical features. The diagnosis of BWS was confirmed by hypermethylation of the H19 gene on chromosome 11p15.5. Conclusion: This case describes a novel presentation of BWS and underscores the diagnostic potential of routine prenatal screens.
CFTR ΔF508 Mutation Detection from Dried Blood Samples in the First Trimester of Pregnancy: A Possible Routine Prenatal Screening Strategy for Cystic Fibrosis?
Authors: Konialis Christopher P. , Hagnefelt Birgitta , Kazamia Constantina , Karapanou Sophia , Pangalos Constantinos
Published: September 2006

Objective: The implementation and evaluation of a proposed wide-scale prenatal screening strategy, based on DNA isolated from dried blood spots in the first trimester of pregnancy, for the early detection of pregnancies at risk for cystic fibrosis (CF). Methods: The screening was performed in conjunction with routine biochemical marker screening for Down’s syndrome risk in the first trimester of pregnancy. DNA was isolated from 1,233 dried blood spots and analyzed for the presence of the CF transmembrane regulator ΔF508 mutation. Women carriers were offered and accepted the option for additional full testing of their partners in order to assess the risk for the fetus. Results: All 1,233 samples were successfully analyzed, identifying 23 ΔF508 carriers, corresponding to a ΔF508 carrier rate of ∼1/55 (1.8%). All partners of the women carriers were further tested without revealing any need for further prenatal testing in this group. Conclusions: This study reveals the relatively high frequency of the ΔF508 CF mutation in the Greek population. More importantly, we demonstrate that the proposed prenatal screening strategy, based on the ease and cost-effectiveness of the analysis for the detection of a single common mutation, can be considered as a feasible and practical approach for wide-scale prenatal screening for CF, following the sequential model. It is applied early on in pregnancy, allowing for the timely management of families at risk for the corresponding genetic disorders. Finally, it can easily be extended to include screening for other common genetic disorders in specific population groups.
Detection of ΔF508del Using Quantitative Real-Time PCR, Comparison of the Results Obtained by Fluorescent PCR
Authors: Nagy Bálint , Richárd Nagy Gyula , Lázár Levente , Bán Zoltán , Papp Zoltán
Published: September 2006

Objective: Cystic fibrosis (CF) is the most common autosomal recessive genetic disorder in the Caucasian population. The molecular diagnosis is difficult since there are about 1,000 mutations in the CF transmembrane regulator gene. The ΔF508del is the cause of the CF in 64% of the cases in Hungary. Our aim was to compare two polymerase chain reaction (PCR)-based method for the detection of ΔF508del. Methods: One hundred and sixteen DNA samples isolated from different tissues (84 blood samples, 18 chorionic villus samples and 14 amniotic fluid samples) were involved in the study. Fluorescent PCR with DNA fragment analysis and quantitative real-time PCR with melting curve analysis were performed on the DNA samples for the detection of ΔF508del. Results: Sixty-five healthy normal samples, 43 heterozygous samples, 6 ΔF508del homozygous samples and 2 ΔF508C homozygous samples were detected by using quantitative real-time PCR combined with melting curve analysis. The fluorescent PCR method did not detect the ΔF508C mutation and these two samples were diagnosed as normal healthy ones. Conclusions: The quantitative real-time PCR with melting curve analysis is a reliable and fast method for the detection of ΔF508del. The results are ready in 1 h following the DNA isolation. The applied primer-probe set with melting curve analysis gives additional information for the presence of other mutations in the ΔF508del region.
Long-Term Outcome of Infants with Twin-to-Twin Transfusion Syndrome
Authors: Hikino Shunji , Ohga Shouichi , Kanda Takashi , Nakashima Toshinori , Yamamoto Junko , Nakayama Hideki , Nakano Hitoo , Hara Toshiro
Published: September 2006

Objective: To clarify the long-term neurodevelopmental outcome of twin-to-twin transfusion syndrome (TTTS) survivors. Methods: From January 1994 to December 2003, 33 newborns with TTTS who were derived from 18 monochorionic twin gestations were enrolled for the study. The development and growth at 3 or 6 years of age were compared between TTTS survivors and weight-matched singleton controls. Results: The mortality in TTTS (8/33: 24%) was significantly higher than that of the controls (7/80: 9%). Of all 12 TTTS patients who were diagnosed before 25 weeks and born before 28 weeks of gestation, in 10 (83%) it led to neonatal or intrauterine death. The morbidity of cerebral palsy, epilepsy, and mental retardation did not differ between TTTS and control patients. The morbidity and severity of neurological deficits at school age were similar in both groups. No growth parameters at 3 or 6 years of age differed between TTTS and controls. Conclusions: Morbidity, growth and development of TTTS survivors attained comparable levels of weight-matched controls, despite the higher neonatal mortality. These results suggest that the early management of TTTS is critical for refining the total outcome of the affected twins.
Local Perfusion of the Tumor Necrosis Factor α Blocker Infliximab to the Inner Ear Improves Autoimmune Neurosensory Hearing Loss
Authors: van Wijk F. , Staecker H. , Keithley E. , Lefebvre P.P.
Published: September 2006

Objective: To evaluate the effect of transtympanic administration of tumor necrosis factor α (TNF-α) blockers to patients suffering from autoimmune inner ear disease (AIED). Study Design: Nonrandomized, prospective pilot study. Setting: Tertiary referral center. Patients: 9 patients (4 men and 5 women; aged 51.22 ± 13.11 years) presenting with autoimmune sensorineural hearing loss who responded to oral steroid treatment. Two groups of patients were treated. Group A consisted of 5 patients with AIED who could not be tapered off steroids. Group B consisted of 4 patients who were treated with intratympanic anti-TNF-α antibody therapy alone after a relapse of hearing loss following discontinuation of steroids. Intervention: A Silverstein MicroWickTM local delivery system was placed in the round window niche and the patients were treated for 4 weeks with a weekly infusion of infliximab, a monoclonal antibody against TNF-α. Main Outcome Measure(s): Evaluation of hearing thresholds at 250–8000 Hz was performed before and after implantation of the Silverstein MicroWick and local delivery of the TNF-α blocker. Results: Local administration of the TNF-α blocker allowed methylprednisolone to be tapered off without loss of hearing function in 4/5 steroid-dependent patients. Four additional patients were treated only with anti-TNF-α perfusion to the round window membrane without concomitant systemic administration of methylprednisolone. In 3 of these 4 patients, the pure tone average improved to 22.6 ± 15.7 dB, resulting in hearing recovery comparable to treatment with systemic methylprednisolone. The 7 responding patients showed a significant reduction of recurrence of hearing loss to 0.028 ± 0.072 episodes per month over the 4.3 ± 2.4 months of the post-treatment period compared to 0.84 ± 0.4 recurrences per week seen in the pretreatment period. Conclusions: The results of this pilot trial demonstrate that in patients with AIED, transtympanic delivery of the TNF-α blocker infliximab once weekly for 4 weeks allowed steroids to be tapered off, resulted in hearing improvement and reduced disease relapses. These preliminary efficacy and safety results appear encouraging enough to warrant further follow-up and studies for better determination of the potential clinical utility of local administration of infliximab for autoimmune hearing loss.
Biomechanical Modeling and Design Optimization of Cartilage Myringoplasty Using Finite Element Analysis
Authors: Lee Chia-Fone , Hsu Lee-Ping , Chen Peir-Rong , Chou Yuan-Fang , Chen Jyh-Horng , Liu Tien-Chen
Published: September 2006

The purpose of this study was to determine the acoustic transfer characteristics of cartilage for optimal cartilage myringoplasty. In order to do so, we developed a cartilage plate/tympanic membrane-coupled model using finite element analysis. Cartilage specimens of the tragus were obtained from fresh human cadavers, and the parameters of the tragus were determined by curve fitting and cross-calibration. A cartilage plate was used to repair an eardrum perforation, and the new coupled tympanic membrane-cartilage complex was loaded into our 3-dimensional biomechanical model of the middle ear for analysis. Our results show that first the β-damping value of the cartilage plate depends on frequency. The value of β damping was close to 3 × 10–4 s at lower frequencies and 5 × 10–6 s at higher frequencies. Secondly, reducing cartilage thickness leads to an improvement of its acoustic transfer qualities. From an acoustics point of view, the 0.1- to 0.2-mm cartilage plate seems to be most preferable with regard to tympanic membrane vibration. Furthermore, thicknesses of 0.2 mm at lower frequencies and 0.1 mm at higher frequencies were regarded as good compromises between sufficient mechanical stability and low acoustic transfer loss.
Loss of the Lysophosphatidylcholine Effector, G2A, Ameliorates Aortic Atherosclerosis in Low-Density Lipoprotein Receptor Knockout Mice
Authors: Parks Brian W. , Lusis Aldons J. , Kabarowski Janusz H.S.
Published: September 2006

Objective—

Lysophosphatidylcholine is a major product of low-density lipoprotein (LDL) oxidation and secretory phospholipase A
2
-mediated lipid hydrolysis within atherosclerotic lesions. The G2A receptor mediates chemotaxis of cultured macrophages and T cells to lysophosphatidylcholine, supporting a pro-atherogenic role for this receptor in vivo. We investigated the ability of G2A to modulate atherosclerosis in mice.

Methods and Results—

We measured atherosclerosis in G2A
+/+
and G2A
−/−
LDL receptor knockout (LDLR
−/−
) mice. Consistent with a previous study, early lesion size at the aortic sinus was unaffected by G2A deficiency. However, G2A deficiency attenuated lesion progression at this site (42% to 44% reduction in average lesion area) and led to robust suppression of atherosclerosis throughout the aorta after short and extended periods of diet intervention (reduction in aortic lesion coverage: 62% to 73% at 9 weeks, 75% to 84% at 20 weeks). In G2A
−/−
LDLR
−/−
mice, intimal macrophage accumulation at lesion-prone sites of the aorta was significantly reduced in the absence of any detectable effect on T cell recruitment. Examination of lipoprotein profiles revealed elevated levels of circulating high-density lipoprotein (HDL) cholesterol in G2A
−/−
LDLR
−/−
mice compared with their G2A
+/+
LDLR
−/−
counterparts after extended periods of diet intervention (54% increase in mean HDL cholesterol concentration).

Conclusion—

G2A provides a pro-atherogenic stimulus in vivo consistent with its chemotactic action but to which a pleiotropy of effects, including modulation of lipoprotein metabolism, may also contribute.
Procoagulant Microparticles
Authors: Morel Olivier , Toti Florence , Hugel Bénédicte , Bakouboula Babé , Camoin-Jau Laurence , Dignat-George Françoise , Freyssinet Jean-Marie
Published: September 2006

Apoptosis and vascular cell activation are main contributors to the release of procoagulant microparticles (MPs), deleterious partners in atherothrombosis. Elevated levels of circulating platelet, monocyte, or endothelial-derived MPs are associated with most of the cardiovascular risk factors and appear indicative of poor clinical outcome. In addition to being a valuable hallmark of vascular cell damage, MPs are at the crossroad of atherothrombosis processes by exerting direct effects on vascular or blood cells. Under pathological circumstances, circulating MPs would support cellular cross-talk leading to vascular inflammation and tissue remodeling, endothelial dysfunction, leukocyte adhesion, and stimulation. Exposed membrane phosphatidylserine and functional tissue factor (TF) are 2 procoagulant entities conveyed by circulating MPs. At sites of vascular injury, P-selectin exposure by activated endothelial cells or platelets leads to the rapid recruitment of MPs bearing the P-selectin glycoprotein ligand-1 and blood-borne TF, thereby triggering coagulation. Within the atherosclerotic plaque, sequestered MPs constitute the main reservoir of TF activity, promoting coagulation after plaque erosion or rupture. Lesion-bound MPs, eventually harboring proteolytic and angiogenic effectors are additional actors in plaque vulnerability. Pharmacological strategies aimed at modulating the release of procoagulant MPs appear a promising therapeutic approach of both thrombotic processes and bleeding disorders.
Antioxidants Relieve Phosphatase Inhibition and Reduce PDGF Signaling in Cultured VSMCs and in Restenosis
Authors: Kappert Kai , Sparwel Jan , Sandin Åsa , Seiler Alexander , Siebolts Udo , Leppänen Olli , Rosenkranz Stephan , Östman Arne
Published: September 2006

Objective—

Growth factor– and reactive oxygen species (ROS)-induced activation of VSMCs is involved in vascular disease. This study investigates whether inhibitory oxidation of protein tyrosine phosphatases (PTPs) contributes to signaling in VSMCs in vitro and in vivo, and analyzes whether ROS- and growth factor–dependent vascular smooth muscle cell (VSMC) signaling is blunted by antioxidants that are able to activate oxidized PTPs.

Methods and Results—

Signaling induced by H
2
O
2
and platelet-derived growth factor (PDGF) was analyzed in VSMCs with or without the antioxidants N-acetyl-cysteine (NAC) and tempol. Effects of antioxidants on PDGF-stimulated chemotaxis and proliferation were determined. In vivo effects of antioxidants were analyzed in the rat carotid balloon-injury model, by analyzing neointima formation, cell proliferation, PDGF β-receptor status, and PTP expression and activity. NAC treatment prevented H
2
O
2
-induced PTP inhibition, and reduced H
2
O
2
- and ligand-induced PDGF β-receptor phosphorylation, PDGF-induced proliferation, and chemotaxis of VSMCs. Antioxidants inhibited neointima formation and reduced PDGF receptor phosphorylation in the neointima and also increased PTP activity.

Conclusion—

PTP-inhibition was identified as an intrinsic component of H
2
O
2
- and PDGF-induced signaling in cultured VSMCs. The reduction in PDGF β-receptor phosphorylation in vivo, and the increase in PTP activity, by antioxidants indicate activation of oxidized PTPs as a previously unrecognized mechanism for the antirestenotic effects of antioxidants. The findings thus suggest, in general terms, reactivation of oxidized PTPs as a novel antirestenotic strategy.
The Role of Human Antigen R, an RNA-binding Protein, in Mediating the Stabilization of Toll-Like Receptor 4 mRNA Induced by Endotoxin
Authors: Lin Feng-Yen , Chen Yung-Hsiang , Lin Yi-Wen , Tsai Jen-Sung , Chen Jaw-Wen , Wang Hsiao-Jung , Chen Yuh-Lien , Li Chi-Yuan , Lin Shing-Jong
Published: September 2006

Objective—

Lipopolysaccharide (LPS) interacts with toll-like receptor 4 (TLR4) and induces proliferation of vascular smooth muscle cells (VSMCs) which plays a causal role in atherogenesis. The role of TLR4 expression and regulation in LPS-stimulated VSMCs remains unclear. TLR4 mRNAs often contain AU-rich elements (AREs) in their 3′ untranslated regions (3′UTR) which have a high affinity for RNA-binding proteins. It is not know whether the RNA-binding protein, human antigen R (HuR), regulates TLR4 expression in human aortic smooth muscle cells (HASMCs).

Methods and Results—

Stimulation of HASMCs with LPS significantly increased the cytosolic HuR level in vitro. Immunoprecipitation and RT-PCR demonstrated that LPS markedly increased the interaction of HuR and 3′UTR of TLR4 mRNA. The reporter plasmid, which contains the 3′UTR of TLR4 mRNA, significantly increased luciferase reporter gene expression in LPS-induced HASMCs. These data suggest that the 3′UTR of TLR4 mRNA confers LPS responsiveness and that HuR modulates 3′UTR-mediated gene expression. Knock-down of HuR inhibited LPS-induced TLR4 mRNA stability in HASMCs and luciferase reporter gene expression in CMV-Luciferase-TLR4 3′UTR-transfected HASMCs. In addition, inhibition of NADPH oxidase activity by diphenylene iodonium, knock-down of Rac1 gene expression by siRNA, and decrease of p38 MAPK activity by SB203580 significantly decreased the cytosolic HuR level, which mediates TLR4 mRNA stability.

Conclusion—

Activation of NADPH oxidase and the MAPK-signaling pathway contribute to HuR-mediated stabilization of TLR4 mRNA induced by LPS in HASMCs. In the balloon injured rabbit aorta model, systemic inflammation induced by LPS caused intimal hyperplasia and increased TLR4 and HuR expression.
Melagatran Reduces Advanced Atherosclerotic Lesion Size and May Promote Plaque Stability in Apolipoprotein E– Deficient Mice
Authors: Bea Florian , Kreuzer Joerg , Preusch Michael , Schaab Sandra , Isermann Berend , Rosenfeld Michael E. , Katus Hugo , Blessing Erwin
Published: September 2006

Objective—

Inflammatory mechanisms are involved in atherosclerotic plaque rupture and subsequent thrombin formation. Thrombin not only plays a central role in thrombus formation and platelet activation, but also in the induction of inflammatory processes. We assessed the hypothesis that melagatran, a direct thrombin inhibitor, attenuates plaque progression and promotes stability of advanced atherosclerotic lesions.

Methods and Results—

Melagatran (500 μmol/kg/d) or control diet was administered to apolipoprotein E–deficient mice (n=54) with advanced atherosclerotic lesions. Treatment reduced lesion progression in brachiocephalic arteries (
P
<0.005). Morphometric analysis confirmed that thrombin inhibition promoted plaque stability and resulted in thicker fibrous caps (28.4±14.2 μm versus 20.8±12.0 μm;
P
<0.05), increased media thickness (29.3±9.6 μm versus 24.4±6.7 μm;
P
<0.05), and smaller necrotic cores (73 537±41301 μm
2
versus 126 819±51730 μm
2
;
P
<0.0005). Electro mobility shift assays revealed reduced binding activity of nuclear factor κB (
P
<0.05) and activator protein-1 (
P
<0.05) in aortas of treated mice. Furthermore, immunohistochemistry demonstrated reduced staining for matrix metalloproteinase (MMP)-9 (
P
<0.05). Melagatran had no significant effect on early lesion formation in C57BL/6J mice.

Conclusions—

The direct thrombin inhibitor melagatran reduces lesion size and may promote plaque stability in apolipoprotein E–deficient mice, possibly through reduced activation of proinflammatory transcription factors and reduced synthesis of MMP-9.
Impact of Model, Methodological, and Parameter Uncertainty in the Economic Analysis of Vaccination Programs
Authors: Brisson M. , Edmunds W. J.
Published: September 2006

Guidelines for economic evaluations insist that the sensitivity of model results to alternative parameter values should be thoroughly explored. However, differences in model construction and analytical choices (such as the choice of a cost-effectiveness or cost-benefit framework) also introduce uncertainty in results, though these are rarely subjected to a thorough sensitivity analysis. In this article, the authors quantify the effect of model, methodological, and parameter uncertainty, taking varicella vaccination as an example. They used 3 different models (a static model, a dynamic model that only looks at the effect of vaccination on varicella, and a dynamic model that also assesses the implications of vaccination for zoster epidemiology) and 2 forms of analysis (cost-benefit and cost-utility). They also varied the discount rate and time frame of analysis. Probabilistic sensitivity analyses were performed to estimate the impact of parameter uncertainty. In their example, model and methodological choice had a profound effect on estimated cost-effectiveness, but parameter uncertainty played a relatively minor role. Under cost-utility analysis, the probabilistic sensitivity analysis suggested that there was a near certainty that vaccination dominates no vaccination, or the other way around, depending on model choice and perspective. Under cost-benefit analysis, vaccination always appeared to be attractive. Thus, the authors clearly show that model and methodological assumptions can have greater impact on results than parameter estimates, although sensitivity analyses are rarely performed on these sources of uncertainty.
A Simulation Model to Estimate the Cost and Effectiveness of Alternative Dialysis Initiation Strategies
Authors: Lee Chris P. , Chertow Glenn M. , Zenios Stefanos A.
Published: September 2006

Background. Patients with end-stage renal disease (ESRD) require dialysis to maintain survival. The optimal timing of dialysis initiation in terms of cost-effectiveness has not been established.

Methods . We developed a simulation model of individuals progressing towards ESRD and requiring dialysis. It can be used to analyze dialysis strategies and scenarios. It was embedded in an optimization frame worked to derive improved strategies.

Results. Actual (historical) and simulated survival curves and hospitalization rates were virtually indistinguishable. The model overestimated transplantation costs (10%) but it was related to confounding by Medicare coverage. To assess the model's robustness, we examined several dialysis strategies while input parameters were perturbed. Under all 38 scenarios, relative rankings remained unchanged. An improved policy for a hypothetical patient was derived using an optimization algorithm.

Conclusion. The model produces reliable results and is robust. It enables the cost-effetiveness analysis of dialysis strategies.
Increasing the Efficiency of Monte Carlo Cohort Simulations with Variance Reduction Techniques
Authors: Shechter Steven M. , Schaefer Andrew J. , Braithwaite R. Scott , Roberts Mark S.
Published: September 2006

The authors discuss techniques for Monte Carlo (MC) cohort simulations that reduce the number of simulation replications required to achieve a given degree of precision for various output measures. Known as variance reduction techniques, they are often used in industrial engineering and operations research models, but they are seldom used in medical models. However, most MC cohort simulations are well suited to the implementation of these techniques. The authors discuss the cost of implementation versus the benefit of reduced replications.
An Iterative Bayesian Approach to Health Technology Assessment: Application to a Policy of Preoperative Optimization for Patients Undergoing Major Elective Surgery
Authors: Fenwick Elisabeth , Palmer Steve , Claxton Karl , Sculpher Mark , Abrams Keith , Sutton Alex
Published: September 2006

Purpose. This article presents an iterative framework for managing the dynamic process of health technology assessment. The framework uses Bayesian statistical decision theory and value of information (VOI) analysis to inform decision making regarding appropriate patient management and to direct future research effort over the lifetime of a technology. Within the article, the framework is applied to a policy decision regarding preoperative patient management before major elective surgery, for which trial data are available.

Method. The evidence available prior to the trial is used to determine the appropriate method of patient management and to ascertain whether, at the time of commissioning, the trial was potentially worthwhile. The prior information is then updated with the trial data via a Bayesian analysis using informative priors. This post trial information set is then used to reassess the appropriate method for patient management and to determine whether there is a requirement for any further research.

Results. Prior to the trial, preoperative optimization with dopexamine is identified as the appropriate method of patient management. The results of the VOI analysis suggest that a short-term trial was potentially worthwhile (population expected value of perfect information [EVPI] = £48 million). Following the trial, the uncertainty surrounding the choice of appropriate patient management and the potential worth of further research had increased (population EVPI = £67 million).

Conclusions. The article demonstrates the value and practicality of applying the iterative framework to the dynamic process of health technology assessment. It is only by formally incorporating all of the information available to decision makers, through informed priors, that the appropriate decisions can be made.
Collective Equipoise, Disappointment, and the Therapeutic Misconception: On the Consequences of Selection for Clinical Research
Authors: Byrne Margaret M. , Thompson Peter
Published: September 2006

Private information induces individuals to self-select as subjects into clinical research trials, and it induces researchers to select which trials they conduct. The authors show that selection can induce ex ante therapeutic misconception and ex post disappointment among research subjects, and it undermines the rationale of collective equipoise as an ethical basis for clinical trials. Selection provides a reason to make nontrivial payments to subjects, and it implies that researchers should not design experiments to maximize statistical power.
Casein Kinases I of the Silkworm, Bombyx mori: Their Possible Roles in Circadian Timing and Developmental Determination
Authors: Trang Le Thi Dieu , Sehadova Hana , Ichihara Naoyuki , Iwai Sachio , Mita Kazuei , Takeda Makio
Published: September 2006

Doubletime (DBT), a homolog of casein kinase I[.epsilon] (CKI[.epsilon]), is an essential circadian clock component and developmental regulator in Drosophila melanogaster. The authors cloned a dbt homolog from the silkworm, Bombyx mori( Bmdbt), and examined its spatial and temporal expression in comparison to a CKI[.alpha] homolog ( BmCKI[.alpha]). Four Bmdbt splice variants and 2 BmCKI[.alpha] splice variants were detected, and their expression patterns varied in different tissues. The level of Bmdbt transcript in the brain was constant under LD 12:12 while those of BmCKI[.alpha] transcripts fluctuated with a decrease at ZT12. In situ hybridization showed presumably identical distribution of dbt, CKI[.alpha], and per transcripts in the putative clock neurons of the head ganglia, as well as in the retina, where CKI-and PER-like immunoreactivities were colocalized, suggesting a possible involvement of both CKIs in the B. mori circadian system. Signals were detected at 4 Ia1 neurons in each dorsolateral protocerebrum, 6 to 8 cells in the pars intercerebralis, about 6 cells in the suboesophageal ganglion, 2 neurons in the frontal ganglion, and most of the photoreceptors. All these cells contained dbt, CKI[.alpha], and per antisense transcripts. The Northern analysis of dbtand CKI[.alpha] transcripts at different developmental stages showed that both genes were expressed at relatively high levels during early embryogenesis and in the ovary. The levels of CKI[.alpha] transcripts were also high in the late larval stages until the mid-fifth instar and then suddenly disappeared before larval-pupal ecdysis. In contrast, the transcriptional activity of both genes was low in diapausing eggs.
Interval Timer Control of Puberty in Photoinhibited Siberian Hamsters
Authors: Park Jin Ho , Kauffman Alexander S. , Paul Matthew J. , Butler Matthew P. , Beery Annaliese K. , Costantini Ruth M. , Zucker Irving
Published: September 2006

Puberty, which is markedly delayed in male Siberian hamsters ( Phodopus sungorus) born into short day lengths, is controlled by an interval timer regulated by the duration of nocturnal melatonin secretion. Properties of the interval timer were assessed by perturbing normal patterns of melatonin secretion in males gestated and maintained thereafter in 1 of 2 short day lengths, 10 h light/day (10L) or 12L. Melatonin secretion of short-day hamsters was suppressed by constant light treatment or modified by daily injection of propranolol to mimic nocturnal melatonin durations typical of long-day hamsters. Constant light treatment during weeks 3 to 5 induced early incomplete gonadal growth in 12L but not 10L hamsters but did not affect late onset of gonadal development indicative of puberty in either photoperiod. Propranolol treatment during postnatal weeks 3 to 5 induced transient growth of the testes and ultimately delayed the timing of puberty by 3 weeks. Similar treatments between weeks 5 and 7 or on alternate weeks for 24 weeks did not affect the interval timer. The first 2 weeks after weaning may constitute a critical period during which the interval timer is highly responsive to photoperiod. Alternatively, the hamsters' photoperiodic history rather than age or developmental stage may be the critical variable. The interpolation of long-day melatonin signals at the time of weaning does not appear to reset the interval timer to its zero position but may reduce timer responsiveness to long-day melatonin signals several weeks later.
Lithium Leads to an Increased FRQ Protein Stability and to a Partial Loss of Temperature Compensation in the Neurospora Circadian Clock
Authors: Jolma Ingunn W. , Falkeid Grete , Bamerni Murad , Ruoff Peter
Published: September 2006

In many organisms, the presence of lithium leads to an increase of the circadian period length. In Neurospora crassa, it was earlier found that lithium results in a decrease of overall growth and increased circadian periods. In this article, the authors show that lithium leads to a reduction of FRQ degradation with elevated FRQ levels and to a partial loss of temperature compensation. At a concentration of 13 mM lithium, FRQ degradation is reduced by about 60% while, surprisingly, the activity of the 20S proteasome remains unaffected. Experiments and model calculations have shown that the stability of FRQ is dependent on its phosphorylation state and that increased FRQ protein stabilities lead to increased circadian periods, consistent with the observed increase of the period when lithium is present. Because in Neurospora the proteasome activity is unaffected by lithium concentrations that lead to significant FRQ stabilization, it appears that lithium acts as an inhibitor of kinases that affect phosphorylation of FRQ and other proteins. A competition between Li+ and Mg2+ ions for Mg2+-binding sites may be a mechanism to how certain kinases are inhibited by Li+. A possible kinase in this respect is GSK-3, which in other organisms is known to be inhibited by lithium. The partial loss of temperature compensation in the presence of lithium can be understood as an increase in the overall activation energy of FRQ degradation. This increase in activation energy may be related to a reduction in FRQ phosphorylation so that more kinase activity, that is, higher temperature and longer times, is required to achieve the necessary amount of FRQ phosphorylation leading to turnover. Using a modified Goodwin oscillator as a semiquantitative model for the Neurospora clock, the effects of lithium can be described by adding lithium inhibitory terms of FRQ degradation to the model.
IRAG mediates NO/cGMP-dependent inhibition of platelet aggregation and thrombus formation
Authors: Antl Melanie , von Brühl Marie-Luise , Eiglsperger Christina , Werner Matthias , Konrad Ildiko , Kocher Thomas , Wilm Matthias , Hofmann Franz , Massberg Steffen , Schlossmann Jens
Published: September 2006

Defective regulation of platelet activation/aggregation is a predominant cause for arterial thrombosis, the major complication of atherosclerosis triggering myocardial infarction and stroke. A central regulatory pathway conveying inhibition of platelet activation/aggregation is nitric oxide (NO)/cyclic GMP (cGMP) signaling by cGMP-dependent protein kinase I (cGKI). However, the regulatory cascade downstream of cGKI mediating platelet inhibition is still unclear. Here, we show that the inositol-1,4,5-trisphosphate receptor–associated cGMP kinase substrate (IRAG) is abundantly expressed in platelets and assembled in a macrocomplex together with cGKIβ and the inositol-1,4,5-trisphosphate receptor type I (InsP3RI). cGKI phosphorylates IRAG at Ser664 and Ser677 in intact platelets. Targeted deletion of the IRAG-InsP3RI interaction in IRAGΔ12/Δ12 mutant mice leads to a loss of NO/cGMP-dependent inhibition of fibrinogen-receptor activation and platelet aggregation. Intracellular calcium transients were not affected by DEA/NO or cGMP in mutant platelets. Furthermore, intravital microscopy shows that NO fails to prevent arterial thrombosis of the injured carotid artery in IRAGΔ12/Δ12 mutants. These findings reveal that interaction between IRAG and InsP3RI has a central role in NO/cGMP-dependent inhibition of platelet aggregation and in vivo thrombosis.
Aberrant transcriptional regulation of the MLL fusion partner EEN by AML1-ETO and its implication in leukemogenesis
Authors: Ma Li-Heng , Liu Han , Xiong Hui , Chen Bing , Zhang Xiao-Wei , Wang Yue-Ying , Le Huang-Ying , Huang Qiu-Hua , Zhang Qing-Hua , Li Bo-Liang , Chen Zhu , Chen Sai-Juan
Published: September 2006

The EEN (extra eleven nineteen) gene, located on chromosome 19p13, was cloned as a fusion with MLL from a patient with acute myeloid leukemia (AML) with translocation t(11;19)(q23;p13). In this study, we characterized the genomic structure of the EEN gene, including its 5′ regulatory region and transcription start site (TSS). We found that Sp1 could bind to the guanine-cytosine (GC)–stretch of the EEN promoter and was critical for the normal EEN expression, whereas the leukemia-associated fusion protein AML1-ETO could aberrantly transactivate the EEN gene through an AML1 binding site. Of note, overexpressed EEN showed oncogenic properties, such as transforming potential in NIH3T3 cells, stimulating cell proliferation, and increasing the activity of transcriptional factor AP-1. Retroviral transduction of EEN increased self-renewal and proliferation of murine hematopoietic progenitor cells. Moreover, Kasumi-1 and HL60-cell growth was inhibited with down-regulation of EEN by RNAi. These findings demonstrate that EEN might be a common target in 2 major types of AML associated with MLL or AML1 translocations, and overexpression of EEN may play an essential role in leukemogenesis.
Successful bone marrow transplantation for IPEX syndrome after reduced-intensity conditioning
Authors: Rao Aarati , Kamani Naynesh , Filipovich Alexandra , Lee Susan Molleran , Davies Stella M. , Dalal Jignesh , Shenoy Shalini
Published: September 2006

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare, fatal autoimmune disorder caused by mutations in the FOXP3 gene leading to the disruption of signaling pathways involved in regulatory T-lymphocyte function. Lifelong multiagent immunosuppression is necessary to control debilitating autoimmune manifestations such as colitis and food allergies. Allogeneic hematopoietic stem cell transplantation (HSCT) can restore T-cell regulatory function but has been previously associated with poor outcome. We describe successful HSCT in 4 patients with IPEX syndrome using a novel reduced-intensity conditioning regimen that resulted in stable donor engraftment, reconstitution of FOXP3+ T regulatory CD4+ cells, and amelioration of gastrointestinal symptoms.
Phenotypic heterogeneity is an evolutionarily conserved feature of the endothelium
Authors: Yano Kiichiro , Gale Daniel , Massberg Steffen , Cheruvu Pavan K. , Monahan-Earley Rita , Morgan Ellen S. , Haig David , von Andrian Ulrich H. , Dvorak Ann M. , Aird William C.
Published: September 2006

Mammalian endothelial cells (ECs) display marked phenotypic heterogeneity. Little is known about the evolutionary mechanisms underlying EC heterogeneity. The last common ancestor of hagfish and gnathostomes was also the last common ancestor of all extant vertebrates, which lived some time more than 500 million years ago. Features of ECs that are shared between hagfish and gnathostomes can be inferred to have already been present in this ancestral vertebrate. The goal of this study was to determine whether the hagfish endothelium displays phenotypic heterogeneity. Electron microscopy of the aorta, dermis, heart, and liver revealed ultrastructural heterogeneity of the endothelium. Immunofluorescent studies demonstrated marked differences in lectin binding between vascular beds. Intravital microscopy of the dermis revealed histamine-induced adhesion of leukocytes in capillaries and postcapillary venules, but no such adhesion in arterioles. Together, these data suggest that structural, molecular, and functional heterogeneity of the endothelium evolved as an early feature of this cell lineage.
IgA Fc receptor I signals apoptosis through the FcRγ ITAM and affects tumor growth
Authors: Kanamaru Yutaka , Tamouza Houda , Pfirsch Séverine , El Mehdi Delphine , Guérin-Marchand Claudine , Pretolani Marina , Blank Ulrich , Monteiro Renato C.
Published: September 2006

The IgA Fc receptor (FcαRI) has dual proinflammatory and anti-inflammatory functions that are transmitted through the immunoreceptor tyrosine-based activation motifs (ITAMs) of the associated FcRγ subunit. Whereas the involvement of FcαRI in inflammation is well documented, little is known of its anti-inflammatory mechanisms. Here we show that monomeric targeting of FcαRI by anti-FcαRI Fab or serum IgA triggers apoptosis in human monocytes, monocytic cell lines, and FcαRI+ transfectants. However, the physiologic ligand IgA induced apoptosis only when cells were cultured in low serum conditions, indicating differences with induction of anti-inflammatory signaling. Apoptosis signaling required the FcRγ ITAM, as cells transfected with FcαRI or with a chimeric FcαRI-FcRγ responded to death-activating signals, whereas cells expressing a mutated FcαRIR209L unable to associate with FcRγ, or an ITAM-mutated chimeric FcαRI-FcRγ, did not respond. FcαRI-mediated apoptosis signals were blocked by treatment with the pan-caspase inhibitor zVAD-fmk, involved proteolysis of procaspase-3, and correlated negatively with SHP-1 concentration. Anti-FcαRI Fab treatment of nude mice injected subcutaneously with FcαRI+ mast-cell transfectants prevented tumor development and halted the growth of established tumors. These findings demonstrate that, on monomeric targeting, FcαRI functions as an FcRγ ITAM-dependent apoptotic module that may be fundamental for controlling inflammation and tumor growth.
Human T-cell leukemia virus type-1 Tax oncoprotein regulates G-protein signaling
Authors: Twizere Jean-Claude , Springael Jean-Yves , Boxus Mathieu , Burny Arsène , Dequiedt Franck , Dewulf Jean-François , Duchateau Julie , Portetelle Daniel , Urbain Patrice , Lint Carine Van , Green Patrick L. , Mahieux Renaud , Parmentier Marc , Willems Luc , Kettmann Richard
Published: September 2006

Human T-cell leukemia virus type-1 (HTLV-1) is associated with adult T-cell leukemia (ATL) and neurological syndromes. HTLV-1 encodes the oncoprotein Tax-1, which modulates viral and cellular gene expression leading to T-cell transformation. Guanine nucleotide–binding proteins (G proteins) and G protein–coupled receptors (GPCRs) constitute the largest family of membrane proteins known and are involved in the regulation of most biological functions. Here, we report an interaction between HTLV-1 Tax oncoprotein and the G-protein β subunit. Interestingly, though the G-protein β subunit inhibits Tax-mediated viral transcription, Tax-1 perturbs G-protein β subcellular localization. Functional evidence for these observations was obtained using conditional Tax-1–expressing transformed T-lymphocytes, where Tax expression correlated with activation of the SDF-1/CXCR4 axis. Our data indicated that HTLV-1 developed a strategy based on the activation of the SDF-1/CXCR4 axis in the infected cell; this could have tremendous implications for new therapeutic strategies.
Expression of Livin, an antiapoptotic protein, is an independent favorable prognostic factor in childhood acute lymphoblastic leukemia
Authors: Choi Jaewon , Hwang Yu Kyeong , Sung Ki Woong , Lee Soo Hyun , Yoo Keon Hee , Jung Hye Lim , Koo Hong Hoe , Kim Hee-Jin , Kang Hyong Jin , Shin Hee Young , Ahn Hyo Seop
Published: September 2006

Livin, a member of the inhibitor of apoptosis proteins, has been considered to be a poor prognostic marker in malignancies. However, little is known about the clinical relevance of Livin expression in childhood acute lymphoblastic leukemia (ALL). In this study, the expression of Livin was analyzed in 222 patients with childhood ALL using quantitative reverse transcriptase–polymerase chain reaction (RT-PCR) to investigate a possible association with the clinical features at diagnosis and treatment outcomes. Both Livin expression rates and expression levels were higher in patients with favorable prognostic factors. The expression rate was also higher in patients with a favorable day 7 bone marrow response to induction chemotherapy (P < .001). The Livin expression was related to the absence of relapse (P < .001). Similarly, the relapse-free survival rate (± 95% CI) was higher in patients with Livin expression than in patients without Livin expression (97.9% ± 4.0% versus 64.9% ± 11.8%, P < .001). Multivariate analysis for relapse-free survival demonstrated that Livin expression was an independent favorable prognostic factor in childhood ALL (P = .049). This study suggests that Livin expression is a novel prognostic marker in childhood ALL and thus needs to be incorporated into the patient stratification and treatment protocols.
Human RPS19, the gene mutated in Diamond-Blackfan anemia, encodes a ribosomal protein required for the maturation of 40S ribosomal subunits
Authors: Flygare Johan , Aspesi Anna , Bailey Joshua C. , Miyake Koichi , Caffrey Jacqueline M. , Karlsson Stefan , Ellis Steven R.
Published: September 2006

Diamond-Blackfan anemia (DBA) typically presents with red blood cell aplasia that usually manifests in the first year of life. The only gene currently known to be mutated in DBA encodes ribosomal protein S19 (RPS19). Previous studies have shown that the yeast RPS19 protein is required for a specific step in the maturation of 40S ribosomal subunits. Our objective here was to determine whether the human RPS19 protein functions at a similar step in 40S subunit maturation. Studies where RPS19 expression is reduced by siRNA in the hematopoietic cell line, TF-1, show that human RPS19 is also required for a specific step in the maturation of 40S ribosomal subunits. This maturation defect can be monitored by studying rRNA-processing intermediates along the ribosome synthesis pathway. Analysis of these intermediates in CD34− cells from the bone marrow of patients with DBA harboring mutations in RPS19 revealed a pre-rRNA–processing defect similar to that observed in TF-1 cells where RPS19 expression was reduced. This defect was observed to a lesser extent in CD34+ cells from patients with DBA who have mutations in RPS19.