bluuebunny/crossref_metadata_2025 huggingface dataset:
Vitamin D receptor (VDR) gene polymorphism is associated with left ventricular (LV) mass and predicts left ventricular hypertrophy (LVH) progression in end-stage renal disease (ESRD) patients
Authors: Testa Alessandra , Mallamaci Francesca , Benedetto Francesco A , Pisano Anna , Tripepi Giovanni , Malatino Lorenzo , Thadhani Ravi , Zoccali Carmine
Published: July 2009

Left ventricular hypertrophy (LVH) is a strong cardiovascular risk marker in end-stage renal disease (ESRD) patients. Vitamin D deficiency and/or disturbed vitamin D signaling has been implicated in LVH in experimental models. Because the BsmI vitamin D receptor VDR gene polymorphism may alter VDR function, we performed a cross-sectional and longitudinal study in a cohort of 182 dialysis patients to investigate (1) the relationship between BsmI VDR gene polymorphism and left ventricular mass index (LVMI) measured by echocardiography and (2) the predictive power of this polymorphism for progression in LVH over a 18 ± 2 months of follow-up. As a reference group, we used 175 healthy subjects matched to the study population as for age and sex. The distribution of BsmI genotypes did not significantly deviate from Hardy-Weinberg equilibrium either in patients or in the control group of healthy subjects. The frequency of the B allele of BsmI polymorphism (40.4%) in dialysis patients was similar to that of healthy control subjects (38.6%), and the number of B alleles was directly related to LVMI (r = 0.20, P = .007). This relationship remained robust (β = 0.19, P = .006) in multivariate analysis adjusting for traditional and nontraditional risk factors and antihypertensive and calcitriol treatment. In the longitudinal study, LVMI rose from 60.1 ± 17.9 to 64.2 ± 19.3 g/m2.7 (P < .001), and again, the number of B alleles was associated with LVMI changes both in crude and in fully adjusted analyses. These cross-sectional and longitudinal observations coherently support the hypothesis that altered vitamin D signaling is implicated in LVH in ESRD patients. © 2010 American Society for Bone and Mineral Research
An update on damage to the pelvic floor in childbirth
Authors: Dolan Lucia
Published: July 2009

Caesarean section may reduce the risk of postnatal pelvic floor dysfunction; long‐term benefits are less clear.

Non‐obstetric factors such as age, obesity and family history are independent factors that confer significant risk of pelvic floor dysfunction.

Further research, perhaps using pelvic floor imaging, may improve our understanding of the nature of the injuries.

Learning objectives:

To review the literature on obstetric risk factors for pelvic floor dysfunction.

To be able to counsel women on the place of caesarean section in protecting the pelvic floor.

Ethical issues:

Insufficient information is available for counselling on the impact of obstetric events on pelvic floor symptoms when women have completed their reproductive life.

Please cite this article as: Dolan L. An update on damage to the pelvic floor in childbirth. The Obstetrician & Gynaecologist 2009;11:157–162.
@ TOG
Authors: Barnfield Sonia , Edey Katharine , Keay Stephen
Published: July 2009

In this issue we look at websites related to obstetric emergency courses. Attendance at courses is necessary for all trainees; it is also a CNST requirement that all maternity professionals participate in obstetric emergency training annually.
Pore-Scale Simulation of WAG Floods in Mixed-Wet Micromodels
Authors: van Dijke M.I.J.. I.J. , Lorentzen M.. , Sohrabi M.. , Sorbie K.S.. S.
Published: July 2009

In this paper, the simulation is described of Water-Alternating-Gas injection (WAG) flood cycles in 2D etched glass mixed-wet micromodels, using a 3D pore-scale network model for three-phase immiscible flow in porous media of arbitrary wettability. Although most network model input parameters can be explicitly derived from the experiments, the precise wettability parameters are not directly available. Therefore, a sensitivity study was conducted, using the network model in 2D mode, to obtain the wettability characteristics (i.e., the contact angle values and distribution) and the fraction of water-wet pores. Good qualitative and quantitative agreement was found between the experimental and simulated recoveries over the various WAG cycles, and the final residuals were well reproduced (as well as some observed "random recovery jumps"). The simulated displacement statistics showed many so-called multiple-displacement chains involving oil, up to approximately the third WAG cycle. The experimental and simulated fluid distributions were generally in good agreement in that: (a) different gas fingers were observed during various gasfloods, (b) oil movement was observed mainly during the first WAG cycles, and (c) during waterfloods, significant amounts of gas were displaced. Additionally, previously described simulations of water-wet and oil-wet experiments are compared with the present mixed-wet simulations. There are close similarities between the mixed-wet and oil-wet cases, which both maintain some continuity of oil through wetting films, but these cases are quite different from the water-wet case, which has continuity of water through wetting films in all pores. This paper further validates the pore-scale mechanisms incorporated in a network model capable of predicting three-phase relative permeabilities and capillary pressures for complicated processes, such as WAG.
High Stability of Recombinant Proteins Expressed in Tobacco Chloroplasts
Authors: Molina Andrea , Veramendi Jon
Published: July 2009

The green fluorescent protein and the non-toxic subunit of cholera toxin were expressed in tobacco chloroplasts.
Both recombinant proteins accumulated to levels greater than 20% of the total soluble protein. We did not observe
light-dependent induction of gene expression despite employing the promoter and 5´-UTR from the psbA gene. Both proteins
were stable in young and old leaves. The estimated half-life, determined by pulse-chase labeling, was greater than 48
h. Freeze-drying of pulverized leaves supplied an easy method of post-harvest handling with no significant loss of the recombinant
protein after 7 months of storage at room temperature. These data suggest that both proteins are good candidates
for the expression of fusion proteins (e.g. with antigens) in tobacco chloroplasts.
Temporal Variation in the Availability of Mediterranean Food Resources: Do Badgers Meles meles Track Them?
Authors: Loureiro Filipa , Bissonette John A. , Macdonald David W. , Santos‐Reis Margarida
Published: July 2009

The Mediterranean landscape of Serra de Grândola, Portugal, is one of many habitats inhabited by Eurasian badgers Meles meles, and in this area, the onset of food availability is seasonally predictable, but abundance is often temporally unpredictable and ephemeral. In our study, we investigated the responses of badgers to the temporal pattern of resource availability. We predicted that they would respond both to the seasonal timing of resource availability and to occasional pulses when food items are superabundant. We hypothesised that badgers' diet would reflect the seasonal onset of specific food resources, closely tracking food abundance, and that this tracking would reflect a relationship between the energetic value and water content of each resource and badger requirements at the time. To evaluate our predictions, we assessed the availability of the primary foods of badgers in Serra de Grândola (i.e. insects and fruits) over four years, and we analysed 120 faecal samples over one year to test for any congruence that might suggest tracking. Fruits and insects showed temporal fluctuations in peaks of availability that occurred on an annual basis, suggesting a temporal pulsing dynamic. Comparison of diet results with phenology and availability of food resources showed a high degree of overlap for practically all main items consumed. Moreover, the consumption of Coleoptera, olives Olea europaea and pears Pyrus bourgaeana appeared to be associated, but only partially, with their availability (rColeoptera = 0.21, P = 0.50; rolives = 0.36, P = 0.24; rpears = 0.20, P = 0.54); whilst acorns Quercus suber were closely tracked (racorns = 0.70, P = 0.01). Orthoptera were the only exception, with a negative relation between consumption and availability (rOthoptera = ‐0.31, P = 0.32). This tracking by badgers of primary resources with temporally differing peaks of availability and abundance appeared to involve trade‐offs with energy and water requirements. Acorns peaked simultaneously with olives which, although not as abundant, had a higher fat content. Other minor fruits (e.g. loquats Eriobotrya japonica and figs Ficus carica) also seemed to be tracked; they were important resources for badgers during summer when air temperatures were high. These results have implications for understanding badger ecology in areas with temporally unpredictable resources.
Role of Booster Dose on Antibody Titer after Recombinant Hepatitis B Vaccination
Authors: Ahad Md Abdul , Alim Md Abdul , Guho Abhijit , Islam Quazi Tarikul , Azad Khan Abul Kalam
Published: July 2009

Hepatitis B virus infection is an important public health problem with significant morbidity and mortality. Recombinant hepatitis B vaccination for the prevention of hepatitis B virus infection is in practice in different parts of the world since its availability in 1986. Government of Bangladesh has also included hepatitis B vaccine in EPI schedule since 2005. This study was carried out to assess the seroconversion status among hepatitis B vaccinated individuals. A total of 190 individuals including 150 vaccinated persons and 40 non-vaccinated apparently healthy individuals were included as study population. Sources of vaccinated persons were from both EPI and non-EPI schedule of vaccination. Age and sex matched non-vaccinated individuals served as controls for the study. All individuals constituting the study population were screened for HBsAg by Immunochromatographic strip test and only HBsAg-negative persons were included for estimation of their anti-HBs titer. Out of 150 vaccinated individuals, 133(88.67%) were found to have anti-HBs titer in the protective level (e"10 IU/L), while 17(11.33%) individuals had anti-HBs titer below the protective level (<10 IU/L). All non-vaccinated controls had anti- HBs titers below the protective level. Immune response developed among vaccinated individuals, 67.78%, 23.33% and 8.89% were good-responders, hypo-responders and non-responders respectively. Mean titer of anti-HBs was found significantly higher among recipients who received booster dose than those who received 3 doses schedule (863.39 IU/L vs. 262.40 IU/L), indicating high antibody titer develops after booster dose. Vaccinated group included 85 (56.67%) men and 65 (43.33%) women with protective level of anti-HBs titer found in 85.88% male and 92.31% female individuals.   doi: 10.3329/jom.v10i2.2817 J MEDICINE 2009; 10 : 67-76
A 25 Years Old Male with Primary Duodenal Lymphoma
Authors: Kabir Ahmedul , Chowdhury Faizul Islam , Banik Jayanta , Mitu Umme Kulsum
Published: July 2009

Primary duodenal lymphoma is very atypical, although the gastrointestinal (GI) tract is the most prominent site of extra nodal lymphoma. Here we present a case of 25 years old male, presented with upper abdominal pain and vomiting and eventually diagnosed as a case of duodenal non Hodgkin's lymphoma. The particular interest in this report is the fact that, it is important to have a high index of suspicion to diagnose primary intestinal lymphoma as it has high mortality which requires early diagnosis and treatment.    doi: 10.3329/jom.v10i2.2829   J MEDICINE 2009; 10 : 124-127
Renal Tuberculosis in a Middle Aged Woman Presenting with Asymptomatic Microscopic Haematuria and Erythema Nodosum
Authors: Chowdhury Abdul Wadud , Alam Muhammad Rafiqul , Saha Amitav , Jamil Mohammad Mahbub
Published: July 2009

Erythema nodosum is a common association of tuberculosis (TB), especially in this part of the world. Urogenital TB, although less common than other form of tuberculosis, may be associated with erythema nodosum along with other urinary complaints. Here we present a case of an old lady who presented with erythema nodosum with painless haematuria (microscopic) which was later found to be of tuberculous aetiology. Urine analysis yielded no acid-fast bacilli but culture on special media showed growth of Mycobacterium tuberculosis. Though erythema nodosum is usually associated with primary TB, our case revealed it can be found in cases where pulmonary focus is not the primary origin. The patient responded well to anti-tubercular drugs and is doing well on follow-up. Keywords: Erythema nodosum, Renal Tuberculosis, Urogenital Tuberculosis.   doi: 10.3329/jom.v10i2.2831   J MEDICINE 2009; 10 : 132-134
Safety of Adjuvant Endocrine Therapies in Hormone Receptor–Positive Early Breast Cancertissues
Authors: Sehdev S. , Martin G. , Sideris L. , Lam W. , Brisson S.
Published: July 2009

Postmenopausal patients with hormone-sensitive early breast cancer are typically treated with adjuvant endocrine therapy, which significantly reduces the risk of recurrence. Because treatment is of a long duration, side effects from adjuvant therapy can be problematic. The aromatase inhibitors (AIs) are replacing tamoxifen as first-line treatment agents for early breast cancer. Here, we present the side-effect data associated with AIs in relation to bone, gynecologic, and cardiovascular health and to arthralgia and myalgia. Although AIs have been shown to decrease bone density, increase arthralgia, and affect vaginal health, these adverse events are usually manageable, and several strategies can be followed to improve quality of life in women on AI treatment. To optimize adherence to therapy. It is important that these issues are addressed so that women can benefit from treatment.
Measurement of properties and of the resistance to segregation in heavyweight, self-compacting barite concrete
Authors: Revuelta D. , Barona A. , Navarro D.
Published: July 2009

Heavyweight concrete is used for shielding in structures requiring protection against radiation. The addition of superplasticizers to mixes yields workable, high density materials with low water/cement ratios. This paper discusses the results of adding a polycarboxylate-based superplasticizer to heavyweight barite concrete to obtain a self-compacting mix. The fresh properties were characterized with trials suitable for self-compacting concrete. Since the large differences in constituent densities make segregation a key issue in this type of concrete, a specific trial was designed to check for homogeneity. The flowability, passing ability and resistance to segregation findings showed that the product obtained was a self-compacting concrete.
La integración de los inmigrantes de “segunda generación” en Almería. Un caso de pluralismo fragmentado
Authors: Checa Juan Carlos , Arjona Ángeles
Published: July 2009

El objetivo de este artículo es conocer el proceso de integración de los inmigrantes de “segunda generación” en la provincia de Almería (España). Para ello vamos a analizar la adaptación que están experimentando los jóvenes en las siguientes dimensiones: socioeconómica, relaciones mixtas, referentes culturales, normas y transnacionalidad. Los datos se obtienen a partir de la administración de un cuestionario en diferentes centros educativos y en el ámbito residencial; la muestra final está formada por un total de 390 encuestas. Los resultados muestran que no todos los inmigrantes de segunda generación tienen la misma adaptación; se plantean, por el contrario, situaciones dispares, lo que dibuja un escenario de pluralismo fragmentado. El origen, los años de estancia, el nivel de estudios, la profesión y el hábitat son las variables que predicen fundamentalmente este proceso.
Skulking around the dinosaur: Eliciting cues to children's deception via strategic disclosure of evidence
Authors: Clemens Franziska , Granhag Pär Anders , Strömwall Leif A. , Vrij Aldert , Landström Sara , Hjelmsäter Emma Roos af , Hartwig Maria
Published: July 2009

Research has shown that cues to deception are more salient as an effect of strategic use of evidence (SUE) during interviews. This study examined the feasibility of the SUE‐technique for eliciting cues to children's deception. Experiment 1 investigated verbal cues to deception as a function of early vs. late disclosure of evidence. Eighty‐four children (12–14 years) either guilty or innocent of a mock crime were interviewed. As predicted, deceptive statements were significantly more inconsistent with the evidence than truthful statements, and this was more pronounced as a function of late compared to early disclosure of evidence. In Experiment 2, adult observers (N = 168) made veracity assessments of the videotaped statements. Observers in the late disclosure condition achieved an accuracy rate higher than chance (63.1%), whereas accuracy rates in the early disclosure condition were at chance level (56%). Accuracy rates were significantly higher for truthful (70.2%), than deceptive statements (48.8%). Copyright © 2009 John Wiley & Sons, Ltd.
Nanogap Electrodes
Authors: Li Tao , Hu Wenping , Zhu Daoben
Published: July 2009

Nanogap electrodes (namely, a pair of electrodes with a nanometer gap) are fundamental building blocks for the fabrication of nanometer‐sized devices and circuits. They are also important tools for the examination of material properties at the nanometer scale, even at the molecular scale. In this review, the techniques for the fabrication of nanogap electrodes, the preparation of assembled devices based on the nanogap electrodes, and the potential application of these nanodevices for analysis of material properties are introduced. The history, the research status, and the prospects of nanogap electrodes are also discussed.
Oxygen selective ceramic hollow fiber membranes for partial oxidation of methane
Authors: Wang Haihui , Feldhoff Armin , Caro Jürgen , Schiestel Thomas , Werth Steffen
Published: July 2009

A BaCoxFeyZrzO3−δ (BCFZ) perovskite hollow fiber membrane was used to construct reactors for the partial oxidation of methane (POM) to syngas. The performance of the BCFZ fibers in the POM was studied (i) without any catalyst, (ii) with catalyst‐coated fibers, and (iii) with catalyst packed around the fibers. In addition to the performance in the POM, the stability of the BCFZ hollow fiber membranes was investigated for the different catalyst arrangements. Best stability of the BCFZ hollow fiber membrane reactor in the POM could be obtained if the reforming catalyst is placed behind the oxygen permeation zone. It was found that a direct contact of the catalyst and the fiber must be avoided which could be achieved by coating the fiber with a gold film. © 2009 American Institute of Chemical Engineers AIChE J, 2009
Synthesis and characterization of some novel silicon esters and their application as lubricant base stock solution
Authors: Saxena Kanak , Bisaria C. S. , Saxena A. K.
Published: July 2009

A series of functional organosilanes and their esters were synthesized by the hydrosilylation reaction of SiH group‐bearing organosilicon derivatives with maleic anhydride using Speier's catalyst and their esterification with long‐chain alcohols in the presence of stannous oxide. These products have been characterized using elemental analysis, FT‐IR, 1H, 13C and 29Si NMR. Viscosity, density, pour point, flash point and tribological properties of these compounds have also been evaluated. These esters have a pour point of <−60 °C, a flash point of ∼200 °C (closed‐cup) and excellent load carrying capacity. Copyright © 2009 John Wiley & Sons, Ltd.
Effects of ultrasound in coating nano‐precipitated CaCO3 with stearic acid
Authors: Kow K. W. , Abdullah E. C. , Aziz A. R.
Published: July 2009

Nano‐Precipitated CaCO3 (NPCC) are coated with stearic acid to improve its dispersion in polymer as well as to reduce agglomeration. In this work, coating was done by wet method using ethanol. Ultrasonication was applied to NPCC to de‐agglomerate micron size NPCC into smaller size. Effects of amplitude, temperature and energy input of ultrasonication was investigated. The amplitude was varied from 60% to 100% whereas temperature was varied from 5°C to 45°C. The energy input was stressed up from 3.6 kJ to 180 kJ. Mean diameter of NPCC were observed by using Particle Size Analyzer and Transmission Electron Microscopy (TEM). It was found that mean diameter of NPCC do not vary significantly with temperature. Mean diameter of NPCC, however, decreases exponentially with the energy input. Comparisons were done on NPCC coated with others methods such as dry ball milling and aqueous coating. TEM images show that coating NPCC with ultrasonication is more uniform than other methods. In addition, first derivative mass loss with temperature (DTG) reveals that NPCC coated with ultrasonication do not contain excessive free acid as exhibited by those coated in aqueous and dry ball milling. Copyright © 2009 Curtin University of Technology and John Wiley & Sons, Ltd.
Die erweiterte klassische Erddrucktheorie, auch unter Berücksichtigung verschiedener Erdschichten
Authors: Lohmiller Hermann
Published: July 2009

In [1] wurde eine Methode für die gleichzeitige Berücksichtigung von innerem Reibungswinkel und Kohäsion bei der Ermittlung des aktiven Erddrucks gezeigt. Diese um die Kohäsion erweiterte klassische Erddrucktheorie (EKET) umfasst auch eine unebene Geländeoberfläche mit Linienlasten sowie unstetige Oberflächen‐ und tieferliegenden Fundamentlasten. In der hier vorgestellten Arbeit wird die Berechnung aus [1] auf mehrschichtiges Erdreich ausgedehnt. Außerdem werden in Abhängigkeit von der Tiefe z neben Eah(z) auch deren Verteilung, das heißt, die spezifischen aktiven Erddrücke eah(z) selbst für den allgemeinsten Fall berechnet und dargestellt, ebenfalls die zugehörigen Gleitlinien. Wegen der langwierigen Berechnung nach den komplexen Formeln wurde dazu vom Autor ein Programm mit dem Namen “Erddruck‐1” entwickelt. Damit werden die ausgewählten Beispiele in diesem Beitrag berechnet und zeichnerisch dargestellt.

The extended classic theory of earth pressure, taking into consideration different earth layers.

The paper [1] has included a description of a method of simultaneously taking into consideration the inner friction angle and cohesion, when active earth pressure is determined. The classic earth pressure theory, which has been extended to include cohesion (EKET), also takes into consideration an uneven ground surface, including line loads, and unsteady surface and deeper foundation loads. The article in hand extends the above publication to take account of multilayered soil. Furthermore, depending on the depth z, besides Eah(z) the specific active earth pressures eah(z) are calculated and distributed even for the most general case, including slide lines pertaining to them. A program has been worked out by the author named “Erddruck‐1” for this purpose because of lengthy calculations based on complex formulas, which is designed to calculate selected examples and print out drawings pertaining to them.
Multi‐Input/Multi‐Output Molecular Response System Based on the Dynamic Redox Behavior of 3,3,4,4‐Tetraaryldihydro[5]helicene Derivatives: Reversible Formation/Destruction of Chiral Fluorophore and Modulation of Chiroptical Properties by Solvent Polarity
Authors: Suzuki Takanori , Ishigaki Yusuke , Iwai Tomohiro , Kawai Hidetoshi , Fujiwara Kenshu , Ikeda Hiroshi , Kano Yusuke , Mizuno Kazuhiko
Published: July 2009

3,3,4,4‐Tetaaryldihydro[5]helicenes (1) and 1,1′‐binaphthyl‐2,2′‐diylbis(diarylcarbenium)s (22+) can be reversibly interconverted upon electron transfer, which is accompanied by a vivid color change (electrochromism) as well as by the formation/cleavage of a CC bond (“dynamic redox behavior”). Because only the neutral donor 1 exhibits strong fluorescence, electrochemical input can further modify the fluorescent properties of the pair. Due to the configurational stability of the helicity in 1 and axial chirality in 22+, the redox reaction of optically pure material proceeds stereospecifically, which induces a chiroptical change such as circular dichroism (CD) as an additional output. The CD spectra of dications 22+ exhibit solvent dependency (chiro‐solvatochromism), which is accompanied by solvatochromic behavior based on the π–π interaction of the two cationic chromophores as well as coordinative interaction of the Lewis basic solvent to the Lewis acidic triarylcarbenium moieties. Thus, the present system is endowed with multi‐input functionality for modifying multiple output signals.
Systematic Extraction of Structure–Activity Relationship Information from Biological Screening Data
Authors: Wawer Mathias , Bajorath Jürgen
Published: July 2009

A data mining approach is introduced that automatically extracts SAR information from high‐throughput screening data sets and that helps to select active compounds for chemical exploration and hit‐to‐lead projects. SAR pathways are systematically identified consisting of sequences of similar active compounds with gradual increases in potency. Fully enumerated SAR pathway sets are subjected to pathway scoring, filtering, and mining, and pathways with the most significant SAR information content are prioritized. High‐scoring SAR pathways often reveal activity cliffs contained in screening data. Subsets of SAR pathways are analyzed in SAR trees that make it possible to identify microenvironments of significant SAR discontinuity from which hits are preferentially selected. SAR trees of alternative pathways leading to activity cliffs identify key compounds and help to develop chemically intuitive SAR hypotheses.
Watson's analytical approach for immunofluorescence histogram analysis
Authors: Lampariello Francesco
Published: July 2009

In this short note, the key points of the histogram analysis method proposed by Watson (Cytometry 2001;43:55–68) were examined. The complete relationship among the mean values of the distributions on which that method is based was derived analytically. It was shown that the symmetry assumption is not necessary, and that the assumption of equal variances of the unlabeled and labeled cell distributions cannot be verified a posteriori. Moreover, a possible shift between the unlabeled cell distribution in the test and the negative control may greatly influence the estimation of the labeled cell percentage. Finally, by using an experimental set of histograms, it was shown that the assumptions underlying Watson's analytical method are likely not to be fulfilled in real immunofluorescence data. © 2009 International Society for Advancement of Cytometry
Coxsackievirus B4 and type 1 diabetes pathogenesis: contribution of animal models
Authors: Jaïdane H. , Sané F. , Gharbi J. , Aouni M. , Romond M. B. , Hober D.
Published: July 2009

The role of enteroviruses, in particular type B coxsackieviruses (CV‐B), in type 1 diabetes (T1D) pathogenesis is supported by epidemiological, clinical and experimental observations.

The investigation of T1D pathogenesis benefits from the contribution of animal models called spontaneously diabetic. Among these animals the non‐obese diabetic (NOD) mouse and the bio‐breeding diabetes‐prone (BBDP) rat present a genetic susceptibility manifested by the expression of an autoimmune diabetes similar to the pathology observed in human beings. Other models whose genetic predisposition is less known are of considerable contribution as well. Numerous major observations relative to several aspects of T1D pathogenesis in the context of CV‐B infections, such as susceptibility, diabetogenicity, pancreatotropism, mechanisms of β cells destruction and others, have been deduced thanks to investigations with animal models.

Despite their limits, these models are necessary in improving our knowledge of the role of enteroviruses, like CV‐B4, in the pathogenesis of T1D, and the recent advances ensuing from their contribution may have important therapeutic and preventive spin‐offs. Copyright © 2009 John Wiley & Sons, Ltd.
Acetyl‐CoA carboxylases 1 and 2 show distinct expression patterns in rats and humans and alterations in obesity and diabetes
Authors: Kreuz Sebastian , Schoelch Corinna , Thomas Leo , Rist Wolfgang , Rippmann Jörg F. , Neubauer Heike
Published: July 2009

Background

Acetyl‐CoA carboxylases (ACC) 1 and 2 are central enzymes in lipid metabolism. To further investigate their relevance for the development of obesity and type 2 diabetes, expression of both ACC isoforms was analyzed in obese fa/fa Zucker fatty and Zucker diabetic fatty rats at different ages in comparison to Zucker lean controls.

Methods

ACC1 and ACC2 transcript levels were measured by quantitative real‐time polymerase chain reaction in metabolically relevant tissues of Zucker fatty, Zucker diabetic fatty and Zucker lean control animals. Quantitative real‐time polymerase chain reaction was also applied to measure ACC tissue distribution in human tissues. For confirmation on a protein level, quantitative mass spectrometry was used.

Results

Disease‐related transcriptional changes of both ACC isoforms were observed in various tissues of Zucker fatty and Zucker diabetic fatty rats including liver, pancreas and muscle. Changes were most prominent in oxidative tissues of diabetic rats, where ACC2 was significantly increased and ACC1 was reduced compared with Zucker lean control animals. A comparison of the overall tissue distribution of both ACC isoforms in humans and rats surprisingly revealed strong differences. While in rats ACC1 was mainly expressed in lipogenic and ACC2 in oxidative tissues, ACC2 was predominant in oxidative and lipogenic tissues in humans.

Conclusion

Our data support a potential role for both ACC isoforms in the development of obesity and diabetes in rats. However, the finding of fundamental species differences in ACC1 and ACC2 tissue expression might be indicative for different functions of both isoforms in humans and rats and raises the question to which degree these models are predictive for the physiology and pathophysiology of lipid metabolism in humans. Copyright © 2009 John Wiley & Sons, Ltd.
Tuning Electronic Properties of Biomimetic [2Fe‐2S] Clusters by Ligand Variations (Eur. J. Inorg. Chem. 22/2009)
Authors: Ballmann Joachim , Dechert Sebastian , Demeshko Serhiy , Meyer Franc
Published: July 2009

The cover picture shows the molecular structures of three novel 2,2′‐dithiobiphenyl‐ligated [2Fe‐2S] clusters together with some of their characteristic spectroscopic data. Specifically tailored capping ligands with different substituents in the 3,3′,5,5″positions (tBu, H, Cl) have been applied in order to examine the influence of the ligands on the electronic structures of the [2Fe‐2S] cluster cores. The article by F. Meyer et al. on p. 3219 ff demonstrates that the ligand modifications impose significant changes to the fundamental properties of the clusters, e.g. to their redox potentials. Electrochemical and spectroscopic data in solution and in the solid state (including X‐ray structures) are discussed in detail in this contribution.
Confirmation of immuno‐reactivity of the recombinant major birch pollen allergen Bet v 1a by affinity‐CIEF
Authors: Dullnig Verena , Weiss Richard , Amon Sabine , Rizzi Andreas , Stutz Hanno
Published: July 2009

Affinity‐CIEF has been applied to characterize a recombinant product of the major birch pollen allergen Betula verrucosa isoform 1a (Bet v 1a) immuno‐chemically. For this purpose mAbs of the IgG‐type have been produced in‐lab from two murine hybridoma lines, specified as clones 2 and 5.1. Both IgG clones were characterized by SDS‐PAGE, MALDI‐TOF‐MS and CIEF. The purified IgG solutions had to be dialysed against 10 mmol/L phosphate (pH 7.4) to prevent IgG precipitation and to ensure appropriate CIEF separation. Both tested monoclonal IgGs (mIgGs) comprised four constituents covering pI ranges of 6.98–7.09 and 6.78–7.03 for clones 2 and 5.1 with major peaks at pI 7.09 and 7.03, respectively. When increasing amounts of Bet v 1a (pI 4.95) were incubated with 2.0 μmol/L mIgG, novel peaks were progressively induced in a pI range slightly more acidic than the focusing region of mIgGs. These peaks grew on the expense of original mIgG peaks. All pI values were calculated using two pI marker compounds with a repeatability of better than 0.03 units. New peaks represent complexes between Bet v 1a and mIgG either of 1:1 or of 2:1 binding stoichiometry. At a molar ratio of 2:1, saturation of both IgG paratopes with allergen (Ag) molecules was achieved as indicated by unbound Bet v 1a. The current CIEF approach addresses the proof of single epitope integrity in the course of immuno‐chemical characterization of Bet v 1a. Contrary to traditional immunoassays, affinity CIEF allows for a distinction and relative quantification of mAbs, Ag–antibody complexes and Ag variants coexisting in one sample.
Protein nitration during defense response in Arabidopsis thaliana
Authors: Cecconi Daniela , Orzetti Stefano , Vandelle Elodie , Rinalducci Sara , Zolla Lello , Delledonne Massimo
Published: July 2009

Nitric oxide and reactive oxygen species play a key role in the plant hypersensitive disease resistance response, and protein tyrosine nitration is emerging as an important mechanism of their co‐operative interaction. Up to now, the proteins targeted by this post‐translational modification in plants are still totally unknown. In this study, we analyzed for the first time proteins undergoing nitration during the hypersensitive response by analyzing via 1D‐ and 2D‐western blot the protein extracts from Arabidopsis thaliana plants challenged with an avirulent bacterial pathogen (Pseudomonas syringae pv. Tomato). We show that the plant disease resistance response is correlated with a modulation of nitration of proteins involved in important cellular process, such as photosynthesis, glycolysis and nitrate assimilation. These findings shed new light on the signaling functions of nitric oxide and reactive oxygen species, paving the way on studies on the role of this post‐translational modification in plants.
Determination of liposome–buffer distribution coefficients of charged drugs by capillary electrophoresis frontal analysis
Authors: Franzen Ulrik , Jorgensen Lene , Larsen Claus , Heegaard Niels H. H. , Østergaard Jesper
Published: July 2009

The potential of using CE frontal analysis (CE‐FA) to study the interactions between a range of charged low molecular weight drug substances and liposomes was evaluated. The liposomes used were net negatively charged and consisted of 2‐oleoyl‐1‐palmitoyl‐sn‐glycero‐3‐phosphocholine and 1,2‐dipalmitoyl‐sn‐glycero‐3‐phosphate monosodium salt in a ratio of 80/20 mol%. Apparent distribution coefficients (Dmem), defined as the molar concentration of drug substance in the membrane phase divided by the molar concentration of drug substance in the aqueous phase, were successfully determined for six positively and eight negatively charged drug substances with log Dmem ranging from 1.35 to 3.63. The extent of liposome–buffer distribution was found to be dependent on the drug concentration. The results obtained with the developed CE‐FA method were in good agreement with results obtained by equilibrium dialysis. Furthermore, the CE‐FA method was faster, less labor intensive and required smaller sample volumes (∼50 μL) compared with equilibrium dialysis. Thus, CE‐FA is an efficient and useful tool for the characterization of interactions between liposomes and low molecular weight drug substances.
Extracting long‐term patterns of population changes from sporadic counts of migrant birds
Authors: Flemming Joanna Mills , Cantoni Eva , Field Christopher , McLaren Ian
Published: July 2009

Declines of many North American birds are of conservation concern. For almost 40 years, experienced birders have kept daily counts of migrant landbirds during visits to Seal and Brier Islands, both of which are off Nova Scotia's southern tip. Here we assess the utility of Generalized Additive Models (GAMs) to extract patterns of population change of a common migrant to Seal Island, the Ruby‐crowned Kinglet, while controlling for other influences including season, weather and effort. We also demonstrate, using counts of the Kinglet from Brier Island as well as counts of another common migrant, the Yellow‐rumped Warbler, how our GAM methods can combine data from different geographic areas or distinct species. Most existing analyses of similar long‐term data sets have used linear models to estimate trends. Our results and comparisons suggest that GAMs are a powerful way of extracting more information from such data. Copyright © 2009 John Wiley & Sons, Ltd.
Hybrid testing and modeling of a suspended zipper steel frame
Authors: Stavridis Andreas , Shing P. B.
Published: July 2009

An analytical and experimental study has been conducted to evaluate the seismic performance of a three‐story suspended zipper steel frame. The frame was concentrically braced and had zipper struts to transfer the unbalanced forces induced on the beams due to the buckling of the lower‐story braces. The experimental study was conducted with the hybrid test technique, in which only the bottom‐story braces of the three‐story frame were physically tested, while the behavior of the rest of the frame was modeled using a general structural analysis software. The paper discusses issues pertinent to the calibration of the computer model for the analytical substructure as well as for the entire frame, including the selection of an appropriate damping matrix, and the modeling of the buckling behavior of the braces and bracing connections. The analytical model of the entire frame was validated with the hybrid tests and was able to accurately capture the material and geometric nonlinearities that developed when the braces yielded and buckled. This study has demonstrated the usefulness of hybrid testing in improving analytical models and modeling assumptions and providing information that cannot be obtained from an analytical study alone. The results have shown that the suspended zipper frame can distribute the brace nonlinearity over the first two stories as intended in the design and will not have catastrophic failure under the design‐level earthquakes considered in this study, despite the significant inelastic deformations. Copyright © 2009 John Wiley & Sons, Ltd.
Calpain activation by hepatitis C virus proteins inhibits the extrinsic apoptotic signaling pathway #
Authors: Simonin Yannick , Disson Olivier , Lerat Hervé , Antoine Etienne , Binamé Fabien , Rosenberg Arielle R. , Desagher Solange , Lassus Patrice , Bioulac-Sage Paulette , Hibner Urszula
Published: July 2009

An unresolved question regarding the physiopathology of hepatitis C virus (HCV) infection is the remarkable efficiency with which host defenses are neutralized to establish chronic infection. Modulation of an apoptotic response is one strategy used by viruses to escape immune surveillance. We previously showed that HCV proteins down-regulate expression of BH3-only Bcl2 interacting domain (Bid) in hepatocytes of HCV transgenic mice. As a consequence, cells acquire resistance to Fas-mediated apoptosis, which in turn leads to increased persistence of experimental viral infections in vivo. This mechanism might participate in the establishment of chronic infections and the resulting pathologies, including hepatocellular carcinoma. We now report that Bid is also down-regulated in patients in the context of noncirrhotic HCV-linked tumorigenesis and in the HCV RNA replicon system. We show that the nonstructural HCV viral protein NS5A is sufficient to activate a calpain cysteine protease, leading to degradation of Bid. Moreover, pharmacological inhibitors of calpains restore both the physiological levels of Bid and the sensitivity of cells toward a death receptor–mediated apoptotic signal. Finally, human HCV-related tumors and hepatocytes from HCV transgenic mice that display low Bid expression contain activated calpains. Conclusion: Calpains activated by HCV proteins degrade Bid and thus dampen apoptotic signaling. These results suggest that inhibiting calpains could lead to an improved efficiency of immune-mediated elimination of HCV-infected cells. (Hepatology 2009.)
Modulation of glycosphingolipid metabolism significantly improves hepatic insulin sensitivity and reverses hepatic steatosis in mice #
Authors: Bijl Nora , Sokolović Milka , Vrins Carlos , Langeveld Mirjam , Moerland Perry D. , Ottenhoff Roelof , van Roomen Cindy P. A. A. , Claessen Nike , Boot Rolf G. , Aten Jan , Groen Albert K. , Aerts Johannes M. F. G. , van Eijk Marco
Published: July 2009

Nonalcoholic fatty liver disease (NAFLD) is associated with obesity, insulin resistance, and type 2 diabetes. The hyperinsulinemia that occurs as a consequence of insulin resistance is thought to be an important contributor to the development of fatty liver. We have shown that the iminosugar N-(5′-adamantane-1′-yl-methoxy)-pentyl-1-deoxynojirimycin (AMP-DNM), an inhibitor of the enzyme glucosylceramide synthase, is a potent enhancer of insulin signaling in rodent models for insulin resistance and type 2 diabetes. The present study was designed to assess the impact of AMP-DNM on insulin levels, liver triglyceride synthesis, and gene expression profile. Treatment of ob/ob mice with AMP-DNM restored insulin signaling in the liver, corrected blood glucose values to levels found in lean mice, and decreased insulin concentration. The expression of sterol regulatory element-binding protein 1c target genes involved in fatty acid synthesis normalized. AMP-DNM treatment significantly reduced liver to body weight ratio and reversed hepatic steatosis, comprising fat as well as inflammatory markers. In addition, AMP-DNM treatment corrected to a large extent the gene expression profile of ob/ob mice livers toward the profile of lean mice. Conclusion: Pharmacological lowering of glycosphingolipids with the iminosugar AMP-DNM is a promising approach to restore insulin signaling and improve glucose homeostasis as well as hepatic steatosis. (Hepatology 2009.)
Farnesyltransferase inhibitors reduce ras activation and ameliorate acetaminophen-induced liver injury in mice #
Authors: Saha Banishree , Nandi Dipankar
Published: July 2009

Hepatotoxicity due to overdose of the analgesic and antipyretic acetaminophen (APAP) is a major cause of liver failure in adults. To better understand the contributions of different signaling pathways, the expression and role of Ras activation was evaluated after oral dosing of mice with APAP (400–500 mg/kg). Ras–guanosine triphosphate (GTP) is induced early and in an oxidative stress-dependent manner. The functional role of Ras activation was studied by a single intraperitoneal injection of the neutral sphingomyelinase and farnesyltransferase inhibitor (FTI) manumycin A (1 mg/kg), which lowers induction of Ras-GTP and serum amounts of alanine aminotransferase (ALT). APAP dosing decreases hepatic glutathione amounts, which are not affected by manumycin A treatment. However, APAP-induced activation of c-Jun N-terminal kinase, which plays an important role, is reduced by manumycin A. Also, APAP-induced mitochondrial reactive oxygen species are reduced by manumycin A at a later time point during liver injury. Importantly, the induction of genes involved in the inflammatory response (including iNos, gp91phox, and Fasl) and serum amounts of proinflammatory cytokines interferon-γ (IFNγ) and tumor necrosis factor α, which increase greatly with APAP challenge, are suppressed with manumycin A. The FTI activity of manumycin A is most likely involved in reducing APAP-induced liver injury, because a specific neutral sphingomyelinase inhibitor, GW4869 (1 mg/kg), did not show any hepatoprotective effect. Notably, a structurally distinct FTI, gliotoxin (1 mg/kg), also inhibits Ras activation and reduces serum amounts of ALT and IFN-γ after APAP dosing. Finally, histological analysis confirmed the hepatoprotective effect of manumycin A and gliotoxin during APAP-induced liver damage. Conclusion: This study identifies a key role for Ras activation and demonstrates the therapeutic efficacy of FTIs during APAP-induced liver injury. (Hepatology 2009.)
Long-term exclusive zinc monotherapy in symptomatic Wilson disease: Experience in 17 patients #
Authors: Linn Francisca H. H. , Houwen Roderick H. J. , van Hattum Jan , van der Kleij Stefan , van Erpecum Karel J.
Published: July 2009

Exclusive monotherapy with zinc in symptomatic Wilson disease is controversial. Seventeen symptomatic patients with Wilson disease were treated with zinc only. The mean age at diagnosis and start of treatment was 18 years (range 13–26) with approximately half presenting as adolescents. Presentation was exclusively hepatic, exclusively neurologic, and combined in seven, five, and five patients, respectively. The median follow-up was 14 years (range 2–30). At baseline, two of the 12 patients with hepatic disease exhibited decompensated cirrhosis, five exhibited compensated cirrhosis, and five had less severe disease. Both patients with decompensated cirrhosis improved to a compensated state after initiation of therapy. Two of the five patients with initial compensated cirrhosis progressed to decompensated state, and three remain stable. Three of the five patients with moderate or mild liver disease remain stable and two improved. Apart from decreasing bilirubin levels, no significant changes occurred in the liver biochemistry or function during long-term follow-up. Nine of 10 neurologic patients improved markedly and one deteriorated. Two patients with exclusively neurologic presentation developed liver disease during zinc treatment. Two patients with exclusively hepatic presentation developed mild neurologic symptoms. According to 24-hour urinary copper excretions (213 ± 38 versus 91 ± 23 μg: P = 0.01) and serum non–ceruloplasmin-bound copper concentrations (11 ± 2 versus 7 ± 1 μg/dL: P = 0.1) at the end of follow-up, the efficacy of decoppering was less in the exclusively hepatic than in the neurologic group. The prescribed zinc dose and 24-hour urinary zinc excretions tended to be less in the exclusively hepatic group. Conclusion: The outcome of exclusive zinc therapy is generally good in cases of neurologic disease. A less satisfactory outcome in hepatic disease may relate to less efficient decoppering. (Hepatology 2009.)
Development of a scalable process for high‐yield lentiviral vector production by transient transfection of HEK293 suspension cultures
Authors: Ansorge Sven , Lanthier Stéphane , Transfiguracion Julia , Durocher Yves , Henry Olivier , Kamen Amine
Published: July 2009

Background

Lentiviral vectors (LV) offer several advantages over other gene delivery vectors. Their potential for the integration and long‐term expression of therapeutic genes renders them an interesting tool for gene and cell therapy interventions. However, large‐scale LV production remains an important challenge for the translation of LV‐based therapeutic strategies to the clinic. The development of robust processes for mass production of LV is needed.

Methods

A suspension‐grown HEK293 cell line was exploited for the production of green fluorescent protein‐expressing LV by transient polyethylenimine (PEI)‐based transfection with LV‐encoding plasmid constructs. Using third‐generation packaging plasmids (Gag/Pol, Rev), a vesicular stomatitis virus G envelope and a self‐inactivating transfer vector, we employed strategies to increase volumetric and specific productivity. Functional LV titers were determined using a flow cytometry‐based gene transfer assay.

Results

A combination of the most promising conditions (increase in cell density, medium selection, reduction of PEI–DNA complexes per cell, addition of sodium butyrate) resulted in significantly increased LV titers of more than 150‐fold compared to non‐optimized small‐scale conditions, reaching infectious titers of approximately 108 transducing units/ml. These conditions are readily scalable and were validated in 3‐liter scale perfusion cultures.

Conclusions

Our process produces LV in suspension cultures and is consequently easily scalable, industrially viable and generated more than 1011 total functional LV particles in a single bioreactor run. This process will allow the production of LV by transient transfection in sufficiently large quantities for phase I clinical trials at the 10–20‐liter bioreactor scale. Copyright © 2009 John Wiley & Sons, Ltd.