bluuebunny/crossref_metadata_2025 huggingface dataset:
Familial Aggregation of Atrial Fibrillation
Authors: Christophersen Ingrid Elisabeth , Ravn Lasse Steen , Budtz-Joergensen Esben , Skytthe Axel , Haunsoe Stig , Svendsen Jesper Hastrup , Christensen Kaare
Published: April 2009

Background—

Heritability may play a role in nonfamilial atrial fibrillation (AF). We hypothesized that a monozygotic (MZ) twin whose co-twin was diagnosed with AF would have an increased risk of the disease compared with a dizygotic (DZ) twin in the same situation.

Methods and Results—

A sample of 1137 same-sex twin pairs (356 MZ and 781 DZ pairs) in which one or both members were diagnosed with AF were identified in The Danish Twin Registry. Concordance rates were twice as high for MZ pairs than for DZ pairs regardless of sex (22.0% versus 11.6%,
P
<0.0001). In a Cox regression of event-free survival times, we compared the time span between occurrences of disease in MZ and DZ twins. The unaffected twin was included when his or her twin-sibling (the index twin) was diagnosed with AF. After adjustment for age at entry, MZ twins had a significantly shorter event-free survival time (hazard ratio, 2.0; 95% CI, 1.3 to 3.0), thereby indicating a genetic component. Using biometric models, we estimated the heritability of AF to be 62% (55% to 68%), due to additive genetics. There were no significant differences across sexes.

Conclusions—

All the analyses of twin similarities in the present study indicate that genetic factors play a substantial role in the risk of AF for both sexes. The recurrence risk for co-twins (12% to 22%) is clinically relevant and suggests that co-twins of AF-affected twins belong to a high-risk group for AF.
Phosphodiesterase 2 Mediates Redox-Sensitive Endothelial Cell Proliferation and Angiogenesis by Thrombin via Rac1 and NADPH Oxidase 2
Authors: Diebold Isabel , Djordjevic Talija , Petry Andreas , Hatzelmann Armin , Tenor Hermann , Hess John , Görlach Agnes
Published: April 2009

Cyclic nucleotide phosphodiesterases (PDEs) control the levels of the second messengers cAMP and cGMP in many cell types including endothelial cells. Although PDE2 has the unique property to be activated by cGMP but to hydrolyze cAMP, its role in endothelial function is only poorly understood. Reactive oxygen species (ROS) have been recognized as signaling molecules controlling many endothelial functions. We thus investigated whether PDE2 would link to ROS generation and proliferative responses in human umbilical vein endothelial cells in response to thrombin. Thrombin stimulated the GTPase Rac1, known to activate NADPH oxidases, and enhanced ROS formation, whereas PDE2 inhibition or depletion by short hairpin (sh)RNA prevented these responses. Similar observations were made with 8-Br-cGMP or atrial natriuretic peptide. In agreement, thrombin elevated cGMP but decreased cAMP levels, whereas db-cAMP or forskolin diminished Rac1 activity and ROS production. Subsequently, PDE2 overexpression activated Rac1, increased ROS generation, and enhanced proliferation and in vitro capillary formation. These responses were not observed in the presence of inactive Rac1 or shRNA against the NADPH oxidase subunit NOX2. Inhibition or depletion of PDE2 also prevented thrombin-induced proliferation and capillary formation. Importantly, downregulation of PDE2 by lentiviral shRNA or PDE2 inhibition prevented vessel sprouting from mouse aortic explants and in vivo angiogenesis in a mouse model, respectively. In summary, PDE2 promotes activation of NADPH oxidase-dependent ROS production and subsequent endothelial proliferation and angiogenesis. Targeting PDE2 may provide a new therapeutic approach in diseases associated with endothelial dysfunction, oxidative stress, vascular proliferation, and angiogenesis.
Interleukin-6 Modulates the Expression of the Bone Morphogenic Protein Receptor Type II Through a Novel STAT3–microRNA Cluster 17/92 Pathway
Authors: Brock Matthias , Trenkmann Michelle , Gay Renate E. , Michel Beat A. , Gay Steffen , Fischler Manuel , Ulrich Silvia , Speich Rudolf , Huber Lars C.
Published: April 2009

Dysregulated expression of bone morphogenetic protein receptor type II (BMPR2) is a pathogenetic hallmark of pulmonary hypertension. Downregulation of BMPR2 protein but not mRNA has been observed in multiple animal models mimicking the disease, indicating a posttranscriptional mechanism of regulation. Because microRNAs (miRNAs) regulate gene expression mainly through inhibition of target gene translation, we hypothesized that miRNAs may play a role in the modulation of BMPR2. Performing a computational algorithm on the BMPR2 gene, several miRNAs encoded by the miRNA cluster 17/92 (miR-17/92) were retrieved as potential regulators. Ectopic overexpression of miR-17/92 resulted in a strong reduction of the BMPR2 protein, and a reporter gene system showed that BMPR2 is directly targeted by miR-17-5p and miR-20a. By stimulation experiments, we found that the miR-17/92 cluster is modulated by interleukin (IL)-6, a cytokine involved in the pathogenesis of pulmonary hypertension. Because IL-6 signaling is mainly mediated by STAT3 (signal transducer and activator of transcription 3), the expression of STAT3 was knocked down by small interfering RNA, which abolished the IL-6–mediated expression of miR-17/92. Consistent with these data, we found a highly conserved STAT3-binding site in the promoter region of the miR-17/92 gene (C13orf25). Promoter studies confirmed that IL-6 enhances transcription of C13orf25 through this distinct region. Finally, we showed that persistent activation of STAT3 leads to repressed protein expression of BMPR2. Taken together, we describe here a novel STAT3–miR-17/92—BMPR2 pathway, thus providing a mechanistic explanation for the loss of BMPR2 in the development of pulmonary hypertension.
The Presentation and Clinical Course of Intracranial Developmental Venous Anomalies in Adults
Authors: Hon Jennifer M.L. , Bhattacharya Jo J. , Counsell Carl E. , Papanastassiou Vakis , Ritchie Vaughn , Roberts Richard C. , Sellar Robin J. , Warlow Charles P. , Al-Shahi Salman Rustam
Published: April 2009

Background and Purpose—

Reported risks of hemorrhage from intracranial developmental venous anomalies (DVAs) vary, so we investigated this in a systematic review and population-based study.

Methods—

We systematically reviewed the literature (Ovid Medline and Embase to November 7, 2007) and selected studies of ≥20 participants with ≥1 DVA(s) that described their clinical presentation and/or their clinical course over a specified follow-up period. We also identified every adult first diagnosed with a DVA in Scotland from 1999 to 2003 and followed them in a prospective, population-based study.

Results—

Of 2068 articles detected by the literature search, 15 met our inclusion criteria and described clinical presentation, 8 of which also described the clinical course of DVAs. In the 15 studies of 714 people first presenting with a DVA, 61% were incidental findings, the mode of presentation was unclear in 23%, 6% presented with nonhemorrhagic focal neurological deficit, 6% had caused symptomatic hemorrhage, 4% were associated with epileptic seizure, and <1% were associated with infarction. In studies of the clinical course of 422 people with a DVA, the hemorrhage rate after first presentation ranged from 0% to 1.28% per year. In the population-based study of 93 adults with DVAs, 98% were incidental, 1% presented with symptomatic hemorrhage, and 1% presented with an infarct, but there were no symptomatic hemorrhages or infarcts in 492 person-years of follow-up (0% per person-year; 95% CI, 0% to 0.7%).

Conclusions—

Intracranial DVAs have a benign presentation and clinical course.
Dispatcher Recognition of Stroke Using the National Academy Medical Priority Dispatch System
Authors: Buck Brian H. , Starkman Sidney , Eckstein Marc , Kidwell Chelsea S. , Haines Jill , Huang Rainy , Colby Daniel , Saver Jeffrey L.
Published: April 2009

Background and Purpose—

Emergency medical dispatchers play an important role in optimizing stroke care if they are able to accurately identify calls regarding acute cerebrovascular disease. This study was undertaken to assess the diagnostic accuracy of the current national protocol guiding dispatcher questioning of 911 callers to identify stroke (QA Guide version 11.1 of the National Academy Medical Priority Dispatch System).

Methods—

We identified all Los Angeles Fire Department paramedic transports of patients to University of California Los Angeles Medical Center during the 12-month period from January to December 2005 in a prospectively maintained database. Dispatcher-assigned Medical Priority Dispatch System codes for each of these patient transports were abstracted from the paramedic run sheets and compared to final hospital discharge diagnosis.

Results—

Among 3474 transported patients, 96 (2.8%) had a final diagnosis of stroke or transient ischemic attack. Dispatchers assigned a code of potential stroke to 44.8% of patients with a final discharge diagnosis of stroke or TIA. Dispatcher identification of stroke showed a sensitivity of 0.41, specificity of 0.96, positive predictive value of 0.45, and negative predictive value of 0.95.

Conclusions—

Dispatcher recognition of stroke calls using the widely employed Medical Priority Dispatch System algorithm is suboptimal, with failure to identify more than half of stroke patients as likely stroke. Revisions to the current national dispatcher structured interview and symptom identification algorithm for stroke may facilitate more accurate recognition of stroke by emergency medical dispatchers.
Molecular Mobility in Polycyanurate/Clay Nanocomposites Studied by Dielectric Techniques
Authors: Maroulas P. , Kripotou S. , Pissis P. , Fainleib A. , Bei I. , Bershtein V. , Gomza Y.
Published: April 2009

Nanocomposites, having neat polycyanurate networks (PCN) and modified by polytetramethylene glycol polycyanurate networks (PCN/PTMG) as matrices and montmorillonite (MMT) as filler, were prepared using thermal polymerization, and studied with respect to polymerization kinetics, morphology and in particular, molecular mobility. In order to investigate the influence of the clay modifier and the way of preparation two types of commercial MMT were used, while the mixing was obtained mechanically and by using ultrasound. IR-spectroscopy, Wide Angle X- ray Scattering (WAXS) and dielectric techniques including Dielectric Relaxation Spectroscopy (DRS) and Thermally Stimulated Depolarization Current (TSDC) techniques were used to provide information on polymerization kinetics, morphology and molecular mobility, respectively.
A Micromechanics Model for the Electrical Conductivity of Nanotube-Polymer Nanocomposites
Authors: Seidel Gary D. , Lagoudas Dimitris C.
Published: April 2009

The introduction of carbon nanotubes (CNTs) into nonconducting polymers has been observed to yield orders of magnitude increases in conductivity at very low concentrations of CNTs. These low percolation concentrations have been attributed to both the formation of conductive networks of CNTs within the polymer and to a nanoscale effect associated with the ability of electrons to transfer from one CNT to another known as electron hopping. In the present work, a micromechanics model is developed to assess the impact of the effects of electron hopping and the formation of conductive networks on the electrical conductivity of CNT-polymer nanocomposites. The micromechanics model uses the composite cylinders model as a nanoscale representative volume element where the effects of electron hopping are introduced in the form of a continuum interphase layer, resulting in a distinct percolation concentration associated with electron hopping. Changes in the aspect ratio of the nanoscale representative volume element are used to reflect the changes in nanocomposite conductivity associated with the formation of conductive networks due to the formation of nanotube bundles. The model results are compared with experimental data in the literature for both single- and multi-walled CNT nanocomposites where it is observed that the model developed is able to qualitatively explain the relative impact of electron hopping and nanotube bundling on the nanocomposite conductivity and percolation concentrations.
Pharmacokinetics and Pharmacodynamic, Pharmacokinetic, Pharmacodynamic, and Electrocardiographic Effects of Dapoxetine and Moxifloxacin Compared With Placebo in Healthy Adult Male Subjects
Authors: Modi Nishit B. , Nath Rajneesh , Staehr Peter , Gupta Suneel K. , Aquilina Joseph W. , Rivas David
Published: April 2009

Selective serotonin reuptake inhibitors (SSRIs) may be associated with electrocardiographic effects. The electrocardiographic pharmacodynamics of dapoxetine, a short‐acting SSRI being developed for the treatment of premature ejaculation, are compared with those of placebo and moxifloxacin (positive control) in 2 single‐center, randomized, crossover studies in healthy men. In study 1, subjects receive 2 doses of dapoxetine 120 mg, given 3 hours apart; a single dose of moxifloxacin 400 mg; and 2 doses of placebo, given 3 hours apart. In study 2, subjects receive single doses of dapoxetine 60 mg, dapoxetine 120 mg, moxifloxacin 400 mg, and placebo. Moxifloxacin significantly increases QT and corrects QT intervals (QTc) compared with placebo in both studies (eg, Bazett‐corrected QTc of 11.90 milliseconds [95% confidence interval, 2.68 to 21.11] and 5.06 [95% confidence interval, −2.26 to 12.38]). Dapoxetine 60, 120, and 240 mg do not prolong the QT/QTc interval and have no clinically significant electrocardiographic effects. Dapoxetine and moxifloxacin pharmacokinetics are similar to previous reports. Adverse events are generally mild in severity; nausea is the most common. The results demonstrate that dapoxetine does not have electrocardiographic effects at doses of 60, 120, and 240 mg.
Effect of Ketoconazole on the Pharmacokinetic Profile of Ambrisentan
Authors: Richards Duncan B. , Walker Gennyne A. , Mandagere Arun , Magee Mindy H. , Henderson Linda S.
Published: April 2009

Ambrisentan is an endothelin type A (ETA)–selective receptor antagonist that is metabolized primarily by glucuronidation but also undergoes oxidative metabolism by CYP3A4. The potential for ketoconazole, the archetypal strong inhibitor of CYP3A4, to alter the pharmacokinetic profile of ambrisentan and its oxidative metabolite, 4‐hydroxymethyl ambrisentan, was assessed in an open‐label, nonrandomized, 2‐period, single‐sequence study in 16 healthy men. Participants received a single dose of ambrisentan 10 mg alone and after 4 days of ketoconazole 400 mg administered once daily. In the presence of multiple doses of ketoconazole, single‐dose ambrisentan AUC0–∞ estimate was increased by 35.3%, whereas Cmax was increased by 20.0%. For the 4‐hydroxymethyl ambrisentan metabolite, AUC0–∞ estimate was decreased by 4.0%, whereas Cmax was decreased by 16.5%. Concomitant administration of ambrisentan and ketoconazole was well tolerated. In summary, ketoconazole had no clinically significant effect on the pharmacokinetics or safety profile of ambrisentan; therefore, no changes in ambrisentan dose should be necessary when the drug is administered concomitantly with known CYP3A4 inhibitors.
Tai Chi Qigong for the quality of life of patients with knee osteoarthritis: a pilot, randomized, waiting list controlled trial
Authors: Lee Hwa-Jin , Park Hi-Joon , Chae Younbyoung , Kim Song-Yi , Kim Seung-Nam , Kim Seung-Tae , Kim Je-Ho , Yin Chang-Shik , Lee Hyejung
Published: April 2009

Objective: To evaluate the effects of Tai Chi Qigong training on the quality of life and physical function of patients with osteoarthritis of the knee.

Design: A preliminary, single-blind, randomized controlled trial.

Setting: General community, performed at Hwaseong City Health Center.

Participants: Forty-four elderly subjects (mean age, 69.1 ± 5.4 years) with knee osteoarthritis.

Intervention: The patients were randomized (2:1) to: (1) an eight-week Tai Chi Qigong training programme or (2) a waiting list control group. The programme involved eight weeks of group Tai Chi Qigong sessions, with 60 minutes per session twice a week.

Main outcome measures: The primary outcome was quality of life measured with the Short Form 36 (SF-36) at baseline and week 8. Secondary outcomes included the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) and 6-m walking time.

Results: The training group had statistically significant improvements in the quality of life (changes of SF-36, Qigong versus control: 21.6 ± 16.8 versus 9.8 ± 13.6, P<0.05) and 6-m walking test (change in walking time, Qigong versus control: —1.6 ± 1.7 versus —0.2 ± 0.8 s, P<0.01). The WOMAC scores in the training group were markedly improved, although the differences were not statistically significant.

Conclusions: Tai Chi Qigong training appears to have beneficial effects in terms of the quality of life and physical functioning of elderly subjects with knee osteoarthritis. However, more rigorous trials are needed to confirm the efficacy of this training for patients with osteoarthritis of the knee.
Autoantibodies against galectin-8: their specificity, association with lymphopenia in systemic lupus erythematosus and detection in rheumatoid arthritis and acute inflammation
Authors: Massardo L , Metz C , Pardo E , Mezzano V , Babul M , Jarpa E , Guzmán AM , André S , Kaltner H , Gabius HJ , Jacobelli S , González A , Soza A
Published: April 2009

The role of autoantibodies in the pathogenesis of systemic lupus erythematosus (SLE) has not been completely defined. From more than a hundred autoantibodies described in SLE, relatively few have been associated with clinical manifestations. The glycan-binding proteins of the galectin family can modulate the immune system. Anti-galectin autoantibodies thus could have functional and/or pathogenic implications in inflammatory processes and autoimmunity. We previously reported function-blocking autoantibodies against galectin-8 (Gal-8) in SLE. Here we tested these autoantibodies against a series of other human galectins and demonstrated their specificity for Gal-8, being detectable in 23% of 78 SLE patients. Remarkably, they associated with lymphopenia (50% of 18 anti-Gal-8-positive versus 18% of 60 anti-Gal-8-negative cases, Fisher’s Exact test two-tailed: P < 0.012). Lymphopenia is a common clinical manifestation in SLE, yet of unknown mechanism. In addition, six of eight patients with both lymphopenia and malar rash had anti-Gal-8 in their sera. Occurrence of these autoantibodies was not confined to SLE as we also found them in sera of patients with rheumatoid arthritis (16%) and septicemia (20%). This study thus establishes occurrence of specific anti-Gal-8 autoantibodies in autoimmune rheumatic diseases and in acute inflammation, with an apparent association to a clinical subset in SLE.
Lupus and cancer
Authors: Gayed M , Bernatsky S , Ramsey-Goldman R , Clarke AE , Gordon C
Published: April 2009

Individuals with systemic lupus erythematosus (SLE) have an increased susceptibility to certain types of cancer. Of particular concern are haematologic malignancies, specifically non-Hodgkin lymphoma, where a three- to four-fold increased risk is seen in SLE, compared with the general population. There is some evidence that immunosuppressive exposures play a role, although there appear to be other factors driving the risk. Lupus disease activity, with resultant dysregulated lymphocyte proliferation, may itself be a mediator of the association between SLE and lymphoma. Aside from haematologic malignancy risk, lung cancer also is increased in SLE compared with the general population, and smoking likely drives this risk in large part. Last but not least, cervical dysplasia is a concern in women with SLE, particularly with exposure to immunosuppressants; routine screening for this complication should not be neglected.
From Militant Rejection to Pragmatic Consensus
Authors: Still Clarinda
Published: April 2009

This article examines gender and age differences in Dalit attitudes towards caste inequality, using interviews and ethnographic fieldwork conducted among Madigas in Andhra Pradesh (AP). Madigas express a range of views about their position in society. Some oppose ideas of untouchability and espouse ideologies of equality. They deny the existence of caste and have no respect for what they see as the dying remnants of the old order. Others (especially elderly women) accept patronage and subordination in return for cash and security and exploit the old forms of subservience and deference. The paper argues that Madigas reject ‘caste–as–hierarchy’ and make use of ‘caste–as–identity’ and attempt to use their caste status as a resource which can be invoked when it is beneficial, and downplayed when it is not.
Damage-based Cohesive Zone Model for Rate-depend Interfacial Fracture
Authors: Omiya Masaki , Kishimoto Kikuo
Published: April 2009

Cohesive zone models (CZMs) are being increasingly used to describe local fracture and failure behaviors in a number of material systems. The idea of the cohesive approach is to include a complex behavior around the crack front into the simple cohesive model for crack propagation analysis. Many cohesive laws have been proposed and there are a few rate-depend cohesive zone models. To describe the damage and failure phenomena on the interface, damage-based cohesive zone model (DCZM) is the most reasonable. Therefore, the aim of this article is to develop the phenomenological rate-depend cohesive zone model based on damage mechanics. Based on the internal variable theory of thermodynamics, a continuum interface constitutive model relating interface traction with interface separation has been developed. By introducing an interface damage variable, an evolution equation was derived to characterize the degradation of interfacial rigidity with interface debonding. This constitutive relation is applied to the matrix cracking in composites materials and the shear stress distribution, interface damage evolution, pullout stress, and pullout works were discussed. These results show that the proposed model qualitatively explain the experimental results and is useful for the prediction of the damage states, remaining strength and life time of the rate-depend bonding interface.
Cohesive Zone Model Applied to Creep Crack Initiation at an Interface Edge between Submicron Thick Films
Authors: Do Van Truong  , Kitamura Takayuki
Published: April 2009

A crack initiates at an interface edge between submicron thick films and leads to the malfunction of microelectronic devices. In this study, the cohesive zone model method with a cohesive law based on the damage mechanics concept is developed to simulate the creep crack initiation at an interface edge between tin and silicon films. Experiments on delamination at the Sn/Si interface using a micro-cantilever bend specimen were conducted. The cohesive law is applied to the elements in the UEL user subroutine in the finite element code ABAQUS. The parameters characterizing the cohesive law are calibrated by fitting displacement-time curves obtained by experiments and FEM simulations. It is revealed that the order of stress singularity increases with time and has a significant jump in its value at the crack initiation.
Damage Model for Predicting the Effect of Steel Properties on Ductile Crack Growth Resistance
Authors: Ohata Mitsuru , Fukahori Takuya , Minami Fumiyoshi
Published: April 2009

This study pays attention to reveal material properties that control a resistance curve for ductile crack growth (CTOD-R curve) on the basis of the mechanism for ductile crack growth, so that the R-curve could be numerically predicted only from those properties. Crack growth tests using 3-point bend specimens with a fatigue pre-crack are conducted for two steels that have different ductile crack growth resistance, whereas both steels have the same mechanical properties in terms of strength and work hardening. Observation of crack growth behaviors provides that different mechanisms between ductile crack initiation from fatigue pre-crack and subsequent growth process can be applied. It is shown that two types of ductile properties of steel associated with ductile damage can mainly influence CTOD-R curve; one is a resistance of ductile crack initiation estimated with critical local strain for ductile cracking from a surface of notch root, and the other one is a stress triaxiality dependent ductility obtained with circumferentially notched round-bar specimens. The damage model for numerically simulating the R-curve is proposed taking the above two ductile properties into account, where the ductile crack initiation from crack-tip is in accordance with local strain criterion, and the subsequent crack growth triaxiality dependent damage criterion. The proposed model accurately predicts the measured different R-curves between two steels used that have the same ‘strength properties’, and also the stress triaxiality dependence of R-curve.
Implementing A New Style of Learning in A Taught Postgraduate Medical Ultrasound Programme: Reflections on the First Year
Authors: Gibbs Vivien , Hobbs Julie
Published: April 2009

The successful introduction of an action based learning (ABL) module into the medical ultrasound programme several years ago, has led to further developments using this approach. Conflicting pressures from hospital departments requesting increasing numbers of subject specialty areas to be taught, and university managers requiring modules to be economically viable, resulted in a more creative approach to delivery of the programme. ABL requires students to take responsibility for their own learning, thereby promoting independent learning. This is generally recognised as a more effective method for acquiring knowledge and skills, particularly at postgraduate level. Following completion of the first year of this newly accredited module, the experiences of students and staff were evaluated. Results of the evaluation and feedback demonstrated that students initially struggle to understand the concept of ABL. However, results of student assessments showed that once individuals engage with the process, knowledge and skills can be successfully acquired, demonstrating that this style of learning is a tool which can be potentially used in many aspects of life.
Billet quenching extrusion process as efficient and reliable replacement for conventional extrusion of Al–Cu alloys
Authors: Barbič R. , Dragojevič V. , Smolej A.
Published: April 2009

In order to eliminate the separate solution soaking treatment used for Al–Cu extrudates, the influence of billet heat treatments before the extrusion process on a precipitation hardenable AlCu6PbBi (AA2011) alloy was studied. The hot deformation behaviour of the alloy was studied using compression tests. A comparison of the conventional extrusion process, press quenching and billet quenching (BQ) before extrusion was made in production on a 35 MN press. The transformation kinetics was studied by heat treating homogenised samples in salt baths. The mechanical testing, using tensile tests and the Brinell hardness test, and a microstructural investigation, using light and TEM microscopy, revealed that extrusion using the billet quenching process results in the formation of extrudates with similar mechanical properties, hardness and microstructures as those produced using conventional technology. In the extrudates produced by BQ a supersaturated solid solution is formed directly after cooling in a standing water wave, which makes BQ an efficient and reliable substitute for the conventional extrusion process.
A clinical and immunologic phase 2 trial of Wilms tumor gene product 1 (WT1) peptide vaccination in patients with AML and MDS
Authors: Keilholz Ulrich , Letsch Anne , Busse Antonia , Asemissen Anne Marie , Bauer Sandra , Blau Igor Wolfgang , Hofmann Wolf-Karsten , Uharek Lutz , Thiel Eckhard , Scheibenbogen Carmen
Published: April 2009

This study investigated the immunogenicity of Wilms tumor gene product 1 (WT1)–peptide vaccination in WT1-expressing acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients without curative treatment option. Vaccination consisted of granulocyte-macrophage colony-stimulating factor subcutaneously days 1 to 4, and WT1.126-134 peptide and 1 mg keyhole limpet hemocyanin on day 3. The initial 9 patients received 4 vaccinations biweekly, then monthly, and the subsequent 10 patients received continual biweekly vaccination. Seventeen AML patients and 2 refractory anemia with excess blasts patients received a median of 11 vaccinations. Treatment was well tolerated. Objective responses in AML patients were 10 stable diseases (SDs) including 4 SDs with more than 50% blast reduction and 2 with hematologic improvement. An additional 4 patients had clinical benefit after initial progression, including 1 complete remission and 3 SDs. WT1 mRNA levels decreased at least 3-fold from baseline in 35% of patients. In 8 of 18 patients, WT1-tetramer+ T cells increased in blood and in 8 of 17 patients in bone marrow, with a median frequency in bone marrow of 0.18% at baseline and 0.41% in week 18. This WT1 vaccination study provides immunologic, molecular, and preliminary evidence of potential clinical efficacy in AML patients, warranting further investigations.
Antigen sensitivity is a major determinant of CD8+ T-cell polyfunctionality and HIV-suppressive activity
Authors: Almeida Jorge R. , Sauce Delphine , Price David A. , Papagno Laura , Shin So Youn , Moris Arnaud , Larsen Martin , Pancino Gianfranco , Douek Daniel C. , Autran Brigitte , Sáez-Cirión Asier , Appay Victor
Published: April 2009

CD8+ T cells are major players in the immune response against HIV. However, recent failures in the development of T cell–based vaccines against HIV-1 have emphasized the need to reassess our basic knowledge of T cell–mediated efficacy. CD8+ T cells from HIV-1–infected patients with slow disease progression exhibit potent polyfunctionality and HIV-suppressive activity, yet the factors that unify these properties are incompletely understood. We performed a detailed study of the interplay between T-cell functional attributes using a bank of HIV-specific CD8+ T-cell clones isolated in vitro; this approach enabled us to overcome inherent difficulties related to the in vivo heterogeneity of T-cell populations and address the underlying determinants that synthesize the qualities required for antiviral efficacy. Conclusions were supported by ex vivo analysis of HIV-specific CD8+ T cells from infected donors. We report that attributes of CD8+ T-cell efficacy against HIV are linked at the level of antigen sensitivity. Highly sensitive CD8+ T cells display polyfunctional profiles and potent HIV-suppressive activity. These data provide new insights into the mechanisms underlying CD8+ T-cell efficacy against HIV, and indicate that vaccine strategies should focus on the induction of HIV-specific T cells with high levels of antigen sensitivity to elicit potent antiviral efficacy.
Gene expression profiling of plasma cells at myeloma relapse from tandem transplantation trial Total Therapy 2 predicts subsequent survival
Authors: Nair Bijay , Shaughnessy John D. , Zhou Yiming , Astrid-Cartron Marie , Qu Pingping , van Rhee Frits , Anaissie Elias , Alsayed Yazan , Waheed Sarah , Hollmig Klaus , Szymonifka Jackie , Petty Nathan , Hoering Antje , Barlogie Bart
Published: April 2009

We report on prognostic implications for postrelapse survival (PRS) of a gene expression profiling (GEP)–defined risk score at relapse available in 120 myeloma patients previously enrolled in tandem transplantation trial Total Therapy 2. Among the 71 patients with additional GEP baseline information, 3-year PRS was 71% in 40 patients with low risk present both at baseline and relapse contrasting with only 17% in 28 patients with high risk at relapse, 12 of whom with baseline low-risk status fared better than the remainder (P = .08). On multivariate analysis of relapse parameters available in 104 patients, high risk conferred short PRS (hazard ratio = 4.00, P < .001, R2 = 33%), whereas relapse hyperdiploidy predicted long PRS (hazard ratio = 0.37, P = .022, cumulative R2 = 41%). In case the initial partial response lasted less than 2 years, relapse low-risk identified 26 patients with superior 3-year PRS of 61% versus 9% among 32 with relapse high-risk (P < .001). Based on its PRS predictive power, GEP analysis should be an integral part of new agent trials in search of better therapy for high-risk myeloma.
Compassionate use of sorafenib in FLT3-ITD–positive acute myeloid leukemia: sustained regression before and after allogeneic stem cell transplantation
Authors: Metzelder Stephan , Wang Ying , Wollmer Ellen , Wanzel Michael , Teichler Sabine , Chaturvedi Anuhar , Eilers Martin , Enghofer Erich , Neubauer Andreas , Burchert Andreas
Published: April 2009

Acute myeloid leukemia (AML) patients with internal tandem duplication (ITD) mutations in the Fms-like tyrosine-3 (FLT3) gene have a dismal prognosis. Here we report compassionate-use results with the multikinase and FLT3-ITD inhibitor sorafenib for the treatment of relapsed or refractory FLT3-ITD–positive AML. Sorafenib induced clinically meaningful and very rapid responses in all 6 patients treated either before (n = 2), after (n = 3), or both before and after (n = 1) allogeneic stem cell transplantation (allo-SCT). Sorafenib-induced remissions facilitated allo-SCT in 2 of the 3 refractory patients. Two of the 4 patients who were treated after allo-SCT survived 216 and 221 days, respectively, whereas the other 2 remain in ongoing complete molecular remission. Sorafenib response was associated with an inhibition of the antiapoptotic FLT3-ITD target Stat-5 in vivo. Together, sorafenib monotherapy before or after allo-SCT has remarkable clinical activity in poor risk FLT3-ITD–positive AML and deserves further evaluation in prospective clinical trials.
Exploring the functional interaction between POSH and ALIX and the relevance to HIV-1 release
Authors: Votteler Jörg , Iavnilovitch Elena , Fingrut Orit , Shemesh Vivian , Taglicht Daniel , Erez Omri , Sörgel Stefan , Walther Torsten , Bannert Norbert , Schubert Ulrich , Reiss Yuval
Published: April 2009

Background

The ALG2-interacting protein X (ALIX)/AIP1 is an adaptor protein with multiple functions in intracellular protein trafficking that plays a central role in the biogenesis of enveloped viruses. The ubiquitin E3-ligase POSH (plenty of SH3) augments HIV-1 egress by facilitating the transport of Gag to the cell membrane. Recently, it was reported, that POSH interacts with ALIX and thereby enhances ALIX mediated phenotypes in Drosophila.

Results

In this study we identified ALIX as a POSH ubiquitination substrate in human cells: POSH induces the ubiquitination of ALIX that is modified on several lysine residues in vivo and in vitro. This ubiquitination does not destabilize ALIX, suggesting a regulatory function. As it is well established that ALIX rescues virus release of L-domain mutant HIV-1, HIV-1ΔPTAP, we demonstrated that wild type POSH, but not an ubiquitination inactive RING finger mutant (POSHV14A), substantially enhances ALIX-mediated release of infectious virions derived from HIV-1ΔPTAP L-domain mutant (YPXnL-dependent HIV-1). In further agreement with the idea of a cooperative function of POSH and ALIX, mutating the YPXnL-ALIX binding site in Gag completely abrogated augmentation of virus release by overexpression of POSH. However, the effect of the POSH-mediated ubiquitination appears to be auxiliary, but not necessary, as silencing of POSH by RNAi does not disturb ALIX-augmentation of virus release.

Conclusion

Thus, the cumulative results identified ALIX as an ubiquitination substrate of POSH and indicate that POSH and ALIX cooperate to facilitate efficient virus release. However, while ALIX is obligatory for the release of YPXnL-dependent HIV-1, POSH, albeit rate-limiting, may be functionally interchangeable.
SNP HiTLink: a high-throughput linkage analysis system employing dense SNP data
Authors: Fukuda Yoko , Nakahara Yasuo , Date Hidetoshi , Takahashi Yuji , Goto Jun , Miyashita Akinori , Kuwano Ryozo , Adachi Hiroki , Nakamura Eiji , Tsuji Shoji
Published: April 2009

Background

During this recent decade, microarray-based single nucleotide polymorphism (SNP) data are becoming more widely used as markers for linkage analysis in the identification of loci for disease-associated genes. Although microarray-based SNP analyses have markedly reduced genotyping time and cost compared with microsatellite-based analyses, applying these enormous data to linkage analysis programs is a time-consuming step, thus, necessitating a high-throughput platform.

Results

We have developed SNP HiTLink (SNP
Hi gh T hroughput Link age analysis system). In this system, SNP chip data of the Affymetrix Mapping 100 k/500 k array set and Genome-Wide Human SNP array 5.0/6.0 can be directly imported and passed to parametric or model-free linkage analysis programs; MLINK, Superlink, Merlin and Allegro. Various marker-selecting functions are implemented to avoid the effect of typing-error data, markers in linkage equilibrium or to select informative data.

Conclusion

The results using the 100 k SNP dataset were comparable or even superior to those obtained from analyses using microsatellite markers in terms of LOD scores obtained. General personal computers are sufficient to execute the process, as runtime for whole-genome analysis was less than a few hours. This system can be widely applied to linkage analysis using microarray-based SNP data and with which one can expect high-throughput and reliable linkage analysis.
Transcriptional reprogramming of gene expression in bovine somatic cell chromatin transfer embryos
Authors: Rodriguez-Osorio Nelida , Wang Zhongde , Kasinathan Poothappillai , Page Grier P , Robl James M , Memili Erdogan
Published: April 2009

Background

Successful reprogramming of a somatic genome to produce a healthy clone by somatic cells nuclear transfer (SCNT) is a rare event and the mechanisms involved in this process are poorly defined. When serial or successive rounds of cloning are performed, blastocyst and full term development rates decline even further with the increasing rounds of cloning. Identifying the "cumulative errors" could reveal the epigenetic reprogramming blocks in animal cloning.

Results

Bovine clones from up to four generations of successive cloning were produced by chromatin transfer (CT). Using Affymetrix bovine microarrays we determined that the transcriptomes of blastocysts derived from the first and the fourth rounds of cloning (CT1 and CT4 respectively) have undergone an extensive reprogramming and were more similar to blastocysts derived from in vitro fertilization (IVF) than to the donor cells used for the first and the fourth rounds of chromatin transfer (DC1 and DC4 respectively). However a set of transcripts in the cloned embryos showed a misregulated pattern when compared to IVF embryos. Among the genes consistently upregulated in both CT groups compared to the IVF embryos were genes involved in regulation of cytoskeleton and cell shape. Among the genes consistently upregulated in IVF embryos compared to both CT groups were genes involved in chromatin remodelling and stress coping.

Conclusion

The present study provides a data set that could contribute in our understanding of epigenetic errors in somatic cell chromatin transfer. Identifying "cumulative errors" after serial cloning could reveal some of the epigenetic reprogramming blocks shedding light on the reprogramming process, important for both basic and applied research.
Evaluation of the effect of patient education on rates of falls in older hospital patients: Description of a randomised controlled trial
Authors: Hill Anne-Marie , Hill Keith , Brauer Sandra , Oliver David , Hoffmann Tammy , Beer Christopher , McPhail Steven , Haines Terry P
Published: April 2009

Background

Accidental falls by older patients in hospital are one of the most commonly reported adverse events. Falls after discharge are also common. These falls have enormous physical, psychological and social consequences for older patients, including serious physical injury and reduced quality of life, and are also a source of substantial cost to health systems worldwide. There have been a limited number of randomised controlled trials, mainly using multifactorial interventions, aiming to prevent older people falling whilst inpatients. Trials to date have produced conflicting results and recent meta-analyses highlight that there is still insufficient evidence to clearly identify which interventions may reduce the rate of falls, and falls related injuries, in this population.

Methods and design

A prospective randomised controlled trial (n = 1206) is being conducted at two hospitals in Australia. Patients are eligible to be included in the trial if they are over 60 years of age and they, or their family or guardian, give written consent. Participants are randomised into three groups. The control group continues to receive usual care. Both intervention groups receive a specifically designed patient education intervention on minimising falls in addition to usual care. The education is delivered by Digital Video Disc (DVD) and written workbook and aims to promote falls prevention activities by participants. One of the intervention groups also receives follow up education training visits by a health professional. Blinded assessors conduct baseline and discharge assessments and follow up participants for 6 months after discharge. The primary outcome measure is falls by participants in hospital. Secondary outcome measures include falls at home after discharge, knowledge of falls prevention strategies and motivation to engage in falls prevention activities after discharge. All analyses will be based on intention to treat principle.

Discussion

This trial will examine the effect of a single intervention (specifically designed patient education) on rates of falls in older patients in hospital and after discharge. The results will provide robust recommendations for clinicians and researchers about the role of patient education in this population. The study has the potential to identify a new intervention that may reduce rates of falls in older hospital patients and could be readily duplicated and applied in a wide range of clinical settings.

Trial Registration

ACTRN12608000015347
Dietary intake of folate, vitamin B6, and vitamin B12, genetic polymorphism of related enzymes, and risk of breast cancer: a case-control study in Brazilian women
Authors: Ma Enbo , Iwasaki Motoki , Junko Ishihara , Hamada Gerson Shigeaki , Nishimoto Ines Nobuko , Carvalho Solange Maria Torchia , Motola Juvenal , Laginha Fábio Martins , Tsugane Shoichiro
Published: April 2009

Background

Several studies have determined that dietary intake of B vitamins may be associated with breast cancer risk as a result of interactions between5,10-methylenetetrahydrofolate reductase (MTHFR)andmethionine synthase(MTR) in the one-carbon metabolism pathway. However, the association between B vitamin intake and breast cancer risk in Brazilian women in particular has not yet been investigated.

Methods

A case-control study was conducted in São Paulo, Brazil, with 458 age-matched pairs of Brazilian women. Energy-adjusted intakes of folate, vitamin B6, and vitamin B12were derived from a validated Food Frequency Questionnaire (FFQ). Genotyping was completed forMTHFRA1298C and C677T, andMTRA2756G polymorphisms. A logistical regression model was used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs).

Results

Neither dietary intake of folate, vitamin B6, or vitamin B12norMTHFRpolymorphisms were independently associated with breast cancer risk. Analysis stratified by menopausal status showed a significant association between placement in the highest tertile of folate intake and risk of breast cancer in premenopausal women (OR = 2.17, 95% CI: 1.23–3.83;Ptrend= 0.010). TheMTR2756GG genotype was associated with a higher risk of breast cancer than the 2756AA genotype (OR = 1.99, 95% CI = 1.01–3.92;Ptrend= 0.801), and statistically significant interactions with regard to risk were observed between theMTHFRA1298C polymorphism and folate (P = 0.024) or vitamin B6(P = 0.043), and between theMTHFRC677T polymorphism and folate (P = 0.043) or vitamin B12(P = 0.022).

Conclusion

MTHFRpolymorphisms and dietary intake of folate, vitamin B6, and vitamin B12had no overall association with breast cancer risk. However, increased risk was observed in total women with theMTR2756GG genotype and in premenopausal women with high folate intake. These findings, as well as significant interactions betweenMTHFRpolymorphisms and B vitamins, warrant further investigation.
Small local variations in B-form DNA lead to a large variety of global geometries which can accommodate most DNA-binding protein motifs
Authors: Marathe Arvind , Karandur Deepti , Bansal Manju
Published: April 2009

Background

An important question of biological relevance is the polymorphism of the double-helical DNA structure in its free form, and the changes that it undergoes upon protein-binding. We have analysed a database of free DNA crystal structures to assess the inherent variability of the free DNA structure and have compared it with a database of protein-bound DNA crystal structures to ascertain the protein-induced variations.

Results

Most of the dinucleotide steps in free DNA display high flexibility, assuming different conformations in a sequence-dependent fashion. With the exception of the AA/TT and GA/TC steps, which are 'A-phobic', and the GG/CC step, which is 'A-philic', the dinucleotide steps show no preference for A or B forms of DNA. Protein-bound DNA adopts the B-conformation most often. However, in certain cases, protein-binding causes the DNA backbone to take up energetically unfavourable conformations. At the gross structural level, several protein-bound DNA duplexes are observed to assume a curved conformation in the absence of any large distortions, indicating that a series of normal structural parameters at the dinucleotide and trinucleotide level, similar to the ones in free B-DNA, can give rise to curvature at the overall level.

Conclusion

The results illustrate that the free DNA molecule, even in the crystalline state, samples a large amount of conformational space, encompassing both the A and the B-forms, in the absence of any large ligands. A-form as well as some non-A, non-B, distorted geometries are observed for a small number of dinucleotide steps in DNA structures bound to the proteins belonging to a few specific families. However, for most of the bound DNA structures, across a wide variety of protein families, the average step parameters for various dinucleotide sequences as well as backbone torsion angles are observed to be quite close to the free 'B-like' DNA oligomer values, highlighting the flexibility and biological significance of this structural form.