bluuebunny/crossref_metadata_2025 huggingface dataset:
A flexible framework for optimal biorefinery product allocation
Authors: Sammons Norman , Eden Mario , Yuan Wei , Cullinan Harry , Aksoy Burak
Published: October 2007

The integrated biorefinery has the opportunity to provide a strong, self‐dependent, sustainable alternative for the production of bulk and fine chemicals, e.g., polymers, fiber composites and pharmaceuticals as well as energy, liquid fuels, and hydrogen. Although most of the fundamental processing steps involved in biorefining are well‐known, there is a need for a methodology capable of evaluating the integrated processes in order to identify the optimal set of products and the best route for producing them. The complexity of the product allocation problem for such processing facilities demands a process systems engineering approach utilizing process integration and mathematical optimization techniques to ensure a targeted approach and serve as an interface between simulation work and experimental efforts. The objective of this work is to assist the bioprocessing industries in evaluating the profitability of different possible production routes and product portfolios while maximizing stakeholder value through global optimization of the supply chain. To meet these ends, a mathematical optimization based framework is being developed, which enables the inclusion of profitability measures and other technoeconomic metrics along with process insights obtained from experimental as well as modeling and simulation studies. © 2007 American Institute of Chemical Engineers Environ Prog, 2007
Fuzzy‐based multiuser detector for impulsive CDMA channel
Authors: Hmidat Adel M. , Sharif Bayan S. , Woo Wai L. , Hassan Mohamed A. S.
Published: October 2007

A new fuzzy multiuser detector for non‐Gaussian synchronous direct sequence code division multiple access (DS‐CDMA) is proposed for jointly mitigating the effects of impulsive noise and multiple access interference (MAI). The proposed scheme combines a linear decorrelator and antenna array with a nonlinear preprocessor based on fuzzy logic and rank ordering. The fuzzy rule is incorporated to combat impulsive noise by eliminating outliers from the received signal. The performance of the proposed scheme is assessed by Monte Carlo simulations and the obtained results demonstrate that the proposed fuzzy detector outperforms other reported schemes in terms of bit error rate (BER) and channel capacity. Copyright © 2007 John Wiley & Sons, Ltd.
Neural correlates of orthographic and phonological consistency effects in children
Authors: Bolger Donald J. , Hornickel Jane , Cone Nadia E. , Burman Douglas D. , Booth James R.
Published: October 2007

The objective of this study was to examine the neural correlates of phonological inconsistency (relationship of spelling to sound) and orthographic inconsistency (relationship of sound to spelling) in visual word processing using functional magnetic resonance imaging (fMRI). Children (9‐ to 15‐year‐old) performed a rhyming and spelling task in which two words were presented sequentially in the visual modality. Consistent with previous studies in adults, higher phonological inconsistency was associated with greater activation in several regions including left inferior frontal gyrus and medial frontal gyrus/anterior cingulate cortex. We additionally demonstrated an effect of orthographic inconsistency in these same areas, suggesting that these regions are involved in the integration of orthographic and phonological information and, with respect to the medial frontal/anterior cingulate, greater demands on executive function. Higher phonological and orthographic consistency was associated with greater activation in precuneus/posterior cingulate cortex, the putative steady state system active during resting, suggesting lower demands on cognitive resources for consistent items. Both consistency effects were larger for the rhyming compared with the spelling task suggesting greater demands of integrating spelling and sound in the former task. Finally, accuracy on the rhyming task was negatively correlated with the consistency effect in left fusiform gyrus. In particular, this region showed insensitivity to consistency in low performers, sensitivity to inconsistency (higher activity) in moderate performers, and sensitivity to inconsistency (high activation) and to consistency (deactivation). In general, these results show that the influence of spelling–sound (and sound–spelling) correspondences on processing in fusiform gyrus develops as a function of skill. Hum Brain Mapp, 2008. © 2007 Wiley‐Liss, Inc.
Is early‐onset microsatellite and chromosomally stable colorectal cancer a hallmark of a genetic susceptibility syndrome?
Authors: Kets C.M. , van Krieken J.H.J.M. , van Erp P.E.J. , Feuth T. , Jacobs Y.H.A , Brunner H.G. , Ligtenberg M.J.L. , Hoogerbrugge N.
Published: October 2007

Most colorectal cancers show either microsatellite or chromosomal instability. A subset of colorectal cancers, especially those diagnosed at young age, is known to show neither of these forms of genetic instability and thus might have a distinct pathogenesis. Colorectal cancers diagnosed at young age are suggestive for hereditary predisposition. We investigate whether such early‐onset microsatellite and chromosomally stable colorectal cancers are a hallmark of a genetic susceptibility syndrome. The ploidy status of microsatellite stable (familial) colorectal cancers of patients diagnosed before age 50 (n = 127) was analyzed in relation to the histopathological characteristics and family history. As a control the ploidy status of sporadic colorectal cancer, with normal staining of mismatch repair proteins, diagnosed at the age of 69 years or above (n = 70) was determined. A diploid DNA content was used as a marker for chromosomal stability. Within the group of patients with (familial) early onset microsatellite stable colorectal cancer the chromosomally stable tumors did not differ from chromosomally unstable tumors with respect to mean age at diagnosis, fulfillment of Amsterdam criteria or pathological characteristics. Segregation analysis did not reveal any family with microsatellite and chromosomally stable colorectal cancer in 2 relatives. The prevalence of microsatellite and chromosomally stable colorectal cancer was not significantly different for the early and late onset group (28 and 21%, respectively). We find no evidence that early‐onset microsatellite and chromosomally stable colorectal cancer is a hallmark of a hereditary colorectal cancer syndrome. © 2007 Wiley‐Liss, Inc.
High serum levels of YKL‐40 in patients with squamous cell carcinoma of the head and neck are associated with short survival
Authors: Roslind Anne , Johansen Julia S. , Christensen Ib J. , Kiss Katalin , Balslev Eva , Nielsen Dorte L. , Bentzen Jens , Price Paul A. , Andersen Elo
Published: October 2007

YKL‐40 is a glycoprotein secreted by macrophages, neutrophils and malignant tumor cells. Elevated serum levels of YKL‐40 are associated with poor prognosis in several malignancies. In this study, we examined the prognostic value of serum YKL‐40 before treatment and during follow‐up in patients with squamous cell carcinoma of the head and neck (HNSCC). YKL‐40 was determined by ELISA retrospectively in serum from 173 patients with primary HNSCC before treatment and up to 2 years after treatment. Median follow‐up time was 7.9 years. YKL‐40 protein expression in tumor biopsies was assessed by immunohistochemistry in 50 patients. Pretreatment serum YKL‐40 was elevated in 53%. Patients with high serum YKL‐40 had shorter survival than patients with normal serum YKL‐40 (33 vs. 84 months; p = 0.008). Multivariate Cox analysis including pretreatment serum YKL‐40, age, sex, primary tumor site, TNM classification and treatment demonstrated that TNM classification (HR = 2.61, p = 0.02) and serum YKL‐40 (log‐transformed continuous variable: HR = 1.55, p < 0.0001) were independent prognostic variables of overall survival (OS). Multivariate Cox analysis demonstrated that TNM classification (HR = 5.77, p = 0.001) and serum YKL‐40 (dichotomous variable: HR = 2.75, p = 0.01) were independent predictors of recurrence‐free survival. During follow‐up after radiotherapy, a high serum YKL‐40 (log‐transformed continuous variable) in patients with TNM Stage III and IV disease predicted poorer OS within 6 months (HR = 1.95, p < 0.0001). Immunohistochemical analysis showed YKL‐40 expression in the malignant tumor cells. In conclusion, serum YKL‐40 was demonstrated to be an independent prognostic biomarker of recurrence‐free and overall survival in patients with HNSCC. © 2007 Wiley‐Liss, Inc.
Significance of the expression of major histocompatibility complex class II antigen, HLA‐DR and ‐DQ, with recurrence of papillary thyroid cancer
Authors: Jo Young Suk , Lee Jun Chul , Li Shengjin , Choi Yun‐Sun , Bai Youn‐Sun , Kim Yun‐Jeung , Lee Ihn‐Suk , Rha So Young , Ro Heung‐kyu , Kim Jin‐Man , Shong Minho
Published: October 2007

Normal thyroid epithelial cells lack major histocompatibility complex (MHC) Class II antigen. Oncogenic kinases involved in papillary thyroid carcinoma (PTC) trigger the expression of Class II transactivator and MHC Class II complex. However, the relationship between MHC Class II antigen expression and clinical outcome in PTC is unknown. To investigate the frequency of MHC Class II antigen expression in PTC and to identify the effects of MHC Class II antigen expression on clinical outcomes in PTC patients, the expression of HLA‐DR/‐DQ antigen was analyzed in surgical specimens from 77 PTCs and 44 benign nodules (23 nodular hyperplasias, 21 follicular adenomas). Of the 77 PTC cases, 36 (46.8%) cases expressed HLA‐DR and 41 (53.2%) cases expressed HLA‐DQ. Next, we investigated clinicopathological characteristics and found that HLA‐DR(+) and/or HLA‐DQ(+) PTC tended to present without nodal metastasis. Multivariate analyses clearly showed that HLA‐DR(+) or HLA‐DQ(+) PTC has a low risk of recurrence (HLA‐DR OR = 0.22, CI, 0.06–0.9; p = 0.03, HLA‐DQ OR = 0.25, CI, 0.07–0.9, p = 0.03). The Kaplan–Meier estimate revealed a significantly lower recurrence‐free probability in patients with HLA‐DR(−) PTC and HLA‐DQ(−) PTC (Log‐rank test; χ2 = 4.59 and 6.07, p = 0.03 and 0.01, respectively). In conclusion, PTC frequently expresses MHC Class II antigen, and the expression of MHC Class II antigen correlated inversely with the risk of recurrence of PTC. © 2007 Wiley‐Liss, Inc.
In vitro characterization of micropatterned PLGA‐PHBV8 blend films as temporary scaffolds for photoreceptor cells
Authors: Tezcaner A. , Hicks D.
Published: October 2007

In developed countries the aging population faces increasing risks of blinding retinal diseases, for which there are few effective treatments available. Photoreceptor transplantation represents one approach, but generally results have been disappointing. We hypothesize that micropatterned biodegradable poly(L‐lactic acid‐co‐glycolic acid)/poly(hydroxybutyrate‐co‐hydroxyvaleric acid) (PLGA‐PHBV8) blend films could deliver photoreceptor cells in a more organized manner than bolus injections. Blending of PLGA and PHBV8 was used to optimize the degradation rate of the temporary template. At the end of 8 weeks, for both thin and thick films of PLGA‐PHBV8 a 50% decrease of their initial weight with increasing water uptake was observed. When photoreceptor cells were seeded onto micropatterned PLGA‐PHBV8 films with parallel grooves (21‐ and 42‐μm‐wide grooves and 20 μm ridge width and depth), the cells preferred laminin‐deposited grooves to ridges and expressed rod‐ and cone‐specific markers such as rhodopsin and arrestin. A loss in photoreceptor viability of 50% was observed after 7 days in culture. The effects of either retinal pigment epithelium (RPE)‐derived or Muller glial cell‐derived conditioned media or bFGF on the survival of photoreceptor cells seeded on PLGA‐PHBV8 films were investigated. Addition of either RPE‐ and Muller‐conditioned media increased statistically (p < 0.01) the viability of photoreceptor cells after 7 days of incubation. Our results suggest that such biodegradable micropatterned PLGA‐PHBV8 blend films have a potential to deliver photoreceptor cells to the subretinal space and ensure laminar organization and maintenance of differentiation, and that incorporation of intrinsic factors within the scaffold would enhance the survival rate of transplanted cells. © 2007 Wiley Periodicals, Inc. J Biomed Mater Res, 2008
Effects of intermittent hydrostatic pressure on cell adhesive forces and other related parameters under various resting periods
Authors: Kim Young Jick , Park SuA , Lee Yong Jae , Shin Ji Won , Kim Dong‐Hwa , Heo Su‐Jin , Park Ki Dong , Shin Jung‐Woog
Published: October 2007

The purpose of this study is to investigate the effects of intermittent hydrostatic pressure with various resting periods on the cell adhesive forces and other parameters related to spreading in early stage of cell adhesion. For this, bovine pulmonary arterial endothelium (CPAE, cell line), porcine articular chondrocytes, and human endothelial cells (HECs) were used. The cells were divided into six different experimental groups. Control group was cultured without stimulation, while the constant pressure was applied to group 1 for 2 h. Groups 2–5 were intermittently pressurized for 2 min at a time over a 2‐h period with 5, 10, 15, and 20‐min resting periods, respectively. Each group was then split into two subgroups, depending whether it experienced extra 60 min stabilization period after stimulation. The average adhesive force and the number and area of focal contacts were significantly higher in the group 4 subgroup, which received an extra 60 min of culture than in the other groups. Similarly, other parameters in this subgroup were significantly different from those in the other groups. The focal contact area and adhesive force were closely related (r = 0.990). We concluded that the mechanical stimuli affect cell adhesion and that the length of the resting period influences the adhesive forces generated at the early stages of adhesion. © 2007 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2008
Comparative study of silicone‐hydrogel contact lenses surfaces before and after wear using atomic force microscopy
Authors: Lira M. , Santos L. , Azeredo J. , Yebra‐Pimentel E. , Oliveira M. Elisabete C. D. Real
Published: October 2007

Purpose: The aim of this study was to analyze surface changes of three silicone‐hydrogel contact lenses after daily wear. The lenses used in this study were balafilcon A, lotrafilcon B (both surface‐treated), and galyfilcon A (non surface‐treated). Methods: To understand how and where proteins, lipids, and other contaminants change contact lenses, surface roughness was assessed through Atomic Force Microscopy Tapping Mode™. Roughness parameters were Mean Surface roughness (Ra), Mean‐square‐roughness (Rq), and Maximum roughness (Rmax). The surface topography of unworn and worn lenses was also mapped in great detail. Results: Contact lenses roughness parameters exhibited different values before and after wear and the surface appearance also changed. After wear, balafilcon A and galyfilcon A showed a significant increase on surface roughness parameters, being this increase more accentuated to galyfilcon A. In lotrafilcon B materials no significant changes were observed with wear. Conclusions: The present study suggests that surface treatment of silicone‐hydrogel contact lenses can play a role in the prevention of a significant increase in roughness, and contribute to the better clinical tolerance of these lenses. © 2007 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2008
Vertex suppression in 3‐connected graphs
Authors: Kriesell Matthias
Published: October 2007

To suppress a vertex $v$ in a finite graph G means to delete it and add an edge from a to b if a, b are distinct nonadjacent vertices which formed the neighborhood of $v$. Let $G--x$ be the graph obtained from $G-x$ by suppressing vertices of degree at most 2 as long as it is possible; this is proven to be well defined.

Our main result states that every 3‐connected graph G has a vertex x such that $G -- x$ is 3‐connected unless G is isomorphic to $K_{3,3}$, $K_2 \times K_3$, or to a wheel $K_{1}*C_{\ell}$ for some $\ell \geq 3$. This leads to a generator theorem for 3‐connected graphs in terms of series parallel extensions. © 2007 Wiley Periodicals, Inc. J Graph Theory 57: 41–54, 2008
Morphology of the preimaginal stages of the African emperor moth Bunaeopsis licharbas (Maassen and Weyding): Phylogenetically informative characters within the Saturniinae (Lepidoptera: Saturniidae)
Authors: Rougerie Rodolphe , Estradel Yves
Published: October 2007

The current classification of African representatives of the family Saturniidae is largely unsatisfactory and needs to be revised following a proper and rigorous phylogenetic analysis. In this regard, the use of characters of preimaginal stages in phylogeny reconstruction was already emphasized in the literature; however, few details are known about the morphology of the eggs, larvae, and pupae of these moths. To fill this gap and to provide a preliminary basis for further phylogenetic studies, the early stages of Bunaeopsis licharbas, a member of the tribe Bunaeini within the Saturniinae, are described. Egg chorionic ultrastructure, chaetotaxy of the larva in every instar, and morphology of the pupa are described and illustrated. A total of 22 previously overlooked characters was found and their potential phylogenetic significance is discussed in the light of a comparative study which includes a large set of representatives of all five tribes in the subfamily. Until further phylogenetic analyses, some characters are considered to be potential synapomorphies supporting, in particular, the monophyly of the tribe Bunaeini, the close relationship between this tribe and part of the Urotini, as well as the existence of an Afrotropical lineage within the Saturniinae uniting the tribes Bunaeini, Urotini, and Micragonini. In a group of moths whose preimaginal instars are among the best known within the Lepidoptera, the unexpected, and relatively high number of potentially informative characters found by the present study stresses the value of minute and exhaustive descriptive studies to make use of morphological characters available for phylogenetic studies. J. Morphol., 2008. © 2007 Wiley‐Liss, Inc.
Bone modeling response to voluntary exercise in the hindlimb of mice
Authors: Plochocki Jeffrey H. , Rivera Janelyn P. , Zhang Cathleen , Ebba Sahbina A.
Published: October 2007

The functional adaptation of juvenile mammalian limb bone to mechanical loading is necessary to maintain bone strength. Diaphyseal size and shape are modified during growth through the process of bone modeling. Although bone modeling is a well‐documented response to increased mechanical stress on growing diaphyseal bone, the effect of proximodistal location on bone modeling remains unclear. Distal limb elements in cursorial mammals are longer and thinner, most likely to conserve energy during locomotion because they require less energy to move. Therefore, distal elements are hypothesized to experience greater mechanical loading during locomotion and may be expected to exhibit a greater modeling response to exercise. In this study, histomorphometric comparisons are made between femora and tibiae of mice treated with voluntary exercise and a control group (N = 20). We find that femora of exercised mice exhibit both greater bone growth rates and growth areas than do controls (P < 0.05). The femora of exercised mice also have significantly greater cortical area, bending rigidity, and torsional rigidity (P < 0.05), although bending and torsional rigidity are comparable when standardized by bone length. Histomorphometric and cross‐section geometric properties of the tibial midshaft of exercised and control mice did not differ significantly, although tibial length was significantly greater in exercised mice (P < 0.05). Femora of exercised mice were able to adapt to increased mechanical loading through increases in compressive, bending, and torsional rigidity. No such adaptations were found in the tibia. It is unclear if this is a biomechanical adaptation to greater stress in proximal elements or if distal elements are ontogenetically constrained in a tradeoff of bone strength of distal elements for bioenergetic efficiency during locomotion. J. Morphol., 2008. © 2007 Wiley‐Liss, Inc.
Effect of probiotic (Lactobacillus sporogenes) feeding on egg production and quality, yolk cholesterol and humoral immune response of White Leghorn layer breeders
Authors: Panda Arun K , Rama Rao Savaram S , Raju Manteta VLN , Sharma Sita S
Published: October 2007

The effect of probiotic (Lactobacillus sporogenes) feeding on egg production and quality, yolk cholesterol and humoral immune response of White Leghorn (WL) layer breeders was studied. WL layer breeders (24 weeks) were randomly distributed into three groups of 28 each and were housed in individual California type cages. Considering one bird (individual feeding) as a replicate, 28 such replicates were randomly allotted to one of the three dietary treatments: basal (control) or basal with probiotic supplementation at a rate of 100 or 150 mg kg−1 feed. The probiotic used in the study was a commercial preparation containing L. sporogenes with 6000 million spores g−1 of the product. Dietary supplementation of L. sporogenes at 100 mg (6 × 108 spore) kg−1 diet significantly increased egg production and feed efficiency. However, body weight gain, feed intake, egg weight, specific gravity and Haugh unit was not influenced by probiotic feeding. The eggshell breaking strength, shell weight and shell thickness increased significantly by feeding 100 mg probiotic kg−1 diet. The serum concentration of calcium and protein increased, and that of cholesterol decreased by L. sporogenes supplementation. The yolk cholesterol followed the same trend of serum cholesterol. Feeding of L. sporogenes significantly enhanced antibody production. No difference in antibody production could, however, noticed between the levels (100 or 150 mg) of probiotic. It is concluded that feeding of L. sporogenes at 100 mg (6 × 108 spore) kg−1 diet significantly enhanced the egg production, shell quality and humoral immune response of WL layer breeders during 25–40 weeks of age. Copyright © 2007 Society of Chemical Industry
Clinical results of various reconstructions employed after total gastrectomy
Authors: El Halabi Hatem M. , Lawrence Walter
Published: October 2007

Methods of restoring continuity after total gastrectomy, particularly those creating a “reservoir,” have led to many publications over the last 20 years. These publications are herein reviewed in an attempt to answer questions regarding the clinical value of a jejunal “reservoir”. The conclusion we reached from this review was that such a reconstruction does reduce unpleasant symptoms, aids weight maintenance, and is a valuable operative approach. J. Surg. Oncol. 2008;97:186–192. © 2007 Wiley‐Liss, Inc.
1,1‐bis(3′‐indolyl)‐1‐(p‐methoxyphenyl)methane activates Nur77‐independent proapoptotic responses in colon cancer cells
Authors: Cho Sung Dae , Lei Ping , Abdelrahim Maen , Yoon Kyungsil , Liu Shengxi , Guo Jingjing , Papineni Sabitha , Chintharlapalli Sudhakar , Safe Stephen
Published: October 2007

1,1‐Bis(3′‐indolyl)‐1‐(p‐methoxyphenyl)methane (DIM‐C‐pPhOCH3) is a methylene‐substituted diindolylmethane (C‐DIM) analog that activates the orphan receptor nerve growth factor‐induced‐Bα (NGFI‐Bα, Nur77). RNA interference studies with small inhibitory RNA for Nur77 demonstrate that DIM‐C‐pPhOCH3 induces Nur77‐dependent and ‐independent apoptosis, and this study has focused on delineating the Nur77‐independent proapoptotic pathways induced by the C‐DIM analog. DIM‐C‐pPhOCH3 induced caspase‐dependent apoptosis in RKO colon cancer cells through decreased mitochondrial membrane potential which is accompanied by increased mitochondrial bax/bcl‐2 ratios and release of cytochrome c into the cytosol. DIM‐C‐pPhOCH3 also induced phosphatidylinositol‐3‐kinase‐dependent activation of early growth response gene‐1 which, in turn, induced expression of the proapoptotic nonsteroidal anti‐inflammatory drug‐activated gene‐1 (NAG1) in RKO and SW480 colon cancer cells. Moreover, DIM‐C‐pPhOCH3 also induced NAG‐1 expression in colon tumors in athymic nude mice bearing RKO cells as xenografts. DIM‐C‐pPhOCH3 also activated the extrinsic apoptosis pathway through increased phosphorylation of c‐jun N‐terminal kinase which, in turn, activated C/EBP homologous transcription factor (CHOP) and death receptor 5 (DR5). Thus, the effectiveness of DIM‐C‐pPhOCH3 as a tumor growth inhibitor is through activation of Nur77‐dependent and ‐independent pathways. © 2007 Wiley‐Liss, Inc.
Metastasis‐associated gene expression profile of liver and subcutaneous lesions derived from mouse pheochromocytoma cells
Authors: Ohta Shoichiro , Lai Edwin W. , Morris John C. , Pang Alan L.Y. , Watanabe Morihiro , Yazawa Hiroshi , Zhang Richard , Green Jeffery E. , Chan Wai‐Yee , Sirajuddin Paul , Taniguchi Shun'ichiro , Powers James F. , Tischler Arthur S. , Pacak Karel
Published: October 2007

The development of metastatic cancer is associated with overexpression or downregulation of specific genes and cell regulatory pathways. Some of these genes and pathways may be involved in invasion and dissemination of tumor cells, while others may promote seeding, survival or growth of cells at specific distant sites. In this investigation, gene expression profiles of nonmetastasizing tumors generated by injecting mouse pheochromocytoma cells (MPCs) subcutaneously were compared to those of liver tumors generated by injecting the cells intravenously. Both were compared to the cultured parental cell line. Tumors in the liver have a route of spread, anatomical distribution, and growth environment similar to naturally metastasizing pheochromocytomas, while intravenous injection of cells bypasses the initial steps of metastasis occurring spontaneously from a primary tumor. Eight genes were upregulated in liver tumors, 15 in subcutaneous tumors and seven in both compared to the cultured cells. Using quantitative real‐time PCR, expression of five genes (Metap2, Reck, S100a4, Timp2, and Timp3) was verified as significantly lower in liver tumors than in subcutaneous tumors. Downregulation of these genes has been previously been associated with malignancy of pheochromocytomas. These findings indicate that different microenvironments can differentially affect the expression of metastasis‐related genes in pheochromocytomas, and that overexpression or underexpression of these genes need not be present when the tumor cells are initially disseminated. The hepatic localization of tumors formed by intravenously injected MPC cells and the tumors' gene expression profile resembling that of naturally occurring pheochromocytoma metastases support the use of this model to study pheochromocytoma metastasis. © 2007 Wiley‐Liss, Inc.
Quaternion‐based rigid body rotation integration algorithms for use in particle methods
Authors: Johnson Scott M. , Williams John R. , Cook Benjamin K.
Published: October 2007

The resolution of translational motion in discrete element method and molecular dynamics applications is a straightforward task; however, resolving rotational motion is less obvious. Many applications update rotation using an explicit integration involving products of matrices, which has well‐known drawbacks. Although rigid body rotation has received attention in large‐angle rotation applications, relatively little attention has been dedicated to the unique requirements of particle methods using explicit time‐stepping algorithms. This paper reviews existing explicit
algorithms and shows the benefits of using a quaternion‐based re‐parameterization of both the central difference algorithm and the approach of Munjiza et al. (Int. J. Numer. Meth. Engng 2003; 56:36–55). The improvement not only provides guaranteed orthonormality of the resulting rotation but also allows the assumption of small‐angle rotation to be relaxed and the use of a more accurate Taylor expansion instead. The current and quaternion‐based algorithms are compared for accuracy and computational efficiency. Copyright © 2007 John Wiley & Sons, Ltd.
Pathophysiologie und Therapie der AMD: Therapeutischer Anti‐VEGF‐Einsatz in der Augenheilkunde
Authors: Finger Robert P. , Fleckenstein Monika , Scholl Hendrik P.N. , Holz Frank G.
Published: October 2007

Die altersabhängige Makuladegeneration (AMD) ist in allen Industrienationen die häufigste Erblindungsursache. Allein in Deutschland sind ca. 4,5 Millionen Menschen betroffen. Angesichts der demographischen Entwicklung wird die Anzahl der Betroffenen weiter zunehmen. Die Spätstadien der Erkrankung gehen unter anderem mit einem Verlust der zentralen Sehschärfe und damit der Lesefähigkeit sowie häufig der selbstständigen Lebensführung einher. Umso dringlicher ist die Entwicklung neuer wirksamer Therapieverfahren, mit denen der Verlust des zentralen Sehens verhindert werden kann. Basierend auf neuen Erkenntnissen zur Pathogenese konnte die Antiangiogenese als neue Therapieform der neovaskulären AMD etabliert werden. Mittels wiederholter intravitrealer Injektion antiangiogen wirksamer Präparate können Wachstum und Permeabilität neovaskulärer Membranen bei der AMD günstig beeinflusst werden. Erste Ergebnisse aus Zulassungsstudien und aus der klinischen Praxis sind sehr viel versprechend. Es bleibt abzuwarten, ob die Langzeitergebnisse nach jahre‐ und jahrzehntelanger Therapie und die langfristigen unerwünschten Wirkungen ebenfalls so positiv ausfallen werden.
Ranibizumab bei Makuladegeneration. Angiogenese‐Hemmung gegen Sehverlust
Authors: Mohr‐Andrä Marion , Mohr Klaus
Published: October 2007

Mit Ranibizumab, einem humanisierten Antikörperfragment gegen den vaskulären endothelialen Wachstumsfaktor A (VEGF‐A) steht nun zum ersten Mal ein Arzneimittel zur Verfügung, das den Verlust des Sehvermögens bei der feuchten Form der altersabhängigen Makuladegeneration (AMD) nicht nur aufhalten, sondern zum Teil auch rückgängig machen kann. Allerdings ist die Therapie sehr aufwändig (monatliche Injektion direkt in den Glaskörper des Auges unter aseptischen OP‐Bedingungen) und teuer (reine Arzneimittelkosten: ca. 1500 R/Monat).

Unerwünschte Arzneimittelwirkungen traten in den Zulassungsstudien für Ranibizumab selten auf, und standen meist im Zusammenhang mit der Applikationsmethode (Entzündungen des Auges).

Bevacizumab, ein anderer Inhibitor des VEGF‐A, der zur Therapie des Kolon‐ und Rektumkarzinoms zugelassen ist, wird in den USA im Off‐label‐use als kostengünstigere Alternative verwendet. Vergleichende Studien zur Wirksamkeit und Verträglichkeit von Bevacizumab bei der Indikation AMD fehlen gegenwärtig, sollen aber im Laufe dieses Jahres begonnen werden.
Die neue Karriere des Thalidomids. Ein altes Schlafmittel als Cancerostatikum
Authors: Holzgrabe Ulrike
Published: October 2007

Zusammenfassend kann festgestellt werden, dass Lenalidomid, das strukturell seiner Muttersubstanz Thalidomid sehr ähnlich ist, wesentlich effektiver in der Behandlung des MM und MDS ist als Thalidomid. Außerdem ist das Nebenwirkungsspektrum und auch die Nebenwirkungshäufigkeit günstiger. Hauptnebenwirkung von Lenalidomid ist die Veränderung des Blutbildes, insbesondere die Erniedrigung der weißen Blutkörperchen und der Blutplättchen. Viele Studien zu beiden Substanzen befinden sich in frühen Stadien, sodass eine abschließende Beurteilung noch aussteht. Lenalidomid wird zurzeit auch in Kombination mit anderen Chemotherapeutika für die Behandlung solider Tumore getestet.
Aspergillus fumigatus und Angiogenese. Von einer Zufallsentdeckung zum Rationalen Drug‐Design
Authors: Klein Christian
Published: October 2007

Der Schimmelpilz Aspergillus fumigatus produziert einen potenten Angiogenesehemmstoff, das Fumagillin. Diese Substanz war einer der ersten niedermolekularen Angiogeneseinhibitoren und trug wesentlich dazu bei, diese therapeutische Strategie überhaupt erst interessant zu machen.
Angiogenese‐Inhibitoren der Zukunft. Getreu dem Motto: Von der Versorgung abschnüren!
Authors: Zündorf Ilse , Dingermann Theo
Published: October 2007

Mit dem Wissen um die bei der Angiogenese beteiligten Regulatormoleküle, die sich grob in die drei Gruppen der zirkulierenden Zytokine und Wachstumsfaktoren, der Komponenten der extrazellulären Matrix und der membrangebundenen Proteine einteilen lassen, explodierte quasi die Zahl der möglichen Angiogenese‐Inhibitoren. Das Hauptaugenmerk liegt auf der VEGF‐vermittelten Signalkaskade, die an unterschiedlichsten Stellen inhibiert wird. Die meisten Wirkstoffe in der Entwicklung adressieren die Tyrosinkinase‐Aktivität des VEGF‐Rezeptors. Primäres Einsatzgebiet derartiger Wirkstoffe ist die Tumortherapie. Ganz nebenbei können sich daraus allerdings auch weitere Therapieoptionen für die feuchte Macula‐Degeneration ergeben. Es bleibt allerdings abzuwarten, wie viele der Substanzen in klinischer Testung es wirklich bis zur Marktreife schaffen.
Pharmakoökonomie: Fluch oder Segen für die medizinische Versorgung? Überlegungen nicht nur zu Angiogenese‐Hemmern
Authors: Schöffski Oliver , Cremers Yvonne
Published: October 2007

Innovative neue Arzneimittel wie die Angiogenesehemmer verursachen im Gesundheitssystem hohe Kosten. In diesem Beitrag soll dargestellt werden, wie sich die Gesundheitsökonomie diesem Thema nähert, wie sie versucht Kennzahlen zu ermitteln, durch die eine effiziente Steuerung des Gesundheitswesens möglich wird. Es ist aber nicht zu beschönigen: Es geht im Endeffekt um Rationierung und damit um ein unangenehmes Thema.
Gentherapie bei Morbus Parkinson
Authors: Winckler Thomas
Published: October 2007

Ein neuer gentherapeutischer Ansatz adressiert nicht den Erhalt dopaminerger Neurone, sondern setzt auf die Unterstützung des inhibitorischen GABAergen Systems.
Lactivicin – ein Antibiotikum gegen Penicillin‐resistente Pneumokokken
Authors: Holzgrabe Ulrike
Published: October 2007

β‐Lactam‐Antibiotika wie die Penicilline und Cephalosporine entfalten ihre bakteriostatische Wirkung durch die Hemmung der so genannten Penicillin‐bindenden Proteine (kurz PBPs genannt), die für die Synthese der Bakterienzellwand verantwortlich sind. Eben diese PBPs werden bei der Resistenzentstehung von den Bakterien mutiert, so dass die β‐Lactam‐Antibiotika nur noch eine kleine Affinität zu den PBPs haben.
Hemorrhagic disease of the newborn despite vitamin K prophylaxis at birth
Authors: Flood Veronica H. , Galderisi Faith C. , Lowas Stefanie R. , Kendrick Angela , Boshkov Lynn K.
Published: October 2007

Late hemorrhagic disease of the newborn (HDN) presents 0.5–6 months after birth with mucocutaneous and intracranial bleeding. We describe here two cases of late HDN in infants who received vitamin K. The first case is a previously healthy breastfed male who received one dose of oral vitamin K at birth and developed an intracranial hemorrhage 5 weeks later. He was treated with intravenous vitamin K and recombinant factor VIIa prior to emergent craniectomy. An unrelated infant presented at 5 months of age with diarrhea and easy bruising despite IM vitamin K at birth. These cases illustrate the morbidity associated with late HDN. Pediatr Blood Cancer 2008;50:1075–1077. © 2007 Wiley‐Liss, Inc.
Hospitalization rates of generic metoprolol compared with the original beta‐blocker in an epidemiological database study
Authors: Ahrens Wolfgang , Hagemeier Constantin , Mühlbauer Bernd , Pigeot Iris , Püntmann Isabel , Reineke Achim , Steinbach Monica , Timm Jürgen
Published: October 2007

Purpose

A less favourable galenic profile of generic formulations of the beta‐blocker metoprolol raised the concern of a higher risk for serious cardiovascular (CV) events. We assessed hospital admission rates for CV diseases and prescription prevalences of various drugs using claims data of statutory health insurances (SHIs) to compare the incidence of serious CV events among users of original and generic metoprolol. Index events included hospitalization due to myocardial infarction, hypertensive crisis and stroke.

Methods

Data files of three SHIs were linked with dispensing data of drug prescriptions from each pharmacy's electronic data processing centre on an individual basis. Incidences of hospital admissions among patients receiving original metoprolol and among patients treated with the generic equivalent were compared by logistic regression, stratified for Bremen and the rest of Northern Germany. Risk estimates and confidence intervals were adjusted for confounders.

Results

A total of 49 673 patients receiving metoprolol were identified within a cohort of 3 649 285 insurance members. While the crude analysis revealed a higher risk for index events in patients receiving the generic drug (Bremen: RR 1.45; Northern Germany: RR 1.14), no elevated risk remained after confounder adjustment (Bremen: OR 1.06; Northern Germany: OR 1.04). Among co‐morbid conditions considered as confounders, a previous CV event and an elevated thromboembolic risk exerted the strongest effect on index events.

Conclusions

SHI data are a valuable source for pharmacoepidemiology and health services research in Germany. Incidence rates of serious CV events did not reveal any noticeable differences between the original and the generic group after confounder adjustment. Copyright © 2007 John Wiley & Sons, Ltd.
Is mechanical pain threshold after transcutaneous electrical nerve stimulation (TENS) increased locally and unilaterally? A randomized placebo‐controlled trial in healthy subjects
Authors: Aarskog Reidar , Johnson Mark I. , Demmink Jan Hendrik , Lofthus Anne , Iversen Vegard , Lopes‐Martins Rodrigo , Joensen Jon , Bjordal Jan M.
Published: October 2007

Background and Purpose. It is not fully understood how transcutaneous electrical nerve stimulation (TENS) intensity affects mechanical pain threshold. Method. Sixty‐six healthy volunteers (13 male, 53 female; 132 hands) without prior experience of TENS participated in the study, which comprised a randomized single‐blind controlled trial. TENS was administered for 20 minutes through electrodes (25 × 25 mm) placed on the hands and forearms with a fixed frequency of 100 Hz and pulse duration of 150 µs. TENS intensity was randomized and allocated in a concealed manner so that one arm received TENS with stimulation intensity set at participants' subjective sensory threshold and the other received TENS with stimulation intensity continuously adjusted by physiotherapists to a strong but comfortable non‐painful stimulation. Observers were blinded to stimulation intensity levels. Results. Mechanical pain threshold increased significantly, by a mean total of 0.79 kg/cm2 (95% confidence interval [95% CI]: 0.54–1.04) (p < 0.001) on the strong but comfortable non‐painful stimulation side. The mean change in mechanical pain threshold on the sensory threshold side was 0.19 kg/cm2 and did not reach statistical significance (95% CI–0.15 to 0.51). The mean stimulation intensity level for sensory threshold was 6.7 mA (95% CI: 5.65 to 7.83) which was significantly lower (p < 0.001) than the mean stimulation intensity for the strong stimulation, which was 20.5 mA (95% CI 16.6 to 24.4), respectively. The strong stimulation levels were, on average, 3.05 times higher than sensory threshold, but individual variations were large (range 1.2–6.1). Conclusions. TENS administered at a strong but comfortable non‐painful stimulation intensity increases mechanical pain threshold ipsi‐laterally in healthy subjects, whereas TENS administered at sensory threshold intensity does not. TENS may be ineffective if electrodes are placed contralaterally or distant to the pain site and if stimulation intensity levels are not titrated to subjective strong levels. Further clinical trials are needed to clarify if these findings may also be generalized to populations of chronic pain sufferers. Copyright © 2007 John Wiley & Sons, Ltd.
Free‐energy landscape of kinesin by a realistic lattice model
Authors: Kenzaki Hiroo , Kikuchi Macoto
Published: October 2007

Structural fluctuations in the thermal equilibrium of the kinesin motor domain are studied using a lattice protein model with Gō interactions. By means of the multi‐self‐overlap ensemble Monte Carlo method and the principal component analysis, the free‐energy landscape is obtained. It is shown that kinesins have two subdomains that exhibit partial folding/unfolding at functionally important regions: one is located around the nucleotide binding site and the other includes the main microtubule binding site. These subdomains are consistent with structural variability that was reported recently based on experimentally‐obtained structures. On the other hand, such large structural fluctuations have not been captured by B‐factor or normal mode analyses. Thus, they are beyond the elastic regime, and it is essential to take into account chain connectivity for studying the function of kinesins. Proteins 2008. © 2007 Wiley‐Liss, Inc.
Kinetic and structural properties of triosephosphate isomerase from Helicobacter pylori
Authors: Chu Chen‐Hsi , Lai Yi‐Ju , Huang Haimei , Sun Yuh‐Ju
Published: October 2007

Triosephosphate isomerase (TIM) catalyzes the interconversion between dihydroxyacetone phosphate and D‐glyceraldehyde‐3‐phosphate in the glycolysis–gluconeogenesis metabolism pathway. The Helicobacter pylori TIM gene (HpTIM) was cloned, and HpTIM was expressed and purified. The enzymatic activity of HpTIM for the substrate GAP was determined (Km = 3.46 ± 0.23 mM and kcat = 8.8 × 104 min−1). The crystal structure of HpTIM was determined by molecular replacement at 2.3 Å resolution. The overall structure of HpTIM was (β/α)β(β/α)6, which resembles the common TIM barrel fold, (β/α)8; however, a helix is missing after the second β‐strand. The conformation of loop 6 and binding of phosphate ion suggest that the determined structure of HpTIM was in the “closed” state. A highly conserved Arg‐Asp salt bridge in the “DX(D/N)G” motif of most TIMs is absent in HpTIM because the sequence of this motif is “211SVDG214.” To determine the significance of this salt bridge to HpTIM, four mutants, including K183S, K183A, D213Q, and D213A, were constructed and characterized. The results suggest that this conserved salt bridge is not essential for the enzymatic activity of HpTIM; however, it might contribute to the conformational stability of HpTIM. Proteins 2008. © 2007 Wiley‐Liss, Inc.
The geometry of α‐sheet: Implications for its possible function as amyloid precursor in proteins
Authors: Hayward Steven , Milner‐White E. James
Published: October 2007

α‐sheet has been proposed as the main constituent of the prefibrillar intermediate during amyloid formation. Here the helical parameters of the α‐sheet strand are calculated from average main‐chain dihedral angles reported from molecular dynamics simulations. It is an almost linear polypeptide that forms a right‐handed helix of about 100 Å diameter, with 100 residues and a rise of 30 Å per turn. The strands are curved but untwisted, which implies that neighboring strands need not coil to make interstrand hydrogen bonds. This suggests that compared to β‐sheets in native folded proteins, α‐sheets can be larger and stack more easily to create extensive 3D blocks. It is shown that α‐sheet is related to a category of structures termed “mirror” structures. Mirror structures have repetitive pairs of main‐chain dihedral angles at residues i and i+1 that satisfy the condition ϕi+1 = −ψi, ψi+1 = −ϕi. They are uniquely identified by the two orientations of their peptide planes, specified by ϕi and ψi. Their side chains point alternately in opposite directions. Interestingly, their conformations are insensitive to ϕi and ψi in that the pseudo dihedral angle formed by four consecutive Cα atoms is always close to 180°. There are two types: “β‐mirror” and “α‐mirror” structure; β‐mirror structures relate to β‐sheet by small peptide plane rotations, of less than 90°, while α‐mirror structures are close to α‐sheet and relate to β‐sheet by ∼180° peptide plane flips. Most mirror structures, and in particular the α‐mirror, form wide helices with diameters 50–70 Å. Their gentle curvature, and therefore that of the α‐sheet, arises from the orientation of successive peptide units causing the difference in the bond angles at the C and N atoms of the peptide unit to gradually change the direction of the chain. Proteins 2008. © 2007 Wiley‐Liss, Inc.
Contact rearrangements form coupled networks from local motions in allosteric proteins
Authors: Daily Michael D. , Upadhyaya Tarak J. , Gray Jeffrey J.
Published: October 2007

Allosteric proteins bind an effector molecule at one site resulting in a functional change at a second site. We hypothesize that networks of contacts altered, formed, or broken are a significant contributor to allosteric communication in proteins. In this work, we identify which interactions change significantly between the residue–residue contact networks of two allosteric structures, and then organize these changes into graphs. We perform the analysis on 15 pairs of allosteric structures with effector and substrate each present in at least one of the two structures. Most proteins exhibit large, dense regions of contact rearrangement, and the graphs form connected paths between allosteric effector and substrate sites in five of these proteins. In the remaining 10 proteins, large‐scale conformational changes such as rigid‐body motions are likely required in addition to contact rearrangement networks to account for substrate–effector communication. On average, clusters which contain at least one substrate or effector molecule comprise 20% of the protein. These allosteric graphs are small worlds; that is, they typically have mean shortest path lengths comparable to those of corresponding random graphs and average clustering coefficients enhanced relative to those of random graphs. The networks capture 60–80% of known allostery‐perturbing mutants in three proteins, and the metrics degree and closeness are statistically good discriminators of mutant residues from nonmutant residues within the networks in two of these three proteins. For two proteins, coevolving clusters of residues which have been hypothesized to be allosterically important differ from the regions with the most contact rearrangement. Residues and contacts which modulate normal mode fluctuations also often participate in the contact rearrangement networks. In summary, residue–residue contact rearrangement networks provide useful representations of the portions of allosteric pathways resulting from coupled local motions. Proteins 2008. © 2007 Wiley‐Liss, Inc.
Simultaneous determination of new thioamphetamine designer drugs in plasma by capillary electrophoresis coupled with mass spectrometry
Authors: Boatto Gianpiero , Nieddu Maria , Pirisi Maria Antonietta , Dessì Giuseppina
Published: October 2007

A simple method for the simultaneous identification and quantification of four 2,5‐methylenedioxy derivatives of 4‐thioamphetamine (ALEPH series) in plasma samples was developed. The method consists of solid‐phase extraction (SPE) using a Bond Elut C18 cartridge and capillary electrophoresis coupled with electrospray ionisation mass spectrometry (CE/ESI‐MS). The SPE method used required only simple steps and provided a clean extract from which identification of each drug was feasible, even at low concentrations. The method was validated according to international guidelines. The calibration curves were linear over the concentration range of 50 to 1000 ng/mL for all drugs with correlation coefficients that exceeded 0.998. The lower limits of detection of the drugs were 23–43 ng/mL. The absolute recoveries for the drugs were 64–92% and 75–96% at concentrations of 100 and 500 ng/mL, respectively. The validation data (precision, accuracy, and recovery) show the reproducibility and selectivity of the method. This clean and simple method allows the routine detection of designer drugs such as thioamphetamines which may become a serious problem in the control of illegal drugs. Copyright © 2007 John Wiley & Sons, Ltd.