bluuebunny/crossref_metadata_2025 huggingface dataset:
An ethicist's journey as a patient: are we sliding down the slippery slope to sloppy healthcare?
Authors: McCullough Melissa
Published: September 2011

People who are sick are often the most vulnerable in society. They frequently rely on caring and competent healthcare professionals and should and do have expectations of a safe and caring environment. In a recent unexpected adventure through the healthcare system, the organisation, professionalism, caring and compassion associated with healthcare provision were in very short supply. A lack of basic dignity and humanity were among the most concerning deficits. Any form of dehumanisation of the national health service that leads to unsafe, undignified and degrading treatment not only infringes patients' and clients' human rights but should not be acceptable or excused as a by-product of economic pressures.
In situ hybridisation for the detection of Leishmania species in paraffin wax‐embedded canine tissues using a digoxigenin‐labelled oligonucleotide probe
Authors: Dinhopl N. , Mostegl M. M. , Richter B. , Nedorost N. , Maderner A. , Fragner K. , Weissenböck H.
Published: September 2011

The diagnosis of canine leishmaniosis (CanL) is currently predominantly achieved by cytological or histological identification of amastigotes in biopsy samples, demonstration of specific anti‐Leishmania antibodies and PCR‐based approaches. All these methods have the advantage of being sensitive and more or less specific; nevertheless, most of them also have disadvantages. A chromogenic in situ hybridisation (ISH) procedure with a digoxigenin‐labelled probe, targeting a fragment of the 5.8S rRNA was developed for the detection of all species of Leishmania parasites in routinely paraffin wax‐embedded canine tissues. This method was validated in comparison with traditional techniques (histology, PCR), on various tissues from three dogs with histological changes consistent with a florid leishmaniosis. Amastigote forms of Leishmania gave clear signals and were easily identified using ISH. Various tissues from 10 additional dogs with clinical suspicion or/and a positive serological test but without histological presence of amastigotes did not show any ISH signals. Potential cross‐reactivity of the probe was ruled out by negative outcome of the ISH against selected protozoa (including the related Trypanosoma cruzi) and fungi. Thus, ISH proved to be a powerful tool for unambiguous detection of Leishmania parasites in paraffin wax‐embedded tissues.
Efficacy and safety of a new 450 mg/ml florfenicol formulation administered intramuscularly in the treatment of bacterial bovine respiratory disease
Authors: Thiry J. , Rubion S. , Sarasola P. , Bonnier M. , Hartmann M. , de Haas V.
Published: September 2011

The objective of the study was the safety and efficacy evaluation of a new 450 mg/ml florfenicol formulation in the treatment of naturally occurring respiratory disease when administered intramuscularly, compared with a positive control group treated with the well‐established 300 mg/ml formulation. A total of 174 calves, selected from five sites in France and Spain, aged from 1 to 17 months, showing severe signs of respiratory disease, were randomly assigned to treatment with either the 300 mg/ml (3 ml/45 kg; Nuflor; MSD Animal Health) or 450 mg/ml (2 ml/45 kg; Nuflor Minidose; MSD Animal Health) florfenicol formulation, both administered intramuscularly twice, two days apart. Animals were clinically observed daily for 14 days following treatment initiation. The predominant pathogens present in pretreatment respiratory tract samples were Mannheimia haemolytica and Pasteurella multocida. Mycoplasma bovis and Histophilus somni were also present. All isolates were subjected to in vitro sensitivity testing and found susceptible to florfenicol. In both treatment groups, rectal temperature dropped and clinical index (depression and respiratory signs) significantly improved (P<0.05) after treatment. As a result, 97.7 per cent of the 450 mg/ml florfenicol formulation‐treated animals were considered treatment successes on day 5. On day 14, 67.82 per cent of the animals were classified as treatment successes and among them 63.22 per cent were cured. The intramuscular injection of the new 450 mg/ml florfenicol formulation was found equally efficacious as the original 300 mg/ml formulation.
The effects of plant size and light availability on male and female reproductive success and functional gender in a hermaphrodite tree species,Magnolia stellata
Authors: Setsuko Suzuki , Tomaru Nobuhiro
Published: September 2011

Plant size and light availability may affect male and (or) female reproductive success and their relative contribution (functional gender). To test this hypothesis, we identified parents of 184 seedlings in a local population within a metapopulation of a hermaphroditic, insect-pollinated tree species, Magnolia stellata (Siebold & Zucc.) Maxim., using 14 nuclear and 3 chloroplast microsatellite markers. Parent pairs of all the seedlings were determined, and both seed and pollen parents could be distinguished for 49.5% of the seedlings. We also measured the parents’ plant size (diameter at breast height of the thickest ramet within each genet; DBHt) and the relative photosynthetic photon flux density (rPPFD) they received. The proportion of seedlings that originated from selfing was 20.7%. The number of seedlings parental trees produced as seed parents (S) was positively affected by DBHtand rPPFD. DBHt(but not rPPFD) also positively affected the number of seedlings sired as pollen parents (P). The femaleness of the parental trees (S/(S + P)) was positively affected by DBHt, probably because DBHthad a stronger effect on the trees’ reproductive success as seed parents than on their success as pollen parents. These results suggest that plant size affects not only reproductive success (male and female), but also functional gender.
What Determines the Foreign Ownership Share of a Country's Banking Assets?
Authors: Liang Ping , Gropper Daniel M. , Caudill Steven B.
Published: September 2011

The main purpose of this paper is to examine the roles of economic and political factors in explaining the foreign ownership share of a country's banking assets. In particular, our study includes new market-openness and regulation variables. The General Agreement on Trade in Services is an important element that affects financial sector regulation of every current and potential World Trade Organization member country, and opening financial markets is an important goal of this agreement. We find that the market openness index developed by Barth et al. (2010) bears a statistically significant relation to foreign ownership, as expected, and that regulation, rule of law, and profit opportunities are also important determinants of foreign ownership of bank assets.
ROBOT ASSISTED STROKE REHABILITATION: JOINT TORQUE/FORCE CONVERSION FROM EMG USING SA PROCESS
Authors: PARASURAMAN S. , OYONG ARIF WICAKSONO , JAUW VERONICA LESTARI
Published: September 2011

This paper focuses on the implementation of robot-assisted stroke rehabilitation using electromyography (EMG) as the interface between the robot and subjects. The key issue in implementing EMG for this application is the conversion process of EMG signal into torque/force, which is used as a input to the control system. This paper presents a methodology of EMG signal conversion into estimated joint torque by using simulated annealing (SA) technique. Basic principle of SA, formulation, and implementation to the problem are discussed in this paper. Experimental studies with real life EMG data have been carried out for five subjects. These studies are used to evaluate the feasibility of the methodology proposed for robot-assisted stroke rehabilitation problem. Experimental investigations and results are discussed at the end of the paper.
MRSA: A Challenge to Norwegian Nursing Home Personnel
Authors: Thorstad M. , Sie I. , Andersen B. M.
Published: September 2011

In Norway, methicillin-resistantStaphylococcus aureus(MRSA) is increasing in primary healthcare, associated with imported cases and outbreaks in long-term care. According to Norwegian national guidelines, MRSA-exposed healthcare workers (HCWs) and patients are tested. Carriage of MRSA leads to exclusion from work in healthcare institutions. In this study, 388 staff members in 42 nursing homes in Oslo County responded to questions about personal experience with MRSA and of own attitudes to challenges associated with the control and treatment of MRSA patients. Half (52%) of the nursing staff were concerned of becoming infected with MRSA and the consequences of this would be for own social life, family, economy, and work restriction. The concern was associated with risk factors like old buildings not suitable for modern infection control work, low staffing rate (70% without specific training in healthcare and 32% without formal healthcare education), defective cleaning and decolonization, and lack of formal routines and capacity for isolation of MRSA patients. Since the Norwegian MRSA guideline permits patients with persistent MRSA infections to move freely around in nursing homes, the anxiety of the staff to become infected and excluded from job was real.
Nonlinear Dynamical Integral Inequalities in Two Independent Variables and Their Applications
Authors: Sun Yuangong
Published: September 2011

In this paper, we investigate some nonlinear dynamical integral inequalities involving the forward jump operator in two independent variables. These inequalities provide explicit bounds on unknown functions, which can be used as handy tools to study the qualitative properties of solutions of certain partial dynamical systems on time scales pairs.
Increased Serum Levels of Uric Acid Are Associated with Sudomotor Dysfunction in Subjects with Type 2 Diabetes Mellitus
Authors: Papanas N. , Demetriou M. , Katsiki N. , Papatheodorou K. , Papazoglou D. , Gioka T. , Kotsiou S. , Maltezos E. , Mikhailidis D. P.
Published: September 2011

The aim of this paper was to assess serum uric acid (SUA) levels in patients with type 2 diabetes mellitus (T2DM) with or without sudomotor dysfunction (evaluated by the Neuropad test). We included 36 T2DM patients with sudomotor dysfunction (group A: mean age63.1±2.6years) and 40 age-, gender-, renal function- and T2DM duration-matched patients without sudomotor dysfunction (group B: mean age62.1±3.1years). SUA was significantly higher in group A (P<0.001). There was a significant correlation between SUA and Neuropad time to colour change in both groups (group A:rs=0.819,P<0.001; group B:rs=0.774,P<0.001). There was also a significant positive correlation between SUA and CRP in both groups (group A:rs=0.947,P<0.001; group B:rs=0.848,P<0.001). In conclusion, SUA levels were higher in T2DM patients with sudomotor dysfunction than those without this complication. The potential role of SUA in sudomotor dysfunction merits further study.
Extraskeletal Chondrosarcoma of Labium Majus
Authors: Khan Arshad S. , Bakhshi Girish D. , Shaikh Aftab , Khan Ashraf A. , Khan Adil A. , Chitale Arun
Published: September 2011

Extraskeletal myxoid chondrosarcoma (ESMC) is a rare tumor seen more often in men. It is seen to arise from soft tissue of lower extremity or buttocks. We report a case of soft tissue swelling of left labium majus in a 66-year-old female. Patient underwent wide excision with uneventful postoperative course. Histopathology of specimen confirmed it to be ESMC. Patient refused adjuvant therapy. Followup of 1 year has shown her to be disease- and symptom- free. Only two cases arising from vulva have been reported in literature . This is the third case and first from Indian subcontinent. A brief review of clinical features, diagnosis, treatment, and outcome of patients with extraskeletal chondrosarcoma is presented.
Pathobiology and Chemoprevention of Bladder Cancer
Authors: Tanaka Takuji , Miyazawa Katsuhito , Tsukamoto Tetsuya , Kuno Toshiya , Suzuki Koji
Published: September 2011

Our understanding of the pathogenesis of bladder cancer has improved considerably over the past decade. Translating these novel pathobiological discoveries into therapies, prevention, or strategies to manage patients who are suspected to have or who have been diagnosed with bladder cancer is the ultimate goal. In particular, the chemoprevention of bladder cancer development is important, since urothelial cancer frequently recurs, even if the primary cancer is completely removed. The numerous alterations of both oncogenes and tumor suppressor genes that have been implicated in bladder carcinogenesis represent novel targets for therapy and prevention. In addition, knowledge about these genetic alterations will help provide a better understanding of the biological significance of preneoplastic lesions of bladder cancer. Animal models for investigating bladder cancer development and prevention can also be developed based on these alterations. This paper summarizes the results of recent preclinical and clinical chemoprevention studies and discusses screening for bladder cancer.
Hydroxyurea Therapy Mobilises Arachidonic Acid from Inner Cell Membrane Aminophospholipids in Patients with Homozygous Sickle Cell Disease
Authors: Daak A. A. , Ghebremeskel K. , Elbashir M. I. , Bakhita A. , Hassan Z. , Crawford M. A.
Published: September 2011

The cytotoxic compound hydroxyurea (HU) is effective therapy for sickle cell disease. However, its effect on unsaturated membrane lipids is unknown. Red cell fatty acids were investigated in HU-treated (n=19) and HU-untreated (n=17) sickle cell patients and controls (n=20). The HU-treated compared with the HU-untreated patients had lower arachidonic (AA) acid level in ethanolamine, physphoglycerids (EPG) (22.9±1.2   versus   24.0±1.1%,  P<0.05) serine SPG (22.13±2.2   versus   24.9±2.3%,  P<0.01) phosphoglycerides. The treated patients and controls had comparable levels of docosahexaenoic (DHA) and total n-3 fatty acids in EPG and choline phosphoglycerides (CPG). In contrast, the untreated group had significantly (P<0.05) lower DHA and total n-3 compared with the controls in EPG (2.7±0.4   versus   3.2±0.6%and4.6±0.5   versus   5.2±0.7%) and CPG (0.7±0.2   versus   1.0±0.2%and1.2±0.2   versus   1.4±0.3). HU is known to activate cytosolic phospholipase A2 and cyclooxygenase 2, and from this study, it appears to induce mobilisation of AA from the inner cell membrane EPG and SPG. Hence, eicosanoids generated from the released AA may play a role in clinical improvements which occur in HU-treated patients.
A High-Throughput, High-Accuracy System-Level Simulation Framework for System on Chips
Authors: Sun Guanyi , Xu Shengnan , Wang Xu , Wang Dawei , Tang Eugene , Deng Yangdong , Chan Sun
Published: September 2011

Today's System-on-Chips (SoCs) design is extremely challenging because it involves complicated design tradeoffs and heterogeneous design expertise. To explore the large solution space, system architects have to rely on system-level simulators to identify an optimized SoC architecture. In this paper, we propose a system-level simulation framework, System Performance Simulation Implementation Mechanism, or SPSIM. Based on SystemC TLM2.0, the framework consists of an executable SoC model, a simulation tool chain, and a modeling methodology. Compared with the large body of existing research in this area, this work is aimed at delivering a high simulation throughput and, at the same time, guaranteeing a high accuracy on real industrial applications. Integrating the leading TLM techniques, our simulator can attain a simulation speed that is not slower than that of the hardware execution by a factor of 35 on a set of real-world applications. SPSIM incorporates effective timing models, which can achieve a high accuracy after hardware-based calibration. Experimental results on a set of mobile applications proved that the difference between the simulated and measured results of timing performance is within 10%, which in the past can only be attained by cycle-accurate models.
Lung Cancer Proteomics: Recent Advances in Biomarker Discovery
Authors: Indovina Paola , Marcelli Eleonora , Maranta Pasquale , Tarro Giulio
Published: September 2011

Lung cancer is the most common cause of cancer death in both men and women in Western countries, with a 5-year survival rate of 15%, which is among the lowest of all cancers. The high mortality from lung cancer is due not only to the late stage diagnosis but also to the lack of effective treatments even for patients diagnosed with stage I lung cancer. Therefore, there is an urgent need to identify new markers for early diagnosis and prognosis that could serve to open novel therapeutic avenues. Proteomics can represent an important tool for the identification of biomarkers and therapeutic targets for lung cancer since DNA-based biomarkers did not prove to have adequate sensitivity, specificity, and reproducibility. In this paper we will describe studies focused on the identification of new diagnostic, prognostic, and predictive markers for lung cancer, using proteomics technologies.
A Fixed Point Approach to the Stability of the Cauchy Additive and Quadratic Type Functional Equation
Authors: Jin Sun Sook , Lee Yang-Hi
Published: September 2011

We investigate the stability of the functional equation 2f(x + y) + f(x − y) + f(y − x) − 3f(x) − f(−x) − 3f(y) − f(−y) = 0 by using the fixed point theory in the sense of Cădariu and Radu.
Energy‐Aware Topology Evolution Model with Link and Node Deletion in Wireless Sensor Networks
Authors: Luo Xiaojuan , Yu Huiqun , Wang Xiang
Published: September 2011

Based on the complex network theory, a new topological evolving model is
proposed. In the evolution of the topology of sensor networks, the
energy‐aware mechanism is taken into account, and the phenomenon of
change of the link and node in the network is discussed. Theoretical
analysis and numerical simulation are conducted to explore the
topology characteristics and network performance with different node
energy distribution. We find that node energy distribution has the
weak effect on the degree distribution P(k) that evolves into the scale‐free state, nodes with more
energy carry more connections, and degree correlation is nontrivial
disassortative. Moreover, the results show that, when nodes energy is
more heterogeneous, the network is better clustered and enjoys higher
performance in terms of the network efficiency and the average path
length for transmitting data.
Design of Compact Dual-Polarized Antennas for MIMO Handsets
Authors: Chen Wenhua , Wang Xin , Feng Zhenghe
Published: September 2011

A design method of compact dual-polarized antennas has been proposed for multiple input and multiple output (MIMO) handset application. For the sake of high isolation in dual polarizations, a printed monopole and a hybrid slot antenna are combined using a coplanar waveguide (CPW) and microstrip hybrid feeding structure. The proposed topology will result in orthogonal current distribution modes for the different polarizations, which effectively reduces the mutual coupling of the two modes. The operation mechanism of the feeding structure is analyzed in principle and verified by simulation. Simulated and measured results show this compact dual-polarized antenna achieves isolation between the two ports of better than 25 dB, and the relative bandwidth is wider than 23.5%.
Use ofClostridium perfringensEnterotoxin and the Enterotoxin Receptor-Binding Domain (C-CPE) for Cancer Treatment: Opportunities and Challenges
Authors: Gao Zhijian , McClane Bruce A.
Published: September 2011

Clostridium perfringensenterotoxin (CPE) causes the symptoms associated with several common gastrointestinal diseases. CPE is a 35 kDa polypeptide consisting of three structured domains, that is, C-terminal domain I (responsible for receptor binding), domain II (responsible for oligomerization and membrane insertion), and domain III (which may participate in physical changes when the CPE protein inserts into membranes). Native CPE binds to claudin receptors, which are components of the tight junction. The bound toxin then assembles into a hexameric prepore on the membrane surface, prior to the insertion of this oligomer into membranes to form an active pore. The toxin is especially lethal for cells expressing large amounts of claudin-3 or -4, which includes many cancer cells. Initial studies suggest that native CPE has potential usefulness for treating several cancers where claudin CPE receptors are overexpressed. However, some challenges with immunogenicity, toxicity, and (possibly) the development of resistance may need to be overcome. An alternative approach now being explored is to utilize C-CPE, which corresponds approximately to receptor binding domain I, to enhance paracellular permeability and delivery of chemotherapeutic agents against cancer cells. Alternatively, C-CPE fusion proteins may prove superior to use of native CPE for cancer treatment. Finally, C-CPE may have application for other medical treatments, including vaccination or increasing drug absorption. The coming years should witness increasing exploitation of this otherwise formidable toxin.
SIRT1 Is Essential for Oncogenic Signaling by Estrogen/Estrogen Receptor α in Breast Cancer
Authors: Elangovan Selvakumar , Ramachandran Sabarish , Venkatesan Narayanan , Ananth Sudha , Gnana-Prakasam Jaya P. , Martin Pamela M. , Browning Darren D. , Schoenlein Patricia V. , Prasad Puttur D. , Ganapathy Vadivel , Thangaraju Muthusamy
Published: September 2011

The NAD-dependent histone deacetylase silent information regulator 1 (SIRT1) is overexpressed and catalytically activated in a number of human cancers, but recent studies have actually suggested that it may function as a tumor suppressor and metastasis inhibitor in vivo. In breast cancer, SIRT1 stabilization has been suggested to contribute to the oncogenic potential of the estrogen receptor α (ERα), but SIRT1 activity has also been associated with ERα deacetylation and inactivation. In this study, we show that SIRT1 is critical for estrogen to promote breast cancer. ERα physically interacted and functionally cooperated with SIRT1 in breast cancer cells. ERα also bound to the promoter for SIRT1 and increased its transcription. SIRT1 expression induced by ERα was sufficient to activate antioxidant and prosurvival genes in breast cancer cells, such as catalase and glutathione peroxidase, and to inactivate tumor suppressor genes such as cyclin G2 (CCNG2) and p53. Moreover, SIRT1 inactivation eliminated estrogen/ERα-induced cell growth and tumor development, triggering apoptosis. Taken together, these results indicated that SIRT1 is required for estrogen-induced breast cancer growth. Our findings imply that the combination of SIRT1 inhibitors and antiestrogen compounds may offer more effective treatment strategies for breast cancer. Cancer Res; 71(21); 6654–64. ©2011 AACR.
Direct Effect of Rituximab in B-Cell–Derived Lymphoid Neoplasias: Mechanism, Regulation, and Perspectives
Authors: Bezombes Christine , Fournié Jean-Jacques , Laurent Guy
Published: September 2011

The anti-CD20 monoclonal antibody rituximab is the backbone of treatment for the B-cell malignancies non-Hodgkin lymphoma and chronic lymphocytic leukemia. However, there is a wide variability in response to rituximab treatment, and some patients are refractory to current standard therapies. Rituximab kills B cells by multiple mechanisms of action, including complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity, which are immune-mediated mechanisms, as well as by direct effects on cell signaling pathways and cell membranes following CD20 binding. A large number of events that are affected by rituximab binding have been identified, including lipid raft modifications, kinase and caspase activation, and effects on transcription factors and apoptotic/antiapoptotic molecules. Studies on cell lines and isolated tumor cells have shown that by targeting these pathways, it may be possible to increase or decrease susceptibility to rituximab cell killing. An increased understanding of the direct effects of rituximab may therefore aid in the design of new, rational combinations to improve the outcome of CD20-based therapy for patients who currently have suboptimal outcome following standard treatments. Mol Cancer Res; 9(11); 1435–42. ©2011 AACR.
p16INK4a Expression and Breast Cancer Risk in Women with Atypical Hyperplasia
Authors: Radisky Derek C. , Santisteban Marta , Berman Hal K. , Gauthier Mona L. , Frost Marlene H. , Reynolds Carol A. , Vierkant Robert A. , Pankratz V. Shane , Visscher Daniel W. , Tlsty Thea D. , Hartmann Lynn C.
Published: September 2011

p16, a nuclear protein encoded by the p16INK4a gene, is a regulator of cell-cycle regulation. Previous studies have shown that expression of p16 in tissue biopsies of patients with ductal carcinoma in situ (DCIS) is associated with increased risk of breast cancer, particularly when considered in combination with other markers such as Ki-67 and COX-2. Here, we evaluated how expression of p16 in breast tissue biopsies of women with atypical hyperplasia (AH), a putative precursor lesion to DCIS, is associated with subsequent development of cancer. p16 expression was assessed by immunohistochemistry in archival sections from 233 women with AH diagnosed at the Mayo Clinic. p16 expression in the atypical lesions was scored by percentage of positive cells and intensity of staining. We also studied coexpression of p16, with Ki-67 and COX-2, biomarkers of progression in AH. Risk factor and follow-up data were obtained via study questionnaire and medical records. Forty-seven patients (20%) developed breast cancer with a median follow-up of 14.5 years. Staining of p16 was increased in older patients relative to younger patients (P = 0.0025). Although risk of developing breast cancer was not associated with increased p16 expression, joint overexpression of Ki-67 and COX-2 was found to convey stronger risk of breast cancer in the first 10 years after diagnosis as compared with one negative marker (P < 0.01). However, the addition of p16 levels did not strengthen this association. p16 overexpression, either alone or in combination with COX-2 and Ki-67, does not significantly stratify breast cancer risk in women with AH. Cancer Prev Res; 4(12); 1953–60. ©2011 AACR.
Cardiac Magnetic Resonance Imaging for Noninvasive Assessment of Cardiovascular Disease During the Follow-Up of Patients With Kawasaki Disease
Authors: Tacke Carline E. , Kuipers Irene M. , Groenink Maarten , Spijkerboer Anje M. , Kuijpers Taco W.
Published: September 2011

Background—

Kawasaki disease (KD) is the most common cause of acquired coronary artery disease in childhood. In KD, the American Heart Association recommends echocardiography for routine coronary artery surveillance and nuclear perfusion scans and conventional coronary angiography in select patients. Cardiac MRI (CMRI) may be a noninvasive and radiation-free alternative. We applied CMRI during the follow-up of patients with KD and assessed the performance of CMRI compared with echocardiography.

Methods and Results—

Patients with KD aged ≥8 years were consecutively included. Sixty-three patients (median age, 14.6 years; 74.6% male sex) underwent a comprehensive CMRI protocol including adenosine stress testing to evaluate coronary artery anatomy, ischemia, and myocardial infarction. All patients underwent CMRI without significant complications. On CMRI, 23 coronary artery aneurysms (CAAs) were identified in 15 patients. CMRI detected thrombus formation in 6 CAAs in 4 patients, wall motion disturbances and ischemia in 4 patients, and delayed hyperenhancement indicating myocardial infarction in 5 patients. Wall motion and perfusion abnormalities were noted in territories supplied by affected coronary arteries. CMRI results were compared with recent echocardiography findings. In 6 of the 15 patients with CAAs on CMRI, CAAs were not detected by echocardiography.

Conclusions—

A comprehensive CMRI protocol including adenosine stress testing is feasible to identify coronary artery pathology, ischemia, and myocardial infarction in former patients with KD and compares favorably with echocardiography. CMRI may be used as a noninvasive and radiation-free imaging method for coronary artery surveillance during the long-term follow-up of patients with KD.
Abolishing Myofibroblast Arrhythmogeneicity by Pharmacological Ablation of α-Smooth Muscle Actin Containing Stress Fibers
Authors: Rosker Christian , Salvarani Nicolò , Schmutz Stephan , Grand Teddy , Rohr Stephan
Published: September 2011

Rationale:

Myofibroblasts typically appear in the myocardium after insults to the heart like mechanical overload and infarction. Apart from contributing to fibrotic remodeling, myofibroblasts induce arrhythmogenic slow conduction and ectopic activity in cardiomyocytes after establishment of heterocellular electrotonic coupling in vitro. So far, it is not known whether α-smooth muscle actin (α-SMA) containing stress fibers, the cytoskeletal components that set myofibroblasts apart from resident fibroblasts, are essential for myofibroblasts to develop arrhythmogenic interactions with cardiomyocytes.

Objective:

We investigated whether pharmacological ablation of α-SMA containing stress fibers by actin-targeting drugs affects arrhythmogenic myofibroblast–cardiomyocyte cross-talk.

Methods and Results:

Experiments were performed with patterned growth cell cultures of neonatal rat ventricular cardiomyocytes coated with cardiac myofibroblasts. The preparations exhibited slow conduction and ectopic activity under control conditions. Exposure to actin-targeting drugs (Cytochalasin D, Latrunculin B, Jasplakinolide) for 24 hours led to disruption of α-SMA containing stress fibers. In parallel, conduction velocities increased dose-dependently to values indistinguishable from cardiomyocyte-only preparations and ectopic activity measured continuously over 24 hours was completely suppressed. Mechanistically, antiarrhythmic effects were due to myofibroblast hyperpolarization (Cytochalasin D, Latrunculin B) and disruption of heterocellular gap junctional coupling (Jasplakinolide), which caused normalization of membrane polarization of adjacent cardiomyocytes.

Conclusions:

The results suggest that α-SMA containing stress fibers importantly contribute to myofibroblast arrhythmogeneicity. After ablation of this cytoskeletal component, cells lose their arrhythmic effects on cardiomyocytes, even if heterocellular electrotonic coupling is sustained. The findings identify α-SMA containing stress fibers as a potential future target of antiarrhythmic therapy in hearts undergoing structural remodeling.
Terminal Differentiation, Advanced Organotypic Maturation, and Modeling of Hypertrophic Growth in Engineered Heart Tissue
Authors: Tiburcy Malte , Didié Michael , Boy Oliver , Christalla Peter , Döker Stephan , Naito Hiroshi , Karikkineth Bijoy Chandapillai , El-Armouche Ali , Grimm Michael , Nose Monika , Eschenhagen Thomas , Zieseniss Anke , Katschinski Doerthe M. , Hamdani Nazha , Linke Wolfgang A. , Yin Xiaoke , Mayr Manuel , Zimmermann Wolfram-Hubertus
Published: September 2011

Rationale:

Cardiac tissue engineering should provide “realistic” in vitro heart muscle models and surrogate tissue for myocardial repair. For either application, engineered myocardium should display features of native myocardium, including terminal differentiation, organotypic maturation, and hypertrophic growth.

Objective:

To test the hypothesis that 3D-engineered heart tissue (EHT) culture supports (1) terminal differentiation as well as (2) organotypic assembly and maturation of immature cardiomyocytes, and (3) constitutes a methodological platform to investigate mechanisms underlying hypertrophic growth.

Methods and Results:

We generated EHTs from neonatal rat cardiomyocytes and compared morphological and molecular properties of EHT and native myocardium from fetal, neonatal, and adult rats. We made the following key observations: cardiomyocytes in EHT (1) gained a high level of binucleation in the absence of notable cytokinesis, (2) regained a rod-shape and anisotropic sarcomere organization, (3) demonstrated a fetal-to-adult gene expression pattern, and (4) responded to distinct hypertrophic stimuli with concentric or eccentric hypertrophy and reexpression of fetal genes. The process of terminal differentiation and maturation (culture days 7–12) was preceded by a tissue consolidation phase (culture days 0–7) with substantial cardiomyocyte apoptosis and dynamic extracellular matrix restructuring.

Conclusions:

This study documents the propensity of immature cardiomyocytes to terminally differentiate and mature in EHT in a remarkably organotypic manner. It moreover provides the rationale for the utility of the EHT technology as a methodological bridge between 2D cell culture and animal models.
AMP-Activated Protein Kinase Regulates E3 Ligases in Rodent Heart
Authors: Baskin Kedryn K. , Taegtmeyer Heinrich
Published: September 2011

Rationale:

The degradation of proteins by the ubiquitin proteasome system (UPS) is required for the maintenance of cellular homeostasis in the heart. An important regulator of metabolic homeostasis is AMP-activated protein kinase (AMPK). AMPK activation inhibits protein synthesis and activates autophagy, but whether AMPK plays a role in regulating protein breakdown through the UPS in the heart is not known.

Objective:

To determine whether AMPK enhances UPS-mediated protein degradation by directly regulating the ubiquitin ligases Atrogin-1 and muscle RING finger protein 1 (MuRF1) in the heart.

Methods and Results:

Nutrient deprivation and pharmacological or genetic activation of AMPK increased mRNA expression and protein levels of Atrogin-1 and MuRF1 and consequently enhanced protein degradation in neonatal cardiomyocytes. Inhibition of AMPK abrogated these effects. Using gene reporter and chromatin immunoprecipitation assays, we found that AMPK regulates MuRF1 expression by acting through the myocyte enhancer factor 2 (MEF2). We further validated these findings in vivo using MEF2-LacZ reporter mice. Furthermore, we demonstrated in adult cardiomyocytes that MuRF1 is necessary for AMPK-mediated proteolysis through the UPS in the heart. Consequently, MuRF1 knockout mice were protected from severe cardiac dysfunction during fasting.

Conclusions:

AMPK regulates the transcription of Atrogin-1 and MuRF1 and enhances UPS-mediated protein degradation in heart. Specifically, AMPK regulates MuRF1 through the transcription factor MEF2. The absence of MuRF1 in the heart preserves cardiac function during fasting. The results strengthen the hypothesis that AMPK serves as a modulator of intracellular protein degradation in the heart.
Decreased Nighttime Heart Rate Variability Is Associated With Increased Stroke Risk
Authors: Binici Zeynep , Mouridsen Mette Rauhe , Køber Lars , Sajadieh Ahmad
Published: September 2011

Background and Purpose—

Prediction of stroke in healthy individuals is challenging and there is a diurnal variation of stroke onset. We hypothesized that heart rate variability with a focus on nighttime heart rate variability will predict the risk of stroke in apparently healthy middle-age and elderly subjects.

Methods—

The population-based cohort of the Copenhagen Holter Study, consisting of 678 healthy subjects between age 55 and 75 years with no history of cardiovascular disease or stroke, was evaluated. All underwent 48-hour ambulatory electrocardiogram monitoring. The SD of normal-to-normal RR intervals (SDNN) was selected as the method of measuring heart rate variability. Nighttime SDNN was measured between 02:00 and 02:15
am
and could be evaluated in 653 subjects. Median follow-up was 76 months.

Results—

Nighttime SDNN was lower in women than in men (
P
=0.0008), and in diabetics than nondiabetics (
P
=0.03). However, smoking, cholesterol, systolic blood pressure, and age were not associated with nighttime SDNN. The risk of stroke was significantly associated with nighttime SDNN in a univariate analysis (HR, 0.66; 95% CI, 0.50–0.88;
P
=0.004) and after adjustment for conventional risk factors (HR, 0.67; 95% CI, 0.51–0.89;
P
=0.005) per 10 ms increments of SDNN. Eighty-one percent of all strokes (21/26) occurred in 330 subjects with the lower half of nighttime SDNN (≤38 ms; HR, 4.31; 95% CI, 1.62–11.42;
P
=0.003).

Conclusions—

Nocturnal heart rate variability is a strong marker for the development of stroke in apparently healthy subjects. The mechanism is unknown, but reduced parasympathetic activity may increase the risk of stroke by increasing the risk of arrhythmias.
Stress Worsens Endothelial Function and Ischemic Stroke via Glucocorticoids
Authors: Balkaya Mustafa , Prinz Vincent , Custodis Florian , Gertz Karen , Kronenberg Golo , Kroeber Jan , Fink Klaus , Plehm Ralph , Gass Peter , Laufs Ulrich , Endres Matthias
Published: September 2011

Background and Purpose—

Chronic stress is associated with increased stroke risk. However, the underlying pathophysiological mechanisms are poorly understood. We examined the effects of chronic stress on endothelial function and ischemic brain injury in a mouse model.

Methods—

129/SV mice were treated with glucocorticoid receptor antagonist mifepristone (25 mg kg
−1
/d) or vehicle and exposed to 28 days of chronic stress consisting of exposure to rat, restraint stress, and tail suspension. Heart rate and blood pressure were continuously recorded by telemetry. Endothelial nitric oxide synthase mRNA and protein expression as well as superoxide production and lipid hydroperoxides were quantified. Endothelium-dependent vasorelaxation was measured in aortic rings. Ischemic lesion volume was quantified after 30 minutes filamentous middle cerebral artery occlusion and 72 hours reperfusion.

Results—

Chronic stress caused a significant increase in heart rate, impaired endothelium-dependent vasorelaxation, increased superoxide production, and reduced aortic and brain endothelial nitric oxide synthase levels. Animals exposed to chronic stress showed major increases in ischemic lesion size. These deleterious effects of stress were completely reversed by treatment with mifepristone.

Conclusions—

Chronic stress increases stroke vulnerability likely through endothelial dysfunction, which can be reversed by a glucocorticoid receptor antagonist.
Adaptive Decoding for Brain-Machine Interfaces Through Bayesian Parameter Updates
Authors: Li Zheng , O'Doherty Joseph E. , Lebedev Mikhail A. , Nicolelis Miguel A. L.
Published: September 2011

Brain-machine interfaces (BMIs) transform the activity of neurons recorded in motor areas of the brain into movements of external actuators. Representation of movements by neuronal populations varies over time, during both voluntary limb movements and movements controlled through BMIs, due to motor learning, neuronal plasticity, and instability in recordings. To ensure accurate BMI performance over long time spans, BMI decoders must adapt to these changes. We propose the Bayesian regression self-training method for updating the parameters of an unscented Kalman filter decoder. This novel paradigm uses the decoder's output to periodically update its neuronal tuning model in a Bayesian linear regression. We use two previously known statistical formulations of Bayesian linear regression: a joint formulation, which allows fast and exact inference, and a factorized formulation, which allows the addition and temporary omission of neurons from updates but requires approximate variational inference. To evaluate these methods, we performed offline reconstructions and closed-loop experiments with rhesus monkeys implanted cortically with microwire electrodes. Offline reconstructions used data recorded in areas M1, S1, PMd, SMA, and PP of three monkeys while they controlled a cursor using a handheld joystick. The Bayesian regression self-training updates significantly improved the accuracy of offline reconstructions compared to the same decoder without updates. We performed 11 sessions of real-time, closed-loop experiments with a monkey implanted in areas M1 and S1. These sessions spanned 29 days. The monkey controlled the cursor using the decoder with and without updates. The updates maintained control accuracy and did not require information about monkey hand movements, assumptions about desired movements, or knowledge of the intended movement goals as training signals. These results indicate that Bayesian regression self-training can maintain BMI control accuracy over long periods, making clinical neuroprosthetics more viable.
Learning Rule of Homeostatic Synaptic Scaling: Presynaptic Dependent or Not
Authors: Liu Jian K.
Published: September 2011

It has been established that homeostatic synaptic scaling plasticity can maintain neural network activity in a stable regime. However, the underlying learning rule for this mechanism is still unclear. Whether it is dependent on the presynaptic site remains a topic of debate. Here we focus on two forms of learning rules: traditional synaptic scaling (SS) without presynaptic effect and presynaptic-dependent synaptic scaling (PSD). Analysis of the synaptic matrices reveals that transition matrices between consecutive synaptic matrices are distinct: they are diagonal and linear to neural activity under SS, but become nondiagonal and nonlinear under PSD. These differences produce different dynamics in recurrent neural networks. Numerical simulations show that network dynamics are stable under PSD but not SS, which suggests that PSD is a better form to describe homeostatic synaptic scaling plasticity. Matrix analysis used in the study may provide a novel way to examine the stability of learning dynamics.
On the Relation of Slow Feature Analysis and Laplacian Eigenmaps
Authors: Sprekeler Henning
Published: September 2011

The past decade has seen a rise of interest in Laplacian eigenmaps (LEMs) for nonlinear dimensionality reduction. LEMs have been used in spectral clustering, in semisupervised learning, and for providing efficient state representations for reinforcement learning. Here, we show that LEMs are closely related to slow feature analysis (SFA), a biologically inspired, unsupervised learning algorithm originally designed for learning invariant visual representations. We show that SFA can be interpreted as a function approximation of LEMs, where the topological neighborhoods required for LEMs are implicitly defined by the temporal structure of the data. Based on this relation, we propose a generalization of SFA to arbitrary neighborhood relations and demonstrate its applicability for spectral clustering. Finally, we review previous work with the goal of providing a unifying view on SFA and LEMs.
Diagnosis, Prevention, and Management of Delirium in the ICU
Authors: Hessler Christine S. , Josephson S. Andrew
Published: September 2011

Delirium is a frequent yet underrecognized complication in the ICU that is characterized by fluctuating disturbances in cognition and consciousness. Rapid identification, investigation of possible etiologies, and management of this syndrome is essential, as it has serious immediate and long-term consequences for patients, including increased mortality, longer hospital stays, and possible latent cognitive impairments. Prevention of delirium includes nonpharmacologic interventions such as daily awakenings, early mobilization, and careful choice of sedatives. Management of delirium includes numerous nonpharmacologic environmental measures such as frequent reorientation, minimizing interventions, and removal of restraints, as well as treatment of the underlying etiology. Medical management, which includes management of symptoms with medications such as antipsychotics, is likely overused. Further research is critical to delineate ideal methods in prevention and treatment of this disorder.
How I treat pregnancy-related venous thromboembolism
Authors: Middeldorp Saskia
Published: September 2011

Venous thromboembolism (VTE) complicates ∼ 1 to 2 of 1000 pregnancies, with pulmonary embolism being a leading cause of maternal mortality and deep vein thrombosis an important cause of maternal morbidity, also on the long term. However, a strong evidence base for the management of pregnancy-related VTE is missing. Management is not standardized between physicians, centers, and countries. The management of pregnancy-related VTE is based on extrapolation from the nonpregnant population, and clinical trial data for the optimal treatment are not available. Low-molecular-weight heparin (LMWH) in therapeutic doses is the treatment of choice during pregnancy, and anticoagulation (LMWH or vitamin K antagonists postpartum) should be continued until 6 weeks after delivery with a minimum total duration of 3 months. Use of LMWH or vitamin K antagonists does not preclude breastfeeding. Whether dosing should be based on weight or anti-Xa levels is unknown, and practices differ between centers. Management of delivery, including the type of anesthesia if deemed necessary, requires a multidisciplinary approach, and several options are possible, depending on local preferences and patient-specific conditions.
Integrated genomic analysis of relapsed childhood acute lymphoblastic leukemia reveals therapeutic strategies
Authors: Hogan Laura E. , Meyer Julia A. , Yang Jun , Wang Jinhua , Wong Nicholas , Yang Wenjian , Condos Gregory , Hunger Stephen P. , Raetz Elizabeth , Saffery Richard , Relling Mary V. , Bhojwani Deepa , Morrison Debra J. , Carroll William L.
Published: September 2011

Despite an increase in survival for children with acute lymphoblastic leukemia (ALL), the outcome after relapse is poor. To understand the genetic events that contribute to relapse and chemoresistance and identify novel targets of therapy, 3 high-throughput assays were used to identify genetic and epigenetic changes at relapse. Using matched diagnosis/relapse bone marrow samples from children with relapsed B-precursor ALL, we evaluated gene expression, copy number abnormalities (CNAs), and DNA methylation. Gene expression analysis revealed a signature of differentially expressed genes from diagnosis to relapse that is different for early (< 36 months) and late (≥ 36 months) relapse. CNA analysis discovered CNAs that were shared at diagnosis and relapse and others that were new lesions acquired at relapse. DNA methylation analysis found increased promoter methylation at relapse. There were many genetic alterations that evolved from diagnosis to relapse, and in some cases these genes had previously been associated with chemoresistance. Integration of the results from all 3 platforms identified genes of potential interest, including CDKN2A, COL6A2, PTPRO, and CSMD1. Although our results indicate that a diversity of genetic changes are seen at relapse, integration of gene expression, CNA, and methylation data suggest a possible convergence on the WNT and mitogen-activated protein kinase pathways.
Haploidentical hematopoietic transplantation: current status and future perspectives
Authors: Reisner Yair , Hagin David , Martelli Massimo F.
Published: September 2011

For patients with hematologic malignancies at high risk of relapse who do not have matched donors, a suitable alternative stem cell source is the HLAhaploidentical 2 or 3-loci mismatched family donor who is readily available for nearly all patients. Transplantation across the major HLA barrier is associated with strong T-cell alloreactions, which were originally manifested as a high incidence of severe GVHD and graft rejection. The present review shows how these obstacles to successful transplantation were overcome in the last 15 years, making full haplotype-mismatched transplantation a clinical reality that provides similar outcomes to transplantation from matched unrelated donors. The review also discusses the advantages and drawbacks of current options for full haplotypemismatched transplantation and highlights innovative approaches for re-building immunity after transplantation and improving survival.