bluuebunny/crossref_metadata_2025 huggingface dataset:
Application of poly(acrylic acid) superporous hydrogel microparticles as a super-disintegrant in fast-disintegrating tablets
Authors: Yang Shicheng , Fu Yurong , Jeong Seong Hoon , Park Kinam
Published: April 2004

Poly(acrylic acid) superporous hydrogel (SPH) microparticles possessing a unique porous structure were used as a wicking agent to decrease disintegration time of fast-disintegrating tablets (FDTs). The compression behaviour of poly(acrylic acid) SPH microparticles was evaluated using the Kawakita equation. Effects of various SPH microparticle sizes and a 19-run fractional factorial design were evaluated. The factorial design was based on four factors consisting of ketoprofen, SPH microparticle, filler, and tableting pressure, and each factor contained three levels on the disintegration time and tensile strength of the prepared FDTs. The poly(acrylic acid) SPH microparticles existed in an amorphous state and swelled approximately 80-times in distilled water and 50-times in pH 6.8 0.2 m phosphate buffer. The compressibility of SPH microparticles increased significantly as the microparticle size increased. The FDTs made of SPH microparticles in the range of 75–106 μm showed the fastest disintegration time and higher tensile strength. SPH microparticle, tableting pressure and ketoprofen had significant effects on disintegration time and tensile strength of ketoprofen FDTs. The FDTs that were prepared with 2.5% w/w SPH microparticles of 75–106 μm at 63 MPa pressure possessed a tensile strength of 84.4+4.1 N cm−2 and disintegrated in 15.0+2.0 s. It was concluded that the poly(acrylic acid) SPH microparticles could serve as a good super-disintegrant decreasing the disintegration time of FDTs.
Effects of dialkoxylphenyl compounds with oxime group on macrophage function and the proliferation of lymphocytes
Authors: Yoo Eun Sook , Yoo Eun Sook , Son Ho Jung , Park Joon Seok , Kim Ae Ra , Baik Kyong Up , Park Myung Hwan , Cho Jae Youl , Cho Jae Youl
Published: April 2004

Dialkoxyphenyl compounds have been reported to possess anti-inflammatory activity through inhibition of phosphodieseterase (PDE) type IV. In this study, a series of derivatives of dialkoxyphenyl compounds with an oxime group, which is generally known to be one of the biologically active functional groups, were prepared and evaluated for their ability to inhibit the production of inflammatory mediators in activated macrophages and the proliferation of lymphocytes. The structure–activity relationship (SAR) study with 12 compounds on tumour necrosis factor (TNF)-α inhibition, analysed by the oxime geometry and different size of spacers between the oxime and phenyl group, indicated that there might be at least three possible hydrogen bonding sites in the inhibitor binding pocket of PDE IV. Of them, compound 6 clearly displayed the highest inhibitory effect on in-vitro TNF-α production from lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Compound 6 also suppressed in-vivo TNF-α release from LPS-primed mice, a level comparable with that of the standard PDE IV inhibitor, rolipram. In addition, oxime compounds also significantly inhibited both nitric oxide production from activated RAW264.7 cells and T lymphocyte proliferation elicited by concanavalin A but not IL-2. The data suggest that the oxime group may act as a functional group, capable of interacting with the inhibitor-binding pocket of target PDE IV. Therefore, it is conceivable that compound 6 may have the potential either to be developed as a new anti-inflammatory drug or to be used to develop more potent analogues.
Influence of intravenous methylprednisolone pulse treatment on the disposition of ciclosporin and hepatic CYP3A activity in rats
Authors: Konishi Hiroki , Sumi Masaki , Minouchi Tokuzo , Yamaji Akira , Sumi Masaki , Shibata Nobuhito , Takada Kanji
Published: April 2004

We examined the effects of high-dose methylprednisolone (MP) on the disposition of ciclosporin (CsA) and hepatic microsomal CYP3A activity using rats. Methylprednisolone sodium succinate (MPS), a prodrug of MP, was intravenously administered as repeated doses (66.3 mg kg−1) for 3 days or as a single dose. In MP-treated rats, a significant increase was observed in the total body clearance (CLtot) and elimination rate constant (Ke) of intravenously administered CsA. The enzyme activities of triazolam hydroxylations and erythromycin N-demethylation in hepatic microsomes were also enhanced by about 50% by MP treatment, suggesting that the alteration in the CsA pharmacokinetics was due to significant induction of the hepatic CYP3A responsible for the metabolic conversion of CsA. In contrast, no significant changes in the values of CLtot and Ke were found following a single treatment with MP. On the other hand, MP inhibited the CYP3A-mediated triazolam hydroxylations in a concentration-dependent manner. The difference between the in-vivo and in-vitro inhibitory behaviours of MP was attributed to the rapid elimination of MP after biotransformation from MPS because the plasma MP concentration decreased with a half-life of 15 min immediately after reaching a level close to the inhibition constant for the triazolam 4-hydroxylation reaction (32.4 μm). Although there is a general consideration that MP cannot act as an enzyme inducer at maintenance doses, the present results strongly suggest that high-dose MP is likely to interact pharmacokinetically with CsA by inducing hepatic CYP3A. These results may provide basic explanations for the clinical experience that blood CsA levels are reduced during MP pulse therapy.
Glycyrrhetic acid-loaded microparticles: liver-specific delivery and therapeutic potential against carbon tetrachloride-induced hepatitis
Authors: Takahashi Hiroaki , Onishi Hiraku , Machida Yoshiharu
Published: April 2004

The microparticles (MPs) of an anti-hepatotoxic drug, glycyrrhetic acid (GLA), were prepared using poly(dl-lactic acid-co-glycolic acid) as a drug carrier, and their in-vitro properties, biodistribution and therapeutic effects were investigated. The MPs showed a particle diameter distribution of 1.0–1.4 μm and a drug content of approximately 10% (w/w). In the in-vitro release in a mixture of methanol and phosphate-buffered saline pH 7.4 (3:7, v/v), slow release was observed after an initial burst release of approximately 30% (w/w). After i.v. administration of MPs in normal mice, GLA was mainly distributed to the liver. After i.v. administration in normal mice, the MPs maintained a much higher liver concentration than did GLA solution, and the plasma concentration also tended to be higher for MPs than for GLA solution. As to therapeutic effect, the liver was damaged by repeated injection of carbon tetrachloride (CCl4) in mice every 48 h, and the drugs were administered intravenously as a single dose 3 h after the first injection of CCl4. At 10 mg GLA eq. kg−1, the MPs significantly suppressed the plasma level of glutamic pyruvic transaminase for at least 141 h after administration, while GLA solution did not become significantly effective within 45 h post-administration. MPs are suggested as a possible useful system to prolong the therapeutic effect of GLA.
Involvement of thromboxane A2 (TXA2) in the early stages of oleic acid-induced lung injury and the preventive effect of ozagrel, a TXA2 synthase inhibitor, in guinea-pigs
Authors: Ishitsuka Yoichi , Moriuchi Hiroshi , Hatamoto Keita , Takase Junko , Irikura Mitsuru , Irie Tetsumi , Yang Changqing , Golbidi Saeid
Published: April 2004

An intravenous injection of oleic acid into animals can produce a lung injury with hypoxaemia and pulmonary vascular hyper-permeability. Although oleic acid lung injury is used as a model of acute respiratory distress syndrome (ARDS), the precise mechanisms of the lung injury are still unclear. We have investigated whether thromboxane A2 (TXA2) participated in the lung injury and have evaluated the efficacy of ozagrel, a TXA2 synthase inhibitor, on the lung injury in guinea-pigs. Oleic acid injection increased the plasma level of TXB2, a stable metabolite of TXA2, and the time-course of plasma TXB2 was similar to that of the decreased partial oxygen pressure of arterial blood (Pao2) induced with oleic acid. Ozagrel administered intravenously 30 min before oleic acid injection prevented the decrease in Pao2 and pulmonary vascular hyper-permeability. It also prevented increases in lactate dehydrogenase activity, a measure of lung cell injury, TXB2 and its weight ratio to 6-keto prostaglandin F1 α in bronchoalveolar lavage fluid. Although ozagrel administered simultaneously with oleic acid ameliorated the decrease in Pao2, post treatment showed little effect. We suggest that TXA2 participated in the oleic acid lung injury, as an “early phase” mediator, and rapidly-acting TXA2 synthase inhibitors were effective in the prevention of acute lung injury.
Cetraxate raises levels of calcitonin gene-related peptide and substance P in human plasma
Authors: Katagiri Fumihiko , Sato Yuhki , Itoh Hiroki , Takeyama Masaharu
Published: April 2004

Cetraxate hydrochloride (cetraxate), an anti-ulcer drug, produces a dose-related increase in mucosal blood flow. Recently, it was found that capsaicin-sensitive afferent nerves play an important role in gastric mucosal defence. Capsaicin stimulates afferent nerves and enhances the release of calcitonin gene-related peptide (CGRP) and substance P in the stomach. We studied the effect of cetraxate on human plasma CGRP and substance P in healthy subjects. Cetraxate (800 mg) or placebo were orally administered to five healthy males. Blood samples were taken before, and at 20, 40, 60, 90, 120, 180 and 240 min after administration, followed by the extracting procedure, and submitted to a highly sensitive enzyme immunoassay system for CGRP and substance P. Single administration of cetraxate caused significant increases in plasma CGRP concentration at 60–120 min compared with placebo. Cetraxate significantly increased plasma substance P levels at 40–90 min compared with placebo. In this study, we hypothesized that cetraxate might indirectly stimulate capsaicin-sensitive afferent nerves and increase mucosal blood flow, and that this may be a key mechanism underlying its gastroprotective action.
Losartan but not enalaprilat acutely reduces reperfusion ventricular tachyarrhythmias in hypertrophied rat hearts after low-flow ischaemia
Authors: Butz Silvia , Driamov Sergey , Remondino Andrea , Bellahcene Mohamed , Ziegler André , Zaugg Christian E , Beier Konstantin , Buser Peter T
Published: April 2004

Based on clinical and experimental studies, angiotensin II receptor blockers and angiotensin converting enzyme inhibitors have been proposed to exert acute anti-arrhythmic effects in heart failure patients. Therefore, the goal of this study was to assess acute anti-arrhythmic effects of losartan and enalaprilat in hypertrophied rat hearts during low-flow ischaemia and reperfusion. In dose-finding experiments in non-hypertrophied isolated perfused hearts, we performed dose-response curves of losartan and enalaprilat studying monophasic action potential duration at 90% repolarisation (MAPD90%) and ventricular fibrillation (VF) threshold. Subsequently, we determined the effects of losartan and enalaprilat (in therapeutically relevant concentrations) on ventricular tachyarrhythmias induced by low-flow ischaemia/reperfusion in hearts demonstrating left ventricular (LV) hypertrophy 70 days after aortic banding. We found that neither drug significantly affected MAPD90% (1 nm-1 mm) or VF threshold (1 μm losartan and 10 μm enalaprilat) in non-hypertrophied hearts. Similarly in hypertrophied hearts, neither drug significantly affected the incidence or the duration of ventricular tachyarrhythmias (ventricular tachycardia and VF) during low-flow ischaemia. However, 1 μm losartan significantly reduced the duration of ventricular tachyarrhythmias during reperfusion. In conclusion, neither losartan nor enalaprilat is acutely anti-arrhythmic in hypertrophied rat hearts during low-flow ischaemia. During reperfusion, however, losartan but not enalaprilat exerts acute anti-arrhythmic effects.
Influence of enhancers on the absorption and on the pharmacokinetics of cefodizime using in-vitro and in-vivo models
Authors: Mrestani Yahya , Bretschneider Beate , Neubert Reinhard H H , Härtl Albert , Brandsch Matthias
Published: April 2004

In the development of novel antibiotics, more and more compounds have been found that cannot be absorbed orally and, therefore, must be administered intravenously or intramuscularly. Because of the obvious drawbacks of drug delivery by injection, the development of alternatives with enhanced oral bioavailability has received much attention in pharmaceutical research. Cefodizime, a novel third-generation cephalosporin with significant advantages in the parenteral treatment of common infections, was used as a model drug. Cefodizime behaves as a highly hydrophilic compound, as shown from its extremely low partition coefficient. The effect of cationic absorption enhancers (hexadecyldimethyl-benzylammonium chloride, N-hexadecylpyridinium bromide, dodecyltrimethylammonium bromide and hexadecyltrimethylammonium bromide) on the lipophilicity of cefodizime was investigated by means of the n-octanol/water system. Results showed that the counter-ions had a positive influence on the solubility of cefodizime. These results on partitioning coefficients in the n-octanol/buffer system were confirmed using an in-vitro transport model with artificial and biological membranes (Caco-2-cells). Furthermore, the physiological compatibility of the absorption enhancers was investigated using the active d-glucose transport. The pharmacokinetic profile of cefodizime was evaluated in rabbits after intraduodenal administration with and without an absorption enhancer.
Abrogation of heparan sulfate synthesis inDrosophiladisrupts the Wingless, Hedgehog and Decapentaplegic signaling pathways
Authors: Bornemann Douglas J. , Duncan Jason E. , Staatz William , Selleck Scott , Warrior Rahul
Published: April 2004

Studies in Drosophila and vertebrate systems have demonstrated that heparan sulfate proteoglycans (HSPGs) play crucial roles in modulating growth factor signaling. We have isolated mutations in sister of tout velu (sotv), a gene that encodes a co-polymerase that synthesizes HSPG glycosaminoglycan (GAG) chains. Our phenotypic and biochemical analyses reveal that HS levels are dramatically reduced in the absence of Sotv or its partner co-polymerase Tout velu (Ttv), suggesting that both copolymerases are essential for GAG synthesis. Furthermore, we find that mutations in sotv and ttv impair Hh, Wg and Decapentaplegic(Dpp) signaling. This contrasts with previous studies that suggested loss of ttv compromises only Hh signaling. Our results may contribute to understanding the biological basis of hereditary multiple exostoses (HME), a disease associated with bone overgrowth that results from mutations in EXT1 and EXT2, the human orthologs of ttv and sotv.
Hrb27C, Sqd and Otu cooperatively regulategurkenRNA localization and mediate nurse cell chromosome dispersion inDrosophilaoogenesis
Authors: Goodrich Jennifer S. , Clouse K. Nicole , Schüpbach Trudi
Published: April 2004

Heterogeneous nuclear ribonucleoproteins, hnRNPs, are RNA-binding proteins that play crucial roles in controlling gene expression. In Drosophilaoogenesis, the hnRNP Squid (Sqd) functions in the localization and translational regulation of gurken (grk) mRNA. We show that Sqd interacts with Hrb27C, an hnRNP previously implicated in splicing. Like sqd, hrb27C mutants lay eggs with dorsoventral defects and Hrb27C can directly bind to grk RNA. Our data demonstrate a novel role for Hrb27C in promoting grk localization. We also observe a direct physical interaction between Hrb27C and Ovarian tumor (Otu), a cytoplasmic protein implicated in RNA localization. We find that some otu alleles produce dorsalized eggs and it appears that Otu cooperates with Hrb27C and Sqd in the oocyte to mediate proper grklocalization. All three mutants share another phenotype, persistent polytene nurse cell chromosomes. Our analyses support dual cooperative roles for Sqd,Hrb27C and Otu during Drosophila oogenesis.
Positioning sensory terminals in the olfactory lobe ofDrosophilaby Robo signaling
Authors: Jhaveri Dhanisha , Saharan Sumiti , Sen Anindya , Rodrigues Veronica
Published: April 2004

Olfactory receptor neurons and the interneurons of the olfactory lobe are organized in distinct units called glomeruli. We have used expression patterns and genetic analysis to demonstrate that a combinatorial code of Roundabout(Robo) receptors act to position sensory terminals within the olfactory lobe. Groups of sensory neurons possess distinct blends of Robo and Robo3 and disruption of levels by loss-of-function or ectopic expression results in aberrant targeting. In the wild type, most of the neurons send collateral branches to the contralateral lobe. Our data suggests that guidance of axons across brain hemispheres is mediated by Slit-dependent Robo2 signaling. The location of sensory arbors at distinct positions within the lobe allows short-range interactions with projection neurons leading to formation of the glomeruli.
Functional analysis ofSox8andSox9during sex determination in the mouse
Authors: Chaboissier Marie-Christine , Kobayashi Akio , Vidal Valerie I. P. , Lützkendorf Susanne , van de Kant Henk J. G. , Wegner Michael , de Rooij Dirk G. , Behringer Richard R. , Schedl Andreas
Published: April 2004

Sex determination in mammals directs an initially bipotential gonad to differentiate into either a testis or an ovary. This decision is triggered by the expression of the sex-determining gene Sry, which leads to the activation of male-specific genes including the HMG-box containing gene Sox9. From transgenic studies in mice it is clear that Sox9is sufficient to induce testis formation. However, there is no direct confirmation for an essential role for Sox9 in testis determination. The studies presented here are the first experimental proof for an essential role for Sox9 in mediating a switch from the ovarian pathway to the testicular pathway. Using conditional gene targeting, we show that homozygous deletion of Sox9 in XY gonads interferes with sex cord development and the activation of the male-specific markers Mis and P450scc, and leads to the expression of the female-specific markers Bmp2 and follistatin. Moreover, using a tissue specific knock-out approach, we show that Sox9 is involved in Sertoli cell differentiation, the activation of Mis and Sox8, and the inactivation of Sry. Finally, double knock-out analyses suggest that Sox8 reinforces Sox9 function in testis differentiation of mice.
Her5 acts as a prepattern factor that blocksneurogenin1andcoe2expression upstream of Notch to inhibit neurogenesis at the midbrain-hindbrain boundary
Authors: Geling Andrea , Plessy Charles , Rastegar Sepand , Strähle Uwe , Bally-Cuif Laure
Published: April 2004

Neurogenesis in both vertebrates and invertebrates is tightly controlled in time and space involving both positive and negative regulators. We report here that the bHLH factor Her5 acts as a prepattern gene to prevent neurogenesis in the anlage of the midbrain/hindbrain boundary in the zebrafish neural plate. This involves selective suppression of both neurogenin1(ngn1) and coe2 mRNA expression in a process that is independent of Notch signalling, and where inhibition of either ngn1or coe2 expression is sufficient to prevent neuronal differentiation across the midbrain-hindbrain boundary. A ngn1 transgene faithfully responds to Her5 and deletion analysis of the transgene identifies an E-box in a ngn1 upstream enhancer to be required for repression by Her5. Together our data demonstrate a role of Her5 as a prepattern factor in the spatial definition of proneural domains in the zebrafish neural plate, in a manner similar to its Drosophila homologue Hairy.
A Fasciclin 2 morphogenetic switch organizes epithelial cell cluster polarity and motility
Authors: Szafranski Przemyslaw , Goode Scott
Published: April 2004

Little is known about how intercellular communication is regulated in epithelial cell clusters to control delamination and migration. We investigate this problem using Drosophila border cells as a model. We find that just preceding cell cluster delamination, expression of transmembrane immunoglobulin superfamily member, Fasciclin 2, is lost in outer border cells,but not in inner polar cells of the cluster. Loss of Fasciclin 2 expression in outer border cells permits a switch in Fasciclin 2 polarity in the inner polar cells. This polarity switch, which is organized in collaboration with neoplastic tumor suppressors Discs large and Lethal-giant-larvae, directs cluster asymmetry essential for timing delamination from the epithelium. Fas2-mediated communication between polar and border cells maintains localization of Discs large and Lethal-giant-larvae in border cells to inhibit the rate of cluster migration. These findings are the first to show how a switch in cell adhesion molecule polarity regulates asymmetry and delamination of an epithelial cell cluster. The finding that Discs large and Lethal-giant-larvae inhibit the rate of normal cell cluster movement suggests that their loss in metastatic tumors may directly contribute to tumor motility. Furthermore, our results provide novel insight into the intimate link between epithelial polarity and acquisition of motile polarity that has important implications for development of invasive carcinomas.
Graded potential of neural crest to form cornea, sensory neurons and cartilage along the rostrocaudal axis
Authors: Lwigale Peter Y. , Conrad Gary W. , Bronner-Fraser Marianne
Published: April 2004

Neural crest cells arising from different rostrocaudal axial levels form different sets of derivatives as diverse as ganglia, cartilage and cornea. These variations may be due to intrinsic properties of the cell populations,different environmental factors encountered during migration or some combination thereof. We test the relative roles of intrinsic versus extrinsic factors by challenging the developmental potential of cardiac and trunk neural crest cells via transplantation into an ectopic midbrain environment. We then assess long-term survival and differentiation into diverse derivatives,including cornea, trigeminal ganglion and branchial arch cartilage. Despite their ability to migrate to the periocular region, neither cardiac nor trunk neural crest contribute appropriately to the cornea, with cardiac crest cells often forming ectopic masses on the corneal surface. Similarly, the potential of trunk and cardiac neural crest to form somatosensory neurons in the trigeminal ganglion was significantly reduced compared with control midbrain grafts. Cardiac neural crest exhibited a reduced capacity to form cartilage,contributing only nominally to Meckle's cartilage, whereas trunk neural crest formed no cartilage after transplantation, even when grafted directly into the first branchial arch. These results suggest that neural crest cells along the rostrocaudal axis display a graded loss in developmental potential to form somatosensory neurons and cartilage even after transplantation to a permissive environment. Hox gene expression was transiently maintained in the cardiac neural tube and neural crest at 12 hours post-transplantation to the midbrain,but was subsequently downregulated. This suggests that long-term differences in Hox gene expression cannot account for rostrocaudal differences in developmental potential of neural crest populations in this case.
Role of PPAR γ and EGFR signalling in the urothelial terminal differentiation programme
Authors: Varley Claire L. , Stahlschmidt Jens , Lee Wen-Chun , Holder Julie , Diggle Christine , Selby Peter J. , Trejdosiewicz Ludwik K. , Southgate Jennifer
Published: April 2004

Recently, considerable interest has focused on the ability of activated peroxisome proliferator-activated receptor γ (PPARγ) to promote cytodifferentiation in adipocytes and some carcinoma cells; however, the role of PPARγ in normal epithelial cytodifferentiation is unknown. Using uroplakin (UP) gene expression as a specific correlate of terminal urothelial cytodifferentiation, we investigated the differentiation-inducing effects of PPARγ activation in normal human urothelial (NHU) cells grown as finite cell lines in monoculture. Two high-affinity activators of PPARγ, troglitazone (TZ) and rosiglitazone (RZ) induced the expression of mRNA for UPII and UPIb and, to a lesser extent, UPIa. The specificity of the effect was shown by pretreating cells with a PPARγ antagonist, GW9662, which attenuated the TZ-induced response in a dose-specific manner. The PPARγ-mediated effect on UP gene expression was maximal when there was concurrent inhibition of autocrine-activated epidermal growth factor receptor (EGFR) signalling through either the phosphatidylinositol 3-kinase or extracellular signal-regulated kinase (ERK) pathways. The use of a specific EGFR tyrosine kinase inhibitor, PD153035, correlated with PPARγ dephosphorylation and translocation to the nucleus, indicating a mechanism for regulating the balance between proliferation and differentiation. This is the first identification of specific factors involved in regulating differentiation-associated gene changes in urothelium and the first unambiguous evidence of a role for PPARγ signalling in the terminal differentiation programme of a normal epithelium.
Role of bone marrow cell trafficking in replenishing skeletal muscle SP and MP cell populations
Authors: Rivier François , Alkan Ozan , Flint Alan F. , Muskiewicz Kristina , Allen Paul D. , Leboulch Philippe , Gussoni Emanuela
Published: April 2004

The multipotent nature of skeletal muscle-derived side population cells is demonstrated by their myogenic and hematopoietic potential in vivo. However, whether muscle side population cells are derived from the bone marrow is unclear. To study the long-term contribution of the hematopoietic system to muscle side population, whole bone marrow cells from Ly5.1 males or from e-GFP transgenic male mice were transplanted into lethally irradiated Ly5.2 females. Long-term cell trafficking of donor bone marrow cells to muscle side population was monitored 17 times in a 34-week study. Fluorescence-activated cell sorter analyses were used to detect Ly5.1 and GFP+ donor cells, which were confirmed by fluorescence in situ hybridization of the Y-chromosome. Analyses post-transplantation indicated that whereas cells of donor origin could be found in the muscle, donor bone marrow cells had contributed little to the muscle side population. Attempts to increase cell trafficking by induced muscle damage again confirmed that more than 90% of side population cells present in the muscle were derived from the host. These results demonstrate that muscle side population cells are not replenished by the bone marrow and suggest a non-hematopoietic origin for this cell population.
The lamin B receptor of Drosophila melanogaster
Authors: Wagner Nicole , Weber Daniela , Seitz Sabine , Krohne Georg
Published: April 2004

The lamin B receptor (LBR) is an integral membrane protein of the inner nuclear membrane that has so far been characterized only in vertebrates. Here, we describe the Drosophila melanogaster protein encoded by the annotated gene CG17952 that is the putative ortholog to the vertebrate LBR. The Drosophila lamin B receptor (dLBR) has the following properties in common with the vertebrate LBR. First, structure predictions indicate that the 741 amino acid dLBR protein possesses a highly charged N-terminal domain of 307 amino acids followed by eight transmembrane segments in the C-terminal domain of the molecule. Second, immunolocalization and cell fractionation reveal that the dLBR is an integral membrane protein of the inner nuclear membrane. Third, dLBR can be shown by co-immunoprecipitations and in vitro binding assays to bind to the Drosophila B-type lamin Dm0. Fourth, the N-terminal domain of dLBR is sufficient for in vitro binding to sperm chromatin and lamin Dm0. In contrast to the human LBR, dLBR does not possess sterol C14 reductase activity when it is expressed in the Saccharomyces cerevisiae erg24 mutant, which lacks sterol C14 reductase activity. Our data raise the possibility that, during evolution, the enzymatic activity of this insect protein had been lost.

To determine whether the dLBR is an essential protein, we depleted it by RNA interference in Drosophila embryos and in cultured S2 and Kc167 cells. There is no obvious effect on the nuclear architecture or viability of treated cells and embryos, whereas the depletion of Drosophila lamin Dm0 in cultured cells and embryos caused morphological alterations of nuclei, nuclear fragility and the arrest of embryonic development. We conclude that dLBR is not a limiting component of the nuclear architecture in Drosophila cells during the first 2 days of development.
Identification and functional characterization ofArabidopsisAP180, a binding partner of plant αC-adaptin
Authors: Barth Meike , Holstein Susanne E. H.
Published: April 2004

Clathrin-mediated endocytosis is a well-studied uptake mechanism for nutrients and signalling receptors in mammalian cells that depends on the coordinated interaction of coat proteins and endocytic network proteins to perform the internalization. In this process AP180 promotes the assembly of clathrin triskelia into coated membrane patches at the plasma membrane, while α-adaptin interacts with various network proteins that are in turn required for the budding of the coated pits. The process of clathrin-mediated endocytosis in plants has not been dissected at the molecular level, nor have the members of an analogous uptake machinery been functionally described. In this respect, we have investigated the AP180 and α-adaptin orthologs from Arabidopsis thaliana: At-AP180 and At-αC-Ad. Both plant proteins display the same structural features as their mammalian counterparts and fulfill the same basic functions. To identify their interacting partners, the ear region of At-αC-Ad and the C-terminal region of At-AP180 were used as fusion proteins in pull-down experiments and plasmon-resonance measurements. At-αC-Ad binds several mammalian endocytic proteins, and its interaction with At-AP180 requires the DPF motif. At-AP180 functions as a clathrin assembly protein that promotes the formation of cages with an almost uniform size distribution. Deletion of the single DLL motif abolished the assembly activity of At-AP180 almost completely, but did not affect its binding to triskelia, suggesting the existence of additional binding determinants.
The specific fates of tight junction proteins in apoptotic epithelial cells
Authors: Bojarski Christian , Weiske Jörg , Schöneberg Torsten , Schröder Werner , Mankertz Joachim , Schulzke Jörg-Dieter , Florian Peter , Fromm Michael , Tauber Rudolf , Huber Otmar
Published: April 2004

The polarized morphology of epithelial cells depends on the establishment and maintenance of characteristic intercellular junctions. The dramatic morphological changes observed in apoptotic epithelial cells were ascribed at least in part to the specific fragmentation of components of adherens junctions and desmosomes. Little, however, is known about tight junctions during apoptosis. We have found that after induction of apoptosis in epithelial cells, tight junction proteins undergo proteolytic cleavage in a distinctive manner correlated with a disruption of tight junctions. The transmembrane protein occludin and, likewise, the cytoplasmic adaptor proteins ZO-1 and ZO-2 are fragmented by caspase cleavage. In addition, occludin is cleaved at an extracellular site by a metalloproteinase. The caspase cleavage site in occludin was mapped C-terminally to Asp320 within the C-terminal cytoplasmic domain. Mutagenesis of this site efficiently blocked fragmentation. In the presence of caspase and/or metalloproteinase inhibitors, fragmentation of occludin, ZO-1 and ZO-2 was blocked and cellular morphology was almost fully preserved. Interestingly, two members of the claudin family of transmembrane tight junction proteins exhibited a different behavior. While the amount of claudin-2 protein was reduced similarly to occludin, ZO-1 and ZO-2, claudin-1 was either fully preserved or was even increased in apoptotic cells.
Is the wear factor in total joint replacements dependent on the nominal contact stress in ultra-high molecular weight polyethylene contacts?
Authors: Vassiliou K , Unsworth A
Published: April 2004

The exact dependence of wear factor on contact stress, load and apparent contact area is much disputed in the literature. This study attempts to solve this dispute. Pin-on-plate studies of ultra high molecular weight polyethylene against stainless steel were conducted under different combinations of load (33-250 N), nominal stress (0.56-12.73 MPa) and face diameter, as well as two tests where both stress and load were kept constant, while the diameter was changed. For these tests the centre of the pin face was bored out to create four different average pin diameters with similar face areas. Diameter and load were found to have no significant effect on the wear factor, while the wear factor decreased with increasing contact stress according to the relation K = 2 × 10−6σ−0.84.
An investigation into the effects of the hierarchical structure of tendon fascicles on micromechanical properties
Authors: Screen H R C , Lee D A , Bader D L , Shelton J C
Published: April 2004

During physiological loading, a tendon is subjected to tensile strains in the region of up to 6 per cent. These strains are reportedly transmitted to cells, potentially initiating specific mechano-transduction pathways. The present study examines the local strain fields within tendon fascicles subjected to tensile strain in order to determine the mechanisms responsible for fascicle extension. A hierarchical approach to the analysis was adopted, involving micro and macro examination. Micro examination was carried out using a custom-designed rig, to enable the analysis of local tissue strains in isolated fascicles, using the cell nuclei as strain markers. In macro examination, a video camera was used to record images of the fascicles during mechanical testing, highlighting the point of crimp straightening and macro failure. Results revealed that local tensile strains within a collagen fibre were consistently smaller than the applied strain and showed no further increase once fibres were aligned. By contrast, between-group displacements, a measure of fibre sliding, continued to increase beyond crimp straightening, reaching a mean value of 3.9 per cent of the applied displacement at 8 per cent strain. Macro analysis displayed crimp straightening at a mean load of 1 N and sample failure occurred through the slow unravelling of the collagen fibres. Fibre sliding appears to provide the major mechanism enabling tendon fascicle extension within the rat-tail tendon. This process will necessarily affect local and cellular strains and consequently mechanotransduction pathways.
The application of force-sensing resistor sensors for measuring forces developed by the human hand
Authors: Nikonovas A , Harrison A J L , Hoult S , Sammut D
Published: April 2004

Most attempts to measure forces developed by the human hand have been implemented by placing force sensors on the object of interaction. Other researchers have placed sensors just on the subject's fingertips. In this paper, a system is described that measures forces over the entire hand using thin-film sensors and associated electronics. This system was developed by the authors and is able to obtain force readings from up to 60 thin-film sensors at rates of up to 400 samples/s per sensor. The sensors can be placed anywhere on the palm and/or fingers of the hand. The sensor readings, together with a video stream containing information about hand posture, are logged into a portable computer using a multiplexer, analogue-to-digital converter and software developed for the purpose. The system has been successfully used to measure forces involved in a range of everyday tasks such as driving a vehicle, lifting saucepans and hitting a golf ball. In the latter case, results are compared with those from an instrumented golf club. Future applications include the assessment of hand strength following disease, trauma or surgery, and to enable quantitative ergonomic investigations.
A kinematic method to calculate the workspace of the trapeziometacarpal joint
Authors: Kuo Li-Chieh , Cooney W P , Chen Qing-Shan , Kaufman K R , Su Fong-Chin , An Kai-Nan
Published: April 2004

The specific aim of this study was to develop a quantitative method and a kinematic method to evaluate the maximal workspace of the trapeziometacarpal (TM) joint. Six fresh-frozen human cadaver hands were disarticulated 4 cm proximal to the wrist joint and used in this experiment. The three-dimensional motion data of the TM joint was collected by an electromagnetic tracking device at 30 Hz. The workspace was reconstructed according to a complete set of motion data included circumduction, flexion-extension and abduction-adduction. A spherical fitting technique was used to obtain a sphere encompassing all the motion trajectories and estimating the centre of the sphere. The surface area of the maximal TM workspace, located on the one part of the sphere surface, was calculated by surface integration. The interclass correlation coefficient values for the reliability estimation of the repeated measurements of the radius and surface area of all specimens were 0.91 and 0.98 respectively. The mean coefficients of variance of the measured radius and the surface area were 2.04 per cent and 3.65 per cent respectively. The results also showed that using a spherical model to calculate the maximal workspace as an index for assessing TM joint impairment is practical.
Empirical Studies of Financial Innovation: Lots of Talk, Little Action?
Authors: Frame W. Scott , White Lawrence J
Published: April 2004

This paper reviews the extant empirical studies of financial innovation. Adopting broad criteria and spanning a long time horizon, we found surprisingly few studies (39), with most (23) having been conducted since 1998. Especially striking is that only two studies test hypotheses advanced in many descriptive articles as to the economic/environmental conditions that encourage financial innovation. We offer conjectures as to why empirical studies of financial innovation are comparatively rare, including as a culprit the absence of accessible data. We urge financial regulators to undertake more surveys of financial innovation and to make the resulting data available to researchers.
Japan's Financial Crisis and Economic Stagnation
Authors: Hoshi Takeo , Kashyap Anil K
Published: April 2004

We survey the macroeconomic stagnation and financial problems in Japan. The financial sector assessment includes separate analyses of the commercial banks, the life insurance companies and the government's fiscal investment and loan program (FILP). We estimate that the Japanese taxpayer will have to pay at least another ¥100 trillion (20% of GDP) to cover financial system losses. We explain how the current dysfunctional Japanese banking system misallocates funds by keeping many insolvent firms in business. These inefficient firms crowd out potentially profitable ones and worsen macroeconomic stagnation. A sustained macroeconomic recovery requires serious restructuring aimed at stopping this cycle.
Do Democracies Have Different Public Policies than Nondemocracies?
Authors: Mulligan Casey B , Gil Ricard , Sala-i-Martin Xavier
Published: April 2004

Estimates of democracy's effect on the public sector are obtained from comparisons of 142 countries over the years 1960–90. Based on three tenets of voting theory – that voting mutes policy preference intensity, political power is equally distributed in democracies, and the form of voting processes is important—we expect democracy to affect policies that redistribute, or economically favor the political leadership, or enhance efficiency. We do not find such differences. Instead democracy is correlated with policies that limit competition for public office. Alternative modeling approaches emphasize the degree of competition, and deemphasize the form or even existence of voting processes.
Rational Choice Theory and the Paradox of Not Voting
Authors: Feddersen Timothy J
Published: April 2004

Given the extensive evidence of apparently strategic voter behavior, it is unsettling that there is not a canonical rational choice model of voting in elections with costs to vote. But while a canonical model does not yet exist, the literature appears to be converging toward a “group-based” model of turnout, in which group members participate in elections either because they are directly coordinated and rewarded by leaders as in “mobilization” models or because they believe themselves to be ethically obliged to act in a manner that is consistent with the group's interest as in “ethical agent” models. To appreciate the development of group-based models, it will be useful to begin with a discussion of the decision-theoretic literature on voting, with a focus on the paradox of not voting. Then we will move to the game-theoretic and group-based models of voting. A conclusion highlights some of the problems that group-based models of voting must address.
Understanding Why Crime Fell in the 1990s: Four Factors that Explain the Decline and Six that Do Not
Authors: Levitt Steven D
Published: April 2004

Crime dropped sharply and unexpectedly in the United States in the 1990s. I conclude that four factors collectively explain the entire drop in crime: increases in the number of police, increases in the size of the prison population, the waning of the crack epidemic, and the legalization of abortion in the 1970s. Other common explanations for declining crime appear far less important. The factors identified are much less successful in explaining fluctuations in crime in the preceding two decades. The real puzzle is not why crime fell in the 1990s, but rather, why crime did not begin falling earlier.
Is Housing Unaffordable? Why Isn't It More Affordable?
Authors: Quigley John M , Raphael Steven
Published: April 2004

This paper reviews trends in housing affordability in the U.S. over the past four decades. There is little evidence that owner-occupied housing has become less affordable. In contrast, there have been modest increases in the fraction of income that the median renter household devotes to housing. We find pronounced increases in the rent burdens for poor households. We explore the low-income rental market in more detail, analyzing the relative importance of changes in the income distribution, in housing quality, land use regulation, and zoning in affecting rent burdens. We also sketch out some policies that might improve housing affordability.
Grammont inverted total shoulder arthroplasty in the treatment of glenohumeral osteoarthritis with massive rupture of the cuff
Authors: Sirveaux F. , Favard L. , Oudet D. , Huquet D. , Walch G. , Mole D.
Published: April 2004

We reviewed 80 shoulders (77 patients) at a mean follow-up of 44 months after insertion of a Grammont inverted shoulder prosthesis. Three implants had failed and had been revised. The mean Constant score had increased from 22.6 points pre-operatively to 65.6 points at review. In 96% of these shoulders there was no or only minimal pain. The mean active forward elevation increased from 73° to 138°. The integrity of teres minor is essential for the recovery of external rotation and significantly influenced the Constant score. Five cases of aseptic loosening of the glenoid and seven of dissociation of the glenoid component were noted.

This study confirms the promising early results obtained with the inverted prosthesis in the treatment of a cuff-tear arthropathy. It should be considered in the treatment of osteoarthritis with a massive tear of the cuff but should be reserved for elderly patients.
Long-term deterioration of joint evaluation scores
Authors: Ritter M. A. , Thong A.E. , Davis K.E. , Berend M. E. , Meding J. B. , Faris P. M.
Published: April 2004

We investigated the long-term changes in the Harris Hip and Knee Society scores (HSS and KSS) to determine whether they result from overall functional decline rather than actual changes in the condition of the prosthesis. The HHS for 106 total hip arthroplasties with a minimum follow-up of ten years, no medical complications after operation and no evidence of radiological loosening, and the KSS for 264 total knee arthroplasties with a minimum follow-up of 12 years and no medical complications after operation or signs of radiographical loosening were evaluated.

There were statistically significant drops in the functional scoring components of the joint evaluation systems despite no loosening of the prostheses or other significant medical complications. The HHS declined at an average of 0.67 points per year from between three and ten years after operation (p < 0.0001). Contributing to this were deterioration in gait and limp (p < 0.0004), the use of support aids (p < 0.0001), the distance walked (p < 0.0001) and the ability to climb stairs (p < 0.0455). The functional component of the KSS declined significantly at an average 0.88 points per year betwen the third and 12th years (p < 0.0001). There were significant declines in every component of the functional score including the distance walked (p < 0.0001), the ability to climb stairs (p < 0.0001) and the use of support aids (p < 0.0001). The knee score component of the KSS did not decline significantly (p < 0.9750). The combination of functional and pain scores within the HHS system leads to an inaccurate decline in the entire score. The decline of HHS and Knee Society functional scores in total joint arthroplasties, in the absence of implant-related problems, suggests that deterioration in the functional capacity of ageing patients is an important factor in longitudinal studies using these scoring systems.
The use of structural proximal femoral allografts in complex revision hip arthroplasty
Authors: Graham N. M. , Stockley I.
Published: April 2004

Between April 1992 and November 1998 we used 34 massive proximal femoral allografts for femoral reconstruction at revision hip arthroplasty. Seven patients have died and two have been lost to follow-up. There were thus 25 grafts in 24 patients for review. The mean follow-up was 53 months (16 to 101). By the time of the review two patients had undergone a further revision for failure of the allograft. Another had required secondary plating and grafting at the graft-host junction for symptomatic nonunion. One had recurrence of deep sepsis and was being managed conservatively.

Trochanteric union was considered to have occurred radiologically in 16 of the 25 grafts and union at the host-graft junction in 20. Resorption of the allograft was significant in only two hips. We recommend this technique in cases in which femoral bone loss has been catastrophic.
The posterior cruciate ligament during flexion of the normal knee
Authors: Nakagawa S. , Johal P. , Pinskerova V. , Komatsu T. , Sosna A. , Williams A. , Freeman M. A. R.
Published: April 2004

The posterior cruciate ligament (PCL) was imaged by MRI throughout flexion in neutral tibial rotation in six cadaver knees, which were also dissected, and in 20 unloaded and 13 loaded living (squatting) knees. The appearance of the ligament was the same in all three groups. In extension the ligament is curved concave-forwards. It is straight, fully out-to-length and approaching vertical from 60° to 120°, and curves convex-forwards over the roof of the intercondylar notch in full flexion. Throughout flexion the length of the ligament does not change, but the separations of its attachments do.

We conclude that the PCL is not loaded in the unloaded cadaver knee and therefore, since its appearance in all three groups is the same, that it is also unloaded in the living knee during flexion. The posterior fibres may be an exception in hyperextension, probably being loaded either because of posterior femoral lift-off or because of the forward curvature of the PCL. These conclusions relate only to everyday life: none may be drawn with regard to more strenuous activities such as sport or in trauma.