bluuebunny/crossref_metadata_2025 huggingface dataset:
Dissection of a metastatic gene expression signature into distinct components
Authors: Roepman Paul , de Koning Erica , van Leenen Dik , de Weger Roel A , Kummer J Alain , Slootweg Piet J , Holstege Frank CP
Published: December 2006

Background

Metastasis, the process whereby cancer cells spread, is in part caused by an incompletely understood interplay between cancer cells and the surrounding stroma. Gene expression studies typically analyze samples containing tumor cells and stroma. Samples with less than 50% tumor cells are generally excluded, thereby reducing the number of patients that can benefit from clinically relevant signatures.

Results

For a head-neck squamous cell carcinoma (HNSCC) primary tumor expression signature that predicts the presence of lymph node metastasis, we first show that reduced proportions of tumor cells results in decreased predictive accuracy. To determine the influence of stroma on the predictive signature and to investigate the interaction between tumor cells and the surrounding microenvironment, we used laser capture microdissection to divide the metastatic signature into six distinct components based on tumor versus stroma expression and on association with the metastatic phenotype. A strikingly skewed distribution of metastasis associated genes is revealed.

Conclusion

Dissection of predictive signatures into different components has implications for design of expression signatures and for our understanding of the metastatic process. Compared to primary tumors that have not formed metastases, primary HNSCC tumors that have metastasized are characterized by predominant down-regulation of tumor cell specific genes and exclusive up-regulation of stromal cell specific genes. The skewed distribution agrees with poor signature performance on samples that contain less than 50% tumor cells. Methods for reducing tumor composition bias that lead to greater predictive accuracy and an increase in the types of samples that can be included are presented.
Anthracyclines, Mitoxantrone, Radiotherapy, and Granulocyte Colony-Stimulating Factor: Risk Factors for Leukemia and Myelodysplastic Syndrome After Breast Cancer
Authors: Le Deley Marie-Cécile , Suzan Florence , Cutuli Bruno , Delaloge Suzette , Shamsaldin Akthar , Linassier Claude , Clisant Stéphanie , de Vathaire Florent , Fenaux Pierre , Hill Catherine
Published: December 2006

Purpose

To determine the risk factors for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) after breast cancer.

Patients and Methods

We conducted a case-control study among women treated for breast cancer between 1985 and 2001 in French general hospitals, cancer centers, or clinics. We included 182 AML and MDS patients and 534 matched controls. Breast cancer characteristics, type of treatment, and family history of cancer were compared in both groups.

Results

The risk of AML/MDS was increased after topoisomerase-II inhibitor–based chemotherapy (P < 10−16) and was higher for mitoxantrone-based chemotherapy than for anthracycline-based chemotherapy (relative risk [RR] = 15.6; 95% CI, 7.1 to 34.2; and RR = 2.7; 95% CI, 1.7 to 4.5, respectively). After adjustment for other treatment components, the risk of AML/MDS in patients who received radiotherapy was multiplied by 3.9 (95% CI, 1.4 to 10.8) but was not increased by alkylating agents. Patients receiving granulocyte colony-stimulating factor (G-CSF) support had an increased risk of AML/MDS (RR = 6.3; 95% CI, 1.9 to 21), even when controlling for chemotherapy doses. Similar results were obtained when AML and MDS were considered separately.

Conclusion

This large case-control study demonstrates that the risk of AML/MDS is much higher with mitoxantrone-based chemotherapy than with anthracyclines-based chemotherapy in a population of women recently treated for breast cancer. The risk of AML/MDS associated with mitoxantrone must be kept in mind when using this drug to treat diseases other than breast cancer (eg, prostate cancer or multiple sclerosis). In addition, our study suggests the need to monitor the long-term effects of G-CSF therapy.
Effect of Patient Socioeconomic Status and Body Mass Index on the Quality of Breast Cancer Adjuvant Chemotherapy
Authors: Griggs Jennifer J. , Culakova Eva , Sorbero Melony E.S. , van Ryn Michelle , Poniewierski Marek S. , Wolff Debra A. , Crawford Jeffrey , Dale David C. , Lyman Gary H.
Published: December 2006

Purpose

The purpose of this study was to investigate the relationship between socioeconomic status (SES) and the use of intentionally reduced doses of chemotherapy in the adjuvant treatment of breast cancer.

Patients and Methods

Patients with breast cancer treated with a standard chemotherapy regimen (n = 764) were enrolled in a prospective registry after signing informed consent. Detailed information was collected on patient, disease, and treatment, including chemotherapy doses. Zip code level data on median household income, proportion of people living below the poverty level, and educational attainment were obtained from the US Census. Doses for the first cycle of chemotherapy lower than 85% of standard were considered to be reduced. Univariate analyses and multivariate logistic regression were performed to identify factors associated with the use of reduced first cycle doses.

Results

In univariate analysis, individual education attainment, zip code SES measures, body mass index, and geographic region were all significantly associated with receipt of intentionally reduced doses of chemotherapy. In multivariate analysis, controlling for geography, factors independently associated with reduced doses were obesity (odds ratio [OR], 2.47; 95% CI, 1.36 to 4.51), severe obesity (OR, 4.04; 95% CI, 1.46 to 11.19), and education less than high school (OR, 3.07; 95% CI, 1.57 to 5.99).

Conclusion

Social disparities in breast cancer outcomes may be in part the result of lower quality chemotherapy doses in the adjuvant treatment of breast cancer. Efforts to address such prescribing patterns may help reduce SES disparities in breast cancer survival.
American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer
Authors: Wolff Antonio C. , Hammond M. Elizabeth H. , Schwartz Jared N. , Hagerty Karen L. , Allred D. Craig , Cote Richard J. , Dowsett Mitchell , Fitzgibbons Patrick L. , Hanna Wedad M. , Langer Amy , McShane Lisa M. , Paik Soonmyung , Pegram Mark D. , Perez Edith A. , Press Michael F. , Rhodes Anthony , Sturgeon Catharine , Taube Sheila E. , Tubbs Raymond , Vance Gail H. , van de Vijver Marc , Wheeler Thomas M. , Hayes Daniel F.
Published: December 2006

Purpose

To develop a guideline to improve the accuracy of human epidermal growth factor receptor 2 (HER2) testing in invasive breast cancer and its utility as a predictive marker.

Methods

The American Society of Clinical Oncology and the College of American Pathologists convened an expert panel, which conducted a systematic review of the literature and developed recommendations for optimal HER2 testing performance. The guideline was reviewed by selected experts and approved by the board of directors for both organizations.

Results

Approximately 20% of current HER2 testing may be inaccurate. When carefully validated testing is performed, available data do not clearly demonstrate the superiority of either immunohistochemistry (IHC) or in situ hybridization (ISH) as a predictor of benefit from anti-HER2 therapy.

Recommendations

The panel recommends that HER2 status should be determined for all invasive breast cancer. A testing algorithm that relies on accurate, reproducible assay performance, including newly available types of brightfield ISH, is proposed. Elements to reliably reduce assay variation (for example, specimen handling, assay exclusion, and reporting criteria) are specified. An algorithm defining positive, equivocal, and negative values for both HER2 protein expression and gene amplification is recommended: a positive HER2 result is IHC staining of 3+ (uniform, intense membrane staining of > 30% of invasive tumor cells), a fluorescent in situ hybridization (FISH) result of more than six HER2 gene copies per nucleus or a FISH ratio (HER2 gene signals to chromosome 17 signals) of more than 2.2; a negative result is an IHC staining of 0 or 1+, a FISH result of less than 4.0 HER2 gene copies per nucleus, or FISH ratio of less than 1.8. Equivocal results require additional action for final determination. It is recommended that to perform HER2 testing, laboratories show 95% concordance with another validated test for positive and negative assay values. The panel strongly recommends validation of laboratory assay or modifications, use of standardized operating procedures, and compliance with new testing criteria to be monitored with the use of stringent laboratory accreditation standards, proficiency testing, and competency assessment. The panel recommends that HER2 testing be done in a CAP-accredited laboratory or in a laboratory that meets the accreditation and proficiency testing requirements set out by this document.
Pilot randomised controlled trial of community pharmacy administration of buprenorphine versus methadone
Authors: Cameron Isobel M , Matheson Catriona I , Bond Christine M , Lawrie Thane , McNamee Paul , Robinson Andrew , Robertson George , Eagles Lucy E
Published: December 2006

Objectives

The established regime for opiate substitute prescribing for drug misusers is daily methadone administered under supervision in community pharmacies. Buprenorphine has recently been introduced as an alternative. However there is a lack of evidence of the effectiveness of buprenorphine maintenance therapy (BMT) in the UK treatment setting. This study aimed to assess methods for a randomised controlled trial (RCT) and the feasibility of pharmacy-based supervised self-administration (SSA) of buprenorphine compared to methadone.

Setting

Specialist substance misuse service, general practices and community pharmacies in Aberdeen, Scotland.

Method

The design was a pilot RCT. Opiate-dependent drug misusers, newly referred for maintenance treatment were randomised to receive BMT or methadone maintenance therapy (MMT). Clients and pharmacists were interviewed at baseline and at the end of a 12-week intervention period. Clients completed the quality of life measure EQ-5D. Pharmacy activities were timed.

Key findings

Twenty-one opiate-dependent clients were recruited (BMT = 11, MMT = 10). Recruitment levels improved as the trial progressed. Clients' treatment preferences were evident. Withdrawals occurred early with BMT. Clients found SSA of buprenorphine acceptable, but found daily administration more manageable than three times weekly. Pharmacists found the dispensing of buprenorphine to be an acceptable role, but felt less certain of ensuring against diversion with buprenorphine than they were with methadone. Pharmacy activities associated with buprenorphine took longer than those associated with methadone (mean = 7 min 25 s versus mean = 3 min 27 s, respectively).

Conclusion

Recruitment to a trial comparing MMT to BMT for opiate-dependent clients within a UK treatment setting is feasible. Clients and pharmacists found buprenorphine acceptable.
Why educational interventions are not always effective: a theory-based process evaluation of a randomised controlled trial to improve non-prescription medicine supply from community pharmacies†
Authors: Watson Margaret C , Bond Christine M , Walker Anne , Grimshaw Jeremy
Published: December 2006

Objective

The Theory of Planned Behaviour (TPB) has been used to explore health professionals' intentions to behave in a particular way. This study measured community pharmacists' behavioural intention and actual behaviour as part of an evaluation of a randomised controlled trial (RCT) of two educational interventions to promote the appropriate treatment of vaginal candidiasis in community pharmacies. This study aimed to explore reasons for the success or failure of educational interventions by conducting a theory-based process evaluation alongside the RCT.

Method

The RCT was conducted in 60 community pharmacies in Grampian, Scotland, and compared educational outreach visits and continuing education workshops. A postal questionnaire was conducted, comprising five measures derived from TPB: behaviour; behavioural intention, attitudes, subjective norms, and perceived behavioural control; together with a measure of clinical knowledge of candidiasis and its treatment; and a measure of guideline compliance. Guideline compliance was assessed using four scenarios. Simulated patient visits were made to participating pharmacies to derive objective measures of actual behaviour.

Results

Completed questionnaires were returned from 50 pharmacists (response rate: 83%). Forty (80%) respondents were fully guideline compliant (correct response with all four scenarios). Pharmacists' knowledge was high and they had positive attitudes towards the supply of antifungals, as well as strong intentions to sell them appropriately. No statistically significant differences were shown in questionnaire responses or actual behaviour across the four trial groups.

Conclusion

This evaluation demonstrates that the interventions may have failed because of psychological ceiling effects, i.e. existing attitudes and intentions were already strong. Further studies are needed to identify factors that prevent strong intentions from being put into practice, in order to develop effective interventions.
Perspectives on the role of the community pharmacist in the provision of healthcare to people with intellectual disabilities: exploration of the barriers and solutions
Authors: Di Blasi Amanda , Kendall Sharon , Spark M Joy
Published: December 2006

Objective

The objective of this study was twofold: to gain an understanding of the perceptions of individual pharmacists in relation to their role in the provision of healthcare for people with intellectual disabilities, and to identify barriers impacting on successful implementation of this role; secondly to explore strategies and solutions for improving pharmacists' involvement in the delivery of healthcare to this group.

Setting

A purposeful sample of 10 community pharmacists, located in the Loddon Mallee Region, north central rural Victoria, Australia.

Method

A descriptive qualitative design was adopted in this study. Data collection was via face-to-face, one-to-one, semi-structured interviews. The data were analysed thematically via a three-stage coding process: open, axial and selective coding.

Key findings

The study highlighted factors such as time resources; education, training, and experience in the field of intellectual disabilities; inadequate interprofessional communication; and the client's communication abilities and capacity to understand to be the most significant barriers to the provision of healthcare to people with intellectual disabilities, for this sample of community pharmacists. Suggested solutions to these barriers included emphasising the need for education and training, and increased staff recruitment. Community pharmacists emphasised the need for adequate collaboration with other health professionals, and the importance of communication with people with intellectual disabilities and their carers.

Conclusion

The research study highlighted a significant number of barriers perceived by the sample of community pharmacists, and proposed solutions to overcome these barriers in order to better assist community pharmacists in providing healthcare to people with intellectual disabilities.
The use of consultation skills assessment tools in pharmacist-patient consultations
Authors: Greenwood Katherine , Howe Amanda , Holland Richard
Published: December 2006

Objective

The consultations assessed in this study occurred as part of a larger randomised controlled trial (the HeartMed trial) which was evaluating the impact of home visits by pharmacists to patients with heart failure. Pharmacists are increasingly being expected to take on roles involving extended interviews with patients, but while the doctor-patient consultation has been well researched, such analysis has rarely been undertaken in pharmacy practice. The aim of this study was to analyse the consultation skills used by pharmacists using two validated consultation skills assessment tools (the Henbest and Stewart rating scale and the SEGUE score), and to assess the applicability of these tools to the pharmacist-patient consultation.

Setting

The study involved pharmacist consultations with patients who were aged over 18 years, living in independent accommodation and were prescribed two or more medicines taken on at least a daily basis. These patients were recruited to the HeartMed trial during an acute admission to hospital with heart failure, and were visited by a pharmacist during the first six weeks following hospital discharge.

Method

The pharmacist-patient consultations were tape-recorded, transcribed and evaluated using two different consultation skills tools — the Henbest and Stewart rating scale which assesses ‘patient centredness’ and the SEGUE score which assesses the content of the consultation.

Key findings

Both consultation skills tools were easily applied to the pharmacist-patient consultations. The pharmacists scored well on both the tools despite relatively little formal training.

Conclusions

Existing consultation skills tools can be used to assess pharmacist-patient consultations.
Professional development of pharmaceutical care in type 2 diabetes mellitus: a multidisciplinary conceptual model
Authors: Power Ailsa , Douglas Elizabeth , McGregor Anna Marie , Hudson Steve
Published: December 2006

Objective

To generate a validated model of care providing a framework for continued professional development of the community pharmacist for patients with type 2 diabetes mellitus.

Setting

A purposive sample of medical, nursing and community pharmacist interviewees in 10 health boards in Scotland.

Method

Investigation, using a semi-structured questionnaire approach, of the views held by 19 healthcare practitioners.

Key findings

A model of multidisciplinary diabetes care was generated to aid definition of pharmaceutical care provision. Processes emphasised in the model were: compliance monitoring, agreed multidisciplinary protocols and the continuity of patient education. Potential areas for community pharmacist contributions included the running of diabetes clinics, provision of patient education, near-patient testing, repeat dispensing and identification of clinic defaulters.

Conclusions

Development of the community pharmacists' role for patients with type 2 diabetes mellitus requires extensions to current independently delivered patient-centred services through working in partnership with other professionals. Methods of improved communication and attention to methods of referral, where appropriate, are important focal points. The targeting of this care and the care model that is best suited to particular settings will be subject to local variation. The generation of a diabetes care model offers pharmacists a means of matching learning opportunities to their needs. It is also a step towards the development of appropriate continued professional development tools and systems to equip community pharmacists for the future.
A pharmacovigilance study for monitoring adverse drug reactions with antihypertensive agents at a South Delhi hospital
Authors: Aqil Mohammed , Imam Faisal , Hussain Arshad , Alam M S , Kapur Prem , Pillai K K
Published: December 2006

Objective

The aim of the present study was to conduct a pharmacovigilance study to monitor adverse drug reactions (ADRs) associated with antihypertensive drugs.

Setting

The study was conducted in the medicine outpatient department of the 150-bedded Majeedia Hospital in South Delhi.

Method

The study was conducted by a registered pharmacist by way of one-to-one patient interview by the pharmacist based on a questionnaire (ADR monitoring form) drafted according to World Health Organization (WHO) ADR monitoring guidelines.

Key findings

A total of 22 ADRs were observed in 205 patients (95 males and 110 females) of mean age 49.6 ± 12 years and mean body mass index 25.7 ± 14.9 kg/m2. Out of 22 ADRs, 13 (59.1%) were mild, 8 (36.4%) were moderate and only 1 (4.5%) was classified as severe. Amlodipine was the drug associated with maximum ADRs (36.4%), followed by atenolol (13.6%), metoprolol and nevibilol (4.5% each).

Conclusion

The above pharmacovigilance study presents the ADR profile of antihypertensive medicines prescribed in our university teaching hospital. Calcium channel blockers was the prescribed drug category associated with maximum ADRs, followed by beta-blockers, angiotensin-converting enzyme inhibitors and diuretics.
Pharmacists' role in smoking cessation: an examination of current practice and barriers to service provision
Authors: Edwards David , Freeman Toby , Gilbert Andrew
Published: December 2006

Objective

This study addressed the potential role of pharmacists in helping their patients to quit smoking by providing a summary of their self-reported levels of current activities, confidence, and readiness to change around the provision of brief advice and support for patients who smoke. In addition to investigating which barriers are perceived to be most important, this study also examined the relative importance of confidence, barriers and practice factors in relation to pharmacists' smoking cessation practices.

Method

A 58-item questionnaire was mailed to 720 pharmacists. The questionnaire measured demographic and background variables, level of smoking cessation activity (asking, advising, assessing, assisting and arranging including follow-up), confidence in undertaking smoking-cessation activities, readiness to change, perceived importance of barriers to providing smoking-cessation services, and further education or training in relation to smoking cessation.

Setting

Community pharmacists in South Australia.

Key findings

Respondents indicated high rates of activity in relation to assessing and assisting patients to quit smoking, with lower rates of advising and arranging including following up. Recording of smoking status was very low. Confidence emerged as the most important predictor of smoking-cessation activities, with pharmacist barriers including fear of alienating patients approaching significance. Reported levels of smoking-specific education and training were low.

Conclusions

South Australian pharmacists are contributing to the prevention of tobacco-related harms. With additional support there is a greater scope for involvement. Results indicate a need for a team-based, systematic and multifaceted approach to address barriers and enhance pharmacists' confidence. Further implementation research is required to assess the effectiveness of multifaceted pharmacy support programmes on the uptake and sustainability of smoking-cessation services.
Arginine methyltransferase Capsuléen is essential for methylation of spliceosomal Sm proteins and germ cell formation inDrosophila
Authors: Anne Joël , Ollo Roger , Ephrussi Anne , Mechler Bernard M.
Published: December 2006

Although arginine modification has been implicated in a number of cellular processes, the in vivo requirement of protein arginine methyltransferases(PRMTs) in specific biological processes remain to be clarified. In this study we characterize the Drosophila PRMT Capsuléen, homologous to human PRMT5. During Drosophila oogenesis, catalytic activity of Capsuléen is necessary for both the assembly of the nuage surrounding nurse cell nuclei and the formation of the pole plasm at the posterior end of the oocyte. In particular, we show that the nuage and pole plasm localization of Tudor, an essential component for germ cell formation, are abolished in csul mutant germ cells. We identify the spliceosomal Sm proteins as in vivo substrates of Capsuléen and demonstrate that Capsuléen,together with its associated protein Valois, is essential for the synthesis of symmetric di-methylated arginyl residues in Sm proteins. Finally, we show that Tudor can be targeted to the nuage in the absence of Sm methylation by Capsuléen, indicating that Tudor localization and Sm methylation are separate processes. Our results thus reveal the role of a PRMT in protein localization in germ cells.
Programmed cell death in the embryonic central nervous system ofDrosophila melanogaster
Authors: Rogulja-Ortmann Ana , Lüer Karin , Seibert Janina , Rickert Christof , Technau Gerhard M.
Published: December 2006

Although programmed cell death (PCD) plays a crucial role throughout Drosophila CNS development, its pattern and incidence remain largely uninvestigated. We provide here a detailed analysis of the occurrence of PCD in the embryonic ventral nerve cord (VNC). We traced the spatio-temporal pattern of PCD and compared the appearance of, and total cell numbers in,thoracic and abdominal neuromeres of wild-type and PCD-deficient H99mutant embryos. Furthermore, we have examined the clonal origin and fate of superfluous cells in H99 mutants by DiI labeling almost all neuroblasts, with special attention to segment-specific differences within the individually identified neuroblast lineages. Our data reveal that although PCD-deficient mutants appear morphologically well-structured, there is significant hyperplasia in the VNC. The majority of neuroblast lineages comprise superfluous cells, and a specific set of these lineages shows segment-specific characteristics. The superfluous cells can be specified as neurons with extended wild-type-like or abnormal axonal projections, but not as glia. The lineage data also provide indications towards the identities of neuroblasts that normally die in the late embryo and of those that become postembryonic and resume proliferation in the larva. Using cell-specific markers we were able to precisely identify some of the progeny cells,including the GW neuron, the U motoneurons and one of the RP motoneurons, all of which undergo segment-specific cell death. The data obtained in this analysis form the basis for further investigations into the mechanisms involved in the regulation of PCD and its role in segmental patterning in the embryonic CNS.
Ectodysplasin has a dual role in ectodermal organogenesis: inhibition of Bmp activity and induction of Shh expression
Authors: Pummila Marja , Fliniaux Ingrid , Jaatinen Risto , James Martyn J. , Laurikkala Johanna , Schneider Pascal , Thesleff Irma , Mikkola Marja L.
Published: December 2006

Ectodermal organogenesis is regulated by inductive and reciprocal signalling cascades that involve multiple signal molecules in several conserved families. Ectodysplasin-A (Eda), a tumour necrosis factor-like signalling molecule, and its receptor Edar are required for the development of a number of ectodermal organs in vertebrates. In mice, lack of Edaleads to failure in primary hair placode formation and missing or abnormally shaped teeth, whereas mice overexpressing Eda are characterized by enlarged hair placodes and supernumerary teeth and mammary glands. Here, we report two signalling outcomes of the Eda pathway: suppression of bone morphogenetic protein (Bmp) activity and upregulation of sonic hedgehog (Shh)signalling. Recombinant Eda counteracted Bmp4 activity in developing teeth and, importantly, inhibition of BMP activity by exogenous noggin partially restored primary hair placode formation in Eda-deficient skin in vitro, indicating that suppression of Bmp activity was compromised in the absence of Eda. The downstream effects of the Eda pathway are likely to be mediated by transcription factor nuclear factor-κB (NF-κB), but the transcriptional targets of Edar have remained unknown. Using a quantitative approach, we show in cultured embryonic skin that Eda induced the expression of two Bmp inhibitors, Ccn2/Ctgf (CCN family protein 2/connective tissue growth factor) and follistatin. Moreover, our data indicate that Shh is a likely transcriptional target of Edar, but, unlike noggin, recombinant Shh was unable to rescue primary hair placode formation in Eda-deficient skin explants.
A pump-independent function of the Na,K-ATPase is required for epithelial junction function and tracheal tube-size control
Authors: Paul Sarah M. , Palladino Michael J. , Beitel Greg J.
Published: December 2006

The heterodimeric Na,K-ATPase has been implicated in vertebrate and invertebrate epithelial cell junctions, morphogenesis and oncogenesis, but the mechanisms involved are unclear. We previously showed that the Drosophila Na,K-ATPase is required for septate junction (SJ)formation and that of the three β-subunit loci, only Nrv2 isoforms support epithelial SJ barrier function and tracheal tube-size control. Here we show that Nrv1 is endogenously co-expressed with Nrv2 in the epidermis and tracheal system, but Nrv1 has a basolateral localization and appears to be excluded from the Nrv2-containing SJs. When the normally neuronal Nrv3 is expressed in epithelial cells, it does not associate with SJs. Thus, theβ-subunit is a key determinant of Na,K-ATPase subcellular localization as well as function. However, localization of the Na,K-ATPase to SJs is not sufficient for junctional activity because although several Nrv2/Nrv3 chimericβ-subunits localize to SJs, only those containing the extracellular domain of Nrv2 have junctional activity. Junctional activity is also specific to different α-subunit isoforms, with only some isoforms from the majorα-subunit locus being able to provide full barrier function and produce normal tracheal tubes. Importantly, mutations predicted to inactivate ATPα catalytic function do not compromise junctional activity,demonstrating that the Drosophila Na,K-ATPase has an ion-pump-independent role in junction formation and tracheal morphogenesis. These results define new functions for the intensively studied Na,K-ATPase. Strikingly, the rat α1 isoform has full junctional activity and can rescue Atpα-null mutants to viability, suggesting that the Na,K-ATPase has an evolutionarily conserved role in junction formation and function.
Tbx4is not required for hindlimb identity or post-bud hindlimb outgrowth
Authors: Naiche L. A. , Papaioannou Virginia E.
Published: December 2006

Tbx4 is a crucial gene in the initiation of hindlimb development and has been reported as a determinant of hindlimb identity and a presumptive direct regulator of Fgf10 in the limb. Using a conditional allele of Tbx4, we have ablated Tbx4 function before and after limb initiation. Ablation of Tbx4 before expression in the hindlimb field confirms its requirement for limb bud outgrowth. However, ablation of Tbx4 shortly after onset of expression in the hindlimb field, during limb bud formation, alters neither limb outgrowth nor expression of Fgf10. Instead, post-limb-initiation loss of Tbx4 results in reduction of limb core tissue and hypoplasia of proximal skeletal elements. Loss of Tbx4 during later limb outgrowth produces no limb defects,revealing a brief developmental requirement for Tbx4 function. Despite evidence from ectopic expression studies, our work establishes that loss of Tbx4 has no effect on hindlimb identity as assessed by morphology or molecular markers.
GATA and Nkx factors synergistically regulate tissue-specific gene expression and development in vivo
Authors: Zhang Yuzhen , Rath Nibedita , Hannenhalli Sridhar , Wang Zhishan , Cappola Thomas , Kimura Shioko , Atochina-Vasserman Elena , Lu Min Min , Beers Michael F. , Morrisey Edward E.
Published: December 2006

In vitro studies have suggested that members of the GATA and Nkx transcription factor families physically interact, and synergistically activate pulmonary epithelial- and cardiac-gene promoters. However, the relevance of this synergy has not been demonstrated in vivo. We show that Gata6-Titf1 (Gata6-Nkx2.1) double heterozygous(G6-Nkx DH) embryos and mice have severe defects in pulmonary epithelial differentiation and distal airway development, as well as reduced phospholipid production. The defects in G6-Nkx DH embryos and mice are similar to those observed in human neonates with respiratory distress syndromes, including bronchopulmonary dysplasia, and differential gene expression analysis reveals essential developmental pathways requiring synergistic regulation by both Gata6 and Titf1 (Nkx2.1). These studies indicate that Gata6 and Nkx2.1 act in a synergistic manner to direct pulmonary epithelial differentiation and development in vivo, providing direct evidence that interactions between these two transcription factor families are crucial for the development of the tissues in which they are co-expressed.
Prolonged prophylaxis against venous thromboembolism with enoxaparin in patients undergoing cancer surgery: long-term survival analysis
Authors: Bergqvist D , Agnelli G , Cohen A T , Nilsson P E , Moigne-Amrani A Le , Dietrich-Neto F ,   The Enoxacan II Investigators
Published: December 2006

Objective: ENOXACAN II was a randomized, double-blind trial that showed prolonged (four-week) thromboprophylaxis with enoxaparin to be more effective than and as safe as standard (one-week) thromboprophylaxis in patients undergoing surgery with a curative intent for abdominopelvic cancer. This follow-up study compared long-term, all-cause mortality in both groups.

Methods: Survival rates were calculated on the randomized, treated population ( n = 501). The primary efficacy endpoint was survival at one year. An exploratory analysis including survival data up to 44 months was performed. Because some patients were deemed to have undergone palliative as opposed to curative surgery, and there was a significant difference between the treatment groups in the percentage of patients undergoing palliative surgery, the survival analyses were adjusted for the type of surgery performed.

Results: When adjusted for type of surgery, there was a trend towards reduced mortality among patients undergoing palliative surgery in the prolonged prophylaxis group (hazard ratio [HR] = 0.598, P = 0.3565) that became more pronounced beyond the pre-specified one year follow-up period (HR = 0.469, P = 0.078). This trend may reflect a beneficial effect of prolonged prophylaxis on survival in the palliative surgery group (one-year survival 65.4 versus 50% for standard prophylaxis). In patients undergoing curative surgery, one-year survival rates were equal in the standard and prolonged prophylaxis groups (93.8 and 93.2%, respectively).

Conclusion: Prolonged thromboprophylaxis with enoxaparin may affect long-term survival in palliative surgery for cancer, but further investigation is warranted.
Predictors of clinical and radiological outcome in patients with fractures of the acetabulum and concomitant posterior dislocation of the hip
Authors: Bhandari M. , Matta J. , Ferguson T. , Matthys G.
Published: December 2006

We aimed to identify variables associated with clinical and radiological outcome following fractures of the acetabulum associated with posterior dislocation of the hip. Using a prospective database of 1076 such fractures, we identified 109 patients with this combined injury managed operatively within three weeks and followed up for two or more years. The patients had a mean age of 42 years (15 to 79), 78 (72%) were male, and 84 (77%) had been involved in motor vehicle accidents. Using multivariate analysis the quality of reduction of the fracture was identified as the only significant predictor of radiological grade, clinical function and the development of post-traumatic arthritis (p < 0.001). All patients lacking anatomical reduction developed arthritis whereas only 25.5% (24 patients) with an anatomical reduction did so (p = 0.05).

The quality of the reduction of the fracture is the most important variable in forecasting the outcome for patients with this injury. The interval to reduction of the dislocation of the hip may be less important than previously described.
Intracranial penetration of a halo pin causing an epileptic seizure
Authors: Kingma R. , Peters J. M. , Coene L. N. J. E. M.
Published: December 2006

A 71-year-old man with ankylosing spondylitis and an unstable fracture of the 6th and 7th cervical vertebrae was managed with a halo vest. Eight weeks following application the halo had shifted because of a loose pin. The patient’s only complaint at the time was a headache but this was followed two days later by a seizure. An MR scan of the brain showed a swollen cortex under the right dorsal pin as a result of a perforation of the internal lamina by the pin. The halo was removed and anti-epileptic medication commenced. The patient had no further seizures.
Should we reconsider all-polyethylene tibial implants in total knee replacement?
Authors: Muller S. D. , Deehan D. J. , Holland J. P. , Outterside S. E. , Kirk L. M. G. , Gregg P. J. , McCaskie A. W.
Published: December 2006

The role of modular tibial implants in total knee replacement is not fully defined. We performed a prospective randomised controlled clinical trial using radiostereophotogrammetric analysis to compare the performance of an all-polyethylene tibia with a metal-backed cruciate-retaining condylar design, PFC-∑ total knee replacement for up to 24 months. There were 51 patients who were randomised into two treatment groups. There were 10 subsequent withdrawals, leaving 21 all-polyethylene and 20 metal-backed tibial implants. No patient was lost to follow-up. There were no significant demographic differences between the groups. At two years one metal-backed implant showed migration > 1 mm, but no polyethylene implant reached this level. There was a significant increase in the SF-12 and Oxford knee scores after operation in both groups.

In an uncomplicated primary total knee replacement the all-polyethylene PFC-∑ tibial prosthesis showed no statistical difference in migration from that of the metal-backed counterpart. There was no difference in the clinical results as assessed by the SF-12, the Oxford knee score, alignment or range of movement at 24 months, although these assessment measures were not statistically powered in this study.
Delayed ruptures of the extensor tendon secondary to the use of volar locking compression plates for distal radial fractures
Authors: Al-Rashid M. , Theivendran K. , Craigen M. A. C.
Published: December 2006

The use of volar locking compression plates for the treatment of fractures of the distal radius is becoming increasingly popular because of the stable biomechanical construct, less soft-tissue disturbance and early mobilisation of the wrist. A few studies have reported complications such as rupture of flexor tendons. We describe three cases of rupture of extensor tendons after the use of volar locking compression plates. We recommend extreme care when drilling and placing the distal radial screws to prevent damaging the extensor tendons.
Anti-apoptotic Bcl-2 gene transfection of human articular chondrocytes protects against nitric oxide-induced apoptosis
Authors: Surendran S. , Kim S. H. , Jee B. K. , Ahn S. H. , Gopinathan P. , Han C. W.
Published: December 2006

We stably transfected early passage chondrocytes with an anti-apoptotic Bcl-2 gene in vitro using a retrovirus vector. Samples of articular cartilage were obtained from 11 patients with a mean age of 69 years (61 to 75) who were undergoing total knee replacement for osteoarthritis. The Bcl-2-gene-transfected chondrocytes were compared with non-transfected and lac-Z-gene-transfected chondrocytes, both of which were used as controls. All three groups of cultured chondrocytes were incubated with nitric oxide (NO) for ten days. Using the Trypan Blue exclusion assay, an enzyme-linked immunosorbent assay and flow cytometric analysis, we found that the number of apoptotic chondrocytes was significantly higher in the non-transfected and lac-Z-transfected groups than in the Bcl-2-transfected group (p < 0.05). The Bcl-2-transfected chondrocytes were protected from NO-induced impairment of proteoglycan synthesis.

We conclude that NO-induced chondrocyte death involves a mechanism which appears to be subject to regulation by an anti-apoptotic Bcl-2 gene. Therefore, Bcl-2 gene therapy may prove to be of therapeutic value in protecting human articular chondrocytes.
The efficacy of intra-articular bupivacaine for relief of pain following arthroscopy of the ankle
Authors: Middleton F. , Coakes J. , Umarji S. , Palmer S. , Venn R. , Panayiotou S.
Published: December 2006

The intra-articular injection of local anaesthetic is frequently used for pain relief after arthroscopy. There is, however, no published evidence of the analgesic effect of bupivacaine in the ankle. In a randomised, double-blind study, 35 patients undergoing arthroscopy of the ankle were allocated to receive intra-articular saline or bupivacaine. Pain was assessed using pain scores and additional analgesic requirements. Intra-articular bupivacaine had a significant analgesic effect in the immediate post-operative period, reducing pain scores and the need for additional analgesics.

We recommend the use of intra-articular bupivacaine for post-operative analgesia in ankle surgery.
Relative ability of young and mature muscles to respond to limb lengthening
Authors: Shisha T. , Kiss S. , Pap K. , Simpson H. , Szöke G.
Published: December 2006

The response of the muscle is critical in determining the functional outcome of limb lengthening. We hypothesised that muscle response would vary with age and therefore studied the response of the muscles during tibial lengthening in ten young and ten mature rabbits. A bromodeoxyuridine technique was used to identify the dividing cells.

The young rabbits demonstrated a significantly greater proliferative response to the distraction stimulus than the mature ones. This was particularly pronounced at the myotendinous junction, but was also evident within the muscle belly.

Younger muscle adapted better to lengthening, suggesting that in patients in whom a large degree of muscle lengthening is required it may be beneficial to carry out this procedure when they are young, in order to achieve the optimal functional result.
Limb salvage for osteosarcoma of the distal tibia with resection arthrodesis, autogenous fibular graft and Ilizarov external fixator
Authors: Shalaby S. , Shalaby H. , Bassiony A.
Published: December 2006

We report the results of limb salvage for non-metastatic osteosarcoma of the distal tibia using resection arthrodesis, autogenous fibular graft and fixation by an Ilizarov external fixator.

In six patients with primary osteosarcoma of the distal tibia who refused amputation, treatment with wide en bloc resection and tibiotalar arthrodesis was undertaken. The defect was reconstructed using non-vascularised free autogenous fibular strut graft in three patients and a vascularised pedicular fibular graft in three, all supplemented with iliac cancellous graft at the graft-host junction. An Ilizarov external fixator was used for stabilisation of the reconstruction.

In five patients sound fusion occurred at a mean of 13.2 months (8 to 20) with no evidence of local recurrence or deep infection at final follow-up. The mean post-operative functional score was 70% (63% to 73%) according to the Musculoskeletal Tumour Society scoring system. All five patients showed graft hypertrophy.

Union of the graft was faster in cases reconstructed by vascularised fibular grafts. One patient who had a poor response to pre-operative chemotherapy developed local tumour recurrence at one year post-operatively and required subsequent amputation.
Fractures of the distal third of the humerus with palsy of the radial nerve
Authors: Livani B. , Belangero W. D. , Castro de Medeiros R.
Published: December 2006

Fractures of the distal third of the humerus may be complicated by complete lesions of the radial nerve which may be entrapped or compressed by bone fragments. Indirect reduction and internal fixation may result in a permanent nerve lesion.

We describe the treatment of these lesions by insertion of a bridge plate using the minimally-invasive percutaneous technique. Six patients were operated on and showed complete functional recovery. Healing of the fractures occurred at a mean of 2.7 months (2 to 3) and complete neurological recovery by a mean of 2.3 months (1 to 5). In one patient infection occurred which resolved after removal of the implant.
Liposarcoma in adult limbs treated by limb-sparing surgery and adjuvant radiotherapy
Authors: Issakov J. , Soyfer V. , Kollender Y. , Bickels J. , Meller I. , Merimsky O.
Published: December 2006

Between December 1995 and March 2003, 38 adult patients with intermediate or high-grade liposarcoma in a limb were treated by limb-sparing surgery and post-operative radiotherapy. The ten-year local recurrence-free survival was 83%, the ten-year metastasis-free survival 61%, the ten-year disease-free survival 51% and the ten-year overall survival 67%. Analysis of failure and success showed no association with the age of the patients, gender, the location of the primary tumour, the type of liposarcoma and the quality of resection.

Our results indicate that liposarcoma may recur even ten years after the end of definitive therapy and may spread to unexpected sites as for soft-tissue sarcoma.
Long-term outcome of undisplaced fatigue fractures of the femoral neck in young male adults
Authors: Pihlajamäki H. K. , Ruohola J.-P. , Weckström M. , Kiuru M. J. , Visuri T. I.
Published: December 2006

The incidence and long-term outcome of undisplaced fatigue fractures of the femoral neck treated conservatively were examined in Finnish military conscripts between 1970 and 1990.

From 106 cases identified, 66 patients with 70 fractures were followed for a mean of 18.3 years (11 to 32). The original medical records and radiographs were studied and physical and radiological follow-up data analysed for evidence of risk factors for this injury. The development of avascular necrosis and osteoarthritis was determined from the follow-up radiographs and MR scans.

The impact of new military instructions on the management of hip-related pain was assessed following their introduction in 1986. The preventive regimen (1986) improved awareness and increased the detected incidence from 13.2 per 100 000 service-years (1970 to 1986) to 53.2 per 100 000 (1987 to 1990). No patient developed displacement of the fracture or avascular necrosis of the femoral head, or suffered from adverse complications. No differences were found in MRI-measured hip joint spaces at final follow-up. The mean Harris Hip Score was 97 (70 to 100) and the Visual Analogue Scale 5.85 mm (0 to 44).

Non-operative treatment, including avoidance of or reduced weight-bearing, gave favourable short- and long-term outcomes. Undisplaced fatigue fractures of the femoral neck neither predispose to avascular necrosis nor the subsequent development of osteoarthritis of the hip.
Indometacin as prophylaxis for heterotopic ossification after the operative treatment of fractures of the acetabulum
Authors: Karunakar M. A. , Sen A. , Bosse M. J. , Sims S. H. , Goulet J. A. , Kellam J. F.
Published: December 2006

Our study was designed to compare the effect of indometacin with that of a placebo in reducing the incidence of heterotopic ossification in a prospective, randomised trial. A total of 121 patients with displaced fractures of the acetabulum treated by operation through a Kocher-Langenbeck approach was randomised to receive either indometacin (75 mg) sustained release, or a placebo once daily for six weeks. The extent of heterotopic ossification was evaluated on plain radiographs three months after operation. Significant ossification of Brooker grade III to IV occurred in nine of 59 patients (15.2%) in the indometacin group and 12 of 62 (19.4%) receiving the placebo.

We were unable to demonstrate a statistically significant reduction in the incidence of severe heterotopic ossification with the use of indometacin when compared with a placebo (p = 0.722). Based on these results we cannot recommend the routine use of indometacin for prophylaxis against heterotopic ossification after isolated fractures of the acetabulum.