bluuebunny/crossref_metadata_2025 huggingface dataset:
Trends in depressive symptoms, anxiety symptoms and visits to healthcare specialists: A national study among Icelandic adolescents
Authors: Sigfusdottir Inga D. , Asgeirsdottir Bryndis B. , Sigurdsson Jon F. , Gudjonsson Gisli H.
Published: June 2008

Aims: The aim of the study was to examine trends in adolescent depression and anxiety symptoms from 1997 to 2006, using four time-points (1997, 2000, 2003, and 2006), and adolescent mental health service use in the same period, using three time-points (1997, 2000, and 2006). Methods: Four cross-sectional population-based samples of 14- and 15-year-old students, attending the compulsory 9th and 10th grades of the Icelandic secondary school system, completed questionnaires relating to mental health. In total, 21,245 students participated in the four studies. Results: Anxiety symptoms increased significantly for both boys and girls, throughout the period from 1997 to 2006. Depressive symptoms increased significantly for girls, while there were no significant changes in depression among boys. During the same time period, the proportion of adolescents who visited healthcare specialists, i.e. psychiatrists, psychologists and social workers, increased significantly. The results revealed that regular visits (six times or more during 1 year) to psychiatrists and psychologists increased significantly over the same period among girls but not among boys. Conclusions: The findings show that symptoms of depression and anxiety have increased among adolescents in Iceland. Future work would benefit from further research into the trends in risk and protective factors associated with these outcomes. The findings call particular attention to the increasing risk for depression and anxiety symptoms among girls.
A rural Ethiopian population undergoing epidemiological transition over a generation: Butajira from 1987 to 2004
Authors: Berhane Yemane , Wall Stig , Fantahun Mesganaw , Emmelin Anders , Mekonnen Wubegzier , Högberg Ulf , Worku Alemayehu , Tesfaye Fikru , Molla Mitike , Deyessa Negussie , Kumie Abera , Hailemariam Damen , Enqueselassie Fikre , Byass Peter
Published: June 2008

Aims: To describe the epidemiological development of a rural Ethiopian population from 1987 to 2004 in terms of mortality and associated sociodemographic factors. Methods: A rural population comprising 10 communities was defined in 1987 and has since been followed by means of regular household visits. After an initial census, births, deaths and migration events were recorded, together with key background factors, on an open cohort basis. Over 97,000 individuals were observed during a total of over 700,000 person years. Results: The initial population of 28,614 increased by an average of 3.64% annually to 54,426 from 1987 to 2004, and also grew older on average. Birth and mortality rates fell, but were still subject to short-term variation due to external factors. Overall mortality was 13.5 per 1000 person years. Increasing mortality in some adult age groups was consistent with increasing AIDS-related deaths, but a new local hospital in 2002 may have contributed to later falls in overall mortality. Sex, age group, time period, literacy, water source, house ownership and distance to town were all significantly associated with mortality differentials. Conclusions: This population has undergone a complex epidemiological transition during a generation. Detailed long-term surveillance of this kind is essential for describing such processes. Many factors that significantly affect mortality cannot be directly controlled by the health sector and will only improve with general development.
The evidenced-based care behind the early management of head injured children
Authors: Bayreuther Jane , Maconochie Ian
Published: June 2008

Trauma remains the highest cause of death in children over the age of 1. Head injury accounts for the highest mortality. There is much information on the treatment of head injuries and indications for CT scanning. This review aims to summarise the key differences between paediatric and adult victims of trauma and outline the key steps in management of head injured children, from prevention through to who should have a CT scan and initial management in the emergency department (ED) if transfer is required to a PICU or neurosurgical unit. Information is also provided on recommendations for follow up of children who do not require PICU or neurosurgical care.
Focused assessment with sonography for trauma: the FAST scan
Authors: Christie-Large M. , Michaelides D. , James SLJ
Published: June 2008

Focused assessment with sonography for trauma or focused abdominal sonography for trauma — the FAST scan, has become a useful modality for the initial evaluation of patients with blunt abdominal trauma. The technique is used to identify free fluid in the abdomen and pelvis and to detect the presence of a pericardial effusion. FAST can be performed by any trained individual, not necessarily a sonographer or radiologist, aiding in the immediate availability of this technique in the emergency situation. We will discuss the applications and sensitivity of this technique in trauma and review the potential pitfalls and limitations which need to be understood if this technique is to be safely applied. The use of FAST for the detection of pneumothoraces in trauma and other advances in FAST scanning, such as scoring systems and paediatric FAST are also reviewed.
Coagulopathy in trauma: optimising haematological status
Authors: McDonald Vickie , Ryland Kim
Published: June 2008

It is estimated that 10 000 people per year die following trauma in England and Wales and 30—40% do so due to uncontrolled haemorrhage. By the time the patient reaches hospital, coagulopathy is often already installed and needs to be corrected promptly to prevent further haemorrhage and allow effective treatment of injuries. The coagulopathy is multifactorial with the leading causes being acidosis, hypothermia and massive transfusion. Early recognition of the condition is imperative using standard coagulation testing; however, there are limitations in this setting. Newer methods of testing `global haemostasis' using thromboelastography are becoming more popular but need further validation. Treatment of coagulopathy requires a multidisciplinary approach. Blood product transfusion remains the cornerstone of management but newer pharmacological agents such as recombinant factor VIIa are increasingly being used. Here we review the pathogenesis, investigation and management of the coagulopathy of trauma.
Domiciliary humidification improves lung mucociliary clearance in patients with bronchiectasis
Authors: Hasani A , Chapman TH , McCool D , Smith RE , Dilworth JP , Agnew JE
Published: June 2008

Inspired air humidification has been reported to show some benefit in bronchiectatic patients. We have investigated the possibility that one effect might be to enhance mucociliary clearance. Such enhancement might, if it occurs, help to lessen the risks of recurrent infective episodes. Using a radioaerosol technique, we measured lung mucociliary clearance before and after 7 days of domiciliary humidification. Patients inhaled high flow saturated air at 37 °C via a patient-operated humidification nasal inhalation system for 3 h per day. We assessed tracheobronchial mucociliary clearance from the retention of 99mTc-labelled polystyrene tracer particles monitored for 6 h, with a follow-up 24-h reading. Ten out of 14 initially recruited patients (age 37–75 years; seven females) completed the study (two withdrew after their initial screening and two prior to the initial clearance test). Seven patients studied were non-smokers; three were ex-smokers (1–9 pack-years). Initial tracer radioaerosol distribution was closely similar between pre- and post-treatment. Following humidification, lung mucociliary clearance significantly improved, the area under the tracheobronchial retention curve decreased from 319 ± 50 to 271 ± 46%h ( p < 0.07). Warm air humidification treatment improved lung mucociliary clearance in our bronchiectatic patients. Given this finding plus increasing laboratory and clinical interest in humidification mechanisms and effects, we believe further clinical trials of humidification therapy are desirable, coupled with analysis of humidification effects on mucus properties and transport.
The Role of Intuition in Collective Learning and the Development of Shared Meaning
Authors: Sadler-Smith Eugene
Published: June 2008

The problem and the solution. Intuitions are rapid, affectively charged judgments arrived at without conscious awareness of the reasoning processes involved. Intuiting is one of the principal means by which managers and other professionals are able arrive at judgments in relation to complex problems in loosely structured environments. Intuition has the potential to influence, inform, and enhance not only the learning of the individual actor but the development of shared meaning, also. This article explicates a theoretical model based on “feed-forward” and “feedback” relationships between “intuiting” and “interpreting.” Some of the implications of intuition as a difficult-to-articulate and difficult-to-capture aspect of human capital are explored. Suggestions are offered both for how intuition may be nurtured and managed in the institutional setting of business organizations, and how researchers might further examine the role that intuition plays in collective learning processes and the development of shared meaning.
Sprawl, Spatial Location, and Politics
Authors: Williamson Thad
Published: June 2008

This study explores how spatial characteristics commonly associated with suburban sprawl (including density, reliance on the automobile, neighborhood age, and commuting patterns) help predict voting patterns and individual ideological orientation. I find that, at the county level, greater reliance on automobile commuting and younger housing stock were strong predictors of greater support for the Republican candidate in the 2000 and 2004 presidential elections, controlling for demographic factors. Using the 2000 Social Capital Community Benchmark Survey (SCCBS), I also find that greater automobile reliance and younger housing stock, measured at the census tract level, are strong predictors of more conservative ideological orientation among individuals, controlling for other individual and contextual factors. I go on to explore three possible mechanisms driving the relationship between sprawling spatial environments and conservative political outlooks: self-selection, shifting self-interest based on spatial location within the metropolitan area, and shifting social perceptions resulting from the character of the built environment.
Strange Bedfellows
Authors: Wilhelm Teena
Published: June 2008

This research examines the relationship between courts and legislatures in a comparative perspective. Specifically, I examine how (a) the ideological composition of the bench, (b) the propensity of court involvement in a given policy area, and (c) the disposition of court decisions in a given policy area influence the ideology of bill introductions and policy enactments by state legislatures. By examining HMO regulation and education policy in the American states during the 1990s, I find evidence that judicial influence does affect legislative policymaking, in both the introduction and enactment stages, across both policy areas. Although traditional scholarship has depicted the judicial branch as having minimal effect on policy formation, and subsequently social change, the findings of this study suggest that we have overlooked an important policymaking role of the judicial branch. Furthermore, state policy research has not given adequate attention to judicial influence as an explanation for policy formation in the American states.
Using testimonial novels to think about social justice
Authors: Bickford Donna M.
Published: June 2008

This article argues that testimonial novels are an important curricular addition in classrooms that take seriously the responsibility to educate students about social justice and civic responsibility in a global context. The addition of testimonial novels to our literature courses lets us internationalize our curriculum by including courses and texts that focus on social justice. I explore the ways in which thinking about our curricular and pedagogical choices through a lens of social justice achieves a number of important educational goals. It encourages critical thinking, allows the development of effective oral communication and writing skills, helps cultivate an appreciation of literature and reading, and creates possibilities for students to see themselves as effective actors in political arenas and social struggles, as global citizens with commitments and responsibilities.
Review: Evaluating combination therapies for asthma: pros, cons, and comparative benefits
Authors: Bjermer Leif
Published: June 2008

Combination therapies with inhaled corticosteroids (ICS) and either long-acting β2 agonists (LABA) or leukotriene receptor antagonists (LTRA) are commonly used to help patients maintain control of their asthma. LABA and LTRA have different mechanisms of action and both provide complementary benefits when combined with ICS. This paper compares the two regimens based on recent clinical trial data, evaluates their efficacy on various clinical and quality of life outcomes, and discusses the importance of therapy choice in people with specific asthma phenotypes. The potential of new dosing strategies, including adjustable maintenance therapy and single-inhaler maintenance and reliever therapy is also reviewed. Given the variety of outcomes, phenotypes, and treatment strategies that must be considered, the importance of individualized management is emphasized.
Review: Tissue remodeling and angiogenesis in asthma: the role of the eosinophil
Authors: Nissim Ben Efraim A.H. , Levi-Schaffer F.
Published: June 2008

This review covers the role of eosinophils in asthma-associated tissue remodeling and angiogenesis focusing on angiogenesis which is a recently discovered feature of asthma. In addition, novel directions for eosinophil-targeted/angiogenesis-targeted pharmacological intervention are discussed as new approaches in the treatment of asthma.
Ultrasound Examination of the Knee: Commonly Encountered Pathology
Authors: Descamps Marjanne J. L. , Karunanithy Narayan , Mitchell Adam W. M. , Lim Adrian K. P.
Published: June 2008

This pictorial essay describes the role of musculoskeletal ultrasound (MSUS) in the investigation of common problems involving the knee. The aim is to highlight the usefulness of MSUS as a relatively inexpensive and portable imaging technique for evaluating a wide range of traumatic and non-traumatic conditions.
Attitudes of Post-menopausal Women to Transvaginal Ultrasound
Authors: Al Inizi Shamma , Johnson Gerry , Jain Aparna , Thwaini Hadeel , Dillon Bernice , Morris Julie , Hirsch Peter , Onon Toli
Published: June 2008

Objectives: To assess the attitudes of post-menopausal women having a transvaginal ultrasound (TVUS) examination.

Methods: A cross-sectional questionnaire survey included 100 consecutive post-menopausal women undergoing TVUS for different indications.

They were asked to complete two questionnaires, one before and one after the examination. The main outcomes were acceptability of TVUS, anxiety, embarrassment (before and during) and pain/discomfort (during) the examination.

Results: The incidence of anxiety prior to TVUS was significantly higher than anxiety during and after (p<0·001). Good rapport, with reassurance from the staff may have reduced anxiety. Pre-examination anxiety (reported by 43% of women) was mostly due to the procedure and fear of results (77%). Post-examination anxiety was due mainly to anticipation of results. Women found TVUS less painful and less embarrassing than they had expected. The majority of women did not have a specific preference regarding the gender of the sonographer or the presence of a chaperone during the examination. All women attending for TVUS found the procedure acceptable and would 'recommend it to friends or family'.

Conclusions: Post-menopausal women find TVUS acceptable. Before attending they are anxious about both the procedure and the result. Women can be reassured that TVUS is unlikely to be as painful or embarrassing as they fear. Anxiety about results persists after the examination.
Kinetics of texture evolution during rapid solutionising of cold rolled Al–Mg–Si alloy
Authors: Saimoto S. , Gabryel C. , Cooley J. , Jin H.
Published: June 2008

A study of recrystallisation texture evolution was performed in an ageable Al–Mg–Si alloy to assess the sheet formability of autobody sheet before age hardening, by using quantitative orientation distribution function (ODF) determination during presolutionising anneal treatments. It was found that preannealing of cold rolled sheet near 250°C results in the largest amount of cube texture upon subsequent solutionising at 560°C. The apparent activation enthalpy is near 2˙5 eV if the iron solute content is below 0˙5 ppm atomic. The formation of cube oriented grains occurs below 300°C and grain growth above this temperature appears to be inhibited by iron solute drag of the grain boundaries. It was discovered that the volume fraction ratio of the cube and {02¯1} <100> is correlated to the average R value.
Creep of dilute tin based lead free solder alloys as replacements of Sn–Pb solders
Authors: Mahmudi R. , Geranmayeh A. R. , Noori H. , Nayyeri G. , Pishbin F.
Published: June 2008

The present paper reports behaviour of Sn–0˙7Cu, Sn–1Zn and Sn–0˙7Cu–1Zn tin based lead free solder alloys at the room temperature creep together with pure Sn and Sn–37Pb as the materials for comparison. Stress exponent values in the range 7˙8–9˙7, depending on the alloy type, determined by indentation and impression methods were in good agreement. All three tin based alloys showed creep resistances higher than pure Sn. The addition of 1%Zn to Sn resulted in the formation of fine Zn rich phase which increased both the hardness and creep resistance of the material, as indicated by the steady state creep rates. The same amount of Zn added to Sn–0˙7Cu deteriorated the creep resistance due to the fact that the formation of both Zn particles and Cu6Sn5 intermetallics was suppressed. Among the tested materials, Sn–1Zn which exhibited relatively high creep resistances could be considered as a suitable alternative for the Sn–37Pb solder alloy.
Abnormalities of the large ribosomal subunit protein, Rpl35a, in Diamond-Blackfan anemia
Authors: Farrar Jason E. , Nater Michelle , Caywood Emi , McDevitt Michael A. , Kowalski Jeanne , Takemoto Clifford M. , Talbot C. Conover , Meltzer Paul , Esposito Diane , Beggs Alan H. , Schneider Hal E. , Grabowska Agnieszka , Ball Sarah E. , Niewiadomska Edyta , Sieff Colin A. , Vlachos Adrianna , Atsidaftos Eva , Ellis Steven R. , Lipton Jeffrey M. , Gazda Hanna T. , Arceci Robert J.
Published: June 2008

Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by anemia, congenital abnormalities, and cancer predisposition. Small ribosomal subunit genes RPS19, RPS24, and RPS17 are mutated in approximately one-third of patients. We used a candidate gene strategy combining high-resolution genomic mapping and gene expression microarray in the analysis of 2 DBA patients with chromosome 3q deletions to identify RPL35A as a potential DBA gene. Sequence analysis of a cohort of DBA probands confirmed involvement RPL35A in DBA. shRNA inhibition shows that Rpl35a is essential for maturation of 28S and 5.8S rRNAs, 60S subunit biogenesis, normal proliferation, and cell survival. Analysis of pre-rRNA processing in primary DBA lymphoblastoid cell lines demonstrated similar alterations of large ribosomal subunit rRNA in both RPL35A-mutated and some RPL35A wild-type patients, suggesting additional large ribosomal subunit gene defects are likely present in some cases of DBA. These data demonstrate that alterations of large ribosomal subunit proteins cause DBA and support the hypothesis that DBA is primarily the result of altered ribosomal function. The results also establish that haploinsufficiency of large ribosomal subunit proteins contributes to bone marrow failure and potentially cancer predisposition.
Differences across health care systems in outcome and cost-utility of surgical and conservative treatment of chronic low back pain: a study protocol
Authors: Melloh Markus , Röder Christoph , Elfering Achim , Theis Jean-Claude , Müller Urs , Staub Lukas P , Aghayev Emin , Zweig Thomas , Barz Thomas , Kohlmann Thomas , Wieser Simon , Jüni Peter , Zwahlen Marcel
Published: June 2008

Background

There is little evidence on differences across health care systems in choice and outcome of the treatment of chronic low back pain (CLBP) with spinal surgery and conservative treatment as the main options. At least six randomised controlled trials comparing these two options have been performed; they show conflicting results without clear-cut evidence for superior effectiveness of any of the evaluated interventions and could not address whether treatment effect varied across patient subgroups. Cost-utility analyses display inconsistent results when comparing surgical and conservative treatment of CLBP. Due to its higher feasibility, we chose to conduct a prospective observational cohort study.

Methods

This study aims to examine if

1. Differences across health care systems result in different treatment outcomes of surgical and conservative treatment of CLBP

2. Patient characteristics (work-related, psychological factors, etc.) and co-interventions (physiotherapy, cognitive behavioural therapy, return-to-work programs, etc.) modify the outcome of treatment for CLBP

3. Cost-utility in terms of quality-adjusted life years differs between surgical and conservative treatment of CLBP.

This study will recruit 1000 patients from orthopaedic spine units, rehabilitation centres, and pain clinics in Switzerland and New Zealand. Effectiveness will be measured by the Oswestry Disability Index (ODI) at baseline and after six months. The change in ODI will be the primary endpoint of this study.

Multiple linear regression models will be used, with the change in ODI from baseline to six months as the dependent variable and the type of health care system, type of treatment, patient characteristics, and co-interventions as independent variables. Interactions will be incorporated between type of treatment and different co-interventions and patient characteristics. Cost-utility will be measured with an index based on EQol-5D in combination with cost data.

Conclusion

This study will provide evidence if differences across health care systems in the outcome of treatment of CLBP exist. It will classify patients with CLBP into different clinical subgroups and help to identify specific target groups who might benefit from specific surgical or conservative interventions. Furthermore, cost-utility differences will be identified for different groups of patients with CLBP. Main results of this study should be replicated in future studies on CLBP.
Are cultural dimensions relevant for explaining cross-national differences in antibiotic use in Europe?
Authors: Deschepper Reginald , Grigoryan Larissa , Lundborg Cecilia Stålsby , Hofstede Geert , Cohen Joachim , Kelen Greta Van Der , Deliens Luc , Haaijer-Ruskamp Flora M
Published: June 2008

Background

Antibiotics are widely-used medicines for which a more prudent use has been advocated to minimize development of resistance. There are considerable cross-national differences that can only partially be explained by epidemiological difference and variations in health care structure. The aim of this study was to explore whether cross-national differences in use of antibiotics (prescribed and non-prescribed) are associated with differences between national cultures as described in Hofstede's model of cultural dimensions (Power Distance, Individualism, Masculinity, Uncertainty Avoidance and Long-Term Orientation).

Methods

Country-level data of prescribed antibiotic use and self-medication with antibiotics were correlated to country-specific scores of cultural dimensions obtained from Hofstede. Data on use of antibiotics were provided by three European studies, based on different methods and/or countries: Self-medication with Antibiotics and Resistance in Europe (SAR), based on a survey in 2003 on reported use of antibiotics in 19 countries, the European Surveillance on Antimicrobial Consumption, based on distribution and reimbursement of antibiotics in ambulatory care (1997–2002), and the 2002 interview-based Eurobarometer study, asking whether respondents had taken antibiotics in the previous 12 months. These studies provided data on antibiotics use for 27 European countries in total, for which scores of cultural dimensions were also available. The SAR-study differentiated between prescribed antibiotics and self-medication with antibiotics.

Results

Significant positive correlations were found for Power Distance Index with use of prescribed antibiotics in the three studies (rho between 0.59 and 0.62) and with self-medication (rho = 0.54) in the SAR study. Positive significant correlations were found for the Uncertainty Avoidance Index with the use of antibiotics as reported in two studies (rho between 0.57 and 0.59; for the SAR study the correlations were insignificant). Masculinity was not significantly correlated, except in one study after controlling for GDP (r = 0.81). For Individualism and Long-Term Orientation no significant correlations were found.

Conclusion

Power Distance is a cultural aspect associated with antibiotic use, suggesting that the culture-specific way people deal with authority is an important factor in explaining cross-national differences in antibiotic use. There are indications that Uncertainty Avoidance also plays a role but further research is needed to better understand the complex effect of cultural dimensions.
Identification of glycosaminoglycan binding regions in the Plasmodium falciparum encoded placental sequestration ligand, VAR2CSA
Authors: Resende Mafalda , Nielsen Morten A , Dahlbäck Madeleine , Ditlev Sisse B , Andersen Pernille , Sander Adam F , Ndam Nicaise T , Theander Thor G , Salanti Ali
Published: June 2008

Background

Pregnancy malaria is caused by Plasmodium falciparum-infected erythrocytes binding the placental receptor chondroitin sulfate A (CSA). This results in accumulation of parasites in the placenta with severe clinical consequences for the mother and her unborn child. Women become resistant to placental malaria as antibodies are acquired which specifically target the surface of infected erythrocytes binding in the placenta. VAR2CSA is most likely the parasite-encoded protein which mediates binding to the placental receptor CSA. Several domains have been shown to bind CSA in vitro; and it is apparent that a VAR2CSA-based vaccine cannot accommodate all the CSA binding domains and serovariants. It is thus of high priority to define minimal ligand binding regions throughout the VAR2CSA molecule.

Methods

To define minimal CSA-binding regions/peptides of VAR2CSA, a phage display library based on the entire var2csa coding region was constructed. This library was screened on immobilized CSA and cells expressing CSA resulting in a limited number of CSA-binding phages. Antibodies against these peptides were affinity purified and tested for reactivity against CSA-binding infected erythrocytes.

Results

The most frequently identified phages expressed peptides residing in the parts of VAR2CSA previously defined as CSA binding. In addition, most of the binding regions mapped to surface-exposed parts of VAR2CSA. The binding of a DBL2X peptide to CSA was confirmed with a synthetic peptide. Antibodies against a CSA-binding DBL2X peptide reacted with the surface of infected erythrocytes indicating that this epitope is accessible for antibodies on native VAR2CSA on infected erythrocytes.

Conclusion

Short continuous regions of VAR2CSA with affinity for multiple types of CSA were defined. A number of these regions localize to CSA-binding domains and to surface-exposed regions within these domains and a synthetic peptide corresponding to a peptide sequence in DBL2 was shown to bind to CSA and not to CSC. It is likely that some of these epitopes are involved in native parasite CSA adhesion. However, antibodies directed against single epitopes did not inhibit parasite adhesion. This study supports phage display as a technique to identify CSA-binding regions of large proteins such as VAR2CSA.
Cancer Stem Cells in Head and Neck Squamous Cell Cancer
Authors: Prince Mark E.P. , Ailles Laurie E.
Published: June 2008

Appropriate treatment of head and neck squamous cell cancer (HNSCC) remains one of the most difficult challenges in head and neck oncology. Overall survival of patients with HNSCC remains at approximately 50% at 5 years. Surgical therapy can be mutilating and often has significant effects on swallowing, speech, and physical appearance. The addition of chemotherapy to radiation treatment has shown efficacy in organ preservation in some sites in the head and neck, but has resulted in limited improvement in survival rates. HNSCC resistance to chemotherapy has limited the usefulness of chemotherapy in the treatment of this disease. We have recently demonstrated that human head and neck squamous cell cancers contain a tumorigenic, so-called cancer stem cell, subpopulation of cells that can self-renew and produce differentiated cells that form the bulk of the tumor. These tumorigenic HNSCC cells have a distinct phenotype and can be identified by a surface marker. Current treatment for HNSCC regimens may selectively kill the differentiated cancer cells, producing tumor regression while sparing the cancer stem cells, leading to tumor regrowth and relapse. It is important for us to understand why HNSCC does not respond to chemotherapy and to identify new targeted treatments that can overcome resistance and improve patient outcomes. Further study of HNSCC stem cells will increase our knowledge of this devastating disease and allow us to develop novel treatments.
Medulloblastoma Stem Cells
Authors: Fan Xing , Eberhart Charles G.
Published: June 2008

Medulloblastoma and other embronal brain tumors are similar in appearance and differentiation potential to neural stem and progenitor cells. Expression studies performed using human tumor samples, as well as the analysis of murine transgenic models, suggest that both multipotent cerebellar stem cells and lineage-restricted progenitors of the external germinal layer can be transformed into medulloblastoma by genetic alterations. These molecular changes frequently involve constitutive activation of signaling pathways such as Wnt, Hedgehog, and Notch, which play a key role in non-neoplastic neural stem cells. Pharmacologic blockade of the Hedgehog and Notch pathways suppresses the growth of medulloblastoma in culture and in vivo and may prove effective in targeting the small cancer stem-cell subpopulation required for tumor initiation and long-term propagation.
Mathematical Models of Cancer Stem Cells
Authors: Michor Franziska
Published: June 2008

Human cancers are thought to be sustained in their growth by a pathologic counterpart of normal adult stem cells: cancer stem cells. This concept was first developed in human myeloid leukemias and is today being extended to solid tumors such as breast and brain cancers. A quantitative understanding of cancer stem cells requires a mathematical framework to describe the dynamics of cancer initiation and progression, the response to treatment, and the evolution of resistance. In this review, I use chronic myeloid leukemia as an example to discuss how mathematical and computational techniques have been used to gain insights into the biology of cancer stem cells.
Melanoma Stem Cells: The Dark Seed of Melanoma
Authors: Zabierowski Susan E. , Herlyn Meenhard
Published: June 2008

Cells with stem-cell markers and features have recently been identified in melanoma tissues and cell lines. Melanoma stem-like cells possess many traits of tumor-initiating or tumor stem cells including self-renewal capacity, high tumorigenicity, and differentiation into various mesenchymal lineages, including melanocytic cells. Four subpopulations of melanoma-initiating cells have been distinguished: CD20+, CD133+, label-retaining or slow-cycling cells, and side-population cells with high efflux activities. Whether these are distinct or overlapping populations is currently under investigation. Ongoing studies are dissecting and characterizing the hierarchy of these subpopulations within a malignant lesion. Understanding these and the dynamics of clonal dominance will aid in the development of novel therapeutic strategies.
“Stemness” Genomics Law Governs Clinical Behavior of Human Cancer: Implications for Decision Making in Disease Management
Authors: Glinsky Gennadi V.
Published: June 2008

One of the most significant accomplishments of translational oncogenomics is a realistic promise of efficient diagnostic tests that would facilitate implementation of the concept of individualized cancer therapies. Recent discovery of the BMI1 pathway rule indicates that gene expression signatures (GESs) associated with the “stemness” state of a cell might be informative as molecular predictors of cancer therapy outcome. We illustrate a potential clinical utility of this concept using GESs derived from genomic analysis of embryonic stem cells (ESCs) during transition from self-renewing, pluripotent state to differentiated phenotypes. Signatures of multiple stemness pathways (signatures of BMI1, Nanog/Sox2/Oct4, EED, and Suz12 pathways; transposon exclusion zones and ESC pattern 3 signatures; signatures of Polycomb-bound and bivalent chromatin domain transcription factors) seem informative in stratification of cancer patients into low- and high-intensity treatment groups on the basis of prediction of the long-term therapy outcome. A stemness cancer therapy outcome predictor (CTOP) algorithm combining scores of nine stemness signatures outperforms individual signatures and demonstrates a superior prognostic accuracy in retrospective supervised analysis of large cohorts of breast, prostate, lung, and ovarian cancer patients. Our analysis suggests that stemness genomics law governs clinical behavior of human malignancies and defines epigenetic boundaries of therapy-resistant and -sensitive tumors within distinct stemness/differentiation programs. One of the main conclusions of our analysis is that near-term progress in practical implementation of the concept of personalized cancer therapies would depend on timely delivery to practicing physicians of relevant scientific information regarding the outcome of prospective trials validating prognostic performance of CTOP tests in a clinical setting.
Altered Endocrine and Autocrine Metabolism of Vitamin D in a Mouse Model of Gastrointestinal Inflammation
Authors: Liu Nancy , Nguyen Lisa , Chun Rene F. , Lagishetty Venu , Ren Songyang , Wu Shaoxing , Hollis Bruce , DeLuca Hector F. , Adams John S. , Hewison Martin
Published: June 2008

The active form of vitamin D, 1,25-dihydroxyvitamin D3, [1,25(OH)2D3] has potent actions on innate and adaptive immunity. Although endocrine synthesis of 1,25(OH)2D3 takes place in the kidney, the enzyme that catalyzes this, 25-hydroxyvitamin D-1α-hydroxylase (CYP27b1 in humans, Cyp27b1 in mice), is expressed at many extra-renal sites including the colon. We have shown previously that colonic expression of CYP27b1 may act to protect against the onset of colitis. To investigate this further, we firstly characterized changes in Cyp27b1 expression in a mouse model of colitis. Mice treated with dextran sodium sulfate (DSS) showed weight loss, histological evidence of colitis, and increased expression of inflammatory cytokines. This was associated with decreased renal expression of Cyp27b1 (5-fold, P = 0.013) and lower serum 1,25(OH)2D3 (51.8 ± 5.9 pg/nl vs. 65.1 ± 1.6 in controls, P < 0.001). However, expression of CYP27b1 was increased in the proximal colon of DSS mice (4-fold compared with controls, P < 0.001). Further studies were carried out using Cyp27b1 null (−/−) mice. Compared with +/− controls the Cyp27b1 −/− mice showed increased weight loss (4.9% vs. 22.8%, P < 0.001) and colitis. This was associated with raised IL-1 in the distal colon and IL-17 in the proximal and distal colon. Conversely, DSS-treated Cyp27b1−/− mice exhibited lower IL-10 in the proximal colon and toll-like receptors 2 and 4 in the distal colon. These data indicate that both local and endocrine synthesis of 1,25(OH)2D3 affect colitis in DSS-treated mice. Lack of Cyp27b1 exacerbates disease in this model, suggesting that similar effects may occur with vitamin D deficiency.
Glucocorticoids Increase Neuropeptide Y and Agouti-Related Peptide Gene Expression via Adenosine Monophosphate-Activated Protein Kinase Signaling in the Arcuate Nucleus of Rats
Authors: Shimizu Hiroshi , Arima Hiroshi , Watanabe Minemori , Goto Motomitsu , Banno Ryoichi , Sato Ikuko , Ozaki Nobuaki , Nagasaki Hiroshi , Oiso Yutaka
Published: June 2008

Recent studies suggest that the AMP-activated protein kinase (AMPK) signaling in the hypothalamus is the master regulator of energy balance. We reported in previous studies that glucocorticoids play a permissive role in the regulation of orexigenic neuropeptide Y (Npy) gene expression in the arcuate nucleus. In this study, we examined whether any cross talk occurs between glucocorticoids and AMPK signaling in the hypothalamus to regulate Npy as well as agouti-related peptide (Agrp) gene expression in the arcuate nucleus. In the hypothalamic organotypic cultures, the addition to the medium of the AMPK activator, 5-aminoimidazole-4-carboxamide-1-b-d-ribofuranoside, increased phosphorylated AMPK (p-AMPK) as well as phosphorylated acetyl-coenzyme A carboxylase (p-ACC) in the explants, accompanied by significant increases in Npy and Agrp gene expression in the arcuate nucleus. The incubation with dexamethasone (DEX) also activated AMPK signaling in the explants, accompanied by significant increases in Npy and Agrp gene expression in the arcuate nucleus. The addition of the AMPK inhibitor compound C to the medium, which blocked increases of p-AMPK and p-ACC by DEX, significantly attenuated Npy and Agrp gene expression stimulated by DEX. Furthermore, p-AMPK and p-ACC levels in the arcuate nucleus were significantly decreased in adrenalectomized rats compared with sham-operated rats, and a replacement of glucocorticoids reversed the AMPK signaling in adrenalectomized rats. Thus, our data demonstrated that glucocorticoids up-regulate the Npy and Agrp gene expression in the arcuate nucleus through AMPK signaling, suggesting that the activation of the hypothalamic APMK signaling by glucocorticoids might be essential to the energy homeostasis.
Skeletal Overexpression of Connective Tissue Growth Factor Impairs Bone Formation and Causes Osteopenia
Authors: Smerdel-Ramoya Anna , Zanotti Stefano , Stadmeyer Lisa , Durant Deena , Canalis Ernesto
Published: June 2008

Connective tissue growth factor (CTGF), a member of the CCN family of proteins, is expressed in skeletal cells, and the ctgf null mutation leads to neonatal lethality due to defects in skeletal development. To define the function of CTGF in the postnatal skeleton, we created transgenic mice overexpressing CTGF under the control of the human osteocalcin promoter. CTGF transgenic female and male mice exhibited a significant decrease in bone mineral density, compared with wild-type littermate controls. Bone histomorphometry revealed that CTGF overexpression caused decreased trabecular bone volume due to impaired osteoblastic activity because mineral apposition and bone formation rates were decreased. Osteoblast and osteoclast number and bone resorption were not altered. Calvarial osteoblasts and stromal cells from CTGF transgenics displayed decreased alkaline phosphatase and osteocalcin mRNA levels and reduced bone morphogenetic protein (BMP) signaling mothers against decapentaplegic, Wnt/β-catenin, and IGF-I/Akt signaling. In conclusion, CTGF overexpression in vivo causes osteopenia, secondary to decreased bone formation, possibly by antagonizing BMP, Wnt, and IGF-I signaling and activity.
Pancreatic Progenitor Cells—Recent Studies
Authors: Ku Hsun Teresa
Published: June 2008

Past studies of pancreatic progenitor cell biology relied mostly on histological analyses. Recent studies, using genetic labeling and tracing of progenitors, direct single cell analyses, colony assays, and enrichment of the minor population of progenitor cells through the use of cell surface markers, have strongly suggested that pancreatic progenitor cells with various frequency and lineage potentials, including the multipotent progenitors that give rise to endocrine, exocrine, and duct cells, exist in the developing and adult pancreas. In this review, it is therefore proposed that pancreatic progenitor cells may be organized in a hierarchy, in which the most primitive pan-pancreatic multipotent progenitors are at the top and rare, and the monopotent progenitors are at the bottom and abundant. This model may explain why only drastic injuries lead to effective activation of the progenitor cell compartment of the higher hierarchy, whereas under steady state, pregnancy, and milder injuries, recruitment of preexisting mature cells or their immediate monopotent progenitors could be sufficient to restore metabolic homeostasis. It is also proposed that the morphologically defined ductal cells are likely to be functionally heterogeneous and that endocrine progenitor cell activity should be determined based on functional analyses rather than histological locations.
Src family kinases are required for WNT5 signaling through the Derailed/RYK receptor in theDrosophilaembryonic central nervous system
Authors: Wouda Rene R. , Bansraj Monique R. K. S. , de Jong Anja W. M. , Noordermeer Jasprina N. , Fradkin Lee G.
Published: June 2008

Members of the RYK/Derailed family have recently been shown to regulate axon guidance in both Drosophila and mammals by acting as Wnt receptors. Little is known about how the kinase activity-deficient RYKs transduce Wnt signals. Here, we show that the non-receptor Src family tyrosine kinases, SRC64B and SRC42A, are involved in WNT5-mediated signaling through Derailed in the Drosophila embryonic central nervous system. Analysis of animals lacking SRC64B and SRC42A reveals defects in commissure formation similar to those observed in Wnt5 and derailed mutants. Reductions in SRC64B expression levels suppress a Wnt5/derailed-dependent dominant gain-of-function phenotype,and increased levels of either SRC64B or SRC42A enhance Wnt5/derailed-mediated axon commissure switching. Derailed and SRC64B form a complex, which contains catalytically active SRC64B, the formation or stability of which requires SRC64B kinase activity. Furthermore,Derailed is phosphorylated in a SRC64B-dependent manner and coexpression of Derailed and SRC64B results in the activation of SRC64B. The mammalian orthologs of Derailed and SRC64B also form complexes, suggesting that Src roles in RYK signaling are conserved. Finally, we show that coexpression of WNT5 and Derailed has no apparent effect upon TCF/LEF-dependent transcription,suggesting that the WNT5/Derailed signaling pathway is unlikely to directly regulate canonical Wnt pathway targets. Together, these findings indicate that the Src family kinases play novel roles in WNT5/Derailed-mediated signaling.
Induction of mirror-image supernumerary jaws in chicken mandibular mesenchyme by Sonic Hedgehog-producing cells
Authors: Brito José M. , Teillet Marie-Aimée , Le Douarin Nicole M.
Published: June 2008

Previous studies have shown that Sonic Hedgehog (Shh) signaling is crucial for the development of the first branchial arch (BA1) into a lower-jaw in avian and mammalian embryos. We have already shown that if Shhexpression is precociously inhibited in pharyngeal endoderm, neural crest cells migrate to BA1 but fail to survive, and Meckel's cartilage and associated structures do not develop. This phenotype can be rescued by addition of an exogenous source of Shh. To decipher the role of Shh, we explored the consequences of providing an extra source of Shh to the presumptive BA1 territory. Grafting quail fibroblasts engineered to produce Shh (QT6-Shh), at the 5- to 8-somite stage, resulted in the induction of mirror-image extra lower jaws, caudolateral to the normal one. It turns out that the oral opening epithelium, in which Shh, Fgf8 and Bmp4 are expressed in a definite pattern, functions as an organizing center for lower-jaw development. In our experimental design, the extra source of Shh activates Fgf8, Bmp4 and Shh genes in caudal BA1 ectoderm in a spatial pattern similar to that of the oral epithelium, and regularly leads to the formation of two extra lower-jaw-organizing centers with opposite rostrocaudal polarities. These results emphasize the similarities between the developmental processes of the limb and mandibular buds, and show that in both cases Shh-producing cells create a zone of polarizing activity for the structures deriving from them.
Pectoralis major inverse plasty for functional reconstruction in patients with anterolateral deltoid deficiency
Authors: Resch H. , Povacz P. , Maurer H. , Koller H. , Tauber M.
Published: June 2008

After establishing anatomical feasibility, functional reconstruction to replace the anterolateral part of the deltoid was performed in 20 consecutive patients with irreversible deltoid paralysis using the sternoclavicular portion of the pectoralis major muscle. The indication for reconstruction was deltoid deficiency combined with massive rotator cuff tear in 11 patients, brachial plexus palsy in seven, and an isolated axillary nerve lesion in two. All patients were followed clinically and radiologically for a mean of 70 months (24 to 125). The mean gender-adjusted Constant score increased from 28% (15% to 54%) to 51% (19% to 83%). Forward elevation improved by a mean of 37°, abduction by 30° and external rotation by 9°.

The pectoralis inverse plasty may be used as a salvage procedure in irreversible deltoid deficiency, providing subjectively satisfying results. Active forward elevation and abduction can be significantly improved.
Limb-sparing surgery preserves more function than amputation
Authors: Aksnes L. H. , Bauer H. C. F. , Jebsen N. L. , Foller̊s G. , Allert C. , Haugen G. S. , Hall K. S.
Published: June 2008

We evaluated the long-term functional outcome in 118 patients treated for osteosarcoma or Ewing’s sarcoma in the extremities a minimum of five years after treatment. We also examined if impaired function influenced their quality of life and ability to work.

The function was evaluated according to the Musculoskeletal Tumor Society (MSTS) score and the Toronto Extremity Salvage Score (TESS). Quality of life was assessed by using the Short Form-36 (SF-36).

The mean age at follow-up was 31 years (15 to 57) and the mean follow-up was for 13 years (6 to 22). A total of 67 patients (57%) initially had limb-sparing surgery, but four had a secondary amputation. The median MSTS score was 70% (17% to 100%) and the median TESS was 89% (43% to 100%). The amputees had a significantly lower MSTS score than those with limb-sparing surgery (p < 0.001), but there was no difference for the TESS. Tumour localisation above knee level resulted in significantly lower MSTS scores and TESS (p = 0.003 and p = 0.02, respectively).

There were no significant differences in quality of life between amputees and those with limb-sparing surgery except in physical functioning. Of the patients 11% (13) did not work or study. In multivariate analysis, amputation, tumour location above the knee and having muscular pain were associated with low physical function.

We conclude that most of the bone tumour survivors managed well after adjustment to their physical limitations. A total of 105 are able to work and have an overall good quality of life.