bluuebunny/crossref_metadata_2025 huggingface dataset:
Unrelated Bone Marrow Transplantation for β‐Thalassemia Patients: The Experience of the Italian Bone Marrow Transplant Group
Authors: LA NASA GIORGIO , ARGIOLU FRANCA , GIARDINI CLAUDIO , PESSION ANDREA , FAGIOLI FRANCA , CAOCCI GIOVANNI , VACCA ADRIANA , DE STEFANO PIERO , PIRAS EUGENIA , LEDDA ANTONIO , PIRODDI ANTONIO , LITTERA ROBERTO , NESCI SONIA , LOCATELLI FRANCO
Published: December 2005

Abstract: Bone marrow transplantation (BMT) remains the only potentially curative treatment for patients with thalassemia major. However, most candidates for BMT do not have a suitable family donor. In order to evaluate whether BMT from an HLA‐matched unrelated volunteer donor can offer a probability of cure comparable to that obtained when the donor is a compatible sibling, we carried out a study involving 68 thalassemia patients transplanted in six Italian BMT Centers. Thirty‐three males and 35 females (age range, 2‐37 years; median age, 15) were transplanted from unrelated volunteer donors, all selected using high‐resolution molecular typing of both HLA class I and II loci. Fourteen patients were classified in risk class 1; 16 in risk class 2; and 38 in risk class III of the Pesaro classification system. Nine patients (13%) had either primary or secondary graft failure. Fourteen patients (20%) died from transplant‐related causes. Grade II‐IV acute graft‐versus‐host disease (GVHD) developed in 24 cases (40%), and chronic GVHD in 10 cases (18%). Overall survival (OS) in the cohort of 68 patients was 79.3% (CI 67‐88%), whereas the Kaplan‐Meier estimates of disease‐free survival (DFS) with transfusion independence was 65.8% (CI 54‐77%). In the group of 30 thalassemic patients in risk classes 1 and 2, the probability of OS and DFS were 96.7% (CI 90‐100%) and 80.0% (CI 65‐94%), respectively, whereas in the 38 patients in class 3 OS was 65.2% (CI 49‐80%) and DFS was 54.5% (CI 38‐70%). These data show that when donor selection is based on stringent compatibility criteria, the results of unrelated transplantation in thalassemia patients are comparable to those obtained when the donor is a compatible sibling.
Successful Correction of the Human Cooley's Anemia β‐Thalassemia Major Phenotype Using a Lentiviral Vector Flanked by the Chicken Hypersensitive Site 4 Chromatin Insulator
Authors: MALIK PUNAM , ARUMUGAM PARITHA I. , YEE JING‐KUAN , PUTHENVEETIL GEETHA
Published: December 2005

Abstract: β‐Thalassemias are the most common single‐gene disorders and are potentially amenable to gene therapy. While retroviral vectors carrying the human β‐globin cassette were notoriously unstable and expressed poorly, considerable progress has now been made using lentiviral vectors (LVs), which stably transmit the β‐globin expression cassette. Mouse studies using LVs have shown correction of the β‐thalassemia‐intermedia phenotype and a partial, variable correction of the mouse β‐thalassemia major phenotype, despite the use of β‐globin‐hypersensitive sites that are known to result in position‐independent effects. Our group used the α‐globin‐hypersensitive site in self‐inactivating (SIN) LVs with long‐term expression in secondary mice that resisted methylation‐associated proviral silencing. However, these vectors also suffered from chromatin position effects. We therefore flanked a SIN‐lentiviral vector carrying the human β‐globin expression cassette with a chromatin insulator and studied expression in bone marrow from four patients with transfusion‐dependent human thalassemia major. We demonstrated normal levels of human β‐globin expression in erythroid cells produced in in vitro cultures for unilineage erythroid differentiation. There was restoration of effective erythropoiesis and reversal of the abnormally elevated apoptosis that characterizes β‐thalassemia. The gene‐corrected human β‐thalassemia progenitor cells were transplanted into immune‐deficient mice, where they underwent normal erythroid differentiation, expressed normal levels of human β‐globin, and displayed normal effective erythropoiesis 3‐4 months after xenotransplantation. Variability of β‐globin expression in erythroid colonies derived in vitro or from xenograft bone marrow was similar to that seen in normal control subjects. Results show genetic correction of primitive human progenitor cells and normalization of the human thalassemia major phenotype.
Treatment of Hepatitis C Virus Infection in Thalassemia
Authors: BUTENSKY ELLEN , PAKBAZ ZAHRA , FOOTE DRUCILLA , WALTERS MARK C. , VICHINSKY ELLIOTT P. , HARMATZ PAUL
Published: December 2005

Abstract:Treatment of hepatitis C virus (HCV) in the general population has improved over the last decade. Patients treated with peginterferon alfa (PegIFN) and ribavirin (RBV) combination therapy demonstrate overall 50‐55% sustained viral response (SVR) with rates as high as 80% in patients with genotypes 2 and 3. Because RBV induces hemolysis and subsequently increases blood transfusion requirements, combination therapy has been considered contraindicated for hemoglobinopathies. This report reviews the response to interferon alfa and RBV (IFN/RBV) and PegIFN/RBV combination therapies in patients treated in the Northern California Comprehensive Thalassemia Center. A total of six thalassemia major patients were treated with IFN/RBV (n= 5; age: 4‐38 years) or with PegIFN/RBV (n= 1; age: 26 years). Quantitative HCV RNA polymerase chain reaction and liver iron level assessment were completed. Transfusion volumes were obtained from patients' medical records. On IFN/RBV combination, four of five patients demonstrated SVR. The one patient on PegIFN/RBV showed end‐treatment viral response after 6 months of therapy (genotype 3), but subsequently relapsed. Liver iron pretreatment level ranged from 0.2 to 22 mg/g dry weight, with a mean ± SD of 7.9 ± 7.7. Transfusion requirement increased by a median of 43.5% (range: 32‐137%). Five of the six patients had liver iron measurements within 1 year following completion of treatment, with quantitative liver iron increasing in two patients by 2.5 mg/g dry weight, decreasing in two patients by 3 and 14 mg/g dry weight, and remaining unchanged in one patient. All patients were able to complete combination therapy, although dose reductions were required. Patients with thalassemia and high iron overload can obtain SVR after combination therapy with rates similar to those in the general population and without significant complications. Although transfusion requirements increased in most patients, iron burden was not necessarily increased.
Coagulation and Splenectomy: An Overview
Authors: CAPPELLINI M.D , GRESPI E. , CASSINERIO E. , BIGNAMINI D. , FIORELLI G.
Published: December 2005

Abstract: Venous thromboembolic events, such as pulmonary embolism, deep venous thrombosis, and portal vein thrombosis, have been observed in adult thalassemia patients, mainly in β‐thalassemia intermedia. The clinical findings are consistent with the observation of several alterations that indicate a state of activation of the hemostatic mechanisms in thalassemias. These alterations have usually been related to high platelet counts due to splenectomy and/or liver dysfunction. In a retrospective study of a large cohort of adults with thalassemia, we found a larger prevalence of venous thromboembolic events in transfusion‐independent patients with thalassemia intermedia (29%) than in regularly transfused patients with thalassemia major (2%); moreover, the higher prevalence occurred particularly in splenectomized thalassemia intermedia patients. More recently, a multicenter study involving 56 tertiary referral centers in 7 countries was planned to assess the magnitude of thrombotic risk in thalassemia patients. The total number of patients who had thrombotic events was 146 (1.65%) out of 8860, with a prevalence of 0.9% in thalassemia major and 4% in thalassemia intermedia. The highest prevalence was confirmed in splenectomized patients. The observation that thrombotic events are more frequent in β‐thalassemia patients who are not receiving regular transfusions (thalassemia intermedia or thalassemia major patients in less developed countries with limited transfusion resources) or in thalassemic patients who have undergone splenectomy strongly supports the procoagulant activity of circulating damaged red blood cells.
Transfusion Safety: Where Are We Today?
Authors: LUBAN NAOMI L.C.
Published: December 2005

Abstract: Over the past decades, the incidence of clinically significant transfusion‐transmitted diseases has been dramatically reduced. These reductions have occurred because of a multifocal approach to the collection, processing, and release of blood and blood components. Research has focused on characterizing specific pathogens and their infectious patterns, especially the early viremic phase. Donor motivation and characteristics have been investigated, and restrictive eligibility criteria have been established. Regulatory oversight has been strengthened in the United States and hemovigilance systems established in many countries of the European Union, Canada, and Japan to identify new and emerging infectious and noninfectious transfusion risks. Such systems are required because many emerging pathogens will elude the stringent and sensitive donor testing already in place which, unfortunately, requires advanced technologies. Despite the remarkable progress, the processes of delivering a transfusion to a patient provide additional opportunity for risk, but have been less‐ well studied and the solutions have been less‐well defined. Specific areas of concern include the collection and correct identification of patient samples, selection of modified or unique products, blood administration process, and establishment of specific indications for transfusion. In this chapter, we review the status of transfusion safety in the United States and discuss some emerging infectious and noninfectious risks of transfusion that will become future areas for basic and translational research. The disparities that exist in blood safety in developing countries' red cell alloimmunization and autoimmunity will not be covered.
Pulmonary Hypertension in β‐Thalassemia
Authors: AESSOPOS ATHANASIOS , FARMAKIS DIMITRIOS
Published: December 2005

Abstract: Cardiac involvement represents the leading cause of mortality in both forms of β‐thalassemia, namely, thalassemia major (TM) and thalassemia intermedia (TI), and pulmonary hypertension (PHT) is part of the cardiopulmonary complications of the disease. PHT was initially documented in a small group of TI patients with right heart failure. In a subsequent study of a large 110‐patient series, aged 32.5 ± 11.4 years, age‐related PHT was encountered in nearly 60% of cases, having caused right heart failure in six of them; interestingly, all patients had preserved left ventricular systolic function. Conflicted evidence, however, existed with respect to the development of PHT in heterogeneously treated and young TM populations. To resolve this discrepancy, a recent study compared cardiac disease between two large aged‐matched groups of TM (n= 131) and TI (n= 74) patients, both treated uniformly in the currently accepted manner (regular transfusion and chelation therapy in TM, absence of any particular treatment in TI); well‐treated TM patients, in contrast to TI patients, did not develop PHT, while systolic left ventricular dysfunction was present only in TM cases. PHT in β‐thalassemia results from a rather complex pathophysiology, in which chronic tissue hypoxia seems to hold a key role. Although both forms of the disease share a common molecular background, the diverse severity of the genetic defect and of the resulting clinical phenotype require a different therapeutic approach. Regular lifelong therapy in TM patients eliminates chronic hypoxia, thereby preventing PHT, whereas the absence of systematic treatment in TI leads to a cascade of reactions that compensate for chronic anemia, but at the same time allow the development of PHT.
T2* Magnetic Resonance and Myocardial Iron in Thalassemia
Authors: PENNELL DUDLEY J.
Published: December 2005

Abstract: Magnetic resonance T2* values of the myocardium are directly related to tissue iron levels. Minor effects from myocardial oxygenation and fibrosis are overwhelmed by the highly dominant iron effect in clinically relevant levels of myocardial iron overload. Myocardial T2* values less than 20 ms indicate iron overload, and this is considered severe when T2* is less than 10 ms. Decreasing myocardial T2* levels are associated with systolic and diastolic ventricular dysfunction. Most recorded cases of heart failure in thalassemia to date have occurred in patients with very low T2* values (in the severe range). Exceptions to this have occurred in patients with other causes of heart failure such as concomitant congenital heart disease. In patients presenting with heart failure who undergo aggressive chelation with continuous intravenous deferoxamine, longitudinal studies show that myocardial T2* increases, and this is accompanied by increases in ejection fraction and relief of heart failure. In cross‐sectional studies, the myocardial T2* and ejection fraction of patients on deferiprone was superior to that of patients on deferoxamine. Randomized controlled prospective trials comparing these two drugs for their action in clearing myocardial iron, as measured by myocardial T2*, are under way and should report in 2005/2006. These trials will clarify the role of different chelators in the management of myocardial iron overload and may be valuable in reducing the toll of death in thalassemia from heart failure.
Hemolysis‐Associated Pulmonary Hypertension in Thalassemia
Authors: MORRIS CLAUDIA R. , KUYPERS FRANS A. , KATO GREGORY J. , LAVRISHA LISA , LARKIN SANDRA , SINGER TITI , VICHINSKY ELLIOTT P.
Published: December 2005

Abstract: Accumulating evidence supports the existence of a condition involving hemolysis‐associated pulmonary hypertension (PHT). Hemolysis‐induced release of cell‐free hemoglobin and red blood cell arginase, resulting in impaired nitric oxide bioavailability, endothelial dysfunction, and PHT, has been reported in sickle cell disease. Since thalassemia is also a condition of chronic hemolysis, these patients are at risk. The data demonstrate that hemolysis‐induced dysregulation of arginine metabolism and PHT also occurs in thalassemia. Erythrocyte release of arginase during hemolysis contributes to the development of PHT. Therapies that maximize arginine and nitric oxide bioavailability may benefit patients with thalassemia.
Fertility and Pregnancy in Thalassemia Major
Authors: TUCK SUSAN M.
Published: December 2005

Abstract: Over the last 15 years, 22 women with thalassemia major have completed 29 pregnancies at the Royal Hospital in London. The major pre‐pregnancy issues, medications, and pregnancy care are reviewed. Experience suggests that, with proper care and guidance, pregnancies among women with thalassemia major are practical and can have successful outcomes.
A Simple Model to Assess and Improve Adherence to Iron Chelation Therapy with Deferoxamine in Patients with Thalassemia
Authors: PAKBAZ ZAHRA , FISCHER ROLAND , TREADWELL MARSHA , YAMASHITA ROBERT , FUNG ELLEN B. , CALVELLI LISA , QUIROLO KEITH , FOOTE DRUCILLA , HARMATZ PAUL , VICHINSKY ELLIOTT P.
Published: December 2005

Abstract: Adherence to deferoxamine (DFO) is vital for the long‐term survival of patients with thalassemia; however, currently no measure exists to quantify adherence directly. In this study, 90 patients with thalassemia major underwent liver iron concentration (LIC) assessment by SQUID biosusceptometer, were asked to rate their adherence to DFO using a Numerical Likert Scale (NLS), and were educated about complications of iron overload. Of 38% (n= 28) of patients who rated themselves as very compliant, 19 had elevated LIC related to inadequate dosing of DFO and nine reported nonadherence in the past. Adherence improved after counseling and LIC decreased by 25% (7‐60%) in eight previously noncompliant patients who returned for subsequent LIC over 15 months. In conclusion, the NLS seems to be a simple but reliable tool to assess patients' adherence to DFO. Education and frequent noninvasive LIC assessments can improve adherence and iron burden. Elevated LIC does not necessarily reflect concurrent noncompliance; however, it can be an indication of nonadherence in the past.
Genetic Analysis of Candidate Modifier Polymorphisms in Hb E‐β0‐Thalassemia Patients
Authors: SRIPICHAI ORAPAN , WHITACRE JOHANNA , MUNKONGDEE THONGPERM , KUMKHAEK CHUTIMA , MAKARASARA WATTANAN , WINICHAGOON PRANEE , ABEL KEN , BRAUN ANDREAS , FUCHAROEN SUTHAT
Published: December 2005

Abstract: Hemoglobin E (Hb E)‐β‐thalassemia patients display a range of clinical severities, from nearly asymptomatic to transfusion‐dependent thalassemia major. Given this clinical heterogeneity, additional genetic factors modifying disease severity remain to be discovered. Association studies are being conducted to elucidate the role of genetic polymorphisms as disease severity modifiers in Hb E‐β‐thalassemia patients. Using strict scoring criteria, 1060 Hb E‐β‐thalassemia patients were categorized into mild, moderate, and severe groups. Taking a candidate gene approach, we found no statistically significant differences between the mild and severe patients groups in allelic or genotypic frequencies for single nucleotide polymorphisms within five genes known to influence globin gene expression and erythropoiesis.
Longitudinal Study of Survival and Causes of Death in Patients with Thalassemia Major in Greece
Authors: LADIS VASSILIS , CHOULIARAS GEORGE , BERDOUSI HELEN , KANAVAKIS EMMANUEL , KATTAMIS CHRISTOS
Published: December 2005

Abstract: Iron‐induced organ degeneration is the main factor of mortality in patients with thalassemia major. Since chelation therapy is at a turning point, from the laborious parenteral route to the use of new promising oral agents, we investigated the current status of survival of these patients to present reliable data that will be useful in future comparative studies. Survival probabilities were estimated by the Kaplan‐Meier method, and results were compared by the log‐rank test in a total of 647 thalassemic patients (pts) (52% males) born between 1/1/58 and 1/2/04. Terminal follow‐up was 1/12/04. All transfusion‐dependent pts monitored in our center, or in frequent contact if they had moved elsewhere, were strictly selected, excluding all rarely transfused or intermediate cases. Pts born before 1/1/75 were classified in group A (n= 366), while pts born later were included in group B (n= 281). According to the last 5 years' mean serum ferritin level, pts were divided into three hemosiderosis groups: (1) mild (<2000 μg/L) 49%, (2) moderate (2000‐4000 μg/L) 28%, and (3) severe (>4000 μg/L) 23%. Of the 647 pts, 115 died (mean age: 22.6 ± 6.2 years), most frequently by heart failure (71.3%) followed by sepsis (7.8%). Life expectancy in the entire population was up to 59% at 46 years. Survival was higher for pts born after 1975 than those before (P < .001). Statistically significantly different survival probabilities were found between groups with mild, moderate, or severe hemosiderosis (P < .001). Effective management with improved chelation therapy could lead to better results.
Testis Structure and Function in a Nongenetic Hyperadipose Rat Model at Prepubertal and Adult Ages
Authors: França L. R. , Suescun M. O. , Miranda J. R. , Giovambattista A. , Perello M. , Spinedi E. , Calandra R. S.
Published: December 2005

There are few data for hormonal levels and testis structure and function during postnatal development in rats neonatally treated with monosodium l-glutamate (MSG). In our study, newborn male pups were ip injected with MSG (4 mg/g body weight) every 2 d up to 10 d of age and investigated at prepubertal and adult ages. Plasma levels of leptin, LH, FSH, prolactin, testosterone (T), corticosterone, and free T4 (FT4) were measured. MSG rats displayed elevated circulating levels of corticosterone and hyperadiposity/hyperleptinemia, regardless of the age examined; conversely, circulating prolactin levels were not affected. Moreover, prepubertal MSG rats revealed a significant (P < 0.05) reduction in testis weight and the number of Sertoli (SC) and Leydig cells per testis. Leptin plasma levels were severalfold higher (2.41 vs. 8.07; P < 0.05) in prepubertal MSG rats, and these animals displayed plasma LH, FSH, T, and FT4 levels significantly decreased (P < 0.05). Taken together, these data indicate that testis development, as well as SC and Leydig cell proliferation, were disturbed in prepubertal MSG rats. Adult MSG rats also displayed significantly higher leptin plasma levels (7.26 vs. 27.04; P < 0.05) and lower (P < 0.05) LH and FSH plasma levels. However, T and FT4 plasma levels were normal, and no apparent alterations were observed in testis structure of MSG rats. Only the number of SCs per testis was significantly (P < 0.05) reduced in the adult MSG rats. In conclusion, although early installed hyperadipose/hyperleptinemia phenotype was probably responsible for the reproductive axis damages in MSG animals, it remains to be investigated whether this condition is the main factor for hypothalamus-pituitary-gonadal axis dysfunction in MSG rats.
Maternal Ghrelin Plays an Important Role in Rat Fetal Development during Pregnancy
Authors: Nakahara Keiko , Nakagawa Mari , Baba Yukiko , Sato Miho , Toshinai Koji , Date Yukari , Nakazato Masamitsu , Kojima Masayasu , Miyazato Mikiya , Kaiya Hiroyuki , Hosoda Hiroshi , Kangawa Kenji , Murakami Noboru
Published: December 2005

Ghrelin, an acylated peptide serving as an endogenous ligand for GH secretagogue receptor (GHS-R), was originally isolated from rat and human stomach. In this study, we report the critical role of maternal ghrelin in fetal development. High levels of ghrelin receptor (GHS-R) mRNA were detected in various peripheral fetal tissues beginning at embryonic d 14 and lasting until birth. Fetal GHS-R expression was also confirmed in fetal tissues by immunohistochemistry. Autoradiography revealed that both des-acyl ghrelin and acyl ghrelin bind to fetal tissues. Chronic treatment of mothers with ghrelin resulted in a significant increase in birth weight in comparison to newborns from saline-treated mothers. Even when maternal food intake after ghrelin treatment was restricted through paired feeding, significant stimulation of fetal development still occurred. Conversely, active immunization of mothers against ghrelin decreased fetal body weight during pregnancy. A single ghrelin injection into the mother increased circulating ghrelin levels in the fetus within 5 min of injection, suggesting that maternal ghrelin transits easily to the fetal circulation. High levels of des-acyl ghrelin were detected in fetal blood and amniotic fluid. Both acylated and des-acyl ghrelin increased [3H]thymidine and 5-bromo-2′-deoxyuridine incorporation of cultured fetal skin cells in a dose-dependent manner, and calcium-imaging analysis revealed that acyl and des-acyl ghrelin increased the Ca2+ influx in discrete cultured fetal skin cells, respectively. These results indicate that maternal ghrelin regulates fetal development during the late stages of pregnancy.
A Wnt1-regulated genetic network controls the identity and fate of midbrain-dopaminergic progenitors in vivo
Authors: Prakash Nilima , Brodski Claude , Naserke Thorsten , Puelles Eduardo , Gogoi Robindra , Hall Anita , Panhuysen Markus , Echevarria Diego , Sussel Lori , Weisenhorn Daniela M. Vogt , Martinez Salvador , Arenas Ernest , Simeone Antonio , Wurst Wolfgang
Published: December 2005

Midbrain neurons synthesizing the neurotransmitter dopamine play a central role in the modulation of different brain functions and are associated with major neurological and psychiatric disorders. Despite the importance of these cells, the molecular mechanisms controlling their development are still poorly understood. The secreted glycoprotein Wnt1 is expressed in close vicinity to developing midbrain dopaminergic neurons. Here, we show that Wnt1 regulates the genetic network, including Otx2 and Nkx2-2, that is required for the establishment of the midbrain dopaminergic progenitor domain during embryonic development. In addition, Wnt1 is required for the terminal differentiation of midbrain dopaminergic neurons at later stages of embryogenesis. These results identify Wnt1 as a key molecule in the development of midbrain dopaminergic neurons in vivo. They also suggest the Wnt1-controlled signaling pathway as a promising target for new therapeutic strategies in the treatment of Parkinson's disease.
DrosophilaDok is required for embryonic dorsal closure
Authors: Biswas Romi , Stein David , Stanley E. Richard
Published: December 2005

Embryonic dorsal closure (DC) in Drosophila is a series of morphogenetic movements involving the bilateral dorsal movement of the epidermis (cell stretching) and dorsal suturing of the leading edge (LE) cells to enclose the viscera. The Syk family tyrosine kinase Shark plays a crucial role in this Jun amino-terminal kinase (JNK)-dependent process, where it acts upstream of JNK in LE cells. Using a yeast two-hybrid screen, the unique Drosophila homolog of the downstream of kinase (Dok) family, Ddok,was identified by its ability to bind Shark SH2 domains in a tyrosine phosphorylation-dependent fashion. In cultured S2 embryonic cells, Ddok tyrosine phosphorylation is Src dependent; Shark associates with Ddok and Ddok localizes at the cell cortex, together with a portion of the Shark protein. The embryonic expression pattern of Ddok resembles the expression pattern of Shark. Ddok loss-of-function mutant (DdokPG155)germ-line clones possess DC defects, including the loss of JNK-dependent expression of dpp mRNA in LE cells, and decreased epidermal F-actin staining and LE actin cable formation. Epistatic analysis indicates that Ddok functions upstream of shark to activate JNK signaling during DC. Consistent with these observations, Ddok mutant embryos exhibit decreased levels of tyrosine phosphorylated Shark at the cell periphery of LE and epidermal cells. As there are six mammalian Dok family members that exhibit some functional redundancy, analysis of the regulation of DC by Ddok is expected to provide novel insights into the function of the Dok adapter proteins.
BMP2 and FGF2 cooperate to induce neural-crest-like fates from fetal and adult CNS stem cells
Authors: Sailer Martin H. M. , Hazel Thomas G. , Panchision David M. , Hoeppner Daniel J. , Schwab Martin E. , McKay Ronald D. G.
Published: December 2005

CNS stem cells are best characterized by their ability to self-renew and to generate multiple differentiated derivatives, but the effect of mitogenic signals, such as fibroblast growth factor 2 (FGF2), on the positional identity of these cells is not well understood. Here, we report that bone morphogenetic protein 2 (BMP2) induces telencephalic CNS stem cells to fates characteristic of neural crest and choroid plexus mesenchyme, a cell type of undetermined lineage in rodents. This induction occurs both in dissociated cell culture and cortical explants of embryonic day 14.5 (E14.5) embryos, but only when cells have been exposed to FGF2. Neither EGF nor IGF1 can substitute for FGF2. An early step in this response is activation of β-catenin, a mediator of Wnt activity. The CNS stem cells first undergo an epithelial-to-mesenchymal transition and subsequently differentiate to smooth-muscle and non-CNS glia cells. Similar responses are seen with stem cells from E14.5 cortex, E18.5 cortex and adult subventricular zone, but with a progressive shift toward gliogenesis that is characteristic of normal development. These data indicate that FGF2 confers competence for dorsalization independently of its mitogenic action. This rapid and efficient induction of dorsal fates may allow identification of positional identity effectors that are co-regulated by FGF2 and BMP2.
Host and parasite-derived IKK activities direct distinct temporal phases of NF-κB activation and target gene expression followingToxoplasma gondiiinfection
Authors: Molestina Robert E. , Sinai Anthony P.
Published: December 2005

Activation of NF-κB by the intracellular pathogen Toxoplasma gondii is associated with the localization of phosphorylated IκBα to the parasitophorous vacuole membrane (PVM). This is mediated by a parasite-derived IκB kinase (TgIKK) activity and is independent of host IKK function. In the present study, we examined the roles of host IKK and parasite-derived TgIKK on the temporal modulation of NF-κB activation. Despite the presence of TgIKK activity at the PVM, nuclear translocation of NF-κB and subsequent gene expression exhibited a requirement for the host IKK complex. A detailed kinetic analysis of NF-κB activation revealed a biphasic, hierarchical and temporally regulated response. We propose a novel paradigm for the modulation of NF-κB-dependent gene expression by T. gondii that involves both the host IKK complex and TgIKK activity at different phases of infection. Thus, T. gondii effectively alters gene expression in a temporal dimension by exploiting the NF-κB signaling machinery and subsequently rewiring the activation circuits of the infected host cell.
Activation of Rac1 by RhoG regulates cell migration
Authors: Katoh Hironori , Hiramoto Kiyo , Negishi Manabu
Published: December 2005

Cell migration is essential for normal development and many pathological processes. Rho-family small GTPases play important roles in this event. In particular, Rac regulates lamellipodia formation at the leading edge during migration. The small GTPase RhoG activates Rac through its effector ELMO and the ELMO-binding protein Dock180, which functions as a Rac-specific guanine nucleotide exchange factor. Here we investigated the role of RhoG in cell migration. RNA interference-mediated knockdown of RhoG in HeLa cells reduced cell migration in Transwell and scratch-wound migration assays. In RhoG-knockdown cells, activation of Rac1 and formation of lamellipodia at the leading edge in response to wounding were attenuated. By contrast, expression of active RhoG promoted cell migration through ELMO and Dock180. However, the interaction of Dock180 with Crk was dispensable for the activation of Rac1 and promotion of cell migration by RhoG. Taken together, these results suggest that RhoG contributes to the regulation of Rac activity in migrating cells.
Echolocating bats can use acoustic landmarks for spatial orientation
Authors: Jensen Marianne Egebjerg , Moss Cynthia F. , Surlykke Annemarie
Published: December 2005

We investigated the echolocating bat's use of an acoustic landmark for orientation in a complex environment with no visual information. Three bats of the species Eptesicus fuscus were trained to fly through a hole in a mist net to receive a food reward on the other side. In all experiments, the vocal behavior of the bats was recorded simultaneously using a high-speed video recording system, allowing for a 3D reconstruction of the flight path. We ran three types of experiments, with different spatial relations between the landmark and net hole. In the first experiment, the bat's behavior was studied in test trials with the landmark placed 10 cm to the left of the net opening; between test trials, the positions of the net opening and landmark were moved, but the spatial relationship between the two remained fixed. With the landmark adjacent to the net opening, the bats quickly found the hole. In the second experiment, bats were tested in control trials in which the landmark was moved independently of the hole, breaking the established spatial relationship between the two. In control trials the bats repeatedly crashed into the net next to the landmark, and inspected the area around it. In the final experiment, the landmark was removed altogether from the set-up. Here the bats spent more time per trial searching for the net opening with an increased number of inspections as well as crashes into the net. However, over the course of a test day without the landmark, bats reduced the time spent per trial and focused inspections and crashes around the hole. The behavioral data show for the first time that the echolocating bat can learn to rely on an acoustic landmark to guide spatial orientation.
Theoretical Treatments of Two-Dimensional Two-Phase Flows of Steam and Comparison with Cascade Measurements
Authors: Bakhtar F , White A J , Mashmoushy H
Published: December 2005

During the course of expansion of steam in turbines, the state path crosses the saturation line and hence subsequent turbine stages operate with wet steam. These stages have lower thermodynamic efficiencies than those operating in the superheated region, and currently the phenomena contributing to the increased losses are not fully understood. The development of the nucleation theory has opened the way for the study of condensing flows in turbines. As, with the advances in numerical methods, the equations describing droplet nucleation and growth rates can be combined with the field conservation equations and the set treated numerically, which allows the behaviour of complex nucleating and wet steam flows in turbines to be analysed. This paper outlines and reviews wet steam calculation methods and discusses comparisons between numerical and experimental results. For the most part, the comparisons presented are based on work of the authors and their co-workers, but some more recent calculations by other investigators are also included.
Experimental and Numerical Analyses of Relaxation Processes in LP Steam Turbines
Authors: Kreitmeier F , Greim R , Congiu F , Faelling J
Published: December 2005

Flow fields in low-pressure (LP) steam turbines, starting expansion well above the saturation line, show four pronounced non-equilibrium processes (called relaxation processes). The first one above the saturation line is centred around heterogeneous nucleation/condensation, the second one around subcooling and the subsequent homogeneous nucleation/condensation (‘Wilson point’), and the third and the fourth ones are characterized by thermodynamic and mechanical effects in the established droplet-loaded part of the flow field.

All these relaxation processes are interacting downwards in the progressive expansion in the turbine. In a multistage LP turbine, the most important ones are the second - because it is mainly responsible for the number of droplets (sizes) - and the third - because it creates most of the dissipation. In addition, the first and the fourth ones can damage the flow guiding geometry by corrosion and erosion, respectively.

More than 40 years ago, Gyarmathy formulated the first strictly physical basis for these processes. Subsequently, many researchers have contributed to increase the physical understanding using both experimental and numerical methods. The intuition that the one-dimensional treatment of the flow field in multistage turbines cannot explain the measured droplet sizes behind the blading has been particularly relevant. It became clear that especially the temperature fluctuation within the blading has to be included in homogeneous nucleation/condensation considerations. Also of some importance has been the improved understanding of the first relaxation process, which was initially underestimated.

This article highlights the current situation seen by a turbomachinery company that has been contributing to and supporting this discipline for many decades. A wide literature survey and a critical appraisal of published Baumann factors are included. High quality experimental tools and procedures are introduced on the basis of two generations of split-shaft model LP turbines and Damköhler numbers. Further, an overview of the in-house numerical tools and processes developed for wet steam applications is given.

More recent experimental results on the influence of impurities and conditioning agents in the relaxation processes and newer numerical results on the influence of phase transition in the flow field around a blade row are presented.
Effects of Wake Chopping on Droplet Sizes in Steam Turbines
Authors: Bakhtar F , Heaton A V
Published: December 2005

This paper is a review article and considers the influence of wake chopping on the size distribution of water droplets formed by homogeneous nucleation in steam turbines. The studies by several investigators are summarized. All the studies show that the fluctuations caused by the wakes can broaden the size distributions of the nucleated droplets substantially and account for the polydisperse nature of the droplet distributions and coarse water observed in turbines. The effect of the presence of impurities in steam on its nucleation behaviour is also discussed.
Unsteadiness in Condensing Flow: Dynamics of Internal Flows with Phase Transition and Application to Turbomachinery
Authors: Schnerr G H
Published: December 2005

Steady flows of condensable fluids may become unsteady if one component of the fluid starts to condense. In high-speed expansion flows, typical for large-scale steam turbines, the subcooled vapour state collapses after nucleation, typically in flow regimes close to Mach number 1. After the formation of steady shocks, instantaneous thermal choking initiates self-excited high-frequency oscillations which is the focus of this article. The driving mechanism is the interaction of compressibility and energy supply in flows close to maximum mass flux density and is therefore not controlled by the viscosity of the fluid. Additional viscosity-driven excitation mechanisms exist and superpose the primary diabatic instability, especially in axial cascades. Typical are shedded shear layers from blade trailing edges and the periodic interference of wakes separating from the stator with the rotor blades. This article presents a review of the authors and various co-workers' research, supplemented by important references to complete the subject under consideration. This article starts with an introduction in the most simple flow model of given heat addition in constant area flow and ends with mixed homogeneous/heterogeneous condensation in a transonic axial cascade stage with a high-resolution sliding interface for preservation of submicron condensate convected from the stator into the rotor. Numerical simulations are compared with experiments of flows with and without carrier gas.
Effects of Piston Design Parameters on Piston Secondary Motion and Skirt - Liner Friction
Authors: Mansouri S. H. , Wong V. W.
Published: December 2005

In this article, a previously developed and experimentally validated piston secondary motion model has been improved further numerically and applied to understand the detailed interactions between the piston skirt and the cylinder liner for various piston design parameters. The model considers the roughness of the surfaces and the topography of the skirt in both the axial (barrel profile) and circumferential (ovality) directions. Three modes of lubrication: hydro-dynamic, mixed, and boundary lubrication regimes have been considered and the skirt is partially flooded in most cases. Elastic deformation of the skirt is an essential part of the model. In this model, the piston dynamic behaviour and frictional and impact forces are predicted as functions of crank angle and are examined in detail. Parameters investigated include piston skirt profile, piston-to-liner clearance, surface roughness, and oil availability. The results show that some of these parameters have profound effects on the frictional and impact forces at the piston skirt/liner interface, and therefore, they have the potential to optimize the piston frictional power loss. Correlations and non-dimensional scaling laws are developed to illustrate the basic governing phenomena. These results aim to provide a set of quantitative design guidelines.
The Phase Shift of an Ultrasonic Pulse at an Oil Layer and Determination of Film Thickness
Authors: Reddyhoff T , Kasolang S , Dwyer-Joyce R. S. , Drinkwater B. W.
Published: December 2005

An ultrasonic pulse incident on a lubricating oil film in a machine element will be partially reflected and partially transmitted. The proportion of the wave amplitude reflected, termed the reflection coefficient, depends on the film thickness and the acoustic properties of the oil. When the appropriate ultrasonic frequency is used, the magnitude of the reflection coefficient can be used to determine the oil film thickness. However, the reflected wave has both a real component and an imaginary component, and both the amplitude and the phase are functions of the film thickness. The phase of the reflected wave will be shifted from that of the incident wave when it is reflected. In the present study, this phase shift is explored as the film changes and is evaluated as an alternative means to measure oil film thickness.

A quasi-static theoretical model of the reflection response from an oil film has been, developed. This model relates the phase shift to the wave frequency and the film properties. Measurements of reflection coefficient from a static model oil film and also from a rotating journal bearing have been recorded. These have been used to determine the oil film thickness using both amplitude and phase shift methods. In both cases, the results agree closely with independent assessments of the oil film thickness. The model of ultrasonic reflection is further extended to incorporate mass and damping terms. Experiments show that both the mass and the internal damping of the oil films tested in this work have a negligible effect on ultrasonic reflection.

A potentially very useful application for the simultaneous measurement of reflection coefficient amplitude and phase is that the data can be used to negate the need for a reference. The theoretical relationship between phase and amplitude is fitted to the data. An extrapolation is performed to determine the values of amplitude and phase for an infinitely thick layer. This is equivalent to the reference signal determined by measuring the reflection coefficient directly, but importantly does not require the materials to be separated. This provides a simple and effective means of continuously calibrating the film measurement approach.
On the Dynamics of Elastohydrodynamic Mixed Lubricated Ball Bearings. Part I: Formulation of Stiffness and Damping Coefficients
Authors: Sarangi M , Majumdar B. C. , Sekhar A. S.
Published: December 2005

The problems of stiffness and damping characteristics of isothermal elastohydrodynamic mixed lubricated point contact are evaluated numerically considering surface roughness effect including asperity contact load. A set of equations under steady-state and dynamic conditions is derived from the classical Reynolds equation, using linear perturbation method. The elasticity equation and steady-state Reynolds equation are solved simultaneously for finding the steady-state pressure distribution, using finite difference method. Then, the set of perturbed equations is solved for the dynamic pressure distribution in the contact. A Gaussian surface roughness is adopted to model both surface roughness and mixed lubrication. Total load capacity of the contact is calculated from the lubricant film pressure and contact pressure distribution. Results are compared with those of smooth isothermal cases. The stiffness and damping coefficients of the contact are determined using the dynamic pressures. The asperity contact stiffness is calculated separately. Effect of various design parameters on stiffness and damping characteristics of a ball bearing is investigated.
Experimentally Established Correlation between Acoustic Emission Activity, Load, Speed, and Asperity Contact of Spur Gears Under Partial Elastohydrodynamic Lubrication
Authors: Tan C. K. , Mba D
Published: December 2005

The application of the acoustic emission (AE) technique to condition monitoring of gears is still at a developmental stage. Understanding the source of AE activity at the gear mesh is fundamental if this technique is to be successfully employed for gear diagnostics and prognostics. This article presents results of an experimental programme that showed a correlation between AE r.m.s. activity and asperity contact under partial elastohydrodynamic lubrication. On the basis of experimental observations, it is postulated that AE can monitor and/or measure the effectiveness of a lubricant in minimizing asperity contact. It addition, it is concluded that two distinct types of AE are associated with the sliding and rolling of meshing spur gears.
The Enduring Legacy of ‘Reckless Disregard’
Authors: McArdle David
Published: December 2005

Personal injury at common law has spawned many cases where sports participants have inflicted injury either upon other participants or upon spectators/bystanders. This paper is not an exhaustive analysis of those ‘sports torts' cases but focuses instead upon the impact of Wooldridge v Sumner, a Court of Appeal decision that was legally sound but based upon highly significant errors of fact, and which has subsequently been advanced before the courts in two jurisdictions as authority for untenable propositions that concern both the standard of care and the duty of care owed by sports participants. While a consideration of the authorities prior to Wooldridge illustrates that there was never a basis at common law for the argument that either the standard or the duty of care differed from that pertaining in non-sporting contexts, the case has been appropriated by counsel in order to argue along those lines even though Wooldridge is not authority for either proposition. On some occasions those arguments have actually received the support of the courts of England and Wales and of the Canadian Province of British Columbia. Despite the existence in both jurisdictions of more recent authorities that ought to have heralded the demise of both concepts, they have proved remarkably tenacious.
Fraud Trials: A Brave New World
Authors: Kirk David
Published: December 2005

The management of long fraud trials has come under the spotlight again following the collapse of the Jubilee Line Extension case. Three major changes to fraud trials procedures are in the process of being introduced: the Lord Chief Justice's complex trials management protocol, a new offence of fraud (the Fraud Bill), and the removal of jury trial (implementing s. 43 of the Criminal Justice Act 2003). This article examines these initiatives and debates and considers whether they will improve the quality of justice.
Complicity in Suicide
Authors: Samuels Alec
Published: December 2005

This article addresses the extent to which, if at all, a person may lawfully ‘help’ another person, for example a terminally ill spouse, to take his own life or submit to euthanasia. It considers what intent is required to be proved for a crime and the situation where the intent is mercy. In addition, it looks at the position of a survivor of a suicide pact and whether there is a human right to die. Other questions raised are: How near to voluntary euthanasia is English law now? Is an advance decision ‘no treatment if I am terminally ill’ legally valid? What is the legal duty of the doctor towards a terminally ill patient?
The 2003 Licensing Act: Alcohol Use and Anti-Social Behaviour in England and Wales
Authors: Loveday Barry
Published: December 2005

This article considers the potential impact of the Licensing Act 2003 and the nature of change that may be expected to result from extended opening hours. It looks at recent trends in crime and evidence of the growing significance of alcohol-related offences in England and Wales. It notes that while violent crime as identified by the British Crime Survey continues to fall, there has been a marked increase in ‘stranger violence’ that may be linked to the growth of the night-time economy in many UK towns and cities. The article analyses recent data concerning the use of alcohol by young people and ‘binge drinking’, and it also considers the current debate over the implementation of the Licensing Act, particularly the ability of local residents to influence the determination of extended opening hours. It reviews the role of the local authority as a licensing authority and the potential problem of appeals by licensees against decisions made by the new licensing authority. The article assesses the implications of such appeals in relation to section 17 of the Crime and Disorder Act 1998 and the pervasive influence of the drinks industry in contemporary society.