bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impaired T‐Amplitude Adaptation to Heart Rate Characterizes IKr Inhibition in the Congenital and Acquired Forms of the Long QT Syndrome
Authors: COUDERC JEAN‐PHILIPPE , VAGLIO MARTINO , XIA XIAJUAN , MCNITT SCOTT , WICKER PIERRE , SARAPA NENAD , MOSS ARTHUR J. , ZAREBA WOJCIECH 
Published: October 2007

Introduction: The QTc interval prolongation is not a perfect surrogate marker of the presence of an increased risk for arrhythmic events. In the search for alternative markers, we investigated the T‐amplitude and QT interval adaptation to heart rate (HR) in patients with the congenital long QT syndrome (LQTS) and individuals with sotalol‐induced QT prolongation. Methods and Results: Our investigation is based on the analysis of continuous 12‐lead digital Holter recordings in: 49 LQT1 carriers, 25 LQT2 carriers, 37 healthy individuals off drugs and on 160 mg of sotalol, and 21 of them also on 320 mg of sotalol. The Holter recordings were used to investigate repolarization parameters and their HR dependency. A loss of HR dependency of the T‐amplitude was found as a common feature in individuals with impaired Ikr kinetics: LQT2 carriers and subjects on sotalol. The T‐amplitude/RR slope was significantly (P < 0.05) flatter in LQT2 (0.31 ± 0.27 μV/ms) than in both LQT1 (0.62 ± 0.40 μV/ms) and healthy individuals (0.55 ± 0.29 μV/ms). A dose‐dependent reduction of the T‐amplitude/RR slope was also observed in subjects on sotalol (160 mg dose: 0.26 ± 0.19 μV/ms; 320 mg dose: 0.21 ± 0.14 μV/ms). The QT/RR slope was less effective than T‐amplitude/RR slope in differentiating between congenital and drug‐induced repolarization delay. Conclusions: Impaired adaptation of T‐amplitude to changing HR is a common electrocardiographic feature associated with KCNH2 mutation and Ikr blockade by sotalol. This ECG marker may play an important role in the future of the assessment of the penetrance of KCNH2 mutation and the identification of a drug effect on the Ikr kinetics.
Anatomic Location of Pulmonary Vein Electrical Disconnection with Balloon‐Based Catheter Ablation
Authors: PHILLIPS KAREN P. , SCHWEIKERT ROBERT A. , SALIBA WALID I. , THEMISTOCLAKIS SAKIS , RAVIELE ANTONIO , BONSO ALDO , ROSSILLO ANTONIO , BURKHARDT J. DAVID , CUMMINGS JENNIFER , NATALE ANDREA 
Published: October 2007

Introduction: Balloon‐based catheters are an emerging technology in catheter ablation for atrial fibrillation, which aim to achieve consistent and rapid ablation encirclement of pulmonary veins (PVs). Recent emphasis has been placed on achieving more proximal electrical isolation within the PV–left atrial (LA) junction. We sought to evaluate the precise anatomic level of PV electrical disconnection with current design balloon‐based catheters. Methods and Results: Thirteen patients with drug‐refractory paroxysmal atrial fibrillation undergoing balloon catheter ablation with the endoscopic laser system (CardioFocus) or the high frequency‐focused ultrasound system (ProRhythm) underwent electroanatomic mapping (EAM) of the left atrium. Intracardiac echocardiographic (ICE) imaging was used for visualization of the position of the balloon catheter during energy delivery. Detailed point analysis of the location of electrical disconnection was then documented on EAM and with ICE.Successful electrical isolation was achieved in all 52 PVs. Despite ICE imaging confirming balloon catheter position at the antrum of the PVs, the location of electrical disconnection was demonstrated to be at or near the tubular ostium of the PVs on EAM and on ICE in all patients. Conclusion: Current generation balloon‐based catheter ablation achieves electrical isolation distal in the LA–PV junction. This may limit the results of such systems in treating nonparoxysmal forms of atrial fibrillation.
Autonomic Mechanism to Explain Complex Fractionated Atrial Electrograms (CFAE)
Authors: LIN JIAXIONG , SCHERLAG BENJAMIN J. , ZHOU JING , LU ZHIBING , PATTERSON EUGENE , JACKMAN WARREN M. , LAZZARA RALPH , PO SUNNY S. 
Published: October 2007

Objective: To simulate complex fractionated atrial electrograms (CFAE) during sustained atrial fibrillation (AF) in experimental animals. Background: The mechanism(s) underlying CFAE has not been fully elucidated. Methods: Twenty‐two dogs were subjected to a right and/or left thoracotomy. A gauze patch soaked with acetylcholine (ACh) was placed on the right atrial appendage (RAA) to induce sustained AF. During AF, varying concentrations of ACh (1, 10, 100 mM) were “painted” on the RA where electrograms showed regular organized activity. In another six dogs, anterior right ganglionated plexi (ARGP) near the sino‐atrial node and inferior right GP (IRGP) at the junction of inferior vena cava and atria were sequentially ablated. In five dogs, ACh was injected into ARGP to induce CFAE. Results: During sustained AF, local “painting” with ACh 1 mM and 10 mM induced intermittent CFAE in 1 of 11 and 10 of 11 dogs, respectively. With 100 mM ACh, all 11 showed CFAE (two intermittent, nine continuous). In six other dogs, continuous CFAE induced by topical application of 100 mM ACh were markedly attenuated by ARGP + IRGP ablation. In another five of five dogs, ACh injection into ARGP induced a gradient of CFAE with the continuous CFAE always occurring near the ARGP and CFAE also occurring at left pulmonary vein‐atrial junctions. During ARGP ablation, AF was terminated in all five dogs immediately after regularization of the rotor‐like electrograms or continuous CFAE. Conclusions: This study demonstrates an autonomic basis for CFAE formation, suggesting that graded hyperactive states of the autonomic nervous system (ANS) may induce various types of CFAE observed clinically.
Computer‐Simulated Alternative Modes of U‐Wave Genesis
Authors: DEPOLLI MATJAŽ , AVBELJ VIKTOR , TROBEC ROMAN 
Published: October 2007

Objective: Several hypotheses for the origin of the U wave in electrocardiograms have been proposed. We have set out to explore and test alternative modes for U‐wave genesis via computer simulations. Methods and Results: A spatial model of a left ventricle has been constructed from 12 layers composed of cubic cells. Each cell is assigned its own time‐dependent action potential with its own contribution to the electrical potential at arbitrary points where ECGs are measured. Simulated ECGs show that U waves can be generated using various combinations of action potentials (APs) across the different layers of the ventricular wall. We demonstrate a new mode of U‐wave genesis, even with small differences in the repolarization. Conclusion: The U wave can be generated in the presence of strong intercellular coupling. Myocardial layers with prolonged action potentials, like M cells, are not necessarily needed for U‐wave genesis.
Mutational spectrum of delta‐globin gene in the Portuguese population
Authors: Morgado Ana , Picanço Isabel , Gomes Susana , Miranda Armandina , Coucelo Margarida , Seuanes Filomena , Seixas Maria Teresa , Romão Luísa , Faustino Paula 
Published: October 2007

AbstractThe phenotype of increased Hb A2 typical of β‐thalassaemia (β‐thal) carriers can be reduced to normal or borderline values because of the co‐inheritance of a δ‐globin gene (HBD, MIM #142000) mutation, which may lead to misinterpretation of diagnostic results. To know the spectrum of δ‐globin mutations in the Portuguese population we performed a mutational analysis of the δ‐globin gene in a group of 51 Portuguese β‐thal carriers presenting microcytosis, hypochromia and a normal/borderline Hb A2 level and in another group of 15 individuals suspected to have δ‐globin structural abnormalities. The heterozygosity for the β+IVS‐I‐6T→C (HBB:c. 92+6T>C) mutation was the main cause for the mentioned atypical β‐thal carrier phenotype. Furthermore, eight individuals were double heterozygous for one common β‐thal mutation and the δ+Cd27G→T mutation (Hb A2–Yialousa; HBD:c.82G>T). One of them also presented a novel δ‐globin gene promoter mutation,−80G→A (HBD:c.−130G>A), responsible for about 25% decrease of the promoter activity in transient expression assays. One the other hand, in the other group of 15 individuals suspected to have δ‐globin structural abnormalities observed by biochemical methods, some known Hb A2 variants were identified – Hb A2′ (HBD:c.49G>C), Hb A2‐Babinga (HBD:c.410G>A), and Hb A2‐Wrens (HBD:c.295G>A), and the novel Hb A2‐Fogo [δ64(E8)(Gly→Ser); (HBD:c.193G>A)]. This novel Hb A2 variant was observed segregating in linkage with Hb E (HBB:c.79G>A) in a three generation family. In conclusion, six different δ‐globin mutations were found, being two of them new molecular defects. All δ‐alleles identified were found linked to the expected β‐globin cluster haplotype. All mutations caused a low Hb A2 level and through this could lead to misdiagnosis when inherited together with a β‐thal allele.
Downregulation of neuropilin‐1 in patients with acute myeloid leukemia treated with thalidomide
Authors: Kreuter Michael , Steins Martin , Woelke Katja , Buechner Thomas , Berdel Wolfgang E. , Mesters Rolf M. 
Published: October 2007

AbstractObjective:  Neuropilin‐1 (NRP‐1), a non‐tyrosine kinase receptor functioning as a mediator of angiogenesis and neuronal guidance, was recently found to be significantly overexpressed in newly diagnosed acute myeloid leukemia (AML) patients with significant correlation to survival. The role of NRP‐1 in refractory or relapsed AML patients and its regulation during anti‐angiogenic treatment remain to be elucidated.Methods:  Bone marrow biopsies of 10 patients with refractory or relapsed AML were evaluated for NRP‐1 expression by immunohistochemical analysis, and NRP‐1 expression level was determined before and after start of thalidomide therapy and correlated to response and growth factor expression.Results:  NRP‐1 expression was significantly increased in AML patients [median 7 arbitrary units (AU)] when compared with controls (n = 38, median 2.75 AU). Under thalidomide treatment, a marked difference in the course of NRP‐1 expression between responders and non‐responders was observed, however, without a statistical significance (P = 0.071) being reached. Additionally, a significant correlation of the NRP‐1 expression level to microvessel density could be detected under treatment with thalidomide (P = 0.018).Conclusion:  Our data provide evidence of increased NRP‐1 expression in relapsed or refractory AML. Additionally, our results suggest that thalidomide‐induced antileukemic properties might at least in part be mediated by NRP‐1 downregulation.
Long‐term effects of idiotype vaccination on the specific T‐cell response in peripheral blood and bone marrow of multiple myeloma patients
Authors: Abdalla Amir Osman , Hansson Lotta , Eriksson Ingrid , Näsman‐Glaser Barbro , Mellstedt Håkan , Österborg Anders 
Published: October 2007

AbstractObjectives:  To elucidate long‐term effects of idiotype (Id) vaccination on Id‐specific T cells of multiple myeloma (MM) patients and compare Id‐specific T‐cell responses of peripheral blood with those of bone marrow (BM).Materials and methods:  Id‐specific T‐cell responses of peripheral blood mononuclear cells (PBMC) were compared with those of BM mononuclear cells (BMMC) in 10 MM patients vaccinated with the Id protein at a median time of 41 months since the last immunization. The PBMC responses at late follow‐up were also compared with those during active immunization. The responses were assessed by a proliferation assay, enzyme‐linked immunospot (ELISPOT) (γ‐interferon), cytometric bead array (CBA) for secreted cytokines and quantitative real‐time polymerase chain reaction (QRT‐PCR) for cytokine gene expression.Results:  At the late testing time, an Id‐specific response was detected in PBMC of five patients (ELISPOT, CBA, QRT‐PCR) and in BMMC of four patients (CBA, QRT‐PCR). A response in both compartments was noted only in three patients. The cytokines gene profile was consistent with a predominance of Th2 cells [interleukin (IL)‐4, IL‐5, IL‐10]. Comparison of the Id‐specific responses of PBMC during active immunization with those at the late follow‐up showed that the frequency and magnitude of the responses had decreased significantly by time (proliferation/ELISPOT) (P < 0.02) and shifted at the gene level from a Th1 to a Th2 profile (P < 0.05).Conclusion:  Id‐specific T cells may decline overtime and shift toward a Th2 response and may be found at a similar frequency of patients in blood and BM.
Oxidative stress in red blood cells, platelets and polymorphonuclear leukocytes from patients with myelodysplastic syndrome
Authors: Ghoti Hussam , Amer Johnny , Winder Asher , Rachmilewitz Eliezer , Fibach Eitan 
Published: October 2007

AbstractLow‐risk myelodysplastic syndrome (MDS) is characterized by cytopenia, mainly anemia, because of ineffective hematopoiesis. Some of the patients with ineffective erythropoiesis, with or without ring sideroblasts in their bone marrow, develop severe anemia requiring frequent blood transfusions and consequently develop iron overload. Excess free iron in cells catalyses the generation of reactive oxygen species (ROS) that cause cell and tissue damage. Using flow cytometry techniques, we compared the oxidative status of red blood cells (RBC), platelets and neutrophils in 14 MDS patients with those of normal donors. The results show that ROS were higher while reduced glutathione (GSH) was lower in their RBC and platelets compared with normal cells. In neutrophils, no difference was found in ROS, while the GSH levels were lower. A correlation (r = 0.6) was found between serum ferritin levels of the patients and the ROS in their RBC and platelets. The oxidative stress was ameliorated by a short incubation with the iron‐chelators, the deferrioxamine and deferiprone or with antioxidants such as N‐acetylcysteine, suggesting that MDS patients might benefit from treatment with iron‐chelators and antioxidants.
Synchronous FIP1L1–PDGFRA‐positive chronic eosinophilic leukemia and T‐cell lymphoblastic lymphoma: a bilineal clonal malignancy
Authors: Capovilla Mathieu , Cayuela Jean‐Michel , Bilhou‐Nabera Chrystèle , Gardin Claude , Letestu Remi , Baran‐Marzak Fanny , Fenaux Pierre , Martin Antoine 
Published: October 2007

AbstractSeveral reports of successful empirical treatment of idiopathic hypereosinophilic syndrome with imatinib led to the recent identification of the FIP1L1–PDGFRA fusion gene rearrangement, which characterizes a distinctive group of chronic eosinophilic leukemias. This fusion gene can be detected in eosinophils, neutrophils, mast cells, T cells, B cells and monocytes in FIP1L1–PDGFRA‐positive hypereosinophilic patients suggesting a multilineage involvement. Furthermore, the same FIP1L1–PDGFRA rearrangement was identified in patients with hypereosinophilia and atypical mast cell proliferations, raising the question of a disease with two concomitant lines of differentiation. In addition, a recent report noted two cases with the association of FIP1L1–PDGFRA‐positive chronic eosinophilic leukemia and T‐cell lymphoblastic lymphoma (T‐LBL). We report here the only third case of synchronous chronic eosinophilic leukemia and T‐LBL, both associated with a FIP1L1–PDGFRA fusion transcript, confirming the occurrence of such disease and suggesting a clonal proliferation with two lines of differentiation probably arising from a primitive multipotent medullary stem cell.
Evaluation of bone disease in multiple myeloma patients carrying the t(4;14) chromosomal translocation
Authors: Tosi Patrizia , Terragna Carolina , Testoni Nicoletta , Zamagni Elena , Renzulli Matteo , Tacchetti Paola , Montanari Elena , Perrone Giulia , Ceccolini Michela , Brioli Annamaria , Pallotti Maria C. , Tura Sante , Baccarani Michele , Cavo Michele 
Published: October 2007

AbstractT(4;14) chromosomal abnormality is one of the most adverse prognostic factors predicting for poor outcome in multiple myeloma (MM) patients. It has been recently suggested that bone disease, as evaluated by spinal magnetic resonance imaging (MRI), is relatively infrequent in these patients. In the present study, we aimed at further testing this hypothesis by analyzing the extent of whole bone involvement in patients showing t(4;14) chromosomal translocation as compared with negative patients. For this purpose, 53 consecutive newly diagnosed MM patients (35M, 18F, median age = 55 yr) underwent evaluation of total skeletal X‐ray, whole spine MRI, and at the same time, quantification of markers of bone resorption (urinary N‐terminal telopeptide, pyridinoline, deoxypyridinoline, serum crosslaps), and bone formation (bone alkaline phosphatase and osteocalcin) was performed. The presence of IgH/MMSET fusion gene as a surrogate marker for t(4;14), was detected in 11 patients (20.7%), whose clinical characteristics were similar to those observed in t(4;14) negative patients. The type of marrow involvement at spinal MRI (diffuse vs. focal vs. negative) was the same in both groups of patients, even though overt vertebral fractures were more frequently found in t(4;14) positive cases (82% vs. 43%, P = 0.05); in line with this finding, skeletal lesions were more common in t(4;14) positive patients (mean skeletal score = 8.54 ± 1.36 SE, as compared with 3.42 ± 0.57 SE in t(4;14) negative cases, P = 0.000). These data were confirmed by the evaluation of serum crosslaps, that were significantly increased in patients with t(4;14) abnormality as compared with negative individuals (10 400 pmol/L ± 2160 SE vs. 5640 pmol/L ± 859 SE P = 0.02) Our results indicate that, at variance to what has been previously reported, bone resorption is more prominent in t(4;14) positive patients.
Profiling of diffuse large B‐cell lymphoma by immunohistochemistry: identification of prognostic subgroups
Authors: Sjö Lene Dissing , Poulsen Christian Bjørn , Hansen Mads , Møller Michael Boe , Ralfkiaer Elisabeth 
Published: October 2007

AbstractDiffuse large B‐cell lymphoma (DLBCL) is a frequent lymphoma subtype with a heterogeneous behavior and a variable response to conventional chemotherapy. This clinical diversity is believed to reflect differences in the molecular pathways leading to lymphomagenesis. In this study, we have analyzed pretreatment, diagnostic samples from 108 DLBCL by immunohistology for expression of four markers linked to germinal center B‐cells (CD10, Bcl‐6), postgerminal center B‐cells (MUM1) and apoptosis (Bcl‐2). The results indicate that both CD10 and Bcl‐6 are favorable prognostic indicators, in contrast to Bcl‐2, which is an adverse parameter. Furthermore, using two algorithms for distinction between low‐ and high‐risk patients proposed by Hans et al. (Blood, 2004; 103:275) and Muris et al. (Journal of Pathology, 2006; 208:714), it is shown that both are useful for predicting outcome in DLBCL. However, in this report, the algorithm of Hans et al. was superior to that of Muris et al. These findings confirm and extend other studies and indicate that different prognostic subgroups of DLBCL can be distinguished by simple immunohistological investigations for a limited number of markers. Whether these groups are also relevant for individual treatment decisions will be important to investigate in prospective studies.
Inhibitors of protein kinase C sensitise multiple myeloma cells to common genotoxic drugs
Authors: Baumann Philipp , Armann Jakob , Mandl‐Weber Sonja , Grün Gabriel , Oduncu Fuat , Schmidmaier Ralf 
Published: October 2007

AbstractObjectives:  Despite high dose treatment regimes multiple myeloma (MM) disease is still not curable. Patients become resistant to cytotoxic drugs and die of disease progression. Therefore, besides new cytotoxic compounds drug sensitisers are urgently needed.Methods:  The MM cell lines U266, OPM‐2, RPMI‐8226 and NCI‐H929 were incubated with the common anti‐myeloma drugs like melphalan together with protein kinase C (PKC) inhibitors. Growth inhibition was measured using the water‐soluble tetrazolium salt 4‐[3‐(4‐iodophenyl)‐2‐(4‐nitrophenyl)‐2H‐5‐tetrazolio]‐1,3‐benzene disulfonate (WST‐1 assay), and apoptosis was determined by flow cytometry after staining with fluorescein isothiocyanate‐labeled annexin V (annexin‐V‐FITC) and propidium iodide. Intracellular signalling was shown by western blotting.Results:  In this study we show that the combination of melphalan or doxorubicin with a PKC inhibitor, Gö6976 or enzastaurin, strongly increases cell toxicity. Increase of cytotoxicity is shown to be due to increased induction of apoptosis. Furthermore, we show that the protective effect of human bone marrow stromal cells (hBMSC) is abrogated by the PKC inhibitors. Finally, western blotting experiments revealed that incubation of myeloma cells with cytotoxic drugs like melphalan or doxorubicin leads to increased phosphorylation and therefore degradation of inhibitor of nuclear factor kappa B (IκB) and release of nuclear factor kappa B (NFκB). In contrast, enzastaurin inhibits phosphorylation of IκB.Conclusions:  We conclude that the combination of conventional drugs and PKC inhibitors might be very effective and represents a new strategy in the treatment of MM.
Intracellular HMGB1 transactivates the human IL1B gene promoter through association with an Ets transcription factor PU.1
Authors: Mouri Fumihiko , Tsukada Junichi , Mizobe Takamitsu , Higashi Takehiro , Yoshida Yasuhiro , Minami Yasuhiro , Izumi Hiroto , Kominato Yoshihiko , Kohno Kimitoshi , Tanaka Yoshiya 
Published: October 2007

AbstractHigh mobility group box 1 protein (HMGB1), originally described as a non‐histone, DNA binding protein, was recently identified as a late mediator of inflammation via its extracellular release from activated macrophages/monocytes. In the present study, we report that intracellular HMGB1 synergizes with a macrophage/monocyte‐specific E26 transformation‐specific sequence (Ets) transcription factor PU.1 to transactivate the promoter of the IL1B gene coding a 31‐kDa proIL‐1β protein. The −131 to +12 IL1B promoter, which possesses a PU.1 binding motif essential for its transactivation, was induced when HMGB1 expression vector was transfected into murine RAW264.7 macrophage cells. Our glutathione S‐transferase‐pulldown and coimmunoprecipitation assays demonstrated direct physical interaction of HMGB1 with PU.1. Deletion of the PU.1 winged helix‐turn‐helix DNA‐binding domain inhibited the association of the two proteins. In electrophoretic mobility shift assay using recombinant PU.1 protein, a ternary complex of PU.1, HMGB1 and PU.1‐binding element within the IL1B promoter was generated. The importance of PU.1 was further supported by our observation that induction of the IL1B promoter was obtained only after PU.1 expression in PU.1‐deficient murine EL4 thymoma cells. Thus, our data raise the possibility of a novel mechanism which sustains and amplifies inflammatory reactions through physical interaction of PU.1 with intracellular HMGB1 in macrophages/monocytes.
Stephen's Banded Snake envenomation treated with tiger snake antivenom
Authors: Hession Michael 
Published: October 2007

AbstractDemonstration of the use of Tiger Snake Anti‐venom in Stephen's Banded Snake envenomation is described. The patient presented with a clear history of a bite and a mild headache. Subsequently, the patient developed defibrination coagulopathy. A swab of the bite site reacted to the Tiger anti‐venom on the Commonwealth Serum Laboratories anti‐venom detection kit. Two ampoules of anti‐venom were used. A mild allergic reaction to tiger snake antivenom developed. There was resolution of the coagulopathy.