bluuebunny/crossref_metadata_2025 huggingface dataset:
CARDIOPROTECTIVE EFFECT OF FISH OIL ON ISOPROTERENOL‐INDUCED MYOCARDIAL INFARCTION IN RATS
Authors: PADMA V.V. , DEVI C.S.S.
Published: February 2009

Epidemiological studies indicate a low incidence of cardiac diseases in populations that consume large amounts of seafood. This effect is attributed to the presence of n‐3 polyunsaturated fatty acids in fish oil. In this study, the protective effect of fish oil against isoproterenol induced changes in histopathology; hematology and lysosomal membrane integrity were evaluated in male wistar rats. The rats were fed fish oil for 45 days prior to isoproterenol treatment. The animals were sacrificed by cervical decapitation method 12 h after the second injection of isoproterenol hydrochloride. The results suggest that pretreatment with fish oil prevented isoproterenol‐induced hematological changes. Lysosomal membrane integrity was also protected in fish oil pretreated rats, as indicated by significantly lowered activities of lysosomal hydrolases in serum and concomitant increase in their activity in the lysosomal fraction of heart. The histopathology studies further confirmed the cardioprotective effect of fish oil.

PRACTICAL APPLICATIONS

Fish oil consumption offers cardioprotection by its ability to modulate biological membranes. This study demonstrates the ability of fish oil to modulate hematological parameters and maintain lysosomal membrane integrity, thereby offering multifaceted protection to the heart. Hence, fish oils, especially those of marine origin, have excellent potential as cardioprotective agents.
SUITABILITY OF CRANK'S SOLUTIONS TO FICK'S SECOND LAW FOR WATER DIFFUSIVITY CALCULATION AND MOISTURE LOSS PREDICTION IN OSMOTIC DEHYDRATION OF FRUITS
Authors: OCHOA‐MARTÍNEZ C.I. , RAMASWAMY H.S. , AYALA‐APONTE A.A.
Published: February 2009

Various solutions (Crank's) of Fick's law of diffusion have been used to predict moisture loss (ML) in osmotic dehydration, by correlating experimental data. Selection of a particular solution should depend on the sample geometry and the fulfillment of a number of assumptions made to obtain that solution. Crank developed solutions for long‐time, short‐time, and a solution for diffusion into a sample from a well‐stirred tank for sheets, cylinders and spheres. This work was carried out to find the most suitable Crank's solution to predict ML for a wide range of published data. The long‐time solution and the solution for a well‐agitated tank, for plane sheets, satisfactorily predicted ML of semi‐infinite sheets and semi‐infinite cylinders.

PRACTICAL APPLICATIONS

Crank's solutions of Fick's law for various geometric shapes are used in practice to determine the diffusivity from experimental data for unit operations governed by mass transfer. Once the diffusivity is known, those solutions can be used to predict the kinetics of mass transfer. One of the specific cases where this information is useful is in determining the loss of water for the process of osmotic dehydration. Crank developed solutions for several sets of initial and boundary conditions and for various product geometries. This article evaluates the suitability of Crank's solutions for a wide range of experimental data and indicates the most appropriate solution form to be used for each geometric shape.
The Significance of Statistical Significance:
Authors: Lempert Richard
Published: February 2009

This essay reviews The Cult of Statistical Significance: How the Standard Error Costs Us Jobs, Justice, and Lives, by Stephen T. Ziliak and Deirdre N. McCloskey. The book's core message is that statistical significance should not be equated with substantive significance and that empirical researchers should convey more information about the magnitude of relationships and effects than many now do. This essay summarizes, approves of, and elaborates on Ziliak and McCloskey's message with special attention to concerns of the legal academy. It clarifies appropriate uses of significance tests within the research framework of controlling for plausible rival hypotheses.
Anti-terrorism control orders: liberty and security still in the balance
Authors: Bates Ed
Published: February 2009

The compatibility of anti-terrorism control orders with Arts 5 and 6 of the European Convention for the Protection of Human Rights and Fundamental Freedoms 1950 was the subject of litigation culminating in three House of Lords' judgments in late 2007, and a further case on Art 6 will be argued before a nine-panel House of Lords in March 2009. To date, the litigation has required important modifications to be made to how control orders work, but the regime provided by the Prevention of Terrorism Act 2005 remains essentially intact. The government therefore claims that control orders strike an appropriate balance between the interests of liberty and security. This paper critiques the role played by the courts in challenging control orders under human rights laws. It argues that it is necessary to incorporate the right to freedom of movement into UK law in order to allow a proper balance between liberty and security to be effected by the courts.
The regulation and function of mammalian AMPK‐related kinases
Authors: Bright N. J. , Thornton C. , Carling D.
Published: February 2009

AMP‐activated protein kinase (AMPK) is a key regulator of cellular and whole‐body energy homeostasis. Recently, 12 AMPK‐related kinases (BRSK1, BRSK2, NUAK1, NUAK2, QIK, QSK, SIK, MARK1, MARK2, MARK3, MARK4 and MELK) were identified that are closely related by sequence homology to the catalytic domain of AMPK. The protein kinase LKB1 acts as a master upstream kinase activating AMPK and 11 of the AMPK‐related kinases by phosphorylation of a conserved threonine residue in their T‐loop region. Further sequence analyses have identified the eight‐member SNRK kinase family as distant relatives of AMPK. However, only one of these is phosphorylated and activated by LKB1. Although much is known about AMPK, many of the AMPK‐related kinases remain largely uncharacterized. This review outlines the general similarities in structure and function of the AMPK‐related kinases before examining the specific characteristics of each, including a brief discussion of the SNRK family.
Survival rate, abundance, and residency of long‐finned pilot whales in the Strait of Gibraltar
Authors: Verborgh P. , De Stephanis R. , Pérez S. , Jaget Y. , Barbraud C. , Guinet C.
Published: February 2009

Abstract

Long‐finned pilot whales in the Strait of Gibraltar are distributed over the main shipping routes. This exposes them to risks of collisions and probable acoustic and physical disturbance. This species is also the target of whale‐watching operations. The aim of this study was to estimate the annual population size, survival rate, and population growth rate of pilot whales occurring in the Strait and their inter‐annual variation using photo‐identification. A robust design was used to estimate all three parameters. A total of 10,784 individual pilot whale fins were photographed and analyzed. The population size estimation in summer ranged from a low of 147 individuals in 1999 to a high of 265 individuals in 2003. The annual population growth rate was estimated from mark recapture models to be 5.5%. The survival rate of adults was estimated at 0.982 (95% CI: 0.955–0.993). The same individuals have been observed between years. This suggests that this population is resident in the Strait, at least during summer. This study provides baseline knowledge prior to a predicted increase in shipping traffic throughout the main foraging area due to the opening in 2007 of a major shipping harbor along the Moroccan coast of the Strait.
Introduction: Arthritis and Myositis
Authors: Katz James D. , Nayyar Geeta
Published: February 2009

In this chapter background medical information pertinent to the use of MRI and/or ultrasound in various musculoskeletal conditions is presented. Appreciation of the genetic, biochemical, histological, and immunological features of rheumatic diseases will be of benefit to the technician responsible for performing and interpreting these types of interrogations. For example, recognizing that cartilage disorder predates bone findings in osteoarthritis will help identify early versus late degenerative findings. Similarly, understanding the fibrovascular nature of rheumatoid pannus will help guide the use of more sophisticated ultrasound techniques such as power Doppler.
The MRI View of Synovitis and Tenosynovitis in Inflammatory Arthritis
Authors: McQueen Fiona M.
Published: February 2009

MRI scanning is the current gold standard modality for imaging synovitis and tenosynovitis in patients with inflammatory arthritis. Inflamed synovial membrane within the joints and investing tendon sheaths appears thickened on T1‐weighted sequences and enhances postcontrast. On T2‐weighted sequences, synovitis and synovial effusions typically show a high signal. Studies have shown correlations between the degree of inflammation and vascularity of synovium obtained at biopsy and postcontrast enhancement on matching dynamic MRI scans. Scoring systems have been devised that are based on quantifying synovial membrane thickening and signal intensity on static postcontrast scans and have been validated in multireader settings. Moderate to high reliability has been demonstrated with trained readers and quantification of synovitis in this way is being used increasingly as an outcome measure in clinical trials to assess response to therapy. MRI‐observed synovitis is almost invariable in those with active rheumatoid arthritis, but recent studies have also demonstrated its presence in patients in clinical remission, emphasizing the sensitivity of this technique and the importance of subclinical joint inflammation. MRI‐observed synovitis has been validated against other imaging modalities, including power Doppler ultrasound, and has also been investigated in normal subjects (where mild enhancement can rarely occur). Studies over 1–2 years have suggested that MRI synovial membrane volume and postcontrast enhancement on dynamic imaging can predict the development of erosions. In the long term, an overall score of inflammation incorporating synovitis, tenosynovitis, and bone edema may be a more useful MRI predictor of aggressive erosive disease.
Bone Marrow Edema
Authors: Schett Georg
Published: February 2009

A bone marrow edema pattern on MRI has a similar signal quality as an inflamed synovium and may, in fact, reflect true inflammatory infiltrates rather than a pure accumulation of extracellular fluid. Bone lesions near sites of rheumatoid arthritis–related inflammation are heavily vascularized, contributing to the high water content and enhanced visibility on MRI. However, even without erosive change, periarticular bone marrow lesions may be seen. This chapter describes the nature of bone marrow lesions detected by MRI in patients with inflammatory arthritis.
A Regional Approach to Foot and Ankle MRI
Authors: Stempel Michael Sean
Published: February 2009

This chapter presents a regional anatomic approach to MRI applications in the foot and ankle. From a clinical perspective, patients often describe their symptoms in terms of the part of the foot that hurts and when and how it hurts. Clinical questioning and physical diagnosis pursue this line as well, trying to narrow down the diagnostic possibilities. There are conditions that may blur the anatomic distinctions for forefoot, midfoot, rearfoot, and ankle; involve more than one region of the foot simultaneously; or occur in any area of the foot. The chapter also includes a separate section on the presentations of inflammatory arthritides in foot and ankle joints.
Magnetic Resonance Imaging of the Idiopathic Inflammatory Myopathies
Authors: Curiel Rodolfo Victor , Jones Robert , Brindle Kathleen
Published: February 2009

Idiopathic inflammatory myopathies are chronic diseases clinically characterized by symmetrical proximal muscle weakness. MRI has assumed a major role in the evaluation and management of these conditions. It is sensitive to the presence of inflammation and edema, especially with incorporation of fat suppression sequences, so it is a useful tool for establishing an early diagnosis, for evaluating the extent and number of lesions, and for determining the right site for biopsy. The noninvasive nature of the procedure makes it ideal for serial studies to evaluate response to treatment. Whole‐body MRI can scan a large volume of muscles without prolonged acquisition time and has the potential to identify previously unsuspected sites of involvement. MRI is also an excellent technique for identifying areas of fatty infiltration within the muscles, which usually occurs in the late stages of inflammatory myopathies. In summary, MRI has revolutionized the way muscular diseases are diagnosed and treated.
Ultrasound in the Diagnosis of Noninflammatory Musculoskeletal Conditions
Authors: Hashefi Mandana
Published: February 2009

Sonography is an attractive tool for the diagnosis of musculoskeletal conditions. The clinician can evaluate the anatomic segment during active and/or passive flexion and extension maneuvers, and its real‐time capability allows imaging in positions that trigger symptoms. Scanning the contralateral asymptomatic extremity can be used as a reference for normal anatomy in a given patient. A common application of ultrasound is for the assessment of rotator cuff tendons. It can also be used to assess soft tissue infections, nerve pathology, and various sports‐related injuries.
Complexities of MRI and False Positive Findings
Authors: Khanna Sanjeev , Crues John V.
Published: February 2009

MRI is a robust technology that allows for superior contrast of muscles, tissues, and bones within the body, which enables visualization of soft tissue pathology that cannot be seen with CT or plain film radiography. In order to appreciate the subtle (and sometimes not so subtle) intricacies of MRI, one must have a basic knowledge of the MRI physics involved to acquire an image, which leads to better recognition and a clearer understanding of some of the more important artifacts seen with MRI, including incomplete fat suppression, chemical shift, magnetic susceptibility, magic angle, partial volume, wraparound, and motion artifact. There are, however, many complexities and pitfalls in imaging the rheumatoid wrist. Normal anatomy such as capsular insertion sites and nutrient vessels can mimic erosion sites. The magic angle phenomenon can mimic tendon tears. Alignment abnormalities can be simulated based on wrist positioning. By having a solid understanding of the physics of magnetic resonance, anatomy, and the disease processes involved, many of these pitfalls can be avoided.
MRI in Juvenile Idiopathic Arthritis and Juvenile Dermatomyositis
Authors: Gardner‐Medwin Janet Mary McCrae , Irwin Greg , Johnson Karl
Published: February 2009

The use of MRI in the assessment of the musculoskeletal system in children has important differences from its use in adults. Growth in children has significant impact on the epiphysis and growth plate, which are important structures in the growing child, and there are radiological features that differ from those in adults: disease may alter structures during a period of growth; the pathologies themselves are a distinct group of diseases at variance with adult arthritis and myositis, with a different spectrum of differential diagnoses; and many technical issues are different when imaging a child. These are important considerations in choosing the appropriate imaging. MRI is a powerful and valuable imaging technique in pediatric musculoskeletal pathologies, with considerable potential for future developments to enhance its role in diagnosis, management, and therapeutic intervention for these children.
A pilot study of the immune response to whole inactivated avian influenza H7N1 virus vaccine in mice
Authors: Hovden Arnt‐Ove , Brokstad Karl A. , Major Diane , Wood John , Haaheim Lars R. , Cox Rebecca J.
Published: February 2009

Background Highly pathogenic avian influenza (HPAI) outbreaks in domestic poultry bring humans into close contact with new influenza subtypes and represent a threat to human health. In 1999, an HPAI outbreak of H7N1 virus occurred in domestic poultry in Italy, and a wild‐type virus isolate from this outbreak was chosen as a pandemic vaccine candidate.

Objectives We conducted a pilot study to investigate the kinetics of the humoral immune response induced after immunisation with an egg grown whole inactivated H7N1 virus vaccine in BALB/c mice.

Methods Mice were vaccinated with one or two doses of H7N1 vaccine (15 μg total protein) to investigate the influenza specific antibody secreting cell (IS‐ASC) and serum antibody responses.

Results After the first dose of vaccine, only IgM IS‐ASC were detected in the spleen and bone marrow, whereas IgG, IgA and IgM IS‐ASC were found after the second dose. Low antibody titres were detected after the first immunisation, whilst the second dose of vaccine significantly boosted the HI (range 128–512), neutralising and IgG antibody titres. The IgG subclass response was dominated by IgG2a indicating a dominant Th1 response after the first vaccination, whereas a more mixed Th1/Th2 profile was observed after the second dose.

Conclusions This pilot study shows the value of using a number of immunological methods to evaluate the quality of the immune response to potential pandemic candidate vaccines.
Effect of Soybean Volatile Compounds on Aspergillus flavus Growth and Aflatoxin Production
Authors: Cleveland T.E. , Carter‐Wientjes C.H. , De Lucca A.J. , Boué S.M.
Published: February 2009

ABSTRACT:  Soybean homogenates produced volatile compounds upon exposure to lipase. These induced volatiles were identified by SPME. Seventeen volatile compounds identified by SPME were chosen for determination of their ability to inhibit Aspergillus flavus growth and aflatoxin B1 (AFB1) production in a solid media assay. These volatiles included aldehydes, alcohols, ketones, and furans. Of the tested compounds, the aldehydes showed the greatest inhibition of fungal growth and AFB1 production. These compounds inhibited up to 100% of the observed growth and AFB1 production as compared to the controls. The greatest activity by the aldehydes to disrupt growth was ranked as follows: 2,4 hexadienal > benzaldehyde > 2‐octenal > (E)‐2‐heptenal > octanal > (E)‐2‐hexenal > nonanal > hexanal. The greatest activity by the aldehydes to reduce AFB1 was ranked as follows: (E)‐2‐hexenal > 2,4 hexadienal > (E)‐2‐heptenal > hexanal > nonanal. (E)‐2‐hexenal and (E)‐2‐heptenal were tested further in an A. flavus‐inoculated corn kernel assay. Both compounds prevented colonization by A. flavus and eliminated AFB1 production when exposed to compound volumes < 10 μL as also shown in the solid media assay. The results suggest that soybeans react to lipase by production of potent antifungal volatiles.
Bioremediation of marine oil spills: when and when not – theExxon Valdezexperience
Authors: Atlas Ronald , Bragg James
Published: February 2009

In this article we consider what we have learned from theExxon Valdezoil spill (EVOS) in terms of when bioremediation should be considered and what it can accomplish. We present data on the state of oiling of Prince William Sound shorelines 18 years after the spill, including the concentration and composition of subsurface oil residues (SSOR) sampled by systematic shoreline surveys conducted between 2002 and 2007. Over this period, 346 sediment samples were analysed by GC‐MS and extents of hydrocarbon depletion were quantified. In 2007 alone, 744 sediment samples were collected and extracted, and 222 were analysed. Most sediment samples from sites that were heavily oiled by the spill and physically cleaned and bioremediated between 1989 and 1991 show no remaining SSOR. Where SSOR does remain, it is for the most part highly weathered, with 82% of 2007 samples indicating depletion of total polycyclic aromatic hydrocarbon (Total PAH) of > 70% relative to EVOS oil. This SSOR is sequestered in patchy deposits under boulder/cobble armour, generally in the mid‐to‐upper intertidal zone. The relatively high nutrient concentrations measured at these sites, the patchy distribution and the weathering state of the SSOR suggest that it is in a form and location where bioremediation likely would be ineffective at increasing the rate of hydrocarbon removal.
Application of nitroarene dioxygenases in the design of novel strains that degrade chloronitrobenzenes
Authors: Ju Kou‐San , Parales Rebecca E.
Published: February 2009

Widespread application of chloronitrobenzenes as feedstocks for the production of industrial chemicals and pharmaceuticals has resulted in extensive environmental contamination with these toxic compounds, where they pose significant risks to the health of humans and wildlife. While biotreatment in general is an attractive solution for remediation, its effectiveness is limited with chloronitrobenzenes due to the small number of strains that can effectively mineralize these compounds and their ability to degrade only select isomers. To address this need, we created engineered strains with a novel degradation pathway that reduces the total number of steps required to convert chloronitrobenzenes into compounds of central metabolism. We examined the ability of 2‐nitrotoluene 2,3‐dioxygenase from Acidovorax sp. strain JS42, nitrobenzene 1,2‐dioxygenase (NBDO) from Comamonas sp. strain JS765, as well as active‐site mutants of NBDO to generate chlorocatechols from chloronitrobenzenes, and identified the most efficient enzymes. Introduction of the wild‐type NBDO and the F293Q variant into Ralstonia sp. strain JS705, a strain carrying the modified ortho pathway for chlorocatechol metabolism, resulted in bacterial strains that were able to sustainably grow on all three chloronitrobenzene isomers without addition of co‐substrates or co‐inducers. These first‐generation engineered strains demonstrate the utility of nitroarene dioxygenases in expanding the metabolic capabilities of bacteria and provide new options for improved biotreatment of chloronitrobenzene‐contaminated sites.
Microbial responses to xenobiotic compounds. Identification of genes that allow Pseudomonas putida KT2440 to cope with 2,4,6‐trinitrotoluene
Authors: Fernández Matilde , Duque Estrella , Pizarro‐Tobías Paloma , Van Dillewijn Pieter , Wittich Rolf‐Michael , Ramos Juan L.
Published: February 2009

Pseudomonas putida KT2440 grows in M9 minimal medium with glucose in the presence of 2,4,6‐trinitrotoluene (TNT) at a similar rate than in the absence of TNT, although global transcriptional analysis using DNA microarrays revealed that TNT exerts some stress. Response to TNT stress is regulated at the transcriptional level, as significant changes in the level of expression of 65 genes were observed. Of these genes, 39 appeared upregulated, and 26 were downregulated. The identity of upregulated genes suggests that P. putida uses two kinds of strategies to overcome TNT toxicity: (i) induction of genes encoding nitroreductases and detoxification‐related enzymes (pnrA, xenD, acpD) and (ii) induction of multidrug efflux pump genes (mexEF/oprN) to reduce intracellular TNT concentrations. Mutants of 13 up‐ and 7 downregulated genes were analysed with regards to TNT toxicity revealing the role of the MexE/MexF/OprN pump and a putative isoquinoline 1‐oxidoreductase in tolerance to TNT. The ORF PP1232 whose transcriptional level did not change in response to TNT affected growth in the presence of nitroaromatic compounds and it was found in a screening of 4000 randomly generated mutants.
Quantitative Recovery of Elemental Sulfur and Improved Selectivity in a Chromium‐Reducible Sulfur Distillation
Authors: Gröger Jens , Franke Jennifer , Hamer Kay , Schulz Horst D.
Published: February 2009

Chromium‐reducible sulfur (CRS) distillations are intended to recover only reduced inorganic sulfur compounds (RIS) including elemental sulfur. However, the quantitative recovery of elemental sulfur is not ensured in common CRS‐distillations. The new method presented here was designed to remedy this deficiency. An increase in ethanol concentration assured the quantitative recovery of elemental sulfur in various forms and, in addition, all other RIS‐compounds were quantitatively recovered. Furthermore, the selectivity of the procedure was improved by an additional filtration step to eliminate zinc particles from the Cr(II)‐solution. Thus, the recovery of sulfates and organic sulfur compounds was significantly decreased by a factor of up to 35, depending on the compound analysed. Exhaustive testing with a variety of pure phases, rock and soil samples demonstrated the precision and accuracy of the new method. The new protocol eliminated the constraints of previous procedures. The improved distillation efficiency for elemental sulfur ensured the quantitative recovery of all RIS‐compounds in a single‐step distillation.
Effect of asthma compliance enhancement training on asthma control in patients on combination therapy with salmeterol/fluticasone propionate: a randomised controlled trial
Authors: Ulrik Charlotte Suppli , Claudius Birgitte Kjor , Tamm Michael , Harving Henrik , Siersted Hans Christian , Backer Vibeke , Hellquist Birthe , Dahl Ronald , Høgholm Asbjørn , Jøhnk Ida Karina
Published: February 2009

Objective:  We investigated if a higher proportion of adults with previously uncontrolled asthma can achieve total control when given salmeterol/fluticasone propionate (50/250 µg) bid and compliance enhancement training (CET) compared to those given medication alone.

Methods:  Open comparison of stable, but uncontrolled, adult asthmatics. After a 12‐week treatment period on salmeterol/fluticasone propionate (period 1), patients who failed to achieve control were randomised to continuing treatment with or without CET for 12 weeks (period 2). The primary end point was the proportion achieving total control of their asthma in 7 of the last 8 consecutive weeks of period 2.

Results:  A total of 361 subjects (50.4% males, mean age 40.0 ± 14.4 years) in 29 centres were included, of whom 75.9% were randomised into treatment period 2 (n = 140 in the intervention group). The proportion of subjects achieving total asthma control was 8.8% and 7.6%, respectively, in the intervention and control group [not significant (NS)]. Mean morning peak flow, forced expiratory volume in one second (FEV1), asthma symptom score and quality of life improved significantly over the study period in both treatment groups. Furthermore, proportion of days with use of rescue medication declined from 59.7% ± 34.6% (55.7% ±  35.3%) during screening to 20.3% ± 29.2% (19.4% ± 30.9%) during treatment period 2 (NS).

Conclusion:  CET failed to increase the likelihood of achieving total control in asthmatics on salmeterol/fluticasone propionate compared to subjects receiving medication only. However, both groups had a significant improvement in asthma control.

(Clinical Trials.gov number, NCT00351143)

Please cite this paper as: Ulrik CS, Claudius BK, Tamm M, Harving H, Siersted HC, Backer V, Hellquist B, Dahl R, Høgholm A and Jøhnk IK. Effect of asthma compliance enhancement training on asthma control in patients on combination therapy with salmeterol/fluticasone propionate: a randomised controlled trial. The Clinical Respiratory Journal 2009; 3: 161–168.
Negative Regulation of VEGF Signaling in Human Coronary Artery Endothelial Cells by G Protein‐Coupled Receptor Kinase 5
Authors: Zhou Rui‐Hai , Pesant Stephanie , Cohn Heather I. , Soltys Stephen , Koch Walter J. , Eckhart Andrea D.
Published: February 2009

G protein‐coupled receptor kinase 5 (GRK5) is present in endothelial cells (ECs) and has the potential to regulate EC function through seven transmembrane‐spanning receptor (7TMR) signaling. Recently, it has been appreciated that GRKs can affect receptor tyrosine kinases (RTKs). VEGF, an RTK, is one of the most potent mediators for EC function and angiogenesis; therefore, we determined the role GRK5 plays in VEGF signaling in human coronary artery ECs (HCAECs). GRK5 levels were increased by VEGF treatment in HCAECs. Adenoviral overexpression of GRK5 inhibited migration and proliferation of HCAECs in response to VEGF. GRK5 overexpression in HCAECs significantly suppressed both acute and late activation of Akt and extracellular signal‐related kinase (ERKs) as well as the phosphorylationof GSK‐3β, an endogenous substrate of Akt. Coimmunoprecipitations revealed that GRK5 is physically associated with Akt. This study shows for the first time that GRK5 negatively regulates VEGF signaling in HCAECs and suggests that targeted intervention of GRK5 in ECs might be a novel therapeutic strategy to prevent and treat disorders involving altered EC function.
Optimized Systemic Dosing with CpG DNA Enhances Dendritic Cell‐Mediated Rejection of a Poorly Immunogenic Mammary Tumor in BALB/c Mice
Authors: Cai Quan , Kublo Lyubov , Cumberland Rachel , Gooding William , Baar Joseph
Published: February 2009

To model a clinical trial of dendritic cell (DC) therapy of a poorly immunogenic mammary tumor, we treated BALB/c mice bearing an established TS/A mammary tumor with lysate‐pulsed DCs and CpG DNA. We observed that the dose of CpG DNA required to activate DCs in vitro was insufficient to mediate tumor rejection in vivo. We therefore undertook in vivo studies to identify an optimized dose of CpG DNA for tumor therapy, defined as the lowest and least frequently administered dose of CpG DNA that mediated complete tumor rejection. We show that one priming dose of 15 nanomoles and one booster dose of 10 nanomoles of CpG DNA given 7 days apart, respectively, with lysate‐loaded DCs were sufficient to mediate complete tumor rejection in vivo. This dose of CpG DNA was 42‐fold higher than that required to activate DCs in vitro but was not associated with any toxicity in mice. Also, the cured mice rejected a subsequent challenge with fresh TS/A tumor, and both CD4+ and CD8+ T cells were required for tumor rejection. We conclude that effective DC‐based therapy of a poorly immunogenic TS/A tumor is enhanced by optimized dosing of CpG DNA. Our data have important implications for DC‐based clinical trials of breast cancer immunotherapy.
Prevention of Trauma/Hemorrhagic Shock‐Induced Lung Apoptosis by IL‐6‐Mediated Activation of Stat3
Authors: Moran Ana , Tsimelzon Anna I. , Mastrangelo Mary‐Ann A. , Wu Yong , Yu Bi , Hilsenbeck Susan G. , Poli Valeria , Tweardy David J.
Published: February 2009

Acute lung injury (ALI) occurs in up to 37% of patients following trauma/hemorrhagic shock (T/HS) and, in other settings, is due to alveolar epithelial cell (AEC) apoptosis. To determine if AEC apoptosis is a key contributor to ALI following T/HS and whether or not signal transducer and activator of translation (Stat)3 activation can prevent it, rats were pretreated with a Stat3 inhibitor or placebo and subjected to T/HS or sham protocol and resuscitated without or with interleukin (IL)‐6. T/HS induced apoptosis in up to 15% of lung cells, 82% of which were AEC. Apoptosis increased with increasing duration of shock and required resuscitation. IL‐6 treatment stimulated lung Stat3 activation and prevented AEC apoptosis. Pretreatment of rats with a Stat3 inhibitor blocked the antiapoptotic effect of IL‐6. Mice deficient in Stat3β, a naturally occurring dominant negative isoform of Stat3, were resistant to T/HS‐induced lung apoptosis. T/HS altered the expression of 87% of apoptosis‐related genes. IL‐6 treatment normalized expression of 75% of the genes altered by T/HS; Stat3 inhibition prevented normalization of 65% of the gene whose expression was normalized by IL‐6. Thus, T/HS‐induced AEC apoptosis, which depended on the duration of hypotension, required resuscitation and was prevented by IL‐6‐mediated activation of Stat3, which acted to normalize the apoptosis transcriptome.
In vivo Remote Delivery of DNA Encoding for Hypoxia‐inducible Factor 1 Alpha Reduces Myocardial Infarct Size
Authors: Czibik Gabor , Martinov Vladimir , Ruusalepp Arno , Sagave Julia , Skare Øivind , Valen Guro
Published: February 2009

We tested if remote gene delivery of hypoxia‐inducible factor 1 alpha (HIF‐1α) protected hearts against induced ischemia, hypothesizing that gene delivery into skeletal muscle may lead to secretion of proteins with actions elsewhere.

Murine quadriceps muscles were transfected with DNA encoding for human HIF‐1α, which resulted in a local, but lasting expression (mRNA and protein, where the latter had nuclear localization). Subjection of isolated hearts to global ischemia and reperfusion 1, 4, and 8 weeks after gene delivery resulted in infarct size reduction (p < 0.05). Supporting that this was due to paracrine effects, HL‐1 cells treated with conditioned media from cells transfected with HIF‐1α or serum from HIF‐1α‐treated mice were protected against H2O2‐induced cell death (p < 0.05, respectively). The latter protection was reduced when a heme oxygenase activity blocker was used. Taqman low‐density array of 47 HIF‐1α‐regulated genes at the treatment site showed nine specific upregulations (p < 0.05). Of the corresponding proteins, PDGF‐B and adrenomedullin were upregulated in the heart. HIF‐1α treatment induced an increased vascularization of the heart and skeletal muscle.

In conclusion, remote delivery of DNAfor HIF‐1α was cardioprotective, represented by consistent infarct size reduction, which may be due to release of paracrine factors from the transfected muscle.
The Emergence of Extensively Drug‐Resistant Tuberculosis: A Global Health Crisis Requiring New Interventions: Part II: Scientific Advances that May Provide Solutions
Authors: Ellner Jerrold J.
Published: February 2009

The need for new tuberculosis (TB) diagnostics has never been greater as TB in the HIV‐infected is often sputum smear negative or extrapulmonary and may progress rapidly unless diagnosed and treated appropriately. In addition, the empirical treatment of patients with drug‐resistant TB leads to the acquisition of additional resistance. Fortunately there is a robust and adequately funded developments pipeline including investigational rapid diagnostics that may replace smear, culture, and drug susceptibility testing. The dogma that drug resistance usually develops as a consequence of patient nonadherence has never been entirely plausible. Recent observations indicate that certain mutations in drug resistance genes promote the acquisition of additional resistance. Further, Mycobacterium tuberculosis (MTB) may demonstrate tolerant phenotypes due to induction of a multidrug‐resistant like pump. It will be difficult to “treat our way” out of the problem of extensively drug‐resistant (XDR)‐TB without access to new interventions. Vaccines in development offer a distant hope. Promising new therapeutics in clinical trials may shorten the duration of treatment of TB, which will lessen the development of drug resistance or provide potent new and MTB specific agents that should be effective in treatment of XDR‐TB.
Sunitinib‐Induced Cardiotoxicity Is Mediated by Off‐Target Inhibition of AMP‐Activated Protein Kinase
Authors: Kerkela Risto , Woulfe Kathleen C. , Durand Jean‐Bernard , Vagnozzi Ronald , Kramer David , Chu Tammy F. , Beahm Cara , Chen Ming Hui , Force Thomas
Published: February 2009

Tyrosine kinase inhibitors (TKIs) are transforming the treatment of patients with malignancies. One such agent, sunitinib (Sutent, Pfizer, New York, NY, USA), has demonstrated activity against a variety of solid tumors. Sunitinib is “multitargeted,” inhibiting growth factor receptors that regulate both tumor angiogenesis and tumor cell survival. However, cardiac dysfunction has been associated with its use. Identification of the target of sunitinib‐associated cardiac dysfunction could guide future drug design to reduce toxicity while preserving anticancer activity. Herein we identify severe mitochondrial structural abnormalities in the heart of a patient with sunitinib‐induced heart failure. In cultured cardiomyocytes, sunitinib induces loss of mitochondrial membrane potential and energy rundown. Despite the latter, 5′ adenosine monophosphate‐activated protein kinase (AMPK) activity, which should be increased in the setting of energy compromise, is reduced in hearts of sunitinib‐treated mice and cardiomyocytes in culture, and this is due to direct inhibition of AMPK by sunitinib. Critically, we find that adenovirus‐mediated gene transfer of an activated mutant of AMPK reduces sunitinib‐induced cell death. Our findings suggest AMPK inhibition plays a central role in sunitinib cardiomyocyte toxicity, highlighting the potential of off‐target effects of TKIs contributing to cardiotoxicity. While multitargeting can enhance tumor cell killing, this must be balanced against the potential increased risk of cardiac dysfunction.
Dangerous Friends: The Second and the Later English Duel
Authors: BANKS STEVE
Published: February 2009

The paper considers honour disputes and duelling in the English society of the late eighteenth and early nineteenth centuries. Its author argues that it was the seconds, or friends, of the disputants, who made both the peaceful resolution of disputes socially possible and, if necessary, the carefully structured violence of the duel containable. The second, an independent man of reputation who assayed the honour of his principal, has oft been neglected in modern duelling studies. Here the author examines the nuances, privileges and obligations of his situation and the indispensable role that he played in sustaining honour culture.
Hapalorchis neglecta sp. nov. and H. piesikii sp. nov. (Spiranthinae, Orchidaceae) from the Neotropics
Authors: Szlachetko Dariusz L. , Rutkowski Piotr , Mytnik‐Ejsmont Joanna
Published: February 2009

Two new species of Hapalorchis Schltr. (H. neglecta and H. piesikii) from the Neotropics (Ecuador and Colombia, respectively) are described and illustrated. The taxonomic position of the taxa is briefly discussed.
Taxonomic revision of Rhododendron mariae (Ericaceae) and related taxa
Authors: Jin Xiao‐Feng , Ding Bing‐Yang , Jin Shui‐Hu , Qian Li
Published: February 2009

Based on a literature survey and a field trip with specimen examination, statistical analysis including principal components analysis (PCA) on morphological characters have been carried out on Rhododendron mariae and related taxa. Cluster analysis and PCA showed three independent groups, which corresponded to three species except R. loniceriflorum. As a consequence, nine taxa are reduced to synonyms of R. mariae, and two new combinations, viz R. mariae subsp. microphyton, and R. mariae subsp. flumineum are made. Rhododendron microphyton var. trichanthum is reduced to a synonym of R. mariae subsp. microphyton, and R. malipoense to a synonym of R. mariae subsp. flumineum. Three names are synonymized and a new combination, viz R. chryocalyx subsp. meridionale, is proposed within R. chryocalyx. The third entity, R. naamkwanense, has got two new synonyms. Rhododendron loniceriflorum, with whitish pubescence on the inner corolla surface, is recognized as the fourth distinct species. Each entity is illustrated with line drawings for identification.
Cultivation of a perennial grass for bioenergy on a boreal organic soil – carbon sink or source?
Authors: SHURPALI NARASINHA J. , HYVÖNEN NIINA P. , HUTTUNEN JARI T. , CLEMENT ROBERT J. , REICHSTEIN MARKUS , NYKÄNEN HANNU , BIASI CHRISTINA , MARTIKAINEN PERTTI J.
Published: February 2009

The area under the cultivation of perennial bioenergy crops on organic soils in the northern countries is fast increasing. To understand the impact of reed canary grass (RCG, Phalaris arundinaceae L.) cultivation on the carbon dioxide (CO2) balance of an organic soil, net ecosystem CO2 exchange (NEE) was measured for four years in a RCG cultivated cutover peatland in eastern Finland using the eddy covariance technique. There were striking differences among the years in the annual precipitation. The annual precipitation was higher during 2004 and 2007 and lower during 2005 and 2006 than the 1971–2000 regional mean. During wet growing seasons, moderate temperatures, high surface soil moisture and low evaporative demand favoured high CO2 uptake. During dry seasons, owing to soil moisture and atmospheric stress, photosynthetic activity was severely restricted. The CO2 uptake [gross primary productivity (GPP)] was positively correlated with soil moisture, air temperature and inversely with vapour pressure deficit. Total ecosystem respiration (TER) increased with increasing soil temperature but decreased with increasing soil moisture. The relative responses of GPP and TER to moisture stress were different. While changes in TER for a given change in soil moisture were moderate, variations in GPP were drastic. Also, the seasonal variations in TER were not as conspicuous as those in GPP implying that GPP is the primary regulator of the interannual variability in NEE in this ecosystem. The ecosystem accumulated a total of 398 g C m−2 from the beginning of 2004 until the end of 2007. It retained some carbon during a wet year such as 2004 even after accounting for the loss of carbon in the form of harvested biomass. Based on this CO2 balance analysis, RCG cultivation is found to be a promising after‐use option on an organic soil.
Stability and the Fourier–Mukai transform II
Authors: Yoshioka Kōta
Published: February 2009

We consider the problem of preservation of stability under the Fourier–Mukai transform ℱℰ:D(X)→D(Y) on an abelian surface and aK3 surface. IfYis the moduli space ofμ-stable sheaves onXwith respect to a polarizationH, we have a canonical polarization$\widehat {H}$onYand we have a correspondence between (X,H) and$(Y,\widehat {H})$. We show that the stability with respect to these polarizations is preserved under ℱℰ, if the degree of stable sheaves onXis sufficiently large.
Geometric Weil representation: local field case
Authors: Lafforgue Vincent , Lysenko Sergey
Published: February 2009

Let k be an algebraically closed field of characteristic greater than 2, and let F=k((t)) and G=𝕊p2d. In this paper we propose a geometric analog of the Weil representation of the metaplectic group $\widetilde G(F)$. This is a category of certain perverse sheaves on some stack, on which $\widetilde G(F)$ acts by functors. This construction will be used by Lysenko (in [Geometric theta-lifting for the dual pair S𝕆2m, 𝕊p2n, math.RT/0701170] and subsequent publications) for the proof of the geometric Langlands functoriality for some dual reductive pairs.
Analytic vectors in continuousp-adic representations
Authors: Schmidt Tobias
Published: February 2009

Given a compactp-adic Lie groupGover a finite unramified extensionL/ℚplet GL/ℚpbe the product over all Galois conjugates ofG. We construct an exact and faithful functor from admissibleG-Banach space representations to admissible locallyL-analyticGL/ℚp-representations that coincides with passage to analytic vectors in the caseL=ℚp. On the other hand, we study the functor ‘passage to analytic vectors’ and its derived functors over general basefields. As an application we compute the higher analytic vectors in certain locally analytic induced representations.
Prospective Observational Study of the Impact of VIM-1 Metallo-β-Lactamase on the Outcome of Patients with
Klebsiella pneumoniae
Bloodstream Infections
Authors: Daikos George L. , Petrikkos Panayiotis , Psichogiou Mina , Kosmidis Chris , Vryonis Evangelos , Skoutelis Athanasios , Georgousi Kleoniki , Tzouvelekis Leonidas S. , Tassios Panayotis T. , Bamia Christina , Petrikkos George
Published: February 2009

VIM-1-producing
Klebsiella pneumoniae
(VPKP) is an emerging pathogen. A prospective observational study was conducted to evaluate the importance of VIM production on outcome of patients with
K. pneumoniae
bloodstream infections (BSIs). Consecutive patients with
K. pneumoniae
BSIs were identified and followed up until patient discharge or death. A total of 162 patients were included in the analysis; 67 (41.4%) were infected with VPKP, and 95 were infected with non-VPKP. Fourteen of the patients infected with VPKP were carbapenem resistant (Carb
r
) (MIC > 4 μg/ml), whereas none of the non-VPKP exhibited carbapenem resistance. The patients infected with a Carb
r
organism were more likely (odds ratio, 4.08; 95% confidence interval [CI], 1.29 to 12.85;
P
= 0.02) to receive inappropriate empirical therapy. The all-cause 14-day mortality rates were 15.8% (15 of 95) for patients infected with VIM-negative organisms, 18.9% (10 of 53) for those infected with VIM-positive carbapenem-susceptible organisms, and 42.9% (6 of 14) for those infected with VIM-positive Carb
r
organisms (
P
= 0.044). In Cox regression analysis, age (hazard ratio [HR], 1.03; 95% CI, 1.01 to 1.06;
P
= 0.021), rapidly fatal underlying disease (HR, 2.84; 95% CI, 1.26 to 6.39;
P
= 0.012), and carbapenem resistance (HR, 2.83; 95% CI, 1.08 to 7.41;
P
= 0.035) were independent predictors of death. After adjustment for inappropriate empirical or definitive therapy, the effect of carbapenem resistance on outcome was reduced to a level of nonsignificance. In patients with
K. pneumoniae
BSIs, carbapenem resistance, advanced, age, and severity of underlying disease were independent predictors of outcome, whereas VIM production had no effect on mortality. The higher mortality associated with carbapenem resistance was probably mediated by the failure to provide effective therapy.
Triple Combinations of Lower and Longer Alkyl Gallates and Oxacillin Improve Antibiotic Synergy against Methicillin-Resistant
Staphylococcus aureus
Authors: Shibata Hirofumi , Nakano Tatsuro , Parvez M. Anowar Khasru , Furukawa Yoshihiro , Tomoishi Akio , Niimi Shingo , Arakaki Naokatu , Higuti Tomihiko
Published: February 2009

Using liposome systems, we found that gallates with short alkyl chains were located in the external medium and those with longer alkyl chains were located in the surface region of lipid bilayer. Combinations of these gallates remarkably reduced oxacillin MICs against methicillin-resistant
Staphylococcus aureus
to below the antibiotic breakpoint (≤2 μg/ml).
Chemical Modifications of Antisense Morpholino Oligomers Enhance Their Efficacy against Ebola Virus Infection
Authors: Swenson Dana L. , Warfield Kelly L. , Warren Travis K. , Lovejoy Candace , Hassinger Jed N. , Ruthel Gordon , Blouch Robert E. , Moulton Hong M. , Weller Dwight D. , Iversen Patrick L. , Bavari Sina
Published: February 2009

Phosphorodiamidate morpholino oligomers (PMOs) are uncharged nucleic acid-like molecules designed to inactivate the expression of specific genes via the antisense-based steric hindrance of mRNA translation. PMOs have been successful at knocking out viral gene expression and replication in the case of acute viral infections in animal models and have been well tolerated in human clinical trials. We propose that antisense PMOs represent a promising class of therapeutic agents that may be useful for combating filoviral infections. We have previously shown that mice treated with a PMO whose sequence is complementary to a region spanning the start codon of VP24 mRNA were protected against lethal Ebola virus challenge. In the present study, we report on the abilities of two additional VP24-specific PMOs to reduce the cell-free translation of a VP24 reporter, to inhibit the in vitro replication of Ebola virus, and to protect mice against lethal challenge when the PMOs are delivered prior to infection. Additionally, structure-activity relationship evaluations were conducted to assess the enhancement of antiviral efficacy associated with PMO chemical modifications that included conjugation with peptides of various lengths and compositions, positioning of conjugated peptides to either the 5′ or the 3′ terminus, and the conferring of charge modifications by the addition of piperazine moieties. Conjugation with arginine-rich peptides greatly enhanced the antiviral efficacy of VP24-specific PMOs in infected cells and mice during lethal Ebola virus challenge.