bluuebunny/crossref_metadata_2025 huggingface dataset:
The prevalence of work-related stress, and its association with self-perceived health and sick-leave, in a population of employed Swedish women
Authors: Holmgren Kristina , Dahlin-Ivanoff Synneve , Björkelund Cecilia , Hensing Gunnel
Published: March 2009

Background

Women report more occupational ill-health and are more sick-listed than men. Exploration of women's working conditions would therefore seem to be valuable. In this study we investigated the prevalence of work-related stress and its association with self-perceived health and sick-leave in a population of employed, working Swedish women.

Methods

This cross-sectional population study comprised 424 employed, working women who answered questionnaires on work-related stress, self-perceived health and sick-leave. The odds ratio (OR) with 95% confidence interval (CI) was calculated in order to analyse the association between the exposure variables of work-related stress and outcome variables of ill-health symptoms, self-rated health and sick-leave.

Results

Ten percent of the group reported highperceived stress owing to indistinct organisation and conflicts, and 25% highperceived stress owing to individual demands and commitment. Twenty-two percent reported lowinfluence at workand 33% reported work interference with leisure time. All categories of overall work-related stress were significantly associated with increased odds of high level of illness symptoms, with the highest OR for highperceived stress owing to indistinct organisation and conflictsand highperceived stress owing to individual demands and commitmentwith an OR of 3.17 (CI = 1.51–6.62) and 4.53 (CI = 2.71–7.56) respectively. Highperceived stress owing to indistinct organisation and conflictsand lowinfluence at workwere significantly associated with sick-leave with an OR of 3.85 (CI = 1.59–9.30) and 2.54 (CI = 1.17–5.48) respectively.

Conclusion

This study showed an association between, on the one hand, work-related stress, and on the other hand, illness symptoms and sick-leave. Distinguishing between the occurrence of negative work characteristics, and the immediate perception of stress because of these, resulted in a broad view of women's working conditions and expanded knowledge of work-related stress in women.
Paracrine sonic hedgehog signalling by prostate cancer cells induces osteoblast differentiation
Authors: Zunich Samantha M , Douglas Taneka , Valdovinos Maria , Chang Tiffany , Bushman Wade , Walterhouse David , Iannaccone Philip , Lamm Marilyn LG
Published: March 2009

Background

Sonic hedgehog (Shh) and components of its signalling pathway have been identified in human prostate carcinoma and increased levels of their expression appear to correlate with disease progression and metastasis. The mechanism through which Shh signalling could promote metastasis in bone, the most common site for prostate carcinoma metastasis, has not yet been investigated. The present study determined the effect of Shh signalling between prostate cancer cells and pre-osteoblasts on osteoblast differentiation, a requisite process for new bone formation that characterizes prostate carcinoma metastasis.

Results

LNCaP human prostate cancer cells modified to overexpress Shh (designated LNShh cells) and MC3T3 mouse pre-osteoblasts were maintained as mixed populations within the same culture chamber. In this non-conventional mixed culture system, LNShh cells upregulated the expression of Shh target genesGli1andPatched 1(Ptc1) in MC3T3 cells and this was inhibited by cyclopamine, a specific chemical inhibitor of hedgehog signalling. Concomitantly, MC3T3 cells exhibited time-dependent decreased cell proliferation, upregulated alkaline phosphataseAkp2gene expression, and increased alkaline phosphatase activity indicative of early phase osteoblast differentiation. LNShh cell-induced differentiation was inhibited in MC3T3 cells stably transfected with a dominant negative form of Gli1, a transcription factor that mediates Shh signalling. Interestingly, LNShh cells did not significantly increase the endogenous expression of the osteoblast differentiation transcription factorRunx2and its target genesosteocalcinandosteopontin. Consistent with these results, exogenous Shh peptide did not upregulateRunx2expression in MC3T3 cells. However,Runx2levels were increased in MC3T3 cells by ascorbic acid, a known stimulator of osteoblast differentiation.

Conclusion

Altogether, these data demonstrate that Shh-expressing prostate cancer cells can directly and specifically induce differentiation in pre-osteoblasts via a Gli1-dependent mechanism that does not require transcriptional upregulation ofRunx2. Paracrine activation of the Shh pathway in osteoblast progenitors and subsequent induction of osteoblast differentiation could be a mechanism through which high levels of Shh expression in prostate carcinoma contribute to bone metastasis. Targeting of paracrine Shh signalling may provide an effective therapeutic strategy against prostate carcinoma metastasis in bone.
Recruitment of HIV-1 envelope occurs subsequent to lipid mixing: a fluorescence microscopic evidence
Authors: Chien Miao-Ping , Lin Chi-Hui , Chang Ding-Kwo
Published: March 2009

Entry of the human immunodeficiency virus (HIV) into the target cell is initiated by fusion with the cell membrane, mediated through the envelope glycoproteins gp120 and gp41, following engagement to CD4 and the co-receptor. Previous fusion kinetics studies on the HXB2 envelope protein (Env) revealed that Env recruitment occurred at about 13 min concurrent with the lipid mixing. To resolve the temporal sequence of lipid mixing and recruitment, we employed an inhibitory assay monitored by fluorescence microscopy using a gp41 ectodomain (gp41e) fragment, which blocked Env recruitment in stark contrast to the lack of gp41e effect on the lipid mixing. In addition, to demonstrate the mode of action for the inhibition of gp41e, our results strongly suggested that lipid mixing precedes the Env recruitment because lipid mixing can proceed with Env recruitment inhibited by exogeneous gp41e molecules. Importantly, it was found that the random clustering of Env molecules on the membrane surface occurred at ~1 minute whereas the Env recruitment was observed at 13 minutes after the attachment of Env-expressing cell to the target cell. This > 10-fold temporal discrepancy highlights that the productive assembly of Env molecules leading to fusion requires spatio-temporal coordination of several adjacent Env trimers aggregated via directed movement.
Engineering the vaccinia virus L1 protein for increased neutralizing antibody response after DNA immunization
Authors: Shinoda Kaori , Wyatt Linda S , Irvine Kari R , Moss Bernard
Published: March 2009

Background

The licensed smallpox vaccine, comprised of infectious vaccinia virus, has associated adverse effects, particularly for immunocompromised individuals. Therefore, safer DNA and protein vaccines are being investigated. The L1 protein, a component of the mature virion membrane that is conserved in all sequenced poxviruses, is required for vaccinia virus entry into host cells and is a target for neutralizing antibody. When expressed by vaccinia virus, the unglycosylated, myristoylated L1 protein attaches to the viral membrane via a C-terminal transmembrane anchor without traversing the secretory pathway. The purpose of the present study was to investigate modifications of the gene expressing the L1 protein that would increase immunogenicity in mice when delivered by a gene gun.

Results

The L1 gene was codon modified for optimal expression in mammalian cells and potential N-glycosylation sites removed. Addition of a signal sequence to the N-terminus of L1 increased cell surface expression as shown by confocal microscopy and flow cytometry of transfected cells. Removal of the transmembrane domain led to secretion of L1 into the medium. Induction of binding and neutralizing antibodies in mice was enhanced by gene gun delivery of L1 containing the signal sequence with or without the transmembrane domain. Each L1 construct partially protected mice against weight loss caused by intranasal administration of vaccinia virus.

Conclusion

Modifications of the vaccinia virus L1 gene including codon optimization and addition of a signal sequence with or without deletion of the transmembrane domain can enhance the neutralizing antibody response of a DNA vaccine.
Cell proliferation in the Drosophila adult brain revealed by clonal analysis and bromodeoxyuridine labelling
Authors: von Trotha Jakob W , Egger Boris , Brand Andrea H
Published: March 2009

Background

The production of new neurons during adulthood and their subsequent integration into a mature central nervous system have been shown to occur in all vertebrate species examined to date. However, the situation in insects is less clear and, in particular, it has been reported that there is no proliferation in the Drosophila adult brain.

Results

We report here, using clonal analysis and 5'-bromo-2'-deoxyuridine (BrdU) labelling, that cell proliferation does occur in the Drosophila adult brain. The majority of clones cluster on the ventrolateral side of the antennal lobes, as do the BrdU-positive cells. Of the BrdU-labelled cells, 86% express the glial gene reversed polarity (repo), and 14% are repo negative.

Conclusion

We have observed cell proliferation in the Drosophila adult brain. The dividing cells may be adult stem cells, generating glial and/or non-glial cell types.
High tandem repeat content in the genome of the short-lived annual fish Nothobranchius furzeri: a new vertebrate model for aging research
Authors: Reichwald Kathrin , Lauber Chris , Nanda Indrajit , Kirschner Jeanette , Hartmann Nils , Schories Susanne , Gausmann Ulrike , Taudien Stefan , Schilhabel Markus B , Szafranski Karol , Glöckner Gernot , Schmid Michael , Cellerino Alessandro , Schartl Manfred , Englert Christoph , Platzer Matthias
Published: March 2009

Background

The annual fish Nothobranchius furzeri is the vertebrate with the shortest known life span in captivity. Fish of the GRZ strain live only three to four months under optimal laboratory conditions, show explosive growth, early sexual maturation and age-dependent physiological and behavioral decline, and express aging related biomarkers. Treatment with resveratrol and low temperature significantly extends the maximum life span. These features make N. furzeri a promising new vertebrate model for age research.

Results

To contribute to establishing N. furzeri as a new model organism, we provide a first insight into its genome and a comparison to medaka, stickleback, tetraodon and zebrafish. The N. furzeri genome contains 19 chromosomes (2n = 38). Its genome of between 1.6 and 1.9 Gb is the largest among the analyzed fish species and has, at 45%, the highest repeat content. Remarkably, tandem repeats comprise 21%, which is 4-12 times more than in the other four fish species. In addition, G+C-rich tandem repeats preferentially localize to centromeric regions. Phylogenetic analysis based on coding sequences identifies medaka as the closest relative. Genotyping of an initial set of 27 markers and multi-locus fingerprinting of one microsatellite provides the first molecular evidence that the GRZ strain is highly inbred.

Conclusions

Our work presents a first basis for systematic genomic and genetic analyses aimed at understanding the mechanisms of life span determination in N. furzeri.
Cancer Patient Assessment and Reports of Excellence: Reliability and Validity of Advanced Cancer Patient Perceptions of the Quality of Care
Authors: Teno Joan M. , Lima Julie C. , Lyons Kathleen Doyle
Published: March 2009

Purpose

Consumer perceptions are important measures of the quality of cancer care. This article describes the validation of new measures of the quality of cancer care at the time of diagnosis and treatment for advanced cancer with life-limiting prognosis.

Methods

Focus groups, review of guidelines, and an expert panel were used to construct two surveys of the quality of cancer care. A prospective cohort study examined the reliability and validity of three problem scores (ie, counts of the opportunities to improve the quality of care) that examine care at the time of diagnosis and initial treatment.

Results

At the first interview, 58% of 206 cancer patients (54.9% females; 27.5% with lung cancer; 5.4% with pancreatic cancer; 30.4% with colorectal cancer; 18.6% with breast cancer; mean age, 66.6 years) identified one or more concerns with communication about being diagnosed with advanced cancer. At the second interview, 57.0% of the respondents voiced one or more concerns about treatment communication, and 30.2% expressed one or more concerns about the experience of treatment. Each of the problem scores demonstrated both internal consistency with Cronbach's α > .75 and short-term stability of responses in a subsample that had the survey administered twice in 72 hours. Factor analysis largely confirmed the proposed scale structure. All three measures demonstrated moderate correlations suggesting evidence of construct validity.

Conclusion

The three proposed problem scores demonstrate evidence of reliability and validity that warrants further testing to examine their responsiveness and discriminate validity in larger, more generalizable samples.
Hematologic Response to Three Alternative Dosing Schedules of Azacitidine in Patients With Myelodysplastic Syndromes
Authors: Lyons Roger M. , Cosgriff Thomas M. , Modi Sanjiv S. , Gersh Robert H. , Hainsworth John D. , Cohn Allen L. , McIntyre Heidi J. , Fernando Indra J. , Backstrom Jay T. , Beach C.L.
Published: March 2009

Purpose

Azacitidine (AZA) is effective treatment for myelodysplastic syndromes (MDS) at a dosing schedule of 75 mg/m2/d subcutaneously for 7 days every 4 weeks. The initial phase of this ongoing multicenter, community-based, open-label study evaluated three alternative AZA dosing schedules without weekend dosing.

Patients and Methods

MDS patients were randomly assigned to one of three regimens every 4 weeks for six cycles: AZA 5-2-2 (75 mg/m2/d subcutaneously for 5 days, followed by 2 days no treatment, then 75 mg/m2/d for 2 days); AZA 5-2-5 (50 mg/m2/d subcutaneously for 5 days, followed by 2 days no treatment, then 50 mg/m2/d for 5 days); or AZA 5 (75 mg/m2/d subcutaneously for 5 days).

Results

Of patients randomly assigned to AZA 5-2-2 (n = 50), AZA 5-2-5 (n = 51), or AZA 5 (n = 50), most were French-American-British (FAB) lower risk (refractory anemia [RA]/RA with ringed sideroblasts/chronic myelomonocytic leukemia with < 5% bone marrow blasts, 63%) or RA with excess blasts (30%), and 79 (52%) completed ≥ six treatment cycles. Hematologic improvement (HI) was achieved by 44% (22 of 50), 45% (23 of 51), and 56% (28 of 50) of AZA 5-2-2, AZA 5-2-5, and AZA 5 arms, respectively. Proportions of RBC transfusion–dependent patients who achieved transfusion independence were 50% (12 of 24), 55% (12 of 22), and 64% (16 of 25), and of FAB lower-risk transfusion-dependent patients were 53% (nine of 17), 50% (six of 12), and 61% (11 of 18), respectively. In the AZA 5-2-2, AZA 5-2-5, and AZA 5 groups, 84%, 77%, and 58%, respectively, experienced ≥ 1 grade 3 to 4 adverse events.

Conclusion

All three alternative dosing regimens produced HI, RBC transfusion independence, and safety responses consistent with the currently approved AZA regimen. These results support AZA benefits in transfusion-dependent lower-risk MDS patients.
Value and Limitations of Measuring HER-2 Extracellular Domain in the Serum of Breast Cancer Patients
Authors: Leary Alexandra F. , Hanna Wedad M. , van de Vijver Marc J. , Penault-Llorca Frederique , Rüschoff Josef , Osamura Robert Y. , Bilous Michael , Dowsett Mitch
Published: March 2009

The human epidermal receptor-2 (HER-2) is overexpressed or amplified in 15% to 25% of breast cancers. Determination of HER-2 tumor status offers clinically useful information, as it selects patients who may benefit from treatment with trastuzumab, the monoclonal antibody against HER-2. Currently approved methods for HER-2 testing include immunohistochemistry or fluorescent in situ hybridization using tumor tissue. A fragment of HER-2 composed of its extracellular domain (ECD) can also be detected in the serum of some patients with breast cancer. As an easily accessible tumor marker, it could offer additional useful prognostic or predictive information. This review will briefly address the biology of the circulating HER-2 ECD and discuss the evidence to support the role, if any, for measuring HER-2 ECD levels in women with breast cancer. In particular, we focus on the value and limitations of serum ECD in both early and advanced breast cancer in the following clinical contexts: as a marker of HER-2 tumor tissue status; clinical implications of raised levels in women who have a tumor not overexpressing HER-2; as a prognostic indicator and as a predictor of response to treatment; and as a monitoring tool for early recurrence. On the basis of our review of the literature, we conclude that there is currently insufficient evidence to support the use of serum HER-2 ECD in the routine management of individual patients with breast cancer. This conclusion is in agreement with the 2007 American Society of Clinical Oncology guidelines on the use of biomarkers in breast cancer.
Prospective Evaluation of Whole-Body Cancer Screening With Multiple Modalities Including [18F]Fluorodeoxyglucose Positron Emission Tomography in a Healthy Population: A Preliminary Report
Authors: Nishizawa Sadahiko , Kojima Shinsuke , Teramukai Satoshi , Inubushi Masayuki , Kodama Hironobu , Maeda Yoshiki , Okada Hiroyuki , Zhou Bin , Nagai Yoji , Fukushima Masanori
Published: March 2009

Purpose

To prospectively evaluate the utility of whole-body cancer screening with multiple modalities including [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) in a healthy population. This report summarizes the results of the first three annual screenings.

Participants and Methods

A total of 1,197 healthy volunteers ≥ 35 years old were enrolled between August 2003 and July 2004 and offered annual cancer screening for 5 years with subsequent long-term follow-up. Screening modalities included were whole-body FDG-PET, chest and abdominal computed tomography (CT), brain and pelvic magnetic resonance imaging, several tumor markers, and fecal occult blood testing.

Results

As of the end of 2006, 22 primary cancers were pathologically confirmed. Nineteen of 22 were detected by the screening; 18 in the initial, one in the second, and none in the third. Three were diagnosed after development of symptoms. Of the 18 detected in the initial screening (six thyroid, four lung, three prostate, three breast, one endometrial, and one thymic), 12 were at stage I and 11 were PET positive. PET-negative cancers were detected by CT or the prostate-specific antigen (PSA) test. Sensitivity and specificity were 50.0% (11 of 22) and 93.2% (1,095 of 1,175), respectively, for FDG-PET alone and 81.8% (18 of 22) and 82.0% (963 of 1,175), respectively, for the combination of imaging modalities and PSA.

Conclusion

While FDG-PET alone is insufficient, whole-body cancer screening with selected modalities including FDG-PET has initial performance supporting possible utility by detecting a wide variety of early-stage cancers with reasonable sensitivity. However, the detection of many indolent cancers and false positives necessitate continuing study for appropriate evaluation.
Relationship Over Time Between Psychological Distress and Physical Activity in Colorectal Cancer Survivors
Authors: Chambers Suzanne K. , Lynch Brigid M. , Aitken Joanne , Baade Peter
Published: March 2009

Purpose

Increased physical activity in patients with colorectal cancer is related to improved recurrence-free and overall survival. Psychological distress after cancer may place patients at risk of reduced physical activity, but paradoxically may also act as a motivator for lifestyle change. The relationship between psychological distress and physical activity after cancer over time has not been described. Methods A prospective survey of 1,966 (57% response) colorectal cancer survivors assessed the psychological distress variables of anxiety, depression, somatization, and cancer threat appraisal as predictors of physical activity at 5, 12, 24, and 36 months postdiagnosis; 978 respondents had valid data for all time points.

Results

Higher somatization was associated with greater physical inactivity (relative risk ratio [RRR] = 1.12; 95% CI, 1.1 to 1.2) and insufficient physical activity (RRR = 1.05; 95% CI, 0.90 to 1.0). Respondents with a more positive appraisal of their cancer were significantly (P = .031) less likely to be inactive (RRR = 0.95; 95% CI, 0.90 to 1.0) or insufficiently active (RRR = 0.96). Fatigued and obese respondents and current smokers were more inactive. Respondents whose somatization increased between two time periods were less likely to increase their physical activity over the same period (P < .001). Respondents with higher anxiety at one time period were less likely to have increased their activity at the next assessment (P = .004). There was no association between depression and physical activity.

Conclusion

Cancer survivors who experience somatization and anxiety are at greater risk of physical inactivity. The lack of a clear relationship between higher psychological distress and increasing physical activity argues against distress as a motivator to exercise in these patients.
Malignant Pleural Mesothelioma
Authors: Tsao Anne S. , Wistuba Ignacio , Roth Jack A. , Kindler Hedy Lee
Published: March 2009

Malignant pleural mesothelioma (MPM) is a deadly disease that occurs in 2,000 to 3,000 people each year in the United States. Although MPM is an extremely difficult disease to treat, with the median overall survival ranging between 9 and 17 months regardless of stage, there has been significant progress over the last few years that has reshaped the clinical landscape. This article will provide a comprehensive discussion of the latest developments in the treatment of MPM. We will provide an update of the major clinical trials that impact mesothelioma treatment in the resectable and unresectable settings, discuss the impact of novel therapeutics, and provide perspective on where the clinical research in mesothelioma is moving. In addition, there are controversial issues, such as the role of extrapleural pneumonectomy, adjuvant radiotherapy, and use of intensity-modulated radiotherapy versus hemithoracic therapy that will also be addressed in this manuscript.
Steps and Time to Process Clinical Trials at the Cancer Therapy Evaluation Program
Authors: Dilts David M. , Sandler Alan B. , Cheng Steven K. , Crites Joshua S. , Ferranti Lori B. , Wu Amy Y. , Finnigan Shanda , Friedman Steven , Mooney Margaret , Abrams Jeffrey
Published: March 2009

Purpose

To examine the processes and document the calendar time required for the National Cancer Institute's Cancer Therapy Evaluation Program (CTEP) and Central Institutional Review Board (CIRB) to evaluate and approve phase III clinical trials.

Methods

Process steps were documented by (1) interviewing CTEP and CIRB staff regarding the steps required to activate a trial from initial concept submission to trial activation by a cooperative group, (2) reviewing standard operating procedures, and (3) inspecting trial records and documents for selected trials to identify any additional steps. Calendar time was collected from initial concept submission to activation using retrospective data from the CTEP Protocol and Information Office.

Results

At least 296 distinct processes are required for phase III trial activation: at least 239 working steps, 52 major decision points, 20 processing loops, and 11 stopping points. Of the 195 trials activated during the January 1, 2000, to December 31, 2007, study period, a sample of 167 (85.6%) was used for gathering timing data. Median calendar days from initial formal concept submission to CTEP to trial activation by a cooperative group was 602 days (interquartile range, 454 to 861 days). This time has not significantly changed over the past 8 years. There is a high variation in the time required to activate a clinical trial.

Conclusion

Because of their complexity, the overall development time for phase III clinical trials is lengthy, process laden, and highly variable. To streamline the process, a solution must be sought that includes all parties involved in developing trials.
Phase I Study of Individualized Stereotactic Body Radiotherapy of Liver Metastases
Authors: Lee Mark T. , Kim John J. , Dinniwell Robert , Brierley James , Lockwood Gina , Wong Rebecca , Cummings Bernard , Ringash Jolie , Tse Regina V. , Knox Jennifer J. , Dawson Laura A.
Published: March 2009

Purpose

To report on the outcomes of a phase I study of stereotactic body radiotherapy (SBRT) for treatment of liver metastases.

Patients and Methods

Patients with liver metastases that were inoperable or medically unsuitable for resection, and who were not candidates for standard therapies, were eligible for this phase I study of individualized SBRT. Individualized radiation doses were chosen to maintain the same nominal risk of radiation-induced liver disease (RILD) for three estimated risk levels (5%, 10%, and 20%). Additional patients were treated at the maximal study dose (MSD) in an expanded cohort. Median SBRT dose was 41.8 Gy (range, 27.7 to 60 Gy) in six fractions over 2 weeks.

Results

Sixty-eight patients with inoperable colorectal (n = 40), breast (n = 12), or other (n = 16) liver metastases were treated. Median tumor volume was 75.2 mL (range, 1.19 to 3,090 mL). The highest RILD risk level investigated was safe, with no dose-limiting toxicity. Two grade 3 liver enzyme changes occurred, but no RILD or other grade 3 to 5 liver toxicity was seen, for a low estimated risk of serious liver toxicity (95% CI, 0 to 5.3%). Six (9%) acute grade 3 toxicities (two gastritis, two nausea, lethargy, and thrombocytopenia) and one (1%) grade 4 toxicity (thrombocytopenia) were seen. The 1-year local control rate was 71% (95 CI, 58% to 85%). The median overall survival was 17.6 months (95% CI, 10.4 to 38.1 months).

Conclusion

Individualized six-fraction liver metastases SBRT is safe, with sustained local control observed in the majority of patients.
Phase I and Pharmacokinetic Study of Sorafenib in Patients With Hepatic or Renal Dysfunction: CALGB 60301
Authors: Miller Antonius A. , Murry Daryl J. , Owzar Kouros , Hollis Donna R. , Kennedy Erin B. , Abou-Alfa Ghassan , Desai Apurva , Hwang Jimmy , Villalona-Calero Miguel A. , Dees E. Claire , Lewis Lionel D. , Fakih Marwan G. , Edelman Martin J. , Millard Fred , Frank Richard C. , Hohl Raymond J. , Ratain Mark J.
Published: March 2009

Purpose

We sought to characterize the pharmacokinetics (PK) and determine a tolerable dose of oral sorafenib in patients with hepatic or renal dysfunction.

Patients and Methods

Patients were assigned to one of nine cohorts: cohort 1, bilirubin ≤ upper limit of normal (ULN) and AST ≤ ULN and creatinine clearance (CC) ≥ 60 mL/min; cohort 2, bilirubin more than ULN but ≤ 1.5× ULN and/or AST more than ULN; cohort 3, CC between 40 and 59 mL/min; cohort 4, bilirubin more than 1.5× ULN to ≤ 3× ULN (any AST); cohort 5, CC between 20 and 39 mL/min; cohort 6, bilirubin more than 3× ULN to 10× ULN (any AST); cohort 7, CC less than 20 mL/min; cohort 8, albumin less than 2.5 mg/dL (any bilirubin/AST); and cohort 9, hemodialysis. Sorafenib was administered as a 400-mg dose on day 1 for PK, and continuous daily dosing started on day 8.

Results

Of 150 registered patients, 138 patients were treated. With the exception of cohorts 6 and 7, at least 12 patients per cohort were assessable, and the dose level with prospectively defined dose-limiting toxicity in less than one third of patients by day 29 was considered tolerable. No significant associations between the sorafenib PK and cohort were found.

Conclusion

We recommend the following empiric sorafenib starting doses by cohort: cohort 1, 400 mg twice a day; cohort 2, 400 mg twice a day; cohort 3, 400 mg twice a day; cohort 4, 200 mg twice a day; cohort 5, 200 mg twice a day; cohort 6, not even 200 mg every third day tolerable; cohort 7, not defined; cohort 8, 200 mg each day; and cohort 9, 200 mg each day.
Health Behaviors, Medical Care, and Interventions to Promote Healthy Living in the Childhood Cancer Survivor Study Cohort
Authors: Nathan Paul C. , Ford Jennifer S. , Henderson Tara O. , Hudson Melissa M. , Emmons Karen M. , Casillas Jacqueline N. , Lown E. Anne , Ness Kirsten K. , Oeffinger Kevin C.
Published: March 2009

Childhood cancer survivors are at risk for medical and psychosocial late effects as a result of their cancer and its therapy. Promotion of healthy lifestyle behaviors and provision of regular risk-based medical care and surveillance may modify the evolution of these late effects. This manuscript summarizes publications from the Childhood Cancer Survivor Study (CCSS) that have examined health behaviors, risk-based health care, and interventions to promote healthy lifestyle practices. Long-term survivors use tobacco and alcohol and have inactive lifestyles at higher rates than is ideal given their increased risk of cardiac, pulmonary, and metabolic late effects. Nearly 90% of survivors report receiving some form of medical care. However, only 18% report medical visits related to their prior cancer that include discussion or ordering of screening tests or counseling on how to reduce the specific risks arising from their cancer. One low-cost, peer-driven intervention trial has been successful in improving smoking cessation within the CCSS cohort. On the basis of data from CCSS investigations, several trials to promote improved medical surveillance among high-risk groups within the cohort are underway. Despite their long-term risks, many survivors of childhood cancer engage in risky health behaviors and do not receive adequate risk-based medical care.
Prophylaxis of deep-vein thrombosis in fractures below the knee
Authors: Goel D. P. , Buckley R. , deVries G. , Abelseth G. , Ni A. , Gray R.
Published: March 2009

The incidence of deep-vein thrombosis and the need for thromboprophylaxis following isolated trauma below the knee is uncertain. We have investigated this with a prospective randomised double-blind controlled trial using low molecular weight heparin with saline injection as placebo in patients aged between 18 and 75 years who had sustained an isolated fracture below the knee which required operative fixation. All patients had surgery within 48 hours of injury and were randomised to receive either the placebo or low molecular weight heparin for 14 days, after which they underwent bilateral lower limb venography, interpreted by three independent radiologists. Further follow-up was undertaken at two, six, eight and 12 weeks.

A total of 238 patients fulfilled all the inclusion criteria, with 127 in the low molecular weight heparin group and 111 in the placebo group, all of whom underwent bilateral venography. There was no statistically significant difference in the incidence of deep-vein thrombosis between those patients treated with low molecular weight heparin or the placebo (p = 0.22). The number of deep-vein thromboses in the two groups was 11 (8.7%) and 14 (12.6%), respectively. Age and the type of fracture were significantly associated with the rate of deep-vein thrombosis (p = 0.001 and p = 0.009, respectively) but gender, comorbidities and the body mass index were not.

The overall incidence of deep-vein thrombosis in this series was 11%. There was no clinical or statistical significant reduction in the incidence of deep-vein thrombosis with the use of thromboprophylaxis. However, we accept that owing to a cessation of funding, recruitment to this trial had to be ended prior to establishing the necessary sample size. Our results cannot, therefore, categorically exclude the possibility that low molecular weight heparin treatment could be beneficial. We recommend a further multicentre trial be undertaken to resolve this matter.
Ankle fusion for bone loss around the ankle joint using the Ilizarov technique
Authors: Kovoor C. C. , Padmanabhan V. , Bhaskar D. , George V. V. , Viswanath S.
Published: March 2009

We present the results of ankle fusion using the Ilizarov technique for bone loss around the ankle in 20 patients. All except one had sustained post-traumatic bone loss. Infection was present in 17. The mean age was 33.1 years (7 to 71). The mean size of the defect was 3.98 cm (1.5 to 12) and associated limb shortening before the index procedure varied from 1 cm to 5 cm. The mean time in the external fixator was 335 days (42 to 870). Tibiotalar fusion was performed in 19 patients and tibiocalcaneal fusion in one. Associated problems included diabetes in one patient, pelvic and urethral injury in one, visual injury in one patient and ipsilateral tibial fracture in five. At the final mean follow-up of 51.55 months (24 to 121) fusion had been achieved in 19 of 20 patients. A total of 16 patients were able to return to work. The results were graded as good in 11 patients, fair in six and poor in three. The mean external fixation index was 8.8 days/mm (0 to 30). One patient with diabetes developed severe infection which required early removal of the fixator. Refractures occurred in three patients, two of which were at the site of fusion and one at a previous tibial shaft fracture site. Equinus deformity of the ankle fusion occurred after a further fracture in one patient. There were two patients with residual forefoot equinus, and one developed late valgus at the fusion site.

Poor consolidation of the regenerated bone in two patients was treated by bone grafting in one and by bone and fibular strut grafting in the other. Residual soft-tissue infection was still present in two patients.
Outcome of a hemispherical porous-coated acetabular component with a proximally hydroxyapatite-coated anatomical femoral component
Authors: García-Rey E. , García-Cimbrelo E. , Cordero-Ampuero J.
Published: March 2009

We reviewed 111 hemispherical Duraloc series-500 acetabular components with a minimum follow-up of 12 years. The mean clinical and radiological follow-up was 13.4 years (12 to 15). A Profile hydroxyapatite-coated anatomical femoral component was used in each case. Six patients had a late dislocation, for whom the polyethylene liner was exchanged. Each acetabular component was well fixed and all femoral components showed signs of bone ingrowth. The mean rate of femoral head penetration was 0.10 mm/year (0.021 to 0.481). The probability of not developing femoral cortical hypertrophy and proximal osteopenia by 12 years was 80.2% (95% confidence interval, 72.7 to 87.6) and 77.5% (95% confidence interval, 69.7 to 85.2), respectively. Despite these good clinical results, further follow-up is needed to determine whether these prostheses will loosen with time.
Percutaneous vertebroplasty for the treatment of osteoporotic vertebral compression fractures
Authors: Muijs S. P. J. , Nieuwenhuijse M. J. , Van Erkel A. R. , Dijkstra P. D. S.
Published: March 2009

In a prospective study between August 2002 and August 2005, we studied the quantitative clinical and radiological outcome 36 months after percutaneous vertebroplasty for intractable type-II osteoporotic vertebral compression fractures which had been unresponsive to conservative treatment for at least eight weeks. We also examined the quality of life (QoL). The clinical follow-up involved the use of a pain intensity numerical rating scale (PI-NRS, 0 to 10), the Short-Form 36 (SF-36) QoL questionnaire and an anamnestic questionnaire before and at seven days (PI-NRS only), and one, three, 12 and 36 months post-operatively.

A total of 30 consecutive patients received percutaneous vertebroplasty for 62 vertebral compression fractures with a mean time between fracture and treatment of 7.7 months (2.2 to 39). An immediate, significant and lasting reduction in the average and worst back pain was found, represented by a decrease of 3.1 and 2.7 points after seven days and 3.1 and 2.8 points after 36 months, respectively (p < 0.00). Comparison of the pre- and post-vertebroplasty scores on the various SF-36 domains showed an ultimate significant increase in six of eight domains and both summary scores. Asymptomatic leakage of cement was found in 47 of 58 (81%) of treated vertebrae. Two minor complications occurred, an asymptomatic pulmonary cement embolism and a cement spur along the needle track.

Percutaneous vertebroplasty in the treatment of chronic vertebral compression fractures results in an immediate, significant and lasting reduction in back pain, and overall improvement in physical and mental health.
Extracorporeal irradiation for pelvic reconstruction in Ewing’s sarcoma
Authors: Krieg A. H. , Mani M. , Speth B. M. , Stalley P. D.
Published: March 2009

We review the treatment of pelvic Ewing’s sarcoma by the implantation of extracorporeally-irradiated (ECI) autografts and compare the outcome with that of other reported methods.

We treated 13 patients with ECI autografts between 1994 and 2004. There were seven males and six females with a median age of 15.7 years (interquartile range (IQR) 12.2 to 21.7). At a median follow-up of five years (IQR 1.8 to 7.4), the disease-free survival was 69% overall, and 75% if one patient with local recurrence after initial treatment elsewhere was excluded. Four patients died from distant metastases at a mean of 17 months (13 to 23). There were three complications which required operative intervention; one was a deep infection which required removal of the graft. The functional results gave a mean Musculoskeletal Tumor Society score of 85% (60% to 97%), a mean Toronto extremity salvage score of 86% (69% to 100%) and a mean Harris hip score of 92 (67 to 100).

We conclude that ECI grafting is a suitable form of treatment for localised and resectable pelvic Ewing’s sarcoma.
Imageless computer navigation for placement of the femoral component in resurfacing arthroplasty of the hip
Authors: Olsen M. , Davis E. T. , Waddell J. P. , Schemitsch E. H.
Published: March 2009

We have investigated the accuracy of placement of the femoral component using imageless navigation in 100 consecutive Birmingham Hip Resurfacings. Pre-operative templating determined the native neck-shaft angle and planned stem-shaft angle of the implant. The latter were verified post-operatively using digital anteroposterior unilateral radiographs of the hip.

The mean neck-shaft angle determined before operation was 132.7° (118° to 160°). The mean planned stem-shaft angle was a relative valgus alignment of 9.7° (sd 2.6). The stem-shaft angle after operation differed from that planned by a mean of 2.8° (sd 2.0) and in 86% of cases the final angle measured within ± 5° of that planned. We had no instances of notching of the neck or varus alignment of the implant in our series. A learning curve was observed in the time taken for navigation, but not for accurate placement of the implant.

Navigation in hip resurfacing may afford the surgeon a reliable and accurate method of placement of the femoral component.
Medial unicompartmental knee replacement in the under-50s
Authors: Parratte S. , Argenson J.-N. A. , Pearce O. , Pauly V. , Auquier P. , Aubaniac J.-M.
Published: March 2009

We retrospectively reviewed 35 cemented unicompartmental knee replacements performed for medial unicompartmental osteoarthritis of the knee in 31 patients ≤50 years old (mean 46, 31 to 49). Patients were assessed clinically and radiologically using the Knee Society scores at a mean follow-up of 9.7 years (5 to 16) and survival at 12 years was calculated. The mean Knee Society Function Score improved from 54 points (25 to 64) pre-operatively to 89 (80 to 100) post-operatively (p < 0.0001). Six knees required revision, four for polyethylene wear treated with an isolated exchange of the tibial insert, one for aseptic loosening and one for progression of osteoarthritis.

The 12-year survival according to Kaplan-Meier was 80.6% with revision for any reason as the endpoint. Despite encouraging clinical results, polyethylene wear remains a major concern affecting the survival of unicompartmental knee replacement in patients younger than 50.
Is there a biomechanical explanation for anterior knee pain in patients with patella alta?
Authors: Luyckx T. , Didden K. , Vandenneucker H. , Labey L. , Innocenti B. , Bellemans J.
Published: March 2009

The purpose of this study was to test the hypothesis that patella alta leads to a less favourable situation in terms of patellofemoral contact force, contact area and contact pressure than the normal patellar position, and thereby gives rise to anterior knee pain.

A dynamic knee simulator system based on the Oxford rig and allowing six degrees of freedom was adapted in order to simulate and record the dynamic loads during a knee squat from 30° to 120° flexion under physiological conditions. Five different configurations were studied, with variable predetermined patellar heights.

The patellofemoral contact force increased with increasing knee flexion until contact occurred between the quadriceps tendon and the femoral trochlea, inducing load sharing. Patella alta caused a delay of this contact until deeper flexion. As a consequence, the maximal patellofemoral contact force and contact pressure increased significantly with increasing patellar height (p < 0.01). Patella alta was associated with the highest maximal patellofemoral contact force and contact pressure. When averaged across all flexion angles, a normal patellar position was associated with the lowest contact pressures.

Our results indicate that there is a biomechanical reason for anterior knee pain in patients with patella alta.
Unipolar proximal femoral endoprosthetic replacement for tumour
Authors: Chandrasekar C. R. , Grimer R. J. , Carter S. R. , Tillman R. M. , Abudu A. , Jeys L. M.
Published: March 2009

We undertook a cemental unipolar proximal femoral endoprosthetic replacement in 131 patients with a mean age of 50 years (2 to 84). Primary malignant tumours were present in 54 patients and 67 had metastatic disease. In addition, eight patients had either lymphoma or myeloma and two had non-oncological disorders. The mean follow-up was 27 months (0 to 180). An acetabular revision was required later in 14 patients, 12 of whom had been under the age of 21 years at the time of insertion of their original prosthesis. The risk of acetabular revision in patients over 21 years of age was 8% at five years compared with 36% in those aged under 21 years. All the unipolar hips in this younger age group required revision within 11 years of the initial operation.

We conclude that unipolar replacement should not be used in younger patients and should be avoided in patients with a life expectancy of more than five years.
The risk of iatrogenic injury to the deep peroneal nerve in minimally invasive osteosynthesis of the tibia with the less invasive stabilisation system
Authors: Pichler W. , Grechenig W. , Tesch N. P. , Weinberg A. M. , Heidari N. , Clement H.
Published: March 2009

Percutaneous stabilisation of tibial fractures by locking plates has become an accepted form of osteosynthesis. A potential disadvantage of this technique is the risk of damage to the neurovascular bundles in the anterior and peroneal compartments. Our aim in this anatomical study was to examine the relationship of the deep peroneal nerve to a percutaneously-inserted Less Invasive Stabilisation System tibial plate in the lower limbs of 18 cadavers. Screws were inserted through stab incisions. The neurovascular bundle was dissected to reveal its relationship to the plate and screws.

In all cases, the deep peroneal nerve was in direct contact with the plate between the 11th and the 13th holes. In ten specimens the nerve crossed superficial to the plate, in six it was interposed between the plate and the bone and in the remaining two specimens it coursed at the edge of the plate.

Percutaneous insertion of plates with more than ten holes is not recommended because of the risk of injury to the neurovascular structures. When longer plates are required we suggest distal exposure so that the neurovascular bundle may be displayed and protected.
Joint replacement in Malawi
Authors: Lubega N. , Mkandawire N. C. , Sibande G. C. , Norrish A. R. , Harrison W. J.
Published: March 2009

In Africa the amount of joint replacement surgery is increasing, but the indications for operation and the age of the patients are considerably different from those in the developed world. New centres with variable standards of care and training of the surgeons are performing these procedures and it is important that a proper audit of this work is undertaken.

In Malawi, we have pioneered a Registry which includes all joint replacements that have been carried out in the country. The data gathered include the age, gender, indication for operation, the prosthesis used, the surgical approach, the use of bone graft, the type of cement, pressurising systems and the thromboprophylaxis used. All patients have their clinical scores recorded pre-operatively and then after three and six months and at one year. Before operation all patients are counselled and on consent their HIV status is established allowing analysis of the effect of HIV on successful joint replacement.

To date, 73 total hip replacements (THRs) have been carried out in 58 patients by four surgeons in four different hospitals. The most common indications for THR were avascular necrosis (35 hips) and osteoarthritis (22 hips). The information concerning 20 total knee replacements has also been added to the Registry.
Loosening of the femoral component after unicompartmental knee replacement
Authors: Monk A. P. , Keys G. W. , Murray D. W.
Published: March 2009

We describe a technique for the diagnosis of loosening of the femoral component of the Oxford Unicompartmental Knee Replacement using accurately aligned lateral radiographs in extension and flexion. If gaps are present between the component and cement on one radiograph and not on the other, the component is loose.
Co‐occurrence of self‐reported disordered eating and self‐harm in UK university students
Authors: Wright Fiona , Bewick Bridgette M. , Barkham Michael , House Allan O. , Hill Andrew J.
Published: March 2009

Objectives. Students are reported to have more symptoms of mental health problems than other young people. Disordered eating and self‐harm are common but evidence on comorbidity, especially in community samples, is limited. This study aimed to examine their co‐occurrence, onset timing, and the help‐seeking of UK university students.

Methods. Two surveys were administered to undergraduate students at a single UK university. One was administered electronically (UNIversity Quality of Life and Learning survey) and completed by 5,045 students. The second, questionnaire‐based, was completed by 805 students (Student Well‐Being study). Both surveys included questions about disordered eating, self‐harm thoughts and behaviours, and psychological well‐being.

Results. A strong relationship was found between reports of disordered eating and self‐harm, with co‐occurrence observed in 4.5 and 4.9% of students in the two surveys. Disordered eating and self‐harm often pre‐dated university entrance and there was no evidence of increasing levels of pathology by university year group. A younger age of onset of disordered eating behaviours was reported in those with co‐occurring disordered eating and self‐harm. Help‐seeking rates were low.

Conclusions. The risk of co‐occurrence and earlier onset‐timing of disordered eating are consistent with a limited clinical literature. Information on co‐occurrence of mental health problems, their history, and low rates of help‐seeking identifies some of the challenge to universities and practitioners. These results suggest the value of access to screening resources and the involvement of service‐users in shaping the support provided.