bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular and Functional Analyses of a Human Parvovirus B19 Infectious Clone Demonstrates Essential Roles for NS1, VP1, and the 11-Kilodalton Protein in Virus Replication and Infectivity
Authors: Zhi Ning , Mills Ian P. , Lu Jun , Wong Susan , Filippone Claudia , Brown Kevin E.
Published: May 2006

In an attempt to experimentally define the roles of viral proteins encoded by the B19 genome in the viral life cycle, we utilized the B19 infectious clone constructed in our previous study to create two groups of B19 mutant genomes: (i) null mutants, in which either a translational initiation codon for each of these viral genes was substituted by a translational termination codon or a termination codon was inserted into the open reading frame by a frameshift; and (ii) a deletion mutant, in which half of the hairpin sequence was deleted at both the 5′ and the 3′ termini. The impact of these mutations on viral infectivity, DNA replication, capsid protein production, and distribution was systematically examined. Null mutants of the NS and VP1 proteins or deletion of the terminal hairpin sequence completely abolished the viral infectivity, whereas blocking expression of the 7.5-kDa protein or the putative protein X had no effect on infectivity in vitro. Blocking expression of the proline-rich 11-kDa protein significantly reduced B19 viral infectivity, and protein studies suggested that the expression of the 11-kDa protein was critical for VP2 capsid production and trafficking in infected cells. These findings suggest a previously unrecognized role for the 11-kDa protein, and together the results enhance our understanding of the key features of the B19 viral genome and proteins.
RNA Interference with Measles Virus N, P, and L mRNAs Efficiently Prevents and with Matrix Protein mRNA Enhances Viral Transcription
Authors: Reuter Thorsten , Weissbrich Benedikt , Schneider-Schaulies Sibylle , Schneider-Schaulies Jürgen
Published: May 2006

In contrast to studies with genetically modified viruses, RNA interference allows the analysis of virus infections with identical viruses and posttranscriptional ablation of individual gene functions. Using RNase III-generated multiple short interfering RNAs (siRNAs) against the six measles virus genes, we found efficient downregulation of viral gene expression in general with siRNAs against the nucleocapsid (N), phosphoprotein (P), and polymerase (L) mRNAs, the translation products of which form the ribonucleoprotein (RNP) complex. Silencing of the RNP mRNAs was highly efficient in reducing viral messenger and genomic RNAs. siRNAs against the mRNAs for the hemagglutinin (H) and fusion (F) proteins reduced the extent of cell-cell fusion. Interestingly, siRNA-mediated knockdown of the matrix (M) protein not only enhanced cell-cell fusion but also increased the levels of both mRNAs and genomic RNA by a factor of 2 to 2.5 so that the genome-to-mRNA ratio was constant. These findings indicate that M acts as a negative regulator of viral polymerase activity, affecting mRNA transcription and genome replication to the same extent.
Ultrastructure and Origin of Membrane Vesicles Associated with the Severe Acute Respiratory Syndrome Coronavirus Replication Complex
Authors: Snijder Eric J. , van der Meer Yvonne , Zevenhoven-Dobbe Jessika , Onderwater Jos J. M. , van der Meulen Jannes , Koerten Henk K. , Mommaas A. Mieke
Published: May 2006

The RNA replication complexes of mammalian positive-stranded RNA viruses are generally associated with (modified) intracellular membranes, a feature thought to be important for creating an environment suitable for viral RNA synthesis, recruitment of host components, and possibly evasion of host defense mechanisms. Here, using a panel of replicase-specific antisera, we have analyzed the earlier stages of severe acute respiratory syndrome coronavirus (SARS-CoV) infection in Vero E6 cells, in particular focusing on the subcellular localization of the replicase and the ultrastructure of the associated membranes. Confocal immunofluorescence microscopy demonstrated the colocalization, throughout infection, of replicase cleavage products containing different key enzymes for SARS-CoV replication. Electron microscopy revealed the early formation and accumulation of typical double-membrane vesicles, which probably carry the viral replication complex. The vesicles appear to be fragile, and their preservation was significantly improved by using cryofixation protocols and freeze substitution methods. In immunoelectron microscopy, the virus-induced vesicles could be labeled with replicase-specific antibodies. Opposite to what was described for mouse hepatitis virus, we did not observe the late relocalization of specific replicase subunits to the presumed site of virus assembly, which was labeled using an antiserum against the viral membrane protein. This conclusion was further supported using organelle-specific marker proteins and electron microscopy. Similar morphological studies and labeling experiments argued against the previously proposed involvement of the autophagic pathway as the source for the vesicles with which the replicase is associated and instead suggested the endoplasmic reticulum to be the most likely donor of the membranes that carry the SARS-CoV replication complex.
Nonneutralizing Antibodies Are Able To Inhibit Human Immunodeficiency Virus Type 1 Replication in Macrophages and Immature Dendritic Cells
Authors: Holl Vincent , Peressin Maryse , Decoville Thomas , Schmidt Sylvie , Zolla-Pazner Susan , Aubertin Anne-Marie , Moog Christiane
Published: May 2006

Only five monoclonal antibodies (MAbs) neutralizing a broad range of primary isolates (PI) have been identified up to now. We have found that some MAbs with no neutralizing activities according to the “conventional” neutralization assay, involving phytohemagglutinin-stimulated peripheral blood mononuclear cells as targets, efficiently inhibit the replication of human immunodeficiency virus type 1 (HIV-1) PI in macrophages and immature dendritic cells (iDC). The mechanism of inhibition is distinct from the neutralization of infectivity occurring via Fab fragments and involves the interaction of the F portion with the FcγRs present on macrophages and iDC. We propose that, if such nonneutralizing inhibitory antibodies limit mucosal HIV transmission, they should be induced by vaccination.
Selection and Characterization of Replicon Variants Dually Resistant to Thumb- and Palm-Binding Nonnucleoside Polymerase Inhibitors of the Hepatitis C Virus
Authors: Le Pogam Sophie , Kang Hyunsoon , Harris Seth F. , Leveque Vincent , Giannetti Anthony M. , Ali Samir , Jiang Wen-Rong , Rajyaguru Sonal , Tavares Gisele , Oshiro Connie , Hendricks Than , Klumpp Klaus , Symons Julian , Browner Michelle F. , Cammack Nick , Nájera Isabel
Published: May 2006

Multiple nonnucleoside inhibitor binding sites have been identified within the hepatitis C virus (HCV) polymerase, including in the palm and thumb domains. After a single treatment with a thumb site inhibitor (thiophene-2-carboxylic acid NNI-1), resistant HCV replicon variants emerged that contained mutations at residues Leu419, Met423, and Ile482 in the polymerase thumb domain. Binding studies using wild-type (WT) and mutant enzymes and structure-based modeling showed that the mechanism of resistance is through the reduced binding of the inhibitor to the mutant enzymes. Combined treatment with a thumb- and a palm-binding polymerase inhibitor had a dramatic impact on the number of replicon colonies able to replicate in the presence of both inhibitors. A more exact characterization through molecular cloning showed that 97.7% of replicons contained amino acid substitutions that conferred resistance to either of the inhibitors. Of those, 65% contained simultaneously multiple amino acid substitutions that conferred resistance to both inhibitors. Double-mutant replicons Met414Leu and Met423Thr were predominantly selected, which showed reduced replication capacity compared to the WT replicon. These findings demonstrate the selection of replicon variants dually resistant to two NS5B polymerase inhibitors binding to different sites of the enzyme. Additionally, these findings provide initial insights into the in vitro mutational threshold of the HCV NS5B polymerase and the potential impact of viral fitness on the selection of multiple-resistant mutants.
Cyclin-Dependent Kinase Activity Is Required for Efficient Expression and Posttranslational Modification of Human Cytomegalovirus Proteins and for Production of Extracellular Particles
Authors: Sanchez Veronica , Spector Deborah H.
Published: May 2006

We have previously shown that the addition of the cyclin-dependent kinase (cdk) inhibitor Roscovitine at the beginning of infection of cells with human cytomegalovirus (HCMV) significantly disrupts immediate-early gene expression and the progression of the infection. In the present study, we have examined the effects of cdk inhibition on late viral events by delaying addition of Roscovitine until 24 h postinfection. Although viral DNA replication was inhibited two- to threefold by treatment of infected cells with Roscovitine, the drop did not correspond to the 1- to 2-log-unit decrease in virus titer. Quantification of viral DNA in the supernatant from cells revealed that there was a significant reduction in the production or release of extracellular particles. We observed a lag in the expression of several viral proteins but there was a significant decrease in the steady-state levels of IE2-86. Likewise, the steady-state level of the essential tegument protein UL32 (pp150) was reduced. The levels of pp150 and IE2-86 mRNA were not greatly affected by treatment with Roscovitine and thus did not correlate with the reduced levels of protein. In contrast, the expression of the tegument protein ppUL69 was higher in drug-treated samples, and the protein accumulated in a hyperphosphorylated form. ppUL69 localized to intranuclear aggregates that did not overlap with viral replication centers in cells treated with Roscovitine. Taken together, these data indicate that cdk activity is required at multiple steps during HCMV infection, including the expression, modification, and localization of virus-encoded proteins.
The Role of CD4 T Cells in the Pathogenesis of Murine AIDS
Authors: Li Wen , Green William R.
Published: May 2006

LP-BM5, a retroviral isolate, induces a disease featuring retrovirus-induced immunodeficiency, designated murine AIDS (MAIDS). Many of the features of the LP-BM5-induced syndrome are shared with human immunodeficiency virus-induced disease. For example, CD4 T cells are critical to the development of MAIDS. In vivo depletion of CD4 T cells before LP-BM5 infection rendered genetically susceptible B6 mice MAIDS resistant. Similarly, MAIDS did not develop in B6.nude mice. However, if reconstituted with CD4 T cells, B6.nude mice develop full-blown MAIDS. Our laboratory has shown that the interaction of B and CD4 T cells that is central to MAIDS pathogenesis requires ligation of CD154 on CD4 T cells with CD40 on B cells. However, it is not clear which additional characteristics of the phenotypically and functionally heterogeneous CD4 T-cell compartment are required. Here, in vivo adoptive transfer experiments using B6.nude recipients are employed to compare the pathogenic abilities of CD4 T-cell subsets defined on the basis of cell surface phenotypic or functional differences. Th1 and Th2 CD4 T cells equally supported MAIDS induction. The rare Thy1.2−CD4 subset that expands upon LP-BM5 infection was not necessary for MAIDS. Interestingly, CD45RBlowCD4 T cells supported significantly less disease than CD45RBhighCD4 T cells. Because the decreased MAIDS pathogenesis could not be attributed to inhibition by CD45RBlowCD25+natural T-regulatory cells, an intrinsic property of the CD45RBlowcells appeared responsible. Similarly, there was no evidence that natural T-regulatory cells played a role in LP-BM5-induced pathogenesis in the context of the intact CD4 T-cell population.
Blocking of Interferon-Induced Jak-Stat Signaling by Japanese Encephalitis Virus NS5 through a Protein Tyrosine Phosphatase-Mediated Mechanism
Authors: Lin Ren-Jye , Chang Bi-Lan , Yu Han-Pang , Liao Ching-Len , Lin Yi-Ling
Published: May 2006

Japanese encephalitis virus (JEV), a mosquito-borne flavivirus that causes severe human disease, has been shown to block the interferon (IFN)-induced Janus kinase signal transducer and activation of transcription (Jak-Stat) signaling cascade by preventing Tyk2 tyrosine phosphorylation and Stat activation. In this study, we demonstrate that expression of the JEV nonstructural protein NS5 readily blocked IFN-stimulated Jak-Stat signaling events such as Stat1 nuclear translocation and tyrosine phosphorylation of Tyk2 and Stat1. The region of JEV NS5 responsible for Stat1 suppression was identified using various deletion clones. Deletion of 83 N-terminal residues of JEV NS5, but not the 143 C-terminal residues, abolished its ability to block IFN-stimulated Stat1 activation. The role of JEV NS5 as an IFN antagonist was further demonstrated by its ability to block the induction of interferon-stimulated genes and the antiviral effect of IFN-α against the IFN-sensitive encephalomyocarditis virus, which appears to replicate and kill cells that express NS5 even with alpha IFN treatment. Furthermore, the molecular mechanism responsible for IFN antagonism by NS5 probably involves protein tyrosine phosphatases (PTPs), as the IFN-blocking events in both JEV-infected and NS5-expressing cells were reversed by sodium orthovanadate, a broad-spectrum inhibitor of PTPs. We suggest that JEV NS5 is an IFN antagonist and that it may play a role in blocking IFN-stimulated Jak-Stat signaling via activation of PTPs during JEV infection.
Mutations in Influenza Virus M1 CCHH, the Putative Zinc Finger Motif, Cause Attenuation in Mice and Protect Mice against Lethal Influenza Virus Infection
Authors: Hui Eric Ka-Wai , Smee Donald F. , Wong Min-Hui , Nayak Debi P.
Published: May 2006

Mutations in CCHH, the putative zinc finger motif, apparently do not play an important role in virus replication in MDCK cells in culture (E. K.-W. Hui, K. Ralston, A. K. Judd, and D. P. Nayak, J. Gen. Virol. 84:3105-3113, 2003). In this report, however, we demonstrate that the CCHH motif plays a critical role in virulence in mice and that some CCHH mutants are highly attenuated in BALB/c mice. Some of the mutant viruses replicated the least in mice lungs, induced little or no lung lesions, and caused highly reduced morbidity and mortality. Furthermore, growth patterns of mutant viruses in different cell lines (MDCK, MLE12, 3LL, A549, and 293T) varied. Mutant viruses that were attenuated in mice also grew poorly in mouse and human cells in culture. However, wild-type (WT) and all mutant viruses replicated to the same titer in MDCK (canine) cells or embryonated chicken eggs. Attenuation in mice correlated with reduced growth in mouse cells in culture, suggesting that potential attenuation in a given host can be predicted from the growth characteristics of the virus in cultured cells (preferably lung cells) from the same species. In challenge experiments, mice immunized by infection with attenuated mutant viruses were fully protected from lethal challenge with WT virus. In summary, the replication and attenuating properties of these mutants suggest that the CCHH motif provides a critical determinant for virulence in mouse and that mutations in the CCHH motif yield potential vaccine candidates for the development of live species-specific attenuated influenza virus vaccines.
Deregulation of DNA Damage Signal Transduction by Herpesvirus Latency-Associated M2
Authors: Liang Xiaozhen , Pickering Mary T. , Cho Nam-Hyuk , Chang Heesoon , Volkert Michael R. , Kowalik Timothy F. , Jung Jae U.
Published: May 2006

Infected cells recognize viral replication as a DNA damage stress and elicit a DNA damage response that ultimately induces apoptosis as part of host immune surveillance. Here, we demonstrate a novel mechanism where the murine gamma herpesvirus 68 (γHV68) latency-associated, anti-interferon M2 protein inhibits DNA damage-induced apoptosis by interacting with the DDB1/COP9/cullin repair complex and the ATM DNA damage signal transducer. M2 expression constitutively induced DDB1 nuclear localization and ATM kinase activation in the absence of DNA damage. Activated ATM subsequently induced Chk activation and p53 phosphorylation and stabilization without eliciting H2AX phosphorylation and MRN recruitment to foci upon DNA damage. Consequently, M2 expression inhibited DNA repair, rendered cells resistant to DNA damage-induced apoptosis, and induced a G
1
cell cycle arrest. Our results suggest that γHV68 M2 blocks apoptosis-mediated intracellular innate immunity, which might ultimately contribute to its role in latent infection.
Development of comprehensive disease assessment in systemic vasculitis
Authors: Flossmann O , Bacon P , de Groot K , Jayne D , Rasmussen N , Seo P , Westman K , Luqmani R
Published: May 2006

The systemic vasculitides are multisystem disorders with considerable mortality and morbidity and frequent relapses. In the absence of reliable serological markers, accurate clinical tools are required to assess disease activity and damage for treatment decisions, and for the performance of clinical trials. This article reviews and summarises the development and use of disease assessment tools for determining activity and damage in systemic vasculitis and reports ongoing initiatives for further development of disease assessment tools. A literature search was conducted using PubMed and reference lists for vasculitis, assessment, clinical trials, outcome and prognosis. The findings indicate that comprehensive disease assessment in vasculitis requires documentation of disease activity, chronic irreversible damage and impairment of function.
Proposal for a histopathological consensus classification of the periprosthetic interface membrane
Authors: Morawietz L , Classen R-A , Schröder J H , Dynybil C , Perka C , Skwara A , Neidel J , Gehrke T , Frommelt L , Hansen T , Otto M , Barden B , Aigner T , Stiehl P , Schubert T , Meyer-Scholten C , König A , Ströbel P , Rader C P , Kirschner S , Lintner F , Rüther W , Bos I , Hendrich C , Kriegsmann J , Krenn V
Published: May 2006

Aims:The introduction of clearly defined histopathological criteria for a standardised evaluation of the periprosthetic membrane, which can appear in cases of total joint arthroplasty revision surgery.

Methods:Based on histomorphological criteria, four types of periprosthetic membrane were defined: wear particle induced type (detection of foreign body particles; macrophages and multinucleated giant cells occupy at least 20% of the area; type I); infectious type (granulation tissue with neutrophilic granulocytes, plasma cells and few, if any, wear particles; type II); combined type (aspects of type I and type II occur simultaneously; type III); and indeterminate type (neither criteria for type I nor type II are fulfilled; type IV). The periprosthetic membranes of 370 patients (217 women, 153 men; mean age 67.6 years, mean period until revision surgery 7.4 years) were analysed according to the defined criteria.

Results:Frequency of histopathological membrane types was: type I 54.3%, type II 19.7%, type III 5.4%, type IV 15.4%, and not assessable 5.1%. The mean period between primary arthroplasty and revision surgery was 10.1 years for type I, 3.2 years for type II, 4.5 years for type III and 5.4 years for type IV. The correlation between histopathological and microbiological diagnosis was high (89.7%), and the inter-observer reproducibility sufficient (85%).

Conclusion:The classification proposed enables standardised typing of periprosthetic membranes and may serve as a tool for further research on the pathogenesis of the loosening of total joint replacement. The study highlights the importance of non-infectious, non-particle induced loosening of prosthetic devices in orthopaedic surgery (membrane type IV), which was observed in 15.4% of patients.
Positive immunostaining for thyroid transcription factor-1 in primary and metastatic colonic adenocarcinoma: a note of caution: Figure 1
Authors: Penman D , Downie I , Roberts F
Published: May 2006

Immunohistochemistry for thyroid transcription factor-1 (TTF-1) is considered an important ancillary technique for distinguishing primary pulmonary adenocarcinomas from metastases. A case of metastatic colonic adenocarcinoma in a bronchial biopsy specimen that showed focal positive nuclear staining for TTF-1 is reported here. The primary colonic adenocarcinoma was retrieved from the file and immunostaining also showed focal nuclear positivity for TTF-1. This confirmed the morphological and clinical impression of colonic metastases in the bronchial biopsy specimen. To investigate this apparent aberrant TTF-1 expression, further sections from primary colonic adenocarcinoma were immunostained for TTF-1 using the SPT24 antibody clone. Three of the six cases studied showed focal nuclear positivity with the SPT24 clone. All six cases were subsequently shown to be negative with the 8G7G1 clone. It is concluded that the SPT24 antibody to TTF-1 may show focal nuclear positivity in adenocarcinomas of colorectal origin such that focal staining in small biopsy specimens should be interpreted with caution.
Primary retroperitoneal mucinous cystadenocarcinoma in a male patient
Authors: Thamboo T P , Sim R , Tan S-Y , Yap W-M
Published: May 2006

Primary retroperitoneal mucinous cystadenocarcinomas (PRMCs) are rare. This is the first reported case in the literature in English of PRMC in a man. The 64-year-old man presented with a large retroperitoneal cystic tumour measuring 24×20×16 cm3, which was removed intact. Areas ranging from a benign mucinous cyst to borderline mucinous tumour to mucinous cystadenocarcinoma were observed on microscopy. Strong patchy staining for cytokeratins 7 and 20 and strong diffuse staining for MUC2 and MUC5AC core peptides, similar to staining patterns in ovarian mucinous tumours, were shown in the benign and atypical epithelium. Staining for CA19.9 and carcinoembryonic antigen was also shown by both components. The theory of its origin from the mucinous metaplasia of peritoneal (mesothelial) inclusion cysts, rather than from ectopic ovarian tissue or ovarian teratomas, is supported by the occurrence of such a tumour in a male patient.
An update on molecular genetics of gastrointestinal stromal tumours
Authors: Tornillo L , Terracciano L M
Published: May 2006

Gastrointestinal stromal tumours (GISTs) are the most common primary mesenchymal tumours of the gastrointestinal tract. Most of them show activating mutations of the genes coding for KIT or platelet-derived growth factor receptor α (PDGFRα), two receptor tyrosine kinases (RTKs). The RTK inhibitor Imatinib (Gleevec®, Novartis, Switzerland), induces regression of the tumour. The level of response to treatment, together with other clinicopathological parameters is related to the type and site of the activating mutation, thus suggesting that these tumours should be classified according to the molecular context. This is confirmed also by the phenomenon of the resistance to treatment, which arises because of different mechanisms (second mutation, amplification, activation of other RTKs) and can be fought only by specific RTK inhibitors, that are at present under development. RTK activation involves an homogeneous transduction pathway whose components (MAPK, AKT, PI3K, mTOR and RAS) are possible targets of new molecular treatment. A new paradigm of classification integrating the classic pathological criteria with the molecular changes will permit personalised prognosis and treatment.
Metastatic recurrence of early-stage colorectal cancer is linked to loss of heterozygosity on chromosomes 4 and 14q
Authors: Al-Mulla F , AlFadhli S , Al-Hakim A H , Going J J , Bitar M S
Published: May 2006

Objective:To investigate the prognostic value for loss of heterozygosity (LOH) of chromosomes 4 and 14q in early-stage colorectal cancer (CRC).

Methods:A total of 70, largely microsatellite stable, tumours and their corresponding normal mucosa were subjected to microdissection and analysed for LOH at chromosomes 4 and 14q by using 13 highly polymorphic microsatellite markers. LOH was correlated with the survival of the patients, using univariate, multivariate and Kaplan–Meier’s survival curves.

Result:LOH at D4S2935, D4S1579 and D4S1595 on chromosome 4 was significantly associated with metastatic recurrence of early-stage CRC. For chromosome arm 14q, two minimal regions of deletion were associated with metastatic recurrence and mapped to neighbouring markers D14S275/D14S49 at 14q12–13 and D14S65/D14S250 at 14q32. High-level loss (loss of five to eight of the informative microsatellite markers) on both chromosomes 4 and 14q, to be an independent prognostic indicator in early-stage CRC was shown by multivariate analysis.

Conclusion:Determining the LOH of chromosomes 4 and 14q and their extent in primary tumours of patients with early-stage CRC may constitute a molecular signature of metastatic recurrence. This may be achieved if new finding sheds light on the treatment of this subgroup of patients that have been largely ignored.
MMP-2 but not MMP-9 associated with COX-2 and survival in gastric cancer
Authors: Mrena J , Wiksten J-P , Nordling S , Kokkola A , Ristimäki A , Haglund C
Published: May 2006

Background and aim:Matrix metalloproteinases (MMPs) MMP-2 and MMP-9 can degrade type IV collagen of extracellular matrix and basal membranes. As cyclo-oxygenase-2 (COX-2) has been shown to activate MMPs, creating one of the COX-2-promoted pathways of tumour growth and metastasis, the prognostic role of MMP-2 and MMP-9 in gastric cancer was assessed and their association with COX-2 expression was evaluated.

Materials and methods:Samples were collected from 342 consecutive patients operated on for gastric cancer, of which 315 were acceptable for MMP-2, MMP-9 and COX-2 immunohistochemistry. Specimens were stained with specific antibodies, evaluated and categorised by two interpreters, and then correlated with clinical data and survival.

Results:Epithelial MMP-2 immunoreactivity was associated with male sex, high stage, advanced penetration depth, non-curative surgery, high COX-2 expression and poor survival. Stromal MMP-2 expression correlated with high stage, intestinal type and non-curative surgery whereas MMP-9 correlated only with intestinal type. Stage, intent of surgery and COX-2 were independent prognostic factors.

Conclusions:Epithelial MMP-2 expression in gastric cancer is associated with aggressive forms, COX-2 and poor survival, although MMP-2 was not an independent prognostic factor. In gastric cancer tumour growth is apparently induced by COX-2, and invasion is mediated by MMP-2.
Prognostic significance of expression patterns of c-erbB-2, p53, p16INK4A, p27KIP1, cyclin D1 and epidermal growth factor receptor in oesophageal adenocarcinoma: a tissue microarray study
Authors: Langer R , Von Rahden B H A , Nahrig J , Von Weyhern C , Reiter R , Feith M , Stein H J , Siewert J R , Höfler H , Sarbia M
Published: May 2006

Aims:To correlate immunohistochemical expression patterns and prognosis in oesophageal adenocarcinoma.

Methods:The expression of c-erbB-2, p53, p16INK4A, p27KIP1, cyclin D1 and epidermal growth factor receptor (EGFR) was studied in a series of 137 primarily resected oesophageal adenocarcinoma samples. The expression analysis on protein level was performed on routine paraffin wax-embedded material, with immunohistochemical staining of the samples, assembled on a tissue microarray. The results were correlated with clinicopathological features (pT, pN and G) and survival.

Results:22 (16%) tumours showed an overexpression of the c-erbB-2 oncoprotein. Expression of EGFR was observed in 72 (55%) cases, accumulation of p53 in 68 (52%) cases and of cyclin D1 in 102 (77%) cases. Loss of p16INK4Aexpression was observed in 101 (76%) cases and low expression of p27KIP1in 91 (71%) cases. Expression of these proteins did not correlate with tumour stage, grade, Lauren’s or World Health Organization classification or lymph node status. On univariate survival analysis, more advanced tumour stage (p = 0.002), lymph node involvement (p = 0.003), high tumour grade (p = 0.017) and lack of EGFR expression (p = 0.034) were found to be associated with poorer survival. On multiple regression analysis, only tumour stage (p = 0.03) and lymph node involvement (p = 0.004) were shown to have an association with the survival of the patient.

Conclusion:The immunohistochemical expression of c-erbB-2 oncoprotein, cylin D1, p16INK4A, p27KIP1, p53 and EGFR in most oesophageal adenocarcinomas suggests their implication in the pathogenesis of this entity. None of the molecular markers assessed, however, was of prognostic value. Identification of any marker superior to or even approaching the prognostic value of conventional histopathological markers (pT and pN) was therefore not possible.
Evaluation and ethical review of a tool to explore patient preferences for information and involvement in decision making
Authors: Murtagh F E M , Thorns A
Published: May 2006

Aim:To improve clinical and ethical understanding of patient preferences for information and involvement in decision making.

Objectives:To develop and evaluate a clinical tool to elicit these preferences and to consider the ethical issues raised.

Design:A before and after study.

Setting:Three UK hospices.

Participants:Patients with advanced life-threatening illnesses and their doctors.

Intervention:Questionnaire on information and decision-making preferences.

Main outcome measures:Patient-based outcome measures were satisfaction with the amount of information given, with the way information was given, with family or carer information, and confidence about future decision making. Doctor-based outcome measures were confidence in matching information to patient preference, matching family or carer communication to patient preference, knowing patient preferences and matching future decision making with patient preference.

Results:Of 336 admissions, 101 patients (mean age 67.3 years, 47.5% men) completed the study (control, n = 40; intervention, n = 61). Patient satisfaction with the way information was given (χ2 = 6.38, df = 2, p = 0.041) and family communication (χ2 = 14.65, df = 2, p<0.001) improved after introduction of the tool. Doctor confidence improved across all outcome measures (all p values<0.001).

Conclusions:Patient satisfaction and doctor confidence were improved by administering the questionnaire, but complex ethical issues were raised by implementing and applying this research. The balance of ethical considerations were changed by advanced life-threatening illness, because there is increased risk of harm through delivery of information discordant with the patient’s own preferences. The importance of truly understanding patient preferences towards the end of life is highlighted by this study.
Judgement and the role of the metaphysics of values in medical ethics
Authors: Thornton T
Published: May 2006

Despite its authors’ intentions, the four principles approach to medical ethics can become crudely algorithmic in practice. The first section sets out the bare bones of the four principles approach drawing out those aspects of Beauchamp and Childress’sPrinciples of biomedical ethicsthat encourage this misreading. The second section argues that if the emphasis on the guidance of moral judgement is augmented by a particularist account of what disciplines it, then the danger can be reduced. In the third section, I consider how much the resultant picture diverges from Beauchamp and Childress’s actual position.
The medical ethics of Dr J Marion Sims: a fresh look at the historical record
Authors: Wall L L
Published: May 2006

Vesicovaginal fistula was a catastrophic complication of childbirth among 19th century American women. The first consistently successful operation for this condition was developed by Dr J Marion Sims, an Alabama surgeon who carried out a series of experimental operations on black slave women between 1845 and 1849. Numerous modern authors have attacked Sims’s medical ethics, arguing that he manipulated the institution of slavery to perform ethically unacceptable human experiments on powerless, unconsenting women. This article reviews these allegations using primary historical source material and concludes that the charges that have been made against Sims are largely without merit. Sims’s modern critics have discounted the enormous suffering experienced by fistula victims, have ignored the controversies that surrounded the introduction of anaesthesia into surgical practice in the middle of the 19th century, and have consistently misrepresented the historical record in their attacks on Sims. Although enslaved African American women certainly represented a “vulnerable population” in the 19th century American South, the evidence suggests that Sims’s original patients were willing participants in his surgical attempts to cure their affliction—a condition for which no other viable therapy existed at that time.
The case for physician assisted suicide: how can it possibly be proven?
Authors: Dahl E , Levy N
Published: May 2006

In her paper,The case for physician assisted suicide: not (yet) proven, Bonnie Steinbock argues that the experience with Oregon’s Death with Dignity Act fails to demonstrate that the benefits of legalising physician assisted suicide outweigh its risks. Given that her verdict is based on a small number of highly controversial cases that will most likely occur under any regime of legally implemented safeguards, she renders it virtually impossible to prove the case for physician assisted suicide. In this brief paper, we suggest some ways that may enable us to weigh the risks and benefits of legalisation more fairly and, hopefully, allow us to close the case for physician assisted suicide.
“Because you’re worth it?” The taking and selling of transplantable organs
Authors: Haddow G
Published: May 2006

In the UK, the legal processes underpinning the procurement system for cadaveric organs for transplantation and research after death are under review. The review originated after media reports of hospitals, such as Alder Hey and Bristol, retaining organs after death without the full, informed consent of relatives. The organ procurement systems for research and transplantation are separate and distinct, but given that legal change will be applicable to both, some have argued now is the time to introduce alternative organ transplant procurement systems such as presumed consent or incentive based schemes (despite inconclusive British and American research on the status of public attitudes). Findings are reported in this paper from qualitative and quantitative research undertaken in Scotland in order to ascertain the public acceptability of different procurement systems. Nineteen in depth interviews carried out with donor families about their experiences of donating the organs of the deceased covered their views of organ retention, presumed consent, and financial incentives. This led onto a representative interview survey of 1009 members of the Scottish public. The originality of the triangulated qualitative and quantitative study offers exploration of alternative organ procurement systems from different “sides of the fence”. The findings suggest that the legal changes taking place are appropriate in clarifying the role of the family but can go further in strengthening the choice of the individual to donate.
The rhythm method and embryonic death
Authors: Bovens L
Published: May 2006

Some proponents of the pro-life movement argue against morning after pills, IUDs, and contraceptive pills on grounds of a concern for causing embryonic death. What has gone unnoticed, however, is that the pro-life line of argumentation can be extended to the rhythm method of contraception as well. Given certain plausible empirical assumptions, the rhythm method may well be responsible for a much higher number of embryonic deaths than some other contraceptive techniques.
Uncertainty, responsibility, and the evolution of the physician/patient relationship
Authors: Henry M S
Published: May 2006

The practice of evidence based medicine has changed the role of the physician from information dispenser to gatherer and analyser. Studies and controlled trials that may contain unknown errors, or uncertainties, are the primary sources for evidence based decisions in medicine. These sources may be corrupted by a number of means, such as inaccurate statistical analysis, statistical manipulation, population bias, or relevance to the patient in question. Regardless of whether any of these inaccuracies are apparent, the uncertainty of their presence in physician information should be disclosed to the patient. These uncertainties are not, however, shared by physicians with patients, and have caused a direct increase in patient responsibilities and mistrust. Only when disclosure of uncertainty becomes commonplace in medical practice will the physician/patient relationship evolve to a level of greater understanding and satisfaction for both the physician and patient.
Creativity, self creation, and the treatment of mental illness
Authors: Rothenberg A
Published: May 2006

This paper examines how an understanding of systematic findings about creative processes involved in art, literature, and science can be applied to the effective treatment of mental illness. These findings and applications are illustrated by particular reference to the work of the poet Sylvia Plath and the treatment of a patient who aspired to become a writer.
“Stepford doctors”: an allegory
Authors: Sayers G M
Published: May 2006

The Stepford Wives, a novel by Ira Levin, provides the theme for this allegory. The men of Stepford belong to the Men’s Association. Their wives are “perfect”, in that they do nothing other than clean, cook, preen, and provide satisfaction without argument for their husbands. They are, furthermore, content with their lot, and believe that their previous interests and freedoms were self indulgent. Levin never informs his readers how the men came to obtain total mastery over their “Stepford wives”, although there is the suggestion that the real wives have been replaced by robotic lookalikes.
Motherhood versus patienthood: a conflict of identities
Authors: Dent J R
Published: May 2006

This paper examines a thread that runs through my memoir of illness: the “shock” of becoming a patient and finding that this new identity, “patienthood”, conflicts with the specific, culturally defined role of mother that I idealise as “motherhood”. I have taken four excerpts from my memoir and discuss them in relation to the way I constructed my intersectional and conflicting identities as mother and patient, both during the initial phase of my illness and in the act of writing about them afterwards. My conclusions echo those of many theorists: while there may be no elusive core self, we are each made up of many identities, many stories, all provisional on factors such as ethnicity, gender, or race, and all in a state of continuous flux in response to changing contexts over time. Furthermore, our identities are often shaped by, and are also shaping, that ethical question: how to lead the “good life”. It is all these dimensions that constitute the richness of individual “selfhood”.
Expressing freedom and taking liberties: the paradoxes of aberrant science
Authors: Little M
Published: May 2006

Complete freedom does not exist, despite people’s preparedness to die for it. Scientific freedom is much defended and yet much misunderstood. Scientists have limits imposed on their freedom by the disciplines and discourse communities in which they place themselves. Freedomwithinthese socially constructed constraints needs to be distinguished from taking liberties with the rules and practices that make up these constraints, and validate the activities of special groups within society. Scientists (and the public) perceive taking liberties with science’s rules and practices asaberrant science, and they often react punitively. Aberrant science can be broadly examined under four headings: wicked science, naughty science, dysfunctional science, and ideologically unacceptable science. When we examine examples of perceived aberrant science, we find that these categories of “misconduct” are connected and often confused. Scientific freedom needs to be redefined with due regard to current understandings of scientists as human beings facing powerful social pressures to deliver results of a particular kind.
Prenatal diagnosis and selective abortion: a result of the cultural turn?
Authors: Bromage D I
Published: May 2006

There is a growing trend in obstetric medicine of prenatal diagnosis and the selective abortion of foetuses that are likely to be born with a disability. Reasons commonly given to explain this trend include the financial implications of screening and testing policies, the disruption to families caused by the birth of a child with a disability, and the potential quality of life of the unborn child. This paper reflects upon another possible reason for this. It is argued that it is, in part, a consequence of our attitudes towards disability and a pursuit of aesthetic perfection. These attitudes arise from a social context that may be explained by considering the effect on the disabled community of the transition from modernity to postmodernity. This shift is demonstrated by inspecting some of the synonymous developments in art history. It is suggested that this “cultural turn” may have both helped and hindered people with disabilities, but the hypothesis requires further testing. This could be best achieved with a qualitative study of what motivates parental decision making in the obstetric unit.
Being the monster: women’s narratives of body and self after treatment for breast cancer
Authors: Rosenblatt L
Published: May 2006

Serious illness and its treatment frequently changes a woman’s sense of herself and her body. Narrative medicine posits that individuals permitted to tell their stories regain control over the plotline of the illness, reclaim the central role as protagonist, and thus diminish the sense of helplessness, marginalisation, and isolation that are inevitable aspects of serious disease. The women presented here speak about losses that occur during treatment for advanced cancer. These losses include: loss of the former body; loss of one or both breasts; loss of hair; loss of fertility, and changes in weight, energy, and sexuality. This paper will not review the medical literature on the psychological aspects of change in appearance secondary to disease and/or treatment. As a way of broadening our understanding of what women attempt to communicate to their care providers about who they are and who they are becoming through the experience of illness, this paper will present brief excerpts from the interviews of four women talking about issues of identity and bodily change, using concepts of feminine identity developed by the French psychoanalytic theorist Hélène Cixous in her essay, The laugh of the Medusa.
Sickness, healing, and opera: Wagner’sParsifal: Figure 1
Authors: Dunn K L
Published: May 2006

Richard Wagner’s operaParsifalis examined as a study in illness, pain and healing. Wagner’s intention was to communicate directly to the audience the “emotional content” of the suffering of the character Amfortas. This presentation of suffering allows us to take from the opera some general ideas about the nature of illness and healing and their metaphorical representation in art. Further insights can be gained from the genre of classical tragic drama, of whichParsifalis a modern example.
Dermal, inhalation, and internal exposure to 1,6-HDI and its oligomers in car body repair shop workers and industrial spray painters
Authors: Pronk A , Yu F , Vlaanderen J , Tielemans E , Preller L , Bobeldijk I , Deddens J A , Latza U , Baur X , Heederik D
Published: May 2006

Objectives:To study inhalation and dermal exposure to hexamethylene diisocyanate (HDI) and its oligomers as well as personal protection equipment (PPE) use during task performance in conjunction with urinary hexamethylene diamine (HDA) in car body repair shop workers and industrial spray painters.

Methods:Personal task based inhalation samples (n = 95) were collected from six car body repair shops and five industrial painting companies using impingers with di-n-butylamine (DBA) in toluene. In parallel, dermal exposure was assessed using nitril rubber gloves. Gloves were submerged into DBA in toluene after sampling. Analysis for HDI and its oligomers was performed by LC-MS/MS. Urine samples were collected from 55 workers (n = 291) and analysed for HDA by GC-MS.

Results:Inhalation exposure was strongly associated with tasks during which aerosolisation occurs. Dermal exposure occurred during tasks that involve direct handling of paint. In car body repair shops associations were found between detectable dermal exposure and glove use (odds ratio (OR) 0.22, 95% confidence interval (CI) 0.09 to 0.57) and inhalation exposure level (OR 1.34, 95% CI 0.97 to 1.84 for a 10-fold increase). HDA in urine could be demonstrated in 36% and 10% of car body repair shop workers and industrial painting company workers respectively. In car body repair shops, the frequency of detectable HDA was significantly elevated at the end of the working day (OR 2.13, 95% CI 1.07 to 4.22 for 3–6 pmv0–8 am). In both branches HDA was detected in urine of ∼25% of the spray painters. In addition HDA was detected in urine of a large proportion of non-spray painters in car body repair shops.

Conclusion:Although (spray) painting with lacquers containing isocyanate hardeners results in the highest external exposures to HDI and oligomers, workers that do not perform paint related tasks may also receive a considerable internal dose.
Incidence of dimethylacetamide induced hepatic injury among new employees in a cohort of elastane fibre workers
Authors: Lee C-Y , Jung S-J , Kim S-A , Park K-S , Ha B-G
Published: May 2006

Objective:To investigate the incidence ofN,N-dimethylacetamide (DMA) induced hepatic injury among new elastane fibre workers and to explore factors relating to DMA induced hepatic injury.

Methods:Elastane fibre workers exposed to DMA were monitored for hepatic injury. Four hundred and forty new workers employed from 1 January 2002 to 31 July 2004 were included as study subjects. DMA exposure estimates were based on urinary N-methylacetamide (NMA) concentrations.

Results:There were 28 cases of DMA induced hepatic injury. The overall incidence of DMA induced hepatic injury among new elastane fibre workers was 0.089/person-year. Incidence rates were 7–10 times higher in high exposure groups than in low exposure groups. Fewer DMA induced hepatic injuries occurred among workers employed for a longer period. Workers whose exposure duration was more than seven months showed no hepatic injury in either the high or low exposure groups. Exposure category and duration of employment were significant variables in the multiple logistic regression analysis.

Conclusions:Results suggest the existence of dose dependent DMA induced hepatic injury. The inverse relation between the incidence of DMA induced hepatic injury and duration of employment may reflect a type of healthy survivor effect or tolerance to DMA induced hepatic injury.