bluuebunny/crossref_metadata_2025 huggingface dataset:
Immunopathogenesis of hepatitis B virus infection
Authors: Chang J Judy , Lewin Sharon R
Published: November 2006

Hepatitis B virus (HBV) infection is a non‐cytopathic hepatotropic virus that can lead to severe liver disease including acute hepatitis, cirrhosis and hepatocellular carcinoma. Successful clearance of the virus as well as the establishment of liver disease is largely driven by a complex interaction between the virus and the host immune response. In this review, the immunological events, including both the innate and adaptive immune response are discussed in the setting of both acute and chronic HBV infection and liver disease.
Serase-1B, a new splice variant of polyserase-1/TMPRSS9, activates urokinase-type plasminogen activator and the proteolytic activation is negatively regulated by glycosaminoglycans
Authors: Okumura Yuushi , Hayama Masaki , Takahashi Etsuhisa , Fujiuchi Mieko , Shimabukuro Aki , Yano Mihiro , Kido Hiroshi
Published: November 2006

Polyserase-1 (polyserine protease-1)/TMPRSS9 (transmembrane serine protease 9) is a type II transmembrane serine protease (TTSP) that possesses unique three tandem serine protease domains. However, the physiological function of each protease domain remains poorly understood. We discovered a new splice variant of polyserase-1, termed Serase-1B, which contains 34 extra amino acids consisting a SEA module (a domain found in sea urchin sperm protein, enterokinase and agrin) adjacent to the transmembrane domain and the first protease domain with a mucin-like box at the C-terminus. The tissue distribution of this enzyme by RT (reverse transcription)–PCR analysis revealed high expression in the liver, small intestine, pancreas, testis and peripheral blood CD14+ and CD8+ cells. To investigate the role of Serase-1B, a full-length form recombinant protein was produced. Interestingly, recombinant Serase-1B was partly secreted as a soluble inactive precursor and it was also activated by trypsin. This activated enzyme selectively cleaved synthetic peptides for trypsin and activated protein C, and it was inhibited by several natural serine protease inhibitors, such as aprotinin, α2-antiplasmin and plasminogen activator inhibitor 1. In addition, Serase-1B efficiently converted pro-uPA (urokinase-type plasminogen activator) into active uPA and this activation was strongly inhibited by these natural inhibitors. Furthermore, this activation was also negatively regulated by glycosaminoglycans. Our results indicate that Serase-1B is a novel member of TTSPs that might be involved in uPA/plasmin-mediated proteolysis and possibly implicated in biological events such as fibrinolysis and tumour progression.
Spatial segregation of transport and signalling functions between human endothelial caveolae and lipid raft proteomes
Authors: Sprenger Richard R. , Fontijn Ruud D. , van Marle Jan , Pannekoek Hans , Horrevoets Anton J. G.
Published: November 2006

Lipid rafts and caveolae are biochemically similar, specialized domains of the PM (plasma membrane) that cluster specific proteins. However, they are morphologically distinct, implying different, possibly complementary functions. Two-dimensional gel electrophoresis preceding identification of proteins by MS was used to compare the relative abundance of proteins in DRMs (detergent-resistant membranes) isolated from HUVEC (human umbilical-vein endothelial cells), and caveolae immunopurified from DRM fractions. Various signalling and transport proteins were identified and additional cell-surface biotinylation revealed the majority to be exposed, demonstrating their presence at the PM. In resting endothelial cells, the scaffold of immunoisolated caveolae consists of only few resident proteins, related to structure [CAV1 (caveolin-1), vimentin] and transport (V-ATPase), as well as the GPI (glycosylphosphatidylinositol)-linked, surface-exposed protein CD59. Further quantitative characterization by immunoblotting and confocal microscopy of well-known [eNOS (endothelial nitric oxide synthase) and CAV1], less known [SNAP-23 (23 kDa synaptosome-associated protein) and BASP1 (brain acid soluble protein 1)] and novel [C8ORF2 (chromosome 8 open reading frame 2)] proteins showed different subcellular distributions with none of these proteins being exclusive to either caveolae or DRM. However, the DRM-associated fraction of the novel protein C8ORF2 (∼5% of total protein) associated with immunoseparated caveolae, in contrast with the raft protein SNAP-23. The segregation of caveolae from lipid rafts was visually confirmed in proliferating cells, where CAV1 was spatially separated from eNOS, SNAP-23 and BASP1. These results provide direct evidence for the previously suggested segregation of transport and signalling functions between specialized domains of the endothelial plasma membrane.
Structural studies on the RNA-recognition motif of NELF E, a cellular negative transcription elongation factor involved in the regulation of HIV transcription
Authors: Rao Jampani N. , Neumann Liane , Wenzel Sabine , Schweimer Kristian , Rösch Paul , Wöhrl Birgitta M.
Published: November 2006

The elongation of transcription of HIV RNA at the TAR (transactivation-response element) is highly regulated by positive and negative factors. The cellular negative transcription elongation factor NELF (negative elongation factor) was suggested to be involved in transcriptional regulation of HIV-1 (HIV type 1) by binding to the stem of the viral TAR RNA which is synthesized by cellular RNA polymerase II at the viral long terminal repeat. NELF is a heterotetrameric protein consisting of NELF A, B, C or the splice variant D, and E. In the present study, we determined the solution structure of the RRM (RNA-recognition motif) of the RNA-binding subunit NELF E and studied its interaction with the viral TAR RNA. Our results show that the separately expressed recombinant NELF E RRM has α-helical and β-strand elements adopting a βαββαβ fold and is able to bind to TAR RNA. Fluorescence equilibrium titrations with fluorescently labelled double- and single-stranded oligoribonucleotides representing the TAR RNA stem imply that NELF E RRM binds to the single-stranded TAR RNAs with Kd values in the low-micromolar range.
Primary attachment of murine leukaemia virus vector mediated by particle-associated heparan sulfate proteoglycan
Authors: Kureishy Nina , Faruque Daisy , Porter Colin D.
Published: November 2006

Target cell entry of murine leukaemia virus vectors proceeds via primary attachment, independent of the viral envelope protein and subsequent envelope–receptor interaction. Although much attention has been paid to modifying the latter for target cell specificity, the initial binding interaction has been overlooked, despite its opposing involvement both in providing the virus available for receptor binding and in depleting free virus. As a first step towards modifying primary attachment, both to provide specificity and to enhance vector availability, we sought to determine the nature of this interaction. Following an initial screen of GAGs (glycosaminoglycans) for their ability to inhibit virus binding and transduction, we have shown that production of virus from cells in which GAG sulfation is inhibited, or treatment of virus with heparinase III, reduces both particle attachment and infection. Detection in purified virus preparations of a neo-epitope generated by heparinase III confirmed the presence of virus-associated HSPG [HS (heparan sulfate) proteoglycan], acquired from the producer cell. We propose that host-acquired cell-surface HSPG (potentially including syndecan-2) provides a means of virus attachment to target cells that precedes specific receptor interaction and membrane fusion. Inhibition of HS biosynthesis may provide a sufficiently reduced background of primary binding such that novel mechanisms of attachment, ideally with appropriate target cell specificity, can be introduced.
SREBP-2 positively regulates transcription of the cholesterol efflux gene, ABCA1, by generating oxysterol ligands for LXR
Authors: Wong Jenny , Quinn Carmel M. , Brown Andrew J.
Published: November 2006

Cholesterol accumulation and removal are regulated by two different transcription factors. SREBP-2 (sterol-regulatory-element-binding protein-2) is best known to up-regulate genes involved in cholesterol biosynthesis and uptake, whereas LXR (liver X receptor) is best known for up-regulating cholesterol efflux genes. An important cholesterol efflux gene that is regulated by LXR is the ATP-binding cassette transporter, ABCA1 (ATP-binding cassette transporter-A1). We have previously shown that statin treatment down-regulated ABCA1 expression in human macrophages, probably by inhibiting synthesis of the LXR ligand 24(S),25-epoxycholesterol. However, it was subsequently reported that ABCA1 expression is down-regulated by SREBP-2 through binding of SREBP-2 to an E-box element in ABCA1's proximal promoter. As statin treatment induces SREBP-2 activation, this may provide an alternative explanation for the statin-mediated down-regulation of ABCA1. In the present study, we employed a set of CHO (Chinese-hamster ovary) mutant cell lines to investigate the role of SREBP-2 in the regulation of ABCA1. We observed increased ABCA1 mRNA levels in SREBP-2-overexpressing cells and decreased levels in cells lacking a functional SREBP-2 pathway, which were restored when the SREBP-2 pathway was reinstated. Moreover, ABCA1 gene expression was positively associated with synthesis of 24(S),25-epoxycholesterol in these cell lines. In studies using a human ABCA1 promoter reporter assay, mutation of the E-box motif had a similar response as the wild-type construct to either statin treatment or addition of 24(S),25-epoxycholesterol. By contrast, these responses were completely ablated when the DR4 element to which LXR binds was mutated. These results support the idea that 24(S),25-epoxycholesterol and statin treatment influence ABCA1 transcription via supply of an LXR ligand and not through an SREBP-2/E-box-related mechanism. In addition, our results indicate a critical role of SREBP-2 as a positive regulator of ABCA1 gene expression by enabling the generation of oxysterol ligands for LXR.
Recruitment of histone deacetylase 4 by transcription factors represses interleukin-5 transcription
Authors: Han Songyan , Lu Jun , Zhang Yu , Cheng Cao , Han Liping , Wang Xiuli , Li Lin , Liu Chunyan , Huang Baiqu
Published: November 2006

The critical role of IL-5 (interleukin-5) in eosinophilic inflammation implicates it as a therapeutic target for allergic diseases. The aim of the present study was to elucidate the molecular basis for the involvement of reversible histone acetylation in IL-5 transcriptional regulation. We provide evidence that HDAC4 (histone deacetylase 4) and p300, a known HAT (histone acetyltransferase), reversibly controlled the activity of the IL-5 promoter in vivo and in vitro, with a concurrent alteration of histone H3 acetylation status at the promoter regions. The nucleo-cytoplasmic shuttling of HDAC4 was shown to play an important role in the suppressive function of HDAC4 in IL-5 gene expression. Point mutation and reporter ChIP (chromatin immunoprecipitation) studies determined that the four transcription factors binding on the IL-5 promoter, i.e. C/EBPβ (CAAT/enhancer-binding protein β), GATA3 (GATA binding protein 3), NFAT (nuclear factor of activated T cells) and YY1 (Yin and Yang 1), were essential for the recruitment of HDAC4. Consistent with these observations, HDAC4 was found to form protein complexes with GATA3 and YY1, and to co-exist in the nuclei with GATA3. We propose that the unique regulatory mechanism of IL-5 gene transcription involves the reversible histone modification catalysed by HDAC4 and p300, which are recruited by the transcription factors. The dynamic balance in IL-5 transcriptional regulation is achieved through interactions among HATs/HDACs, histones and transcription factors. These data contribute to understanding the molecular mechanisms of IL-5 regulation, which is crucial to the development of new therapeutic strategies for IL-5-related allergic diseases.
The CEE Generics Pharmaceutical Sector: Ways to Minimise Cultural Heritage Barriers to Mergers and Acquisitions
Authors: Ross Malcolm , Lupina-Dziomdziora Malgorzata
Published: November 2006

Mergers and acquisitions (M&As), which became extremely common in the branded industry in the 1990s, have recently seen a parallel development in the generics medicines industry. However, generics M&As are more susceptible to impact from cultural barriers. These may become apparent post merger, but can also dramatically affect the success of the negotiations. The reasons for this are discussed and several proposals are made for risk reduction through recognising the importance of the culture differences in play and taking adequate measures to reduce their impact.
Strike While the Iron is Hot: Changing the Rules in Essential Health R&D is Urgently Needed, and is within Reach
Authors: 't Hoen Ellen , Arkinstall James
Published: November 2006

The view that strong intellectual property (IP) protection is necessary for drug development forms the backbone of the current health research and development paradigm. But the evidence shows how this system is fundamentally flawed. Neglected diseases, which count for 12 per cent of the disease burden, but for only 1 per cent of all drugs developed, are an example. The World Health Organization (WHO) Commission on Intellectual Property, Innovation and Public Health is a significant addition to this body of evidence. The report outlines how, despite ever stronger IP regimes through the implementation of the Trade-Related Aspects of Intellectual Property Agreement, the quality and quantity of medical innovation is declining. The report concludes that innovation is meaningless if the products developed can not be accessed by those who need them most. It calls for a global plan of action to identify mechanisms that will stimulate the discovery, development and delivery of health tools that address diseases affecting the poor. In a resolution adopted at the 2006 World Health Assembly, countries took heed of this call and committed to looking at ‘securing an enhanced and sustainable basis for needs-driven, essential health research and development relevant to diseases that disproportionately affect developing countries’. Governments, and the WHO, must not squander this opportunity.
Phylogeographic structure of a freshwater crayfish (Decapoda:Parastacidae:Cherax preissii) in south-western Australia
Authors: Gouws Gavin , Stewart Barbara A. , Daniels Savel R.
Published: November 2006

Although phylogeographic patterns of freshwater decapods elsewhere in Australia are well documented, little is known of the phylogeography and biogeography of the endemic freshwater fauna of south-western Australia. Here, the phylogeographic structure of a freshwater crayfish, Cherax preissii Erichson, 1846, was investigated to determine contemporary and historical patterns of gene flow and to examined evolutionary and biogeographical scenarios. Allozyme and cytochrome c oxidase subunit I mitochondrial DNA data were collected from 15 populations, sampled across the known C. preissii distribution. Both markers revealed a clear distinction and separation among populations occurring in the north-western and southern portions of the distribution. Inferences of allopatric fragmentation and molecular dating attributed the divergence of the aquatic fauna of these regions to periods of Pliocene–Pleistocene aridity. Connectivity appeared to be greater within each of these regions. Evidence suggested contemporary, but not ongoing, gene flow, particularly within the southern region. This was possibly facilitated by dispersal during pluvial Pleistocene periods or drainage connectivity during episodic marine regressions. The divergence and distributions of these lineages parallels patterns seen in other freshwater crayfish of the region. More explicit investigation of these and further fine-scale phylogeographic studies may contribute to the understanding of biogeography and evolution in the south-west, and may further refine currently recognised biogeographical regions.
Intracellular protein interaction mapping with FRET hybrids
Authors: You Xia , Nguyen Annalee W. , Jabaiah Abeer , Sheff Mark A. , Thorn Kurt S. , Daugherty Patrick S.
Published: November 2006

A quantitative methodology was developed to identify protein interactions in a broad range of cell types by using FRET between fluorescent proteins. Genetic fusions of a target receptor to a FRET acceptor and a large library of candidate peptide ligands to a FRET donor enabled high-throughput optical screening for optimal interaction partners in the cytoplasm of
Escherichia coli
. Flow cytometric screening identified a panel of peptide ligands capable of recognizing the target receptors in the intracellular environment. For both SH3 and PDZ domain-type target receptors, physiologically meaningful consensus sequences were apparent among the isolated ligands. The relative dissociation constants of interacting partners could be measured directly by using a dilution series of cell lysates containing FRET hybrids, providing a previously undescribed high-throughput approach to rank the affinity of many interaction partners. FRET hybrid interaction screening provides a powerful tool to discover protein ligands in the cellular context with potential applications to a wide variety of eukaryotic cell types.
Toward cropping systems that enhance productivity and sustainability
Authors: Cook R. James
Published: November 2006

The defining features of any cropping system are (
i
) the crop rotation and (
ii
) the kind or intensity of tillage. The trend worldwide starting in the late 20th century has been (
i
) to specialize competitively in the production of two, three, a single, or closely related crops such as different market classes of wheat and barley, and (
ii
) to use direct seeding, also known as no-till, to cut costs and save soil, time, and fuel. The availability of glyphosate- and insect-resistant varieties of soybeans, corn, cotton, and canola has helped greatly to address weed and insect pest pressures favored by direct seeding these crops. However, little has been done through genetics and breeding to address diseases caused by residue- and soil-inhabiting pathogens that remain major obstacles to wider adoption of these potentially more productive and sustainable systems. Instead, the gains have been due largely to innovations in management, including enhancement of root defense by antibiotic-producing rhizosphere-inhabiting bacteria inhibitory to root pathogens. Historically, new varieties have facilitated wider adoption of new management, and changes in management have facilitated wider adoption of new varieties. Although actual yields may be lower in direct-seed compared with conventional cropping systems, largely due to diseases, the yield potential is higher because of more available water and increases in soil organic matter. Achieving the full production potential of these more-sustainable cropping systems must now await the development of varieties adapted to or resistant to the hazards shown to account for the yield depressions associated with direct seeding.
Two different domains of the luciferase gene in the heterotrophic dinoflagellate
Noctiluca scintillans
occur as two separate genes in photosynthetic species
Authors: Liu Liyun , Hastings J. Woodland
Published: November 2006

Noctiluca scintillans
, a heterotrophic unarmored unicellular bioluminescent dinoflagellate, occurs widely in the oceans, often as a bloom. Molecular phylogenetic analysis based on 18S ribosomal DNA sequences consistently has placed this species on the basal branch of dinoflagellates. Here, we report that the structural organization of its luciferase gene is strikingly different from that of the seven luminous species previously characterized, all of which are photosynthetic. The
Noctiluca
gene codes for a polypeptide that consists of two distinct but contiguous domains. One, which is located in the N-terminal portion, is shorter than but similar in sequence to the individual domains of the three-domain luciferases found in all other luminous dinoflagellates studied. The other, situated in the C-terminal part, has sequence similarity to the luciferin-binding protein of the luminous dinoflagellate
Lingulodinium polyedrum
, encoded there by a separate gene. Western analysis shows that the native protein has the same size (≈100 kDa) as the heterologously expressed polypeptide, indicating that it is not a polyprotein. Thus, sequences found in two proteins in the
L. polyedrum
bioluminescence system are present in a single polypeptide in
Noctiluca
.
Angiopoietin-like 4 prevents metastasis through inhibition of vascular permeability and tumor cell motility and invasiveness
Authors: Galaup Ariane , Cazes Aurelie , Le Jan Sebastien , Philippe Josette , Connault Elisabeth , Le Coz Emmanuelle , Mekid Halima , Mir Lluis M. , Opolon Paule , Corvol Pierre , Monnot Catherine , Germain Stephane
Published: November 2006

Angiopoietin-like 4 (ANGPTL4), a secreted protein of the angiopoietin-like family, is induced by hypoxia in both tumor and endothelial cells as well as in hypoxic perinecrotic areas of numerous cancers. Here, we investigated whether ANGPTL4 might affect tumor growth as well as metastasis. Metastatic 3LL cells were therefore xenografted into control mice and mice in which ANGPTL4 was expressed by using
in vivo
DNA electrotransfer. Whereas primary tumors grew at a similar rate in both groups, 3LL cells metastasized less efficiently to the lungs of mice that expressed ANGPTL4. Fewer 3LL emboli were observed in primary tumors, suggesting that intravasation of 3LL cells was inhibited by ANGPTL4. Furthermore, melanoma B16F0 cells injected into the retro-orbital sinus also metastasized less efficiently in mice expressing ANGPTL4. Although B16F0 cells were observed in lung vessels, they rarely invaded the parenchyma, suggesting that ANGPTL4 affects extravasation. In addition, recombinant B16F0 cells that overexpress ANGPTL4 were generated, showing a lower capacity for
in vitro
migration, invasion, and adhesion than control cells. Expression of ANGPTL4 induced reorganization of the actin cytoskeleton through inhibition of actin stress fiber formation and vinculin localization at focal contacts. Together, these results show that ANGPTL4, through its action on both vascular and tumor compartments, prevents the metastatic process by inhibiting vascular activity as well as tumor cell motility and invasiveness.
Four-dimensional ultrafast electron microscopy of phase transitions
Authors: Grinolds Michael S. , Lobastov Vladimir A. , Weissenrieder Jonas , Zewail Ahmed H.
Published: November 2006

Reported here is direct imaging (and diffraction) by using 4D ultrafast electron microscopy (UEM) with combined spatial and temporal resolutions. In the first phase of UEM, it was possible to obtain snapshot images by using timed, single-electron packets; each packet is free of space–charge effects. Here, we demonstrate the ability to obtain sequences of snapshots (“movies”) with atomic-scale spatial resolution and ultrashort temporal resolution. Specifically, it is shown that ultrafast metal–insulator phase transitions can be studied with these achieved spatial and temporal resolutions. The diffraction (atomic scale) and images (nanometer scale) we obtained manifest the structural phase transition with its characteristic hysteresis, and the time scale involved (100 fs) is now studied by directly monitoring coordinates of the atoms themselves.
Escaping the triple trap: Coping strategies of pregnant adolescent survivors of domestic violence in Mulago hospital, Uganda
Authors: Kaye Dan K. , Ekström Anna Mia , Johansson Annika , Bantebya Grace , Mirembe Florence M.
Published: November 2006

Objective: Why domestic violence survivors develop adverse outcomes following domestic violence during pregnancy is unclear, but may depend on how survivors cope with the stress of violence. The objective was to describe strategies pregnant adolescents employ in coping with domestic violence. Methods: This was a qualitative study involving 16 in-depth interviews with adolescent domestic violence survivors who attended the antenatal clinic in Mulago hospital, Kampala, Uganda, from January to May 2004. Theoretical sampling, necessitated by the emergent theory from sequential data collection and analysis, further provided diversity of experiences from adolescents of different ages, parity, pregnancy duration, and socioeconomic status until saturation was reached. Data were analyzed using grounded theory. Findings: Survivors described varied experiences of physical, sexual, and psychological violence. Coping strategies employed were analyzed as: Minimizing damage — decreasing impact and severity of violence, withdrawal — physical or social withdrawal, seeking help and retaliation (fighting back). Coping strategies were influenced by adolescence and pregnancy, and are explained in relation to theories of coping with stress. Conclusions: Coping strategies adopted by pregnant adolescent survivors range from problem-focused approaches to emotion-focused approaches. Coping strategies are influenced markedly by adolescence and pregnancy.
Checkpoint proteins control morphogenetic events during DNA replication stress in Saccharomyces cerevisiae
Authors: Enserink Jorrit M. , Smolka Marcus B. , Zhou Huilin , Kolodner Richard D.
Published: November 2006

In response to DNA replication stress in Saccharomyces cerevisiae, the DNA replication checkpoint maintains replication fork stability, prevents precocious chromosome segregation, and causes cells to arrest as large-budded cells. The checkpoint kinases Mec1 and Rad53 act in this checkpoint. Treatment of mec1 or rad53Δ mutants with replication inhibitors results in replication fork collapse and inappropriate partitioning of partially replicated chromosomes, leading to cell death. We describe a previously unappreciated function of various replication stress checkpoint proteins, including Rad53, in the control of cell morphology. Checkpoint mutants have aberrant cell morphology and cell walls, and show defective bud site selection. Rad53 shows genetic interactions with septin ring pathway components, and, along with other checkpoint proteins, controls the timely degradation of Swe1 during replication stress, thereby facilitating proper bud growth. Thus, checkpoint proteins play an important role in coordinating morphogenetic events with DNA replication during replication stress.
A Dipeptidyl Aminopeptidase–like Protein Remodels Gating Charge Dynamics in Kv4.2 Channels
Authors: Dougherty Kevin , Covarrubias Manuel
Published: November 2006

Dipeptidyl aminopeptidase–like proteins (DPLPs) interact with Kv4 channels and thereby induce a profound remodeling of activation and inactivation gating. DPLPs are constitutive components of the neuronal Kv4 channel complex, and recent observations have suggested the critical functional role of the single transmembrane segment of these proteins (Zagha, E., A. Ozaita, S.Y. Chang, M.S. Nadal, U. Lin, M.J. Saganich, T. McCormack, K.O. Akinsanya, S.Y. Qi, and B. Rudy. 2005. J. Biol. Chem. 280:18853–18861). However, the underlying mechanism of action is unknown. We hypothesized that a unique interaction between the Kv4.2 channel and a DPLP found in brain (DPPX-S) may remodel the channel's voltage-sensing domain. To test this hypothesis, we implemented a robust experimental system to measure Kv4.2 gating currents and study gating charge dynamics in the absence and presence of DPPX-S. The results demonstrated that coexpression of Kv4.2 and DPPX-S causes a −26 mV parallel shift in the gating charge-voltage (Q-V) relationship. This shift is associated with faster outward movements of the gating charge over a broad range of relevant membrane potentials and accelerated gating charge return upon repolarization. In sharp contrast, DPPX-S had no effect on gating charge movements of the Shaker B Kv channel. We propose that DPPX-S destabilizes resting and intermediate states in the voltage-dependent activation pathway, which promotes the outward gating charge movement. The remodeling of gating charge dynamics may involve specific protein–protein interactions of the DPPX-S's transmembrane segment with the voltage-sensing and pore domains of the Kv4.2 channel. This mechanism may determine the characteristic fast operation of neuronal Kv4 channels in the subthreshold range of membrane potentials.
Features and prognoses of infantile patients with atopic dermatitis hospitalized for severe complications
Authors: KATOH Norito , HOSOI Hajime , SUGIMOTO Tohru , KISHIMOTO Saburo
Published: November 2006

Although atopic dermatitis (AD) itself is regarded as a non‐life threatening disease, childhood AD may be rarely accompanied by some serious complications. Six infantile AD patients who were hospitalized because of severe systemic complications, in addition to severe dermatitis on almost the entire body surface, are described. They were complicated by hypoproteinemia, hypovolemia, thrombocytosis, reduced serum immunoglobulin G, elevated serum liver enzymes and growth retardation. They had not been treated with topical corticosteroid before hospitalization. They were treated with topical corticosteroid and their eruption remarkably improved within 20 days (median) of hospitalization. Most of the abnormal clinical data including platelet numbers, serum levels of total protein, and liver enzymes had become normal at the day of discharge. After 30 ± 4 months of follow up, their skin condition was fair with daily application of moisturizer and occasional use of topical corticosteroid, without any systemic problems. Although severe infantile AD may be accompanied by potentially life‐threatening systemic complications, their prognoses concerning AD are favorable if they are treated adequately from the beginning of their infancy.
Dynamic changes in nerve growth factor and substance P in the murine hair cycle induced by depilation
Authors: ZHOU Zhanchao , KAWANA Seiji , AOKI Eri , KATAYAMA Mirei , NAGANO Masatoshi , SUZUKI Hidenori
Published: November 2006

Increasing evidence suggests that various neurotrophins and neuropeptides play an important role in the progression of hair follicle cycling. Among them, nerve growth factor (NGF) and substance P (SP) have attracted special interest recently. However, the interaction between these factors during hair cycling has not yet been systematically studied. We therefore investigated the mutual relationships between NGF and SP and the mechanism by which the anagen stage of the hair cycle is initiated. Fluctuations in numbers of SP‐positive nerve fibers and variations in amounts of SP, NGF, and another neurotrophic factor, glial cell‐derived neurotrophic factor, in skin in the C57BL/6 mouse depilation‐induced hair cycle model, together with the spatiotemporal expression patterns of each of these factors, were followed simultaneously by enzyme‐linked immunosorbent assay and immunohistochemistry. The main finding was that a surge in NGF expression and a rapid increase in NGF content in skin is an initial event within 1 day after depilation, followed by elevation of SP content and numbers of SP‐containing fibers 2 days after the increase in NGF. Our findings suggest that a rapid and abundant increase in NGF plays a key role in the induction and progression of anagen hair cycling through keratinocyte growth promotion. NGF may also induce plastic changes such as sprouting and hyperplasia in dermal nerve fibers and enhance their SP production. Elevated levels of SP in skin may additionally contribute to the progression of consecutive anagen hair cycles.
Paraneoplastic pemphigus mimicking erosive mucosal lichen planus associated with primary hepatocellular carcinoma
Authors: YOKOKURA Hideto , DEMITSU Toshio , KAKURAI Maki , UMEMOTO Naoka , AZUMA Ryuichi , YAMADA Tomoko , SUZUKI Masayuki , JIMBU Yoshinori , YONEDA Kozo , ISHII Norito , HASHIMOTO Takashi
Published: November 2006

A 58‐year‐old Japanese male visited us with painful lesions on the lower lip, oral mucosa and genital region of an 8‐month duration. Histological features of the genital lesion were almost consistent with lichenoid tissue reaction. A few intraepidermal acantholytic keratinocytes were also seen in the suprabasal clefts. Direct immunofluorescence exhibited cell surface immunoglobulin (Ig)G deposition and linear deposition of fibrinogen at the dermoepidermal junction. IgG anti‐desmoglein (Dsg)3 antibody, but not anti‐Dsg1 antibody, was detected in the patient's serum by enzyme‐linked immunosorbent assay. Immunoblotting using normal human epidermal extract detected the 210‐kD envoplakin, 190‐kD periplakin and 130‐kD Dsg3. The diagnosis of paraneoplastic pemphigus (PNP) was made. Subsequent investigation revealed a large space‐occupying lesion in the liver. Histological findings from liver biopsy specimen were consistent with hepatocellular carcinoma. The patient has been alive 38 months after the diagnosis of PNP was made, although the liver mass has slowly enlarged. Our case is clinically and histologically similar to erosive mucosal lichen planus. Immunological studies confirmed the diagnosis of PNP. The results of negative Dsg1 and positive Dsg3 were consistent with clinical features showing severe mucosal involvement without cutaneous erosion. In PNP, the association with non‐hematological solid tumor is extremely rare.
Childhood pemphigus vulgaris: five cases in 16 years
Authors: YAZGANOĞLU K. Didem , BAYKAL Can , KÜÇÜKOĞLU Rıfkiye
Published: November 2006

Pemphigus vulgaris (PV) usually occurs in adults. There are only a few reports of large PV series concerning childhood cases. We report here five cases of PV in patients younger than 16 years. They were analyzed among 169 PV cases out of a total of 192 pemphigus patients diagnosed between 1988–2004. The ratio of childhood cases was 2.9% in our large PV series. This relatively high ratio of childhood patients suggests that PV should not be neglected in the differential diagnosis of bullous lesions in childhood. Four of the five cases were followed up between 2–4 years and all of these four cases showed at least one relapse. PV also seems to show a relapsing course in the pediatric age group like in adults.
Giant malignant peripheral nerve sheath tumor of the scalp
Authors: FUKUSHIMA Satoshi , KAGESHITA Toshiro , WAKASUGI Shoji , MATSUSHITA Shigeto , KAGUCHI Atushi , ISHIHARA Tsuyoshi , ONO Tomomichi
Published: November 2006

Herein, we describe a rare case of giant malignant peripheral nerve sheath tumor of the head in a 38‐year‐old Japanese man. The tumor measured 210 mm at its largest diameter and was ulcerated, hemorrhagic, multilocular and non‐mobile. It should be noted that the patient stubbornly refused to see a doctor for a long time, resulting in the extreme growth of the tumor. We suspect a psychological basis for this behavior. Dermatohistopathological findings of the biopsy indicated ancient schwannoma and total excision was therefore performed. However, after 4 months, the patient developed multiple metastases and died. Post‐mortem skin biopsy revealed features of malignant peripheral nerve sheath tumor. We performed immunohistochemical studies on the primary and recurrent lesions and concluded that there was a difference in the expression of Ki67 and p16. We propose that the expressions of Ki67 and p16 should be checked for all lesions of peripheral nerve sheath tumor for distinguishing benign from malignant forms.
Pustulosis palmaris et plantaris with prominent hyperkeratosis of the soles
Authors: TSUBOI Hiromi , KATSUOKA Kensei
Published: November 2006

A 50‐year‐old woman developed prominent hyperkeratosis on the soles and erythema of her extremities. In this instance it was clinically difficult to distinguish the palmoplantar lesions from psoriasis vulgaris. However, our case proved to be palmoplantar pustulosis (PPP) because, on histology, the extra‐palmoplantar lesions showed none of the typical findings of psoriasis vulgaris, there was a history of sternoclavicular joint pain, and the lesions improved after tonsillectomy. Herein, we consider the relationship between prominent hyperkeratosis of the sole or palm in PPP and bacterial infection.
Theory of mind, humour processing and executive functioning in alcoholism
Authors: Uekermann J. , Channon S. , Winkel K. , Schlebusch P. , Daum I.
Published: November 2006

Aims  Alcoholism is associated with cognitive deficits, which have been interpreted in terms of a specific vulnerability of the frontal lobes to the toxic effects of alcohol. While executive functions in alcoholism have been investigated extensively, only little work has been carried out on social cognition. The aim of the present study was to investigate the association between executive functions, theory of mind and humour processing in alcoholism.

Design, setting, participants and measurements  A comprehensive neuropsychological test battery was administered to 29 alcoholic patients (Alc) and 29 healthy controls (HC). The test battery included measurements of affect, general intellectual abilities, executive functions, humour processing and theory of mind. The two groups were comparable with respect to affective variables, IQ, gender and age.

Findings and conclusions  Group comparisons revealed cognitive as well as affective humour processing deficits of alcoholics in comparison with HC. The observed impairments were related to theory of mind and executive functions. The deficits may contribute to interpersonal problems and are thus of relevance to rehabilitation.
A database on treating drug addiction with traditional Chinese medicine
Authors: Min Xu , Lee Dominic T. S. , Jinhua Xie , Wenjun Dai , Li Chen , Bin Deng , Pingxiang Deng , Wingho Lam , Xiaoyin Tian , Xiaohui Zhang
Published: November 2006

Aims  Traditional Chinese medicine (TCM) has been used to treat drug addiction for more than 160 years and valuable experiences have been accumulated with regard to patients' detoxification and rehabilitation. The aims of this project were (1) to establish a computerized, bilingual (Chinese–English) database on TCM for drug addiction; (2) to analyse the literature published in this field; and (3) to identify those Chinese herbs commonly used for drug addiction treatment.

Design  (1) Paper collection: related papers were collected through electronic databases and hand‐searched materials; (2) data computerization: the Microsoft Access program and Delphi language were used as the major data management systems; (3) paper analysis: annual publications from 1989 to 2003 were classified and calculated; and (4) herbal analysis: the frequency of herbs used and herbal function categories were analysed.

Findings  (1) A special bilingual database that contained 340 works of professional literature, including 85 patent files on TCM for drug addiction, was established, in which more than 90% of the publications originated from mainland China; (2) the literature classification showed a significant increase in the number of publications on clinical and laboratory researches in this field over the past decade; (3) five functional categorizations of Chinese herbs and the 10 most frequently used Chinese herbs as well as three toxic herbs were identified from more than 200 herbs reported in 150 original research articles and 85 patent files.

Conclusions  For the first time, the published data on TCM in the treatment of drug addiction were analysed systematically by using a new database. The results are invaluable for further laboratory and clinical studies to obtain more direct evidence.
Systematic review: managing anaemia in Crohn's disease
Authors: KULNIGG S. , GASCHE C.
Published: November 2006

Background  Anaemia is a serious complication of Crohn's disease that triggers hospitalization and, if not interfered with, may lead to death.

Aims  To systematically summarize and compare the literature on anaemia in Crohn's disease.

Methods  For this systematic review the literature was searched for English‐language articles using anaemia, Crohn* and IBD as key words. 144 articles were identified and sorted according to the following topics: prevalence, aetiology, diagnostic tests and therapy.

Results  The reported prevalence of anaemia varied between 6.2% and 73.7%, with higher reported frequencies in older studies and in in‐patients. Iron deficiency is the most common underlying condition. Vitamin B12 deficiency is related to the extent of ileal resection but has rarely impact on anaemia. Diagnostic criteria are not established and treatment guidelines are missing. Oral iron supplementation seems effective for short periods but intolerance leads to discontinuation in up to 21%. Eleven of 11 studies show that oral iron enhances intestinal inflammation and colon carcinogenesis in animal models of colitis. Intravenous iron supplementation with iron sucrose has been tested in over 250 Crohn's disease patients, is safe, effective and does not carry such hazards.

Conclusions  As disease activity is determining the degree of anaemia in Crohn's disease, implementation of more effective therapy for Crohn's disease will lower its incidence. However, further studies regarding the safety and effectiveness of iron supplementation are needed.
Effect of vitamin E on aminotransferase levels and insulin resistance in children with non‐alcoholic fatty liver disease
Authors: NOBILI V. , MANCO M. , DEVITO R. , CIAMPALINI P. , PIEMONTE F. , MARCELLINI M.
Published: November 2006

Background  Few data are available on the effect of antioxidants in paediatric non‐alcoholic fatty liver disease (NAFLD).

Aim  To compare the effect of a nutritional programme alone or combined with alpha‐tocopherol and ascorbic acid on alanine aminotransferase (ALT) levels, and insulin resistance (IR) in biopsy‐proven NAFLD children.

Methods  In a 12‐month double‐blind placebo study, 90 patients were prescribed a balanced calorie diet (25–30 cal/kg/d), physical exercise, and placebo (group A) or alpha‐tocopherol 600 IU/day plus ascorbic acid 500 mg/day (group B). IR was estimated by the homeostasis model assessment (HOMA‐IR).

Results  At month 12, ALT (32.67 ± 8.09 vs. 32.18 ± 11.39 IU/L; P = NS), HOMA‐IR (1.52 ± 0.66 vs. 1.84 ± 0.95 IU/L; P = NS), and weight loss (32% vs. 35% of excessive body weight; P = NS) did not differ between the two arms. Among subjects who lost ≥20% of their excessive weight, ALT and body weight percentage changes were significantly related (ro = 0.260; P = 0.03). In subjects, who lost more than 1.0 kg, HOMA‐IR significantly decreased (2.20 ± 0.21 to 1.57 ± 0.13 in group A (P ≤ 0.01; −8%); 2.91 ± 0.24 to 1.88 ± 0.16 in group B (−32%; P ≤ 0.0001)). ALT decreased by 36% (59.13 ± 4.11 vs. 30.27 ± 1.46 IU/L; P ≤ 0.001), and 42% (68.19 ± 5.68 vs. 31.92 ± 1.92 IU/L; P ≤ 0.0001). In a multivariate analysis, fasting insulin changes in group A (P = 0.012; F = 7.150).

Conclusions  Diet and physical exercise in NAFLD children seem to lead to a significant improvement of liver function and glucose metabolism beyond any antioxidant therapy.
Systematic review and meta‐analysis: D‐Penicillamine vs. placebo/no intervention in patients with primary biliary cirrhosis – Cochrane Hepato‐Biliary Group
Authors: GONG Y. , KLINGENBERG S. L. , GLUUD C.
Published: November 2006

Background  d‐Penicillamine is used for patients with primary biliary cirrhosis due to its ability to decrease hepatic copper and modulate the immune response. The results on effects of d‐‐penicillamine in randomized‐clinical trials of primary biliary cirrhosis patients are inconsistent.

Aim  To systematically evaluate the benefits and harms of d‐penicillamine for patients with primary biliary cirrhosis.

Methods  We have performed a systematic review with meta‐analyses of randomized‐clinical trials to evaluate the effects of d‐penicillamine for primary biliary cirrhosis. The primary outcomes are mortality and mortality or liver transplantation. We analysed the data by fixed–effect and random–effect models.

Results  Seven randomized trials including 706 patients were analysed. d‐Penicillamine was without significant effects on mortality (RR 1.08, 95% CI: 0.82–1.43, P = 0.56), mortality or liver transplantation (RR 1.11, 95% CI: 0.74–1.68, P = 0.62), pruritus, liver complications, progression of liver histological stage and liver biochemical variables. d‐‐Penicillamine significantly decreased serum alanine aminotransferase activity (weighted mean difference −45 IU/L, 95% CI: −75 to −15, P < 0.05) and led to significantly more adverse events (RR 4.18, 95% CI: 1.38–12.69, P = 0.01).

Conclusion  d‐Penicillamine did not appear to reduce the risk of mortality or morbidity, and led to more adverse events in patients with primary biliary cirrhosis.
An in vitro comparison of different providers to deliver four proton pump inhibitor products through a feeding tube
Authors: DEVLIN J. W. , BAKSHI A. , BUNGAY K. , OLSEN K. M.
Published: November 2006

Background  It is unclear how delivery through a feeding tube compares between esomeprazole in water, lansoprazole oral disintegrating tablet in water, omeprazole/NaHCO3 in water and simplified lansoprazole suspension.

Aim  This in vitro study compared delivery through a narrow calibre (8F) feeding tube among four proton pump inhibitors when given by skilled [nurse; (n = 8)] or unskilled [lay; (n = 8)] providers.

Methods  Following standard instruction, subjects were observed delivering each proton pump inhibitor in a sequential, but random, fashion to evaluate administration quality and time. Delivery was quantified using high‐performance liquid chromatography methods and subject preferences were evaluated.

Results  Delivery (%), similar between lansoprazole oral disintegrating tablet (95.7 ± 3.2) and omeprazole/NaHCO3 (96.1 ± 3.0), was both greater for lansoprazole oral disintegrating tablet than esomeprazole in water (88.9 ± 8.6; P = 0.006) or simplified lansoprazole suspension (86.1 ± 9.5; P = 0.0001) and omeprazole/NaHCO3 than esomeprazole in water (P = 0.004) or simplified lansoprazole suspension (P < 0.001), and was not affected by prior subject experience. Quality was higher with both omeprazole/NaHCO3 and lansoprazole oral disintegrating tablet than simplified lansoprazole suspension. Administration was quicker for lansoprazole oral disintegrating tablet than esomeprazole in water. Subjects preferred lansoprazole oral disintegrating tablet and omeprazole/NaHCO3.

Conclusions  When given through an in vitro feeding tube, omeprazole/NaHCO3 and lansoprazole oral disintegrating tablet lead to greater drug delivery, improved administration quality and higher user satisfaction, than either esomeprazole in water or simplified lansoprazole suspension.