bluuebunny/crossref_metadata_2025 huggingface dataset:
First Nosocomial Outbreak of
Pseudomonas aeruginosa
Producing an Integron-Borne Metallo-β-Lactamase (VIM-2) in the United States
Authors: Lolans K. , Queenan A. M. , Bush K. , Sahud A. , Quinn J. P.
Published: July 2005

Carbapenemases are rare in the United States. This is the first report of a United States nosocomial outbreak of pan-resistant
Pseudomonas aeruginosa
infections due to an integron-borne metallo-β-lactamase, VIM-2. This emergence of carbapenemases on mobile genetic elements in the United States warrants surveillance.
IS
26
-Associated In4-Type Integrons Forming Multiresistance Loci in Enterobacterial Plasmids
Authors: Miriagou Vivi , Carattoli Alessandra , Tzelepi Eva , Villa Laura , Tzouvelekis Leonidas S.
Published: July 2005

Three distinct multiresistant loci from enterobacterial plasmids each comprised an integron and an IS
26
-associated sequence. Sequence comparison suggested a common ancestral structure that derived from an IS
26
insertion into the 5′ conserved segment of an In4-type integron and evolved through acquisition of gene cassettes and IS
26
-mediated recruitment of additional resistance genes of diverse origin.
In Vitro Interaction of Posaconazole and Caspofungin against Clinical Isolates of
Candida glabrata
Authors: Oliveira E. R. , Fothergill A. W. , Kirkpatrick W. R. , Coco B. J. , Patterson T. F. , Redding S. W.
Published: July 2005

Combinations of caspofungin and posaconazole were evaluated by fractional inhibitory concentration index against 119
Candida glabrata
isolates. Synergy was seen in 18% of all isolates and in 4% of fluconazole-resistant isolates at 48 h without evidence of antagonism. This antifungal combination may have utility against this organism.
Nystatin Induces Secretion of Interleukin (IL)-1β, IL-8, and Tumor Necrosis Factor Alpha by a Toll-Like Receptor-Dependent Mechanism
Authors: Razonable Raymund R. , Henault Martin , Watson Harold L. , Paya Carlos V.
Published: July 2005

Nystatin is an antifungal compound with potent proinflammatory properties. Herein, we demonstrate that nystatin induces interleukin (IL)-1β, IL-8, and tumor necrosis factor alpha secretion through its activation of toll-like receptor 1 (TLR1) and TLR2. Hence, a TLR-dependent mechanism could serve as the molecular basis for the proinflammatory properties of nystatin.
Novel Mechanism of Resistance to Oxazolidinones, Macrolides, and Chloramphenicol in Ribosomal Protein L4 of the Pneumococcus
Authors: Wolter Nicole , Smith Anthony M. , Farrell David J. , Schaffner William , Moore Matthew , Whitney Cynthia G. , Jorgensen James H. , Klugman Keith P.
Published: July 2005

Two clinical
Streptococcus pneumoniae
isolates, identified as resistant to macrolides and chloramphenicol and nonsusceptible to linezolid, were found to contain 6-bp deletions in the gene encoding riboprotein L4. The gene transformed susceptible strain R6 so that it exhibited such resistance, with the transformants also showing a fitness cost. We demonstrate a novel bacterial mechanism of resistance to chloramphenicol and nonsusceptibility to linezolid.
Pharmacokinetics of Nelfinavir and Efavirenz in Antiretroviral-Naïve, Human Immunodeficiency Virus-Infected Subjects when Administered Alone or in Combination with Nucleoside Analog Reverse Transcriptase Inhibitors
Authors: Smith Patrick F. , Robbins Gregory K. , Shafer Robert W. , Wu Hulin , Yu Song , Hirsch Martin S. , Merigan Thomas C. , Park Jeong-Gun , Forrest Alan , Fischl Margaret A. , Morse Gene D. ,   the ACTG 384-5006 Team
Published: July 2005

Pharmacokinetic studies were conducted with human immunodeficiency virus-infected patients receiving efavirenz, nelfinavir, or both agents at weeks 4 and 32. Reductions of 25% and 45% were observed in the mean nelfinavir area under the concentration-time curve and minimum concentration of the drug in serum, and there was a 31% more rapid half-life for patients receiving both drugs compared to patients receiving nelfinavir alone. There were no significant differences in efavirenz pharmacokinetics.
In Vivo Transfer of Plasmid-Encoded ACC-1 AmpC from
Klebsiella pneumoniae
to
Escherichia coli
in an Infant and Selection of Impermeability to Imipenem in
K. pneumoniae
Authors: Bidet Philippe , Burghoffer Béatrice , Gautier Valérie , Brahimi Naïma , Mariani-Kurkdjian Patricia , El-Ghoneimi Alaa , Bingen Edouard , Arlet Guillaume
Published: July 2005

We describe in vivo selection of a
Klebsiella pneumoniae
strain with diminished imipenem susceptibility attributable to plasmid-encoded ACC-1 β-lactamase production and loss of a 36-kDa major outer membrane protein, together with transfer of this plasmid from
K. pneumoniae
to
Escherichia coli
in a Tunisian infant.
Isocratic High-Performance Liquid Chromatographic Method with Ultraviolet Detection for Simultaneous Determination of Levels of Voriconazole and Itraconazole and Its Hydroxy Metabolite in Human Serum
Authors: Khoschsorur GholamAli , Fruehwirth Franz , Zelzer Sieglinde
Published: July 2005

A simple, specific method is presented for simultaneous determination of voriconazole and itraconazole and its metabolite, hydroxyitraconazole, in human serum using one-step liquid-liquid extraction and high-performance liquid chromatography. Linearity tests ranged from 0.1 to 8.0 μg/ml; the minimum detectable concentration was 0.03 μg/ml.
In Vitro Synergy Testing of Anidulafungin with Itraconazole, Voriconazole, and Amphotericin B against
Aspergillus
spp. and
Fusarium
spp
Authors: Philip Annie , Odabasi Zekaver , Rodriguez Jose , Paetznick Victor L. , Chen Enuo , Rex John H. , Ostrosky-Zeichner Luis
Published: July 2005

The in vitro interactions of anidulafungin with itraconazole, voriconazole, and amphotericin B were evaluated by using the checkerboard method. For
Aspergillus
spp., anidulafungin with amphotericin B showed indifference for 16/26 isolates, while anidulafungin with either azole showed a synergy trend for 18/26 isolates. All drug combinations showed indifference for 7/7
Fusarium
sp. isolates.
Simple Histidine-Rich Protein 2 Double-Site Sandwich Enzyme-Linked Immunosorbent Assay for Use in Malaria Drug Sensitivity Testing
Authors: Noedl Harald , Bronnert Jan , Yingyuen Kritsanai , Attlmayr Bernhard , Kollaritsch Herwig , Fukuda Mark
Published: July 2005

A simple double-site sandwich enzyme-linked immunosorbent assay (ELISA) for
Plasmodium falciparum
in vitro drug sensitivity tests based on measuring histidine-rich protein 2 (HRP2) is presented. The ELISA uses two commercial monoclonal antibodies and provides a drastically cheaper alternative to the test kits previously used in the HRP2 drug sensitivity test. The assay is simple to establish and perform. The sensitivity is comparable and the drug sensitivity results very closely match those obtained with the commercial ELISA kits (
R
2
= 0.979; P < 0.001; mean log difference at the 50% inhibitory concentration = 0.07).
Inducement and Reversal of Tetracycline Resistance in
Escherichia coli
K-12 and Expression of Proton Gradient-Dependent Multidrug Efflux Pump Genes
Authors: Viveiros Miguel , Jesus Ana , Brito Mafalda , Leandro Clara , Martins Marta , Ordway Diane , Molnar Ana Maria , Molnar Joseph , Amaral Leonard
Published: July 2005

Expression of eight transporter genes of
Escherichia coli
K-12 and its Δ
acrAB
mutant prior to and after induction of both strains to tetracycline resistance and after reversal of induced resistance were analyzed by quantitative reverse transcriptase PCR. All transporter genes were overexpressed after induced resistance with
acrF
being 80-fold more expressed in the Δ
acrAB
tetracycline-induced strain.
Novel Genetic Structure Associated with an Extended-Spectrum β-Lactamase
bla
VEB
Gene in a
Providencia stuartii
Clinical Isolate from Algeria
Authors: Aubert Daniel , Naas Thierry , Lartigue Marie-Frédérique , Nordmann Patrice
Published: July 2005

A ceftazidime-resistant
Providencia stuartii
isolate from Algeria harbored a ca. 160-kb conjugative plasmid that contained a truncated
bla
VEB-1b
gene flanked by three 135-bp repeated elements. This work gives further evidence of the worldwide spread of
bla
VEB
genes that are associated with genetic structures other than class 1 integrons.
Integron-Encoded GES-Type Extended-Spectrum β-Lactamase with Increased Activity toward Aztreonam in
Pseudomonas aeruginosa
Authors: Poirel Laurent , Brinas Laura , Fortineau Nicolas , Nordmann Patrice
Published: July 2005

A
Pseudomonas aeruginosa
strain expresses an extended-spectrum β-lactamase, GES-9, which differs from GES-1 by a Gly243Ser substitution, is inhibited by clavulanic acid and imipenem, and hydrolyzes aztreonam. The
bla
GES-9
gene was located inside a class 1 integron structure containing two copies of a novel insertion sequence belonging to the IS
1111
family.
p38 Mitogen-Activated Protein Kinase-Dependent Hyperinduction of Tumor Necrosis Factor Alpha Expression in Response to Avian Influenza Virus H5N1
Authors: Lee Davy C. W. , Cheung Chung-Yan , Law Anna H. Y. , Mok Chris K. P. , Peiris Malik , Lau Allan S. Y.
Published: July 2005

Avian influenza A virus subtype H5N1 can infect humans to cause a severe viral pneumonia with mortality rates of more than 30%. The biological basis for this unusual disease severity is not fully understood. We previously demonstrated that in contrast to human influenza A virus subtypes including H1N1 or H3N2, the H5N1 virus associated with the “bird flu” outbreak in Hong Kong in 1997 (H5N1/97) hyperinduces proinflammatory cytokines, including tumor necrosis factor alpha (TNF-α), in primary human macrophages in vitro. To delineate the molecular mechanisms involved, we analyzed the role of transcription factor NF-κB and cellular kinases in TNF-α dysregulation. H5N1 and H1N1 viruses did not differ in the activation of NF-κB or degradation of IκB-α in human macrophages. However, we demonstrated that unlike H1N1 virus, H5N1/97 strongly activates mitogen-activated protein kinase (MAPK), including p38 MAPK and extracellular signal-regulated kinases 1 and 2. Specific inhibitors of p38 MAPK significantly reduced the H5N1/97-induced TNF-α expression in macrophages. Taken together, our findings suggest that H5N1/97-mediated hyperinduction of cytokines involves the p38 MAPK signaling pathway. These results may provide insights into the pathogenesis of H5N1 disease and rationales for the development of novel therapeutic strategies.
Mutations That Abrogate Human Immunodeficiency Virus Type 1 Reverse Transcriptase Dimerization Affect Maturation of the Reverse Transcriptase Heterodimer
Authors: Wapling Johanna , Moore Katie L. , Sonza Secondo , Mak Johnson , Tachedjian Gilda
Published: July 2005

The specific impact of mutations that abrogate human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) dimerization on virus replication is not known, as mutations shown previously to inhibit RT dimerization also impact Gag-Pol stability, resulting in pleiotropic effects on HIV-1 replication. We have previously characterized mutations at codon 401 in the HIV-1 RT tryptophan repeat motif that abrogate RT dimerization in vitro, leading to a loss in polymerase activity. The introduction of the RT dimerization-inhibiting mutations W401L and W401A into HIV-1 resulted in the formation of noninfectious viruses with reduced levels of both virion-associated and intracellular RT activity compared to the wild-type virus and the W401F mutant, which does not inhibit RT dimerization in vitro. Steady-state levels of the p66 and p51 RT subunits in viral lysates of the W401L and W401A mutants were reduced, but no significant decrease in Gag-Pol was observed compared to the wild type. In contrast, there was a decrease in processing of p66 to p51 in cell lysates for the dimerization-defective mutants compared to the wild type. The treatment of transfected cells with indinavir suggested that the HIV-1 protease contributed to the degradation of virion-associated RT subunits. These data demonstrate that mutations near the RT dimer interface that abrogate RT dimerization in vitro result in the production of replication-impaired viruses without detectable effects on Gag-Pol stability or virion incorporation. The inhibition of RT activity is most likely due to a defect in RT maturation, suggesting that RT dimerization represents a valid drug target for chemotherapeutic intervention.
Human Cytomegalovirus UL131 Open Reading Frame Is Required for Epithelial Cell Tropism
Authors: Wang Dai , Shenk Thomas
Published: July 2005

Epithelial cells are one of the prominent cell types infected by human cytomegalovirus (HCMV) within its host. However, many cultured epithelial cells, such as ARPE-19 retinal pigmented epithelial cells, are poorly infected by laboratory-adapted strains in cell culture, and little is known about the viral factors that determine HCMV epithelial cell tropism. In this report, we demonstrate that the UL131 open reading frame (ORF), and likely the entire UL131-128 locus, is required for efficient infection of epithelial cells. Repair of the mutated UL131 gene in the AD169 laboratory strain of HCMV restored its ability to infect both epithelial and endothelial cells while compromising its ability to replicate in fibroblasts. ARPE-19 epithelial cells support replication of the repaired AD169 virus as well as clinical isolates of HCMV. Productive infection of cultured epithelial cells, endothelial cells, and fibroblasts with the repaired AD169 virus leads to extensive membrane fusion and syncytium formation, suggesting that the virus may spread through cell-cell fusion.
cis
-Acting Packaging Signals in the Influenza Virus PB1, PB2, and PA Genomic RNA Segments
Authors: Liang Yuying , Hong Ying , Parslow Tristram G.
Published: July 2005

The influenza A virus genome consists of eight negative-sense RNA segments. The
cis
-acting signals that allow these viral RNA segments (vRNAs) to be packaged into influenza virus particles have not been fully elucidated, although the 5′ and 3′ untranslated regions (UTRs) of each vRNA are known to be required. Efficient packaging of the NA, HA, and NS segments also requires coding sequences immediately adjacent to the UTRs, but it is not yet known whether the same is true of other vRNAs. By assaying packaging of genetically tagged vRNA reporters during plasmid-directed influenza virus assembly in cells, we have now mapped
cis
-acting sequences that are sufficient for packaging of the PA, PB1, and PB2 segments. We find that each involves portions of the distal coding regions. Efficient packaging of the PA or PB1 vRNAs requires at least 40 bases of 5′ and 66 bases of 3′ coding sequences, whereas packaging of the PB2 segment requires at least 80 bases of 5′ coding region but is independent of coding sequences at the 3′ end. Interestingly, artificial reporter vRNAs carrying mismatched ends (i.e., whose 5′ and 3′ ends are derived from different vRNA segments) were poorly packaged, implying that the two ends of any given vRNA may collaborate in forming specific structures to be recognized by the viral packaging machinery.
The Receptor for the Subgroup C Avian Sarcoma and Leukosis Viruses, Tvc, Is Related to Mammalian Butyrophilins, Members of the Immunoglobulin Superfamily
Authors: Elleder Daniel , Stepanets Volodymir , Melder Deborah C. , Šenigl Filip , Geryk Josef , Pajer Petr , Plachý Jiří , Hejnar Jiří , Svoboda Jan , Federspiel Mark J.
Published: July 2005

The five highly related envelope subgroups of the avian sarcoma and leukosis viruses (ASLVs), subgroup A [ASLV(A)] to ASLV(E), are thought to have evolved from an ancestral envelope glycoprotein yet utilize different cellular proteins as receptors. Alleles encoding the subgroup A ASLV receptors (Tva), members of the low-density lipoprotein receptor family, and the subgroup B, D, and E ASLV receptors (Tvb), members of the tumor necrosis factor receptor family, have been identified and cloned. However, alleles encoding the subgroup C ASLV receptors (Tvc) have not been cloned. Previously, we established a genetic linkage between
tvc
and several other nearby genetic markers on chicken chromosome 28, including
tva
. In this study, we used this information to clone the
tvc
gene and identify the Tvc receptor. A bacterial artificial chromosome containing a portion of chicken chromosome 28 that conferred susceptibility to ASLV(C) infection was identified. The
tvc
gene was identified on this genomic DNA fragment and encodes a 488-amino-acid protein most closely related to mammalian butyrophilins, members of the immunoglobulin protein family. We subsequently cloned cDNAs encoding Tvc that confer susceptibility to infection by subgroup C viruses in chicken cells resistant to ASLV(C) infection and in mammalian cells that do not normally express functional ASLV receptors. In addition, normally susceptible chicken DT40 cells were resistant to ASLV(C) infection after both
tvc
alleles were disrupted by homologous recombination. Tvc binds the ASLV(C) envelope glycoproteins with low-nanomolar affinity, an affinity similar to that of binding of Tva and Tvb with their respective envelope glycoproteins. We have also identified a mutation in the
tvc
gene in line L15 chickens that explains why this line is resistant to ASLV(C) infection.
The Complete Genome Sequence of J Virus Reveals a Unique Genome Structure in the Family
Paramyxoviridae
Authors: Jack Philippa J. M. , Boyle David B. , Eaton Bryan T. , Wang Lin-Fa
Published: July 2005

J virus (J-V) was isolated from feral mice (
Mus musculus
) trapped in Queensland, Australia, during the early 1970s. Although studies undertaken at the time revealed that J-V was a new paramyxovirus, it remained unclassified beyond the family level. The complete genome sequence of J-V has now been determined, revealing a genome structure unique within the family
Paramyxoviridae
. At 18,954 nucleotides (nt), the J-V genome is the largest paramyxovirus genome sequenced to date, containing eight genes in the order 3′-N-P/V/C-M-F-SH-TM-G-L-5′. The two genes located between the fusion (F) and attachment (G) protein genes, which have been named the small hydrophobic (SH) protein gene and the transmembrane (TM) protein gene, encode putative proteins of 69 and 258 amino acids, respectively. The 4,401-nt J-V G gene, much larger than other paramyxovirus attachment protein genes sequenced to date, encodes a putative attachment protein of 709 amino acids and distally contains a second open reading frame (ORF) of 2,115 nt, referred to as ORF-X. Taken together, these novel features represent the most significant divergence to date from the common six-gene genome structure of
Paramyxovirinae
. Although genome analysis has confirmed that J-V can be classified as a member of the subfamily
Paramyxovirinae
, it cannot be assigned to any of the five existing genera within this subfamily. Interestingly, a recently isolated paramyxovirus appears to be closely related to J-V, and preliminary phylogenetic analyses based on putative matrix protein sequences indicate that these two viruses will likely represent a new genus within the subfamily
Paramyxovirinae
.
Epstein-Barr Virus Nuclear Antigen 2 (EBNA2) Gene Deletion Is Consistently Linked with EBNA3A, -3B, and -3C Expression in Burkitt's Lymphoma Cells and with Increased Resistance to Apoptosis
Authors: Kelly Gemma L. , Milner Anne E. , Tierney Rosemary J. , Croom-Carter Debbie S. G. , Altmann Markus , Hammerschmidt Wolfgang , Bell Andrew I. , Rickinson Alan B.
Published: July 2005

Most Epstein-Barr virus (EBV)-positive Burkitt's lymphomas (BLs) carry a wild-type EBV genome and express EBV nuclear antigen 1 (EBNA1) selectively from the BamHI Q promoter (latency I). Recently we identified a distinct subset of BLs carrying both wild-type and EBNA2 gene-deleted (transformation-defective) viral genomes. The cells displayed an atypical “BamHI W promoter (Wp)-restricted” form of latency where Wp (rather than Qp) was active and EBNA1, -3A, -3B, -3C, and -LP were expressed in the absence of EBNA2 or latent membrane proteins 1 and 2. Here we present data strongly supporting the view that the EBNA2-deleted genome is transcriptionally active in these cells and the wild-type genome is silent. Single-cell cloning of three parental Wp-restricted BL lines generated clones carrying either both viral genomes or the EBNA2-deleted genome only, never clones with the wild-type genome only. All rescued clones displayed the Wp-restricted form of latency characteristic of the parent line and retained the original parent cell phenotype. Interestingly, Wp-restricted parent lines and derived clones were markedly more resistant to inducers of apoptosis than standard latency I BL lines. Furthermore, in vitro infection of EBV-negative BL lines with an EBNA2 gene-deleted virus generated EBV-positive converts with Wp-restricted latency and a similarly marked apoptosis resistance. We postulate that, in the subset of BLs displaying Wp-restricted latency, infection of a tumor progenitor cell with an EBNA2 gene-deleted virus has provided that cell with a survival advantage through broadening antigen expression to include the EBNA3 proteins.
Search for a Prion-Specific Nucleic Acid
Authors: Safar Jiri G. , Kellings Klaus , Serban Ana , Groth Darlene , Cleaver James E. , Prusiner Stanley B. , Riesner Detlev
Published: July 2005

Diversity of prion strains was attributed to an elusive nucleic acid, yet a search spanning nearly two decades has failed to identify a prion-specific polynucleotide. In our search for a prion-specific nucleic acid, we analyzed nucleic acids in purified fractions from the brains of Syrian hamsters infected with Sc237 prions. Purification of Sc237 prions removed nucleic acids larger than 50 nucleotides as measured by return refocusing electrophoresis (RRGE). To determine the size of the largest polynucleotide present in purified fractions at an abundance of one molecule per infectious (ID
50
) unit, we measured prions present after inoculation. In order to account for the rapid clearance of prions after intracerebral inoculation, we determined the number of PrP
Sc
molecules and ID
50
units of prions that were retained in brain. Factoring in clearance after inoculation, we estimate that the largest polynucleotide present in our purified fractions at one molecule per ID
50
unit is ≈25 nucleotides in length. In the same fractions, there were ≈3,000 protease-resistant PrP
Sc
molecules per ID
50
unit after accounting for clearance of PrP
Sc
following inoculation. We compared the resistance of Sc237 and 139H prions to inactivation by UV irradiation at 254 nm. Irradiation of homogenates and microsomes diminished prion infectivity by a factor of ≈1,000 but did not alter the strain-specified properties of the Sc237 and 139H prions. The data reported here combined with the production of synthetic prions argue that the 25-mer polynucleotides found in purified prion preparations are likely to be host encoded and of variable sequence; additionally, these 25-mers are unlikely to be prion specific.
Studies of H5N1 Influenza Virus Infection of Pigs by Using Viruses Isolated in Vietnam and Thailand in 2004
Authors: Choi Young Ki , Nguyen Tien Dzung , Ozaki Hiroichi , Webby Richard J. , Puthavathana Pilaipan , Buranathal Chantanee , Chaisingh Arunee , Auewarakul Prasert , Hanh N. T. H. , Ma Sia Kit , Hui Pui Yan , Guan Yi , Peiris Joseph Sriyal Malik , Webster Robert G.
Published: July 2005

To determine whether avian H5N1 influenza viruses associated with human infections in Vietnam had transmitted to pigs, we investigated serologic evidence of exposure to H5N1 influenza virus in Vietnamese pigs in 2004. Of the 3,175 pig sera tested, 8 (0.25%) were positive for avian H5N1 influenza viruses isolated in 2004 by virus neutralization assay and Western blot analysis. Experimental studies of replication and transmissibility of the 2004 Asian H5N1 viruses in pigs revealed that all viruses tested replicated in the swine respiratory tract but none were transmitted to contact pigs. Virus titers from nasal swabs peaked on day 2, and low titers were detected in the liver of two of the four pigs tested. Our findings indicate that pigs can be infected with highly lethal Asian H5N1 viruses but that these viruses are not readily transmitted between pigs under experimental conditions.
Expression of apoptosis related proteins during malignant progression in chronic ulcerative colitis
Authors: van der Woude C J , Moshage H , Homan M , Kleibeuker J H , Jansen P L M , van Dekken H
Published: July 2005

Background:Chronic ulcerative colitis (CUC) is associated with increased risk of developing colon cancer through a dysplasia (intraepithelial neoplasia)–carcinoma sequence.

Aims:To investigate the expression of apoptosis and inflammatory related proteins in CUC.

Methods:The expression of proteins involved in apoptosis and inflammation (inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), Bcl-xl, Fas, and active caspase 3) was investigated and compared with that seen in sporadic colon carcinoma.

Results:COX-2 was negative in the epithelium of all samples. iNOS was clearly present in inflammatory areas in CUC epithelium, weakly expressed in dysplasia, and absent or weakly expressed in tumour cells. Bcl-xl was absent in CUC, increased in dysplasia, and highly expressed in most carcinomas. Fas expression was positive in the surface epithelium of CUC, dysplasia, and most tumour cells. Activated caspase 3 was weakly positive in all samples, indicating limited apoptosis. Compared with CUC associated carcinoma, iNOS was consistently expressed in sporadic colon carcinoma cells, whereas Bcl-xl was almost absent in these tumour cells and Fas was only weakly expressed. Activated caspase 3 was present in normal mucosal samples and some tumour cells.

Conclusion:Apoptosis related proteins—particularly iNOS, Bcl-xl, and Fas—show a distinct pattern of expression in the CUC to carcinoma sequence, which differs from that seen in sporadic carcinoma, but bears a striking resemblance to that seen during neoplastic progression in Barrett’s oesophagus. These results support a causal role for chronic inflammation in cancer development in CUC, and treatment of ulcerative colitis should aim to minimise inflammation.
A rare presentation of zygomycosis (mucormycosis) and review of the literature: Figure 1
Authors: Karanth M , Taniere P , Barraclough J , Murray J A
Published: July 2005

Zygomycosis (mucormycosis) is a rare fungal infection seen most often in association with prolonged neutropenia. Intestinal zygomycosis is extremely rare and difficult to diagnose, but it is important not to miss, because early medical and surgical treatment can improve survival. This report describes a 56 year old woman who developed this infection while receiving chemotherapy for acute lymphoblastic leukaemia. Medical and surgical measures proved unsuccessful because there was a delay in diagnosis and institution of appropriate treatment.
Change of pathology request forms can reduce unwanted requests and tests
Authors: Bailey J , Jennings A , Parapia L
Published: July 2005

Background:Developments in clinical and laboratory medical practice have resulted in a large increase in laboratory workload, with considerable financial implications. It has been shown that the design of laboratory request cards can influence patterns of test ordering and possibly reduce inappropriate requests.

Aims/Methods:To redesign pathology request cards with a view to reducing inappropriate test requesting.

Results:A redesign of the request cards used by general practitioners in the Bradford area led to a significant reduction in the ordering of specific investigations.

Conclusions:The redesigning of pathology request cards can have a beneficial effect on test requesting.
MUC4 expression is a novel prognostic factor in patients with invasive ductal carcinoma of the pancreas
Authors: Saitou M , Goto M , Horinouchi M , Tamada S , Nagata K , Hamada T , Osako M , Takao S , Batra S K , Aikou T , Imai K , Yonezawa S
Published: July 2005

Background:Many patients with invasive ductal carcinoma of the pancreas (IDC) have a poor outcome. MUC4 expression has been implicated as a marker for diagnosis and progression of IDC, but there are no studies of the relation between MUC4 expression and patient prognosis in IDC.

Aims:To investigate the prognostic significance of MUC4 expression in IDC.

Methods:The expression profiles of MUC4, ErbB2, p27, and MUC1 were investigated in IDC tissues from 135 patients by means of immunohistochemistry.

Results:MUC4 was expressed in 43 of the 135 patients with IDC (31.9%). The survival of 21 patients with high MUC4 expression (>20% of neoplastic cells stained) was significantly worse than that of the 114 patients with low MUC4 expression (<20% of neoplastic cells stained) (p  =  0.0043). Univariate analysis showed that high MUC4 expression (p  =  0.0061), large primary tumour status (>T2) (p  =  0.0436), distant metastasis (p  =  0.0383), lymphatic invasion (p  =  0.0243), and surgical margins (p  =  0.0333) were significant risk factors affecting the outcome of patients with IDC. Backward stepwise multivariate analysis showed that MUC4 expression (p  =  0.0121), lymph node metastasis (p  =  0.0245), and lymphatic invasion (p  =  0.0239) were significant independent risk factors. ErbB2, p27, and MUC1 were not independent risk factors.

Conclusions:This study shows that MUC4 expression in IDC is a new independent factor for poor prognosis and predicts the outcome of patients with IDC.
Patients’ perspective of pathology specimens. A prospective study
Authors: Hock Y L , Balachandar C , Dicken S , Bayley C , Ramaiah S
Published: July 2005

Aim:To determine the degree of patients’ interest in surgical pathology specimens. To assess the impact of patients’ involvement in surgical pathology on their understanding of (and confidence in) the storage and use of pathology specimens.

Methods:Forty seven patients were invited to visit the pathology department and view their specimens postoperatively. Those who visited were asked to complete a questionnaire to assess the effect of the visit.

Results:Thirty three of the 47 patients wished to view their specimens, but only 14 actually made the visit. All those who visited indicated that it made them better able to understand the reason for surgery and tissue retention issues, and more likely to consent to the use of excess tissue for research.

Conclusion:In general, patients are keen to know what happens to and what is wrong with the organs removed at surgery, and their involvement in surgical pathology can have positive and beneficial effects both for themselves and the profession.
Granulomatous reactions cause symptoms or clinically imitate treatment resistance in small lymphocytic lymphoma/chronic lymphocytic leukaemia more frequently than in other non-Hodgkin lymphomas
Authors: Brunner A , Kantner J , Tzankov A
Published: July 2005

Aims:The electronic database of the institute of pathology, Medical University of Innsbruck, was reviewed and patient histories studied to analyse systematically the coincidence of granulomatous reactions and lymphomas in a large patient collective, and to find distinct clinicopathological correlations. Five cases of small lymphocytic lymphoma/chronic lymphocytic leukaemia (CLL) associated with granulomatous reactions in lymph nodes and bone marrow were identified, all clinically associated with signs of progressive disease.

Methods:Cases were acquired by reviewing an electronic database comprising approximately 715 000 patients diagnosed between 1993 and 2003. Histochemical, immunohistochemical, and molecular techniques were used to verify diagnosis and associated infectious diseases. Clinical data were obtained from reviewing the charts.

Results:Of 2044 bone marrow and 411 lymph node non-Hodgkin lymphoma biopsy samples, CLL was most frequently associated with bone marrow (two cases) and lymph node granulomas (three cases). These granulomas were mostly composed of epithelioid cells, with or without giant cells, and in all but one case did not show necrosis. All patients with CLL had clinical symptoms primarily caused by the granulomatous disease: two suffered from acid fast bacilli infections (Mycobacterium tuberculosisand mycobacteria other than tuberculosis) and three presented with clinical manifestations of sarcoidosis (the reason a diagnostic biopsy was performed).

Conclusions:Granulomatous reactions in patients with CLL might obscure diagnosis and imitate disease progression and Richter’s transformation. Careful histological examination, exclusion of infectious agents, and a detailed clinical history are essential for correct diagnosis.
Comparison of liquid based cytology and histology for the evaluation of HER-2 status using immunostaining and CISH in breast carcinoma
Authors: Sartelet H , Lagonotte E , Lorenzato M , Duval I , Lechki C , Rigaud C , Cucherousset J , Durlach A , Graesslin O , Abboud P , Doco-Fenzy M , Quereux C , Costa B , Polette M , Munck J-N , Birembaut P
Published: July 2005

Background:HER-2 amplification is an important prognostic biomarker and treatment determinant in breast carcinoma.

Aims:To correlate immunocytochemical (ICC) expression of HER-2 and gene amplification determined by chromogenic in situ hybridisation (CISH) using liquid based cytology (LBC) with immunohistochemistry (IHC) and CISH using histological samples of the same breast carcinomas.

Methods:Frozen sections and cytobrushings of 103 breast carcinomas were analysed. Four techniques were performed on each tumour: two on LBC samples (ICC, and CISH, both graded as positive, indeterminate, or negative) and two on histological samples (IHC and CISH). Two cell lines (MCF-7, negative; BT 474, positive) were used as controls for cytological analysis. A complementary fluorescence in situ hybridisation technique was carried out in histological samples with low amplification (4–10 dots/nucleus).

Results:Interobserver agreement for the four techniques calculated by the κ coefficient indicated a substantial agreement. Nine cases failed in cytology because of poor cellularity. Among 94 cases, 19 were amplified; 73, 12, and 9 tumours were scored 0 or 1+, 2+, and 3+, respectively by IHC and 75, 13, and 6, respectively, by ICC. CISH found no amplification in 72 tumours. Correlations between the IHC and CISH results in the histological and cytological samples were always significant.

Conclusions:Her-2 status could be determined in LBC samples and correlated well with reference histological methods using in situ hybridisation. ICC was less reliable because of the presence of the cytoplasmic membrane. However, these results should be confirmed by a large multicentre study.
Microsatellite instability and gastric non-invasive neoplasia in a high risk population in Cesena, Italy
Authors: Rugge M , Bersani G , Bertorelle R , Pennelli G , Russo V M , Farinati F , Bartolini D , Cassaro M , Alvisi V
Published: July 2005

Background/Aims:In the natural history of gastric cancer, non-invasive neoplasia (NiN) precedes invasive carcinoma. A histological classification of gastric NiN has recently been proposed by a World Health Organisation international panel of experts. Genetic instability is known to be among the molecular pathways involved in gastric oncogenesis. In this retrospective cross sectional study, microsatellite instability (MSI) was analysed in a consecutive series of NiN and NiN related histological alterations from a northern Italian region at high risk for gastric cancer.

Patients/Methods:Fifty five consecutive cases (indefinite for NiN, 29 cases; low grade NiN, 17 cases; high grade NiN, nine cases) were analysed by radioactive polymerase chain reaction and electrophoresis for microsatellite alterations at six loci (BAT25, BAT26, D2S123, D5S346, D17S250, and D3S1317). MSI was defined according to the Bethesda criteria distinguishing: (1) no instability in the analysed loci; (2) low frequency MSI (MSI-L); and (3) high frequency MSI (MSI-H). Immunohistochemical expression of MLH1 and MSH2 proteins was also analysed in all cases.

Results:Overall, MSI was found in 11 of 55 cases (indefinite for NiN, five of 29 (MSI-L, four; MSI-H, one); low grade NiN, three of 17 (MSI-L, one; MSI-H, two); high grade NiN, three of nine (MSI-L, one; MSI-H, two).

Conclusions:In an Italian high risk area for gastric cancer, MSI is part of the spectrum of genetic alterations in gastric non-invasive neoplasia. In European populations at high risk of gastric cancer, DNA repair system alterations are thought to be among the early molecular events in gastric carcinogenesis.
TRIPLICITY OF QUARKS AND LEPTONS
Authors: MA ERNEST
Published: July 2005

Quarks come in three colors and have electric charges in multiples of one-third. There are also three families of quarks and leptons. Though the first two properties can be understood in terms of unification symmetries such as SU(5), SO(10), or E6, why should there only be three families remains a mystery. We propose how all three properties involving the number three are connected in a fivefold application of the gauge symmetry SU(3).
VALUE-AT-RISK AND EXPECTED SHORTFALL FOR LINEAR PORTFOLIOS WITH ELLIPTICALLY DISTRIBUTED RISK FACTORS
Authors: KAMDEM JULES SADEFO
Published: July 2005

In this paper, we generalize the parametric Δ-VaR method from portfolios with normally distributed risk factors to portfolios with elliptically distributed ones. We treat both the expected shortfall and the Value-at-Risk of such portfolios. Special attention is given to the particular case of a multivariate t-distribution.
(QUASI) SPANNERS FOR MOBILE AD HOC NETWORKS
Authors: BERENBRINK PETRA , FRIEDETZKY THOMAS , MAŇUCH JÁN , STACHO LADISLAV
Published: July 2005

We introduce a notion of t-quasi-spanner as an alternative to classical t-spanners. Our motivation for quasi-spanner comes from a problem of computing a sparse backbone for ad hoc wireless networks with fixed transmission ranges. We study computational complexity of the problem of computing sparsest quasi-spanner. Then we concentrate on the case t = 2 and give a distributed algorithm for computing a 2-quasi-spanner with linear number of edges. Finally, we give a modification of our algorithm which performs well on a class of random ad hoc networks.
MAX-MIN FAIR FLOW CONTROL SENSITIVE TO PRIORITIES
Authors: FATOUROU PANAGIOTA , MAVRONICOLAS MARIOS , SPIRAKIS PAUL
Published: July 2005

Flow control is the dominant technique currently used in communication networks for preventing excess traffic from flooding the network, and for handling congestion. In rate-based flow control, transmission rates of sessions are adjusted in an end-to-end manner through a sequence of operations. In this work, we present a theory of max-min fair, rate-based flow control sensitive to priorities of different sessions, as a significant extension of the classical theory of max-min fair, rate-based flow control to networks supporting applications with diverse requirements on network resources.

Each individual session bears a priority function, which maps the session's priority to a transmission rate; the priority is a working abstraction of the session's priority to bandwidth access. Priority functions enable the specification of requirements on bandwidth access by distributed applications, and the formal handling of such requirements. We present priority max-min fairness, as a novel and well motivated fairness condition which requires that assigned rates correspond, through the priority functions, to priorities comprising a max-min vector. We also introduce priority bottleneck algorithms gradually update a session's rate until when its priority is restricted on a priority bottleneck edge of the network. We establish a collection of interesting combinatorial properties of priority bottleneck algorithms. Most significantly, we show that they can only converge to priority max-min fairness.

As an application of our general theory, we embed priority bottleneck algorithms in the more realistic optimistic framework for rate-based flow control. The optimistic framework allows for both decreases and increases of session rates. We exploit these additionally provided semantics to prove further combinatorial properties for the termination of priority bottleneck algorithms in the optimistic framework. We use these properties to conclude the first optimistic algorithms for efficient, max-min fair, rate-based flow control sensitive to priorities.
ANALYTICAL MODELING FOR MULTI-TIER DYNAMIC RESOURCE RESERVATION ALGORITHMS WITH THRESHOLD DERIVATIONS
Authors: Shamala S. , Othman M. , Johari R. , Saman M. Y.
Published: July 2005

The Multi-Tier (M-Tier) algorithm proposed in [1], has enabled an enhanced correlation between dynamic resource utilization and QoS guarantees. The algorithm favored the delay sensitive applications. Indirectly, this infers that the assignment of priorities practiced in the algorithm is static. In redesigning the algorithm, priority assignments should be able to be implemented dynamically. Thus, enabling an embedded element to provide implementation mobility. This would depend upon the current status of the classified buffers and the tolerance level of the delay sensitive traffic. Integrating control parameters to enable alternation in scheduling priorities is an option to resolve the element of partiality present in the M-Tier algorithm. Thereafter, the proposed algorithm will be denoted as the M-Tier(T) algorithm [2]. The paper proposes a detailed mathematical model for the analysis of dynamic resource reservation algorithms implemented in IP switches. The semi-markov process (SMP) approach utilized provides an accurate performance prediction and representation of resource reservation mechanisms. The algorithm correlates the average packet delay and packet loss ratio parameters to activate the dynamic resource reservation mechanism in a hierarchical manner. The developed models are validated through discrete-event simulation. The performance of the algorithm is studied in terms of average packet delay and network throughput.
HYSTERESIS AND SYNCHRONIZATION IN A TWO-LEVEL SYSTEM DRIVEN BY EXTERNAL NOISE
Authors: JURASZEK JAROSŁAW , DYBIEC BARTŁOMIEJ , GUDOWSKA-NOWAK EWA
Published: July 2005

The paper discusses a combined effect of periodic and random perturbations on the onset of hysteresis in a generic two-state system. The interplay of both noises is investigated pointing out variations in signal tuning to the external driving force and their influence on the area and shape of the hysteresis. As an extension to former studies relating dynamic hysteresis to stochastic resonance and synchronization of passages in a double well system, in the present work the effect of the field asymmetry on the response of the system is analyzed.
Leptin inhibits hypothalamic Npy and Agrp gene expression via a mechanism that requires phosphatidylinositol 3-OH-kinase signaling
Authors: Morrison Christopher D. , Morton Gregory J. , Niswender Kevin D. , Gelling Richard W. , Schwartz Michael W.
Published: July 2005

Phosphatidylinositol 3-OH-kinase (PI3K) and STAT3 are signal transduction molecules activated by leptin in brain areas controlling food intake. To investigate their role in leptin-mediated inhibition of hypothalamic neuropeptide Y ( Npy) and agouti-related peptide ( Agrp) gene expression, male Sprague-Dawley rats ( n = 5/group) were either fed ad libitum or subjected to a 52-h fast. At 12-h intervals, the PI3K inhibitor LY-294002 (LY, 1 nmol) or vehicle was injected intracerebroventricularly (ICV) as a pretreatment, followed 1 h later by leptin (3 μg icv) or vehicle. Fasting increased hypothalamic Npy and Agrp mRNA levels ( P < 0.05), and ICV leptin administration prevented this increase. As predicted, LY pretreatment blocked this inhibitory effect of leptin, such that Npy and Agrp levels in LY-leptin-treated animals were similar to fasted controls. By comparison, leptin-mediated activation of hypothalamic STAT3 signaling, as measured by induction of both phospho-STAT3 immunohistochemistry and suppressor of cytokine signaling-3 ( Socs3) mRNA, was not significantly attenuated by ICV LY pretreatment. Because NPY/AgRP neurons project to the hypothalamic paraventricular nucleus (PVN), we next investigated whether leptin activation of PVN neurons is similarly PI3K dependent. Compared with vehicle, leptin increased the number of c-Fos positive cells within the parvocellular PVN ( P = 0.001), and LY pretreatment attenuated this effect by 35% ( P = 0.043). We conclude that leptin requires intact PI3K signaling both to inhibit hypothalamic Npy and Agrp gene expression and activate neurons within the PVN. In addition, these data suggest that leptin activation of STAT3 is insufficient to inhibit expression of Npy or Agrp in the absence of PI3K signaling.
Effects of 2 wk of GH administration on 24-h indirect calorimetry in young, healthy, lean men
Authors: Hansen Mette , Morthorst Rikke , Larsson Benny , Flyvbjerg Allan , Rasmussen Michael Højby , Ørskov Hans , Astrup Arne , Kjaer Michael , Lange Kai Henrik Wiborg
Published: July 2005

The present study was designed as a randomized, double-blind placebo (Plc)-controlled study to determine the effect of 2 wk of growth hormone administration (GH-adm.) on energy expenditure (EE) and substrate oxidation in healthy humans. Sixteen young healthy men were divided into two groups. The study consisted of two 24-h measurements (indirect calorimetry), separated by 2 wk of either Plc or GH injections (6 IU/day). At baseline, no significant differences were observed between the two groups in any of the measured anthropometric, hormonal, or metabolic parameters, neither did the parameters change over time in the Plc group. GH-adm. resulted in a 4.4% increase in 24-h EE ( P < 0.05) and an increase in fat oxidation by 29% ( P < 0.05). However, a decrease in the respiratory quotient was only observed in the postabsorptive phase after an overnight fast (0.84 ± 0.1 to 0.79 ± 0.1, P < 0.05). Furthermore, lean body mass (LBM) was increased by GH-adm. only [62.8 ± 2.5 kg (baseline) vs. 64.7 ± 2.4 kg (after), P < 0.001]. In conclusion, GH-adm. increases 24-h EE, which may be partly explained by increased LBM. Furthermore, GH-adm. stimulates fat combustion, especially in the postabsorptive state.
Hindlimb unloading and female gender attenuate baroreflex-mediated sympathoexcitation
Authors: Foley C. Michael , Mueller Patrick J. , Hasser Eileen M. , Heesch Cheryl M.
Published: July 2005

Exposure to a period of microgravity or bed rest produces several physiological adaptations. These changes, which include an increased incidence of orthostatic intolerance, have an impact when people return to a 1G environment or resume an upright posture. Compared with males, females appear more susceptible to orthostatic intolerance after exposure to real or simulated microgravity. Decreased arterial baroreflex compensation may contribute to orthostatic intolerance. We hypothesized that female rats would exhibit a greater reduction in arterial baroreflex function after hindlimb unloading (HU) compared with male rats. Mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) were recorded in conscious animals after 13–15 days of HU. Baseline HR was elevated in female rats, and HU increased HR in both genders. Consistent with previous results in males, baroreflex-mediated activation of RSNA was blunted by HU in both genders. Maximum RSNA in response to decreases in MAP was reduced by HU (male control 513 ± 42%, n = 11; male HU 346 ± 38%, n = 13; female control 359 ± 44%, n = 10; female HU 260 ± 43%, n = 10). Maximum baroreflex increase in RSNA was lower in females compared with males in both control and HU rats. Both female gender and HU attenuated baroreflex-mediated increases in sympathetic activity. The combined effects of HU and gender resulted in reduced baroreflex sympathetic reserve in females compared with males and could contribute to the greater incidence of orthostatic intolerance in females after exposure to spaceflight or bed rest.