bluuebunny/crossref_metadata_2025 huggingface dataset:
Stage-Specific Outcomes of Patients With Uterine Leiomyosarcoma: A Comparison of the International Federation of Gynecology and Obstetrics and American Joint Committee on Cancer Staging Systems
Authors: Zivanovic Oliver , Leitao Mario M. , Iasonos Alexia , Jacks Lindsay M. , Zhou Qin , Abu-Rustum Nadeem R. , Soslow Robert A. , Juretzka Margrit M. , Chi Dennis S. , Barakat Richard R. , Brennan Murray F. , Hensley Martee L.
Published: March 2009

Purpose

Uterine leiomyosarcoma (LMS) is staged by the modified International Federation of Gynecology and Obstetrics (FIGO) staging system for uterine cancer. We aimed to determine whether the American Joint Committee on Cancer (AJCC) soft tissue sarcoma (STS) staging system is more accurate in predicting progression-free survival (PFS) and overall survival (OS).

Patients and Methods

Patients with uterine LMS who presented at our institution from 1982 to 2005 were staged retrospectively according to a modified FIGO staging system and the AJCC STS staging system. The predictive accuracy of the two staging systems was compared using concordance estimation.

Results

Two hundred nineteen patients had sufficient clinical and pathologic information to be staged under both systems; 132 patients were upstaged using the AJCC staging system, whereas only four were downstaged. Stage-specific PFS and OS rates for stages I, II, and III differed substantially between the two staging systems. In both systems, there was prognostic overlap between stages II and III. Thus, despite the marked stage-specific differences in 5-year PFS and OS rates for stages I, II, and III, both systems had similar concordance indices.

Conclusion

Estimates of stage-specific PFS and OS for uterine LMS were altered substantially when using the AJCC versus FIGO staging system. Adjuvant treatment strategies should be tested in patients at substantial risk for disease progression and death. Neither the FIGO nor AJCC staging system is ideal for identifying such patients, suggesting a need for a uterine LMS-specific staging system to better target patients for trials of adjuvant therapies.
Weighing the Benefits and Burdens of Mammography Screening Among Women Age 80 Years or Older
Authors: Schonberg Mara A. , Silliman Rebecca A. , Marcantonio Edward R.
Published: March 2009

Purpose

To examine outcomes of mammography screening among women ≥ 80 years to inform decision making.

Patients and Methods

We conducted a cohort study of 2,011 women without a history of breast cancer who were age ≥ 80 years between 1994 and 2004 and who received care at one academic primary care clinic or two community health centers in Boston, MA. Medical record data were abstracted on all screening and diagnostic mammograms, breast ultrasounds and biopsies performed, all breast cancers diagnosed through December 31, 2006, and on sociodemographics. Date and cause of death were confirmed using the National Death Index.

Results

The majority of patients (78.6%) were non-Hispanic white and 51.4% (n = 1,034) had been screened with mammography since age 80 years. Among women who were screened, eight were diagnosed with ductal carcinoma in situ, 16 with early stage disease (1.5%), two with late stage disease, and one died as a result of breast cancer. Many (110; 11%) experienced a false-positive screening mammogram that led to 19 benign breast biopsies, eight refused work-up, and three experienced a false-negative screening mammogram; 97 were screened within 2 years of their death from other causes. There were no significant differences in the rate, stage, recurrence rate, or deaths due to breast cancer between women who were screened and those who were not screened.

Conclusion

The majority of women ≥ 80 years are screened with mammography yet few benefit. Meanwhile, 12.5% experience a burden from screening. The data from this study can be used to inform elderly women's decision making and potentially lead to more rational use of screening.
Pooled Safety and Efficacy Analysis Examining the Effect of Performance Status on Outcomes in Nine First-Line Treatment Trials Using Individual Data From Patients With Metastatic Colorectal Cancer
Authors: Sargent Daniel J. , Köhne Claus Henning , Sanoff Hanna Kelly , Bot Brian M. , Seymour Matthew T. , de Gramont Aimery , Porschen Ranier , Saltz Leonard B. , Rougier Philippe , Tournigand Christopher , Douillard Jean-Yves , Stephens Richard J. , Grothey Axel , Goldberg Richard M.
Published: March 2009

Purpose

Performance status (PS) is a prognostic factor in patients with metastatic colorectal cancer. Clinical trials typically enroll less than 10% of patients with a PS of 2 (PS2); thus, the benefit of systemic chemotherapy in PS2 patients is uncertain.

Patients and Methods

Individual data from 6,286 patients (509 PS2 patients) from nine clinical trials were used to compare treatment efficacy by PS. Progression-free survival (PFS), grade ≥ 3 adverse events, 60-day all-cause mortality, overall survival (OS), and response rate (RR) were explored in the full set of nine trials and in the five trials comparing first-line monotherapy with combination therapy.

Results

Compared with patients with PS of 0 or 1, PS2 patients had significantly higher rates of grade ≥ 3 nausea (8.5% v 16.4%, respectively; P < .0001) and vomiting (7.6% v 11.9%, respectively; P = .006) and 60-day all-cause mortality (2.8% v 12.0%, respectively; P < .0001). PS2 was prognostic for PFS (hazard ratio [HR] = 1.52; P < .0001; median PFS, 7.6 months for PS 0 or 1 v 4.9 months for PS2), OS (HR = 2.18; P < .0001; median OS, 17.3 months for PS 0 or 1 v 8.5 months for PS2), and RR (odds ratio = 0.61; P < .0001; 43.8% for PS 0 or 1 v 32.0% for PS2). The relative benefit and toxicity of experimental versus control treatment and monotherapy versus combination therapy were not different in PS 0 or 1 patients versus PS2 patients.

Conclusion

In clinical trials, PS2 patients derive similar benefit from superior treatment as patients with PS of 0 to 1 but with an increased risk of toxicities and 12% 60-day mortality. Although current treatment provides benefit, new approaches are required to approach 1-year median survival for PS2 patients.
Psychological Status in Childhood Cancer Survivors: A Report From the Childhood Cancer Survivor Study
Authors: Zeltzer Lonnie K. , Recklitis Christopher , Buchbinder David , Zebrack Bradley , Casillas Jacqueline , Tsao Jennie C.I. , Lu Qian , Krull Kevin
Published: March 2009

Psychological quality of life (QOL), health-related QOL (HRQOL), and life satisfaction outcomes and their associated risk factors are reviewed for the large cohort of survivors and siblings in the Childhood Cancer Survivor Study (CCSS). This review includes previously published manuscripts that used CCSS data focused on psychological outcome measures, including the Brief Symptom Inventory (BSI-18), the Medical Outcomes Survey Short Form-36 (SF-36), the Cantril Ladder of Life, and other self-report questionnaires. Comparisons and contrasts are made between siblings and survivors, and to normative data when available, in light of demographic/health information and abstracted data from the medical record. These studies demonstrate that a significant proportion of survivors report more symptoms of global distress and poorer physical, but not emotional, domains of HRQOL. Other than brain tumor survivors, most survivors report both good present and expected future life satisfaction. Risk factors for psychological distress and poor HRQOL are female sex, lower educational attainment, unmarried status, annual household income less than $20,000, unemployment, lack of health insurance, presence of a major medical condition, and treatment with cranial radiation and/or surgery. Cranial irradiation impacted neurocognitive outcomes, especially in brain tumor survivors. Psychological distress also predicted poor health behaviors, including smoking, alcohol use, fatigue, and altered sleep. Psychological distress and pain predicted use of complementary and alternative medicine. Overall, most survivors are psychologically healthy and report satisfaction with their lives. However, certain groups of childhood cancer survivors are at high risk for psychological distress, neurocognitive dysfunction, and poor HRQOL, especially in physical domains. These findings suggest targeting interventions for groups at highest risk for adverse outcomes and examining the positive growth that remains despite the trauma of childhood cancer.
Second Neoplasms in Survivors of Childhood Cancer: Findings From the Childhood Cancer Survivor Study Cohort
Authors: Meadows Anna T. , Friedman Debra L. , Neglia Joseph P. , Mertens Ann C. , Donaldson Sarah S. , Stovall Marilyn , Hammond Sue , Yasui Yutaka , Inskip Peter D.
Published: March 2009

Purpose

To review the reports of subsequent neoplasms (SNs) in the Childhood Cancer Survivor Study (CCSS) cohort that were made through January 1, 2006, and published before July 31, 2008, and to discuss the host-, disease-, and therapy-related risk factors associated with SNs.

Patients and Methods

SNs were ascertained by survivor self-reports and subsequently confirmed by pathology findings or medical record review. Cumulative incidence of SNs and standardized incidence ratios for second malignant neoplasms (SMNs) were calculated. The impact of host-, disease-, and therapy-related risk factors was evaluated by Poisson regression.

Results

Among 14,358 cohort members, 730 reported 802 SMNs (excluding nonmelanoma skin cancers). This represents a 2.3-fold increase in the number of SMNs over that reported in the first comprehensive analysis of SMNs in the CCSS cohort, which was done 7 years ago. In addition, 66 cases of meningioma and 1,007 cases of nonmelanoma skin cancer were diagnosed. The 30-year cumulative incidence of SMNs was 9.3% and that of nonmelanoma skin cancer was 6.9%. Risk of SNs remains elevated for more than 20 years of follow-up for all primary childhood cancer diagnoses. In multivariate analyses, risks differ by SN subtype, but include radiotherapy, age at diagnosis, sex, family history of cancer, and primary childhood cancer diagnosis. Female survivors whose primary childhood cancer diagnosis was Hodgkin's lymphoma or sarcoma and who received radiotherapy are at particularly increased risk. Analyses of risk associated with radiotherapy demonstrated different dose-response curves for specific SNs.

Conclusion

Childhood cancer survivors are at a substantial and increasing risk for SNs, including nonmelanoma skin cancer and meningiomas. Health care professionals should understand the magnitude of these risks to provide individuals with appropriate counseling and follow-up.
Outcome analysis of surgery for disorders of the rotator cuff
Authors: Allom R. , Colegate-Stone T. , Gee M. , Ismail M. , Sinha J.
Published: March 2009

A consecutive series of 372 patients who underwent surgery for disorders of the rotator cuff involving arthroscopic subacromial decompression and open or arthroscopic repairs of the cuff were prospectively investigated as to the comparability of subjective and objective assessment scores of shoulder function. Assessments were made before operation and at 3, 6, 12, 18 and 24 months after surgery using the Disabilities of the Arm, Shoulder, and Hand score, the Oxford shoulder score and the Constant-Murley score, which was used as a reference. All scores were standardised to a scale of 0 to 100 for comparison. Statistical analysis compared the post-operative course and the mean score for the subjective Disabilities to the Arm, Shoulder and Hand score and Oxford shoulder score, with the objective Constant score at each interval. A strong correlation was evident between both subjective scores and the Constant score. We concluded that both the subjective scores would be useful substitutes for the Constant score, obviating the need for a trained investigator and the specialist equipment required to perform the Constant score.
Gelatin-based haemostyptic Spongostan as a possible three-dimensional scaffold for a chondrocyte matrix?
Authors: Anders J. O. , Mollenhauer J. , Beberhold A. , Kinne R. W. , Venbrocks R. A.
Published: March 2009

The gelatin-based haemostyptic compound Spongostan was tested as a three-dimensional (3D) chondrocyte matrix in an in vitro model for autologous chondrocyte transplantation using cells harvested from bovine knees. In a control experiment of monolayer cultures, the proliferation or de-differentiation of bovine chondrocytes was either not or only marginally influenced by the presence of Spongostan (0.3 mg/ml).

In monolayers and 3-D Minusheet culture chambers, the cartilage-specific differentiation markers aggrecan and type-II collagen were ubiquitously present in a cell-associated fashion and in the pericellular matrix. The Minusheet cultures usually showed a markedly higher mRNA expression than monolayer cultures irrespective of whether Spongostan had been present or not during culture. Although the de-differentiation marker type-I collagen was also present, the ratio of type-I to type-II collagen or aggrecan to type-I collagen remained higher in Minusheet 3-D cultures than in monolayer cultures irrespective of whether Spongostan had been included in or excluded from the monolayer cultures. The concentration of GAG in Minusheet cultures reached its maximum after 14 days with a mean of 0.83 ± 0.8 μg/106 cells; mean ±, sem, but remained considerably lower than in monolayer cultures with/without Spongostan.

Our results suggest that Spongostan is in principle suitable as a 3-D chondrocyte matrix, as demonstrated in Minusheet chambers, in particular for a culture period of 14 days. Clinically, differentiating effects on chondrocytes, simple handling and optimal formability may render Spongostan an attractive 3-D scaffold for autologous chondrocyte transplantation.
Does a ‘firebreak’ full-thickness skin graft prevent recurrence after surgery for Dupuytren’s contracture?
Authors: Ullah A. S. , Dias J. J. , Bhowal B.
Published: March 2009

We randomised 79 patients (84 hands, 90 fingers) with Dupuytren’s contracture of the proximal interphalangeal joint to have either a ‘firebreak’ skin graft (39 patients, 41 hands, 44 fingers) or a fasciectomy (40 patients, 43 hands, 46 fingers) if, after full correction, the skin over the proximal phalanx could be easily closed by a Z-plasty. Patients were reviewed after three, six, 12, 24 and 36 months to note any complications, the range of movement and recurrence. Both groups were similar in regard to age, gender and factors considered to influence the outcome such as bilateral disease, family history, the presence of diabetes, smoking and alcohol intake.

The degree of contracture of the metacarpophalangeal and interphalangeal joints of the operated fingers was similar in the two groups and both were comparable in terms of grip strength, range of movement and disability at each follow-up. The recurrence rate was 12.2%.

We did not identify any improvement in correction or recurrence of contracture after firebreak dermofasciectomy up to three years after surgery.
Fractures of the hip and osteoporosis
Authors: Lindner T. , Kanakaris N. K. , Marx B. , Cockbain A. , Kontakis G. , Giannoudis P. V.
Published: March 2009

Failure of fixation is a common problem in the treatment of osteoporotic fractures around the hip. The reinforcement of bone stock or of fixation of the implant may be a solution. Our study assesses the existing evidence for the use of bone substitutes in the management of these fractures in osteoporotic patients. Relevant publications were retrieved through Medline research and further scrutinised. Of 411 studies identified, 22 met the inclusion criteria, comprising 12 experimental and ten clinical reports. The clinical studies were evaluated with regard to their level of evidence. Only four were prospective and randomised.

Polymethylmethacrylate and calcium-phosphate cements increased the primary stability of the implant-bone construct in all experimental and clinical studies, although there was considerable variation in the design of the studies. In randomised, controlled studies, augmentation of intracapsular fractures of the neck of the femur with calcium-phosphate cement was associated with poor long-term results. There was a lack of data on the long-term outcome for trochanteric fractures. Because there were only a few, randomised, controlled studies, there is currently poor evidence for the use of bone cement in the treatment of fractures of the hip.
Accuracy of reconstruction of the hip using computerised three-dimensional pre-operative planning and a cementless modular neck
Authors: Sariali E. , Mouttet A. , Pasquier G. , Durante E. , Catone Y.
Published: March 2009

Pre-operative computerised three-dimensional planning was carried out in 223 patients undergoing total hip replacement with a cementless acetabular component and a cementless modular-neck femoral stem. Components were chosen which best restored leg length and femoral offset. The post-operative restoration of the anatomy was assessed by CT and compared with the pre-operative plan.

The component implanted was the same as that planned in 86% of the hips for the acetabular implant, 94% for the stem, and 93% for the neck-shaft angle. The rotational centre of the hip was restored with a mean accuracy of 0.73 mm (sd 3.5) craniocaudally and 1.2 mm (sd 2) laterally. Limb length was restored with a mean accuracy of 0.3 mm (sd 3.3) and femoral offset with a mean accuracy of 0.8 mm (sd 3.1).

This method appears to offer high accuracy in hip reconstruction as the difficulties likely to be encountered when restoring the anatomy can be anticipated and solved pre-operatively by optimising the selection of implants. Modularity of the femoral neck helped to restore the femoral offset and limb length.
Impaction grafting in association with the Charnley-Kerboull cemented femoral component
Authors: Kerboull L. , Hamadouche M. , Kerboull M.
Published: March 2009

We describe 129 consecutive revision total hip replacements using a Charnley-Kerboull femoral component of standard length with impaction allografting. The mean follow-up was 8.2 years (2 to 16). Additionally, extramedullary reinforcement was performed using struts of cortical allograft in 49 hips and cerclage wires in 30.

There was one intra-operative fracture of the femur but none later. Two femoral components subsided by 5 mm and 8 mm respectively, and were considered to be radiological failures. No further revision of a femoral component was required. The rate of survival of the femoral component at nine years, using radiological failure as the endpoint, was 98%. Our study showed that impaction grafting in association with a Charnley-Kerboull femoral component has a low rate of subsidence. Reconstruction of deficiencies of distal bone with struts of cortical allograft appeared to be an efficient way of preventing postoperative femoral fracture for up to 16 years.
Cytokines and apoptosis in supraspinatus tendinopathy
Authors: Millar N. L. , Wei A. Q. , Molloy T. J. , Bonar F. , Murrell G. A. C.
Published: March 2009

The role of inflammatory cells and their products in tendinopathy is not completely understood. Pro-inflammatory cytokines are upregulated after oxidative and other forms of stress. Based on observations that increased cytokine expression has been demonstrated in cyclically-loaded tendon cells we hypothesised that because of their role in oxidative stress and apoptosis, pro-inflammatory cytokines may be present in rodent and human models of tendinopathy. A rat supraspinatus tendinopathy model produced by running overuse was investigated at the genetic level by custom micro-arrays. Additionally, samples of torn supraspinatus tendon and matched intact subscapularis tendon were collected from patients undergoing arthroscopic shoulder surgery for rotator-cuff tears and control samples of subscapularis tendon from ten patients with normal rotator cuffs undergoing arthroscopic stabilisation of the shoulder were also obtained. These were all evaluated using semiquantitative reverse transcription polymerase chain-reaction and immunohistochemistry.

We identified significant upregulation of pro-inflammatory cytokines and apoptotic genes in the rodent model (p = 0.005). We further confirmed significantly increased levels of cytokine and apoptotic genes in human supraspinatus and subscapularis tendon harvested from patients with rotator cuff tears (p = 0.0008).

These findings suggest that pro-inflammatory cytokines may play a role in tendinopathy and may provide a target for preventing tendinopathies.
Analysis of the outcome in male and female patients using a unisex total knee replacement system
Authors: Dalury D. F. , Mason J. B. , Murphy J. A. , Adams M. J.
Published: March 2009

Gender-specific total knee replacement has generated much interest recently. We reviewed 1970 Sigma knees implanted in 920 women and 592 men with a mean age of 69.7 years.

At a mean follow-up of 7.3 years (minimum, five years), we found minimal differences in the outcome between genders. At the final follow-up, men had a higher overall Knee Society score and more osteolysis (3.8% vs 1.1%). However, there were no significant differences between men and women in terms of complications or improvements in knee function, pain score or range of movement. The estimated ten-year survivorship was 97% in women and 98% in men (p = 0.96).

We concluded that there was little difference in outcome between the genders treated by a modern unisex design of total knee replacement in this large multicentre study.
Is one-stage bilateral sequential total hip replacement as safe as unilateral total hip replacement?
Authors: Kim Y.-H. , Kwon O.-R. , Kim J.-S.
Published: March 2009

We investigated whether simultaneous bilateral sequential total hip replacement (THR) would increase the rate of mortality and complications compared with unilateral THR in both low- and high-risk groups of patients.

We enrolled 978 patients with bilateral and 1666 with unilateral THR in the study. There were no significant pre-operative differences between the groups in regard to age, gender, body mass index, diagnosis, comorbidity as assessed by the grading of the American Society of Anesthesiologists (ASA), the type of prosthesis and the duration of follow-up. The mean follow-up was for 10.5 years (5 to 13) in the bilateral THR group and 9.8 years (5 to 14) in the unilateral group.

The peri-operative mortality rate of patients who had simultaneous bilateral THR (0.31%, three of 978 patients) was similar to that of patients with unilateral THR (0.18%, three of 1666 patients). The peri-operative mortality rate of patients in the bilateral group was similar in high risk and low risk patients (0.70%, two of 285 patients vs 0.14%, one of 693 patients) and this was also true in the unilateral THR group (0.40%, two of 500 patients vs 0.09%, one of 1166 patients). Patients with bilateral THR required more blood transfusions and a longer hospital stay than those in the unilateral THR group. There was no significant difference (p = 0.32) in the overall number of complications between the groups. This was also true for the low-risk (p = 0.81) vs high-risk (p = 0.631) patients.

Our findings confirm that simultaneous sequential bilateral THR is a safe option for patients who are considered to be either high or low risk according to the ASA classification.
Vascularised fibular graft in the management of femoral head osteonecrosis
Authors: Korompilias A. V. , Lykissas M. G. , Beris A. E. , Urbaniak J. R. , Soucacos P. N.
Published: March 2009

The management of osteonecrosis of the femoral head ranges from symptomatic therapy to total hip replacement. Conservative treatment is effective only in small, early-stage lesions. Free vascularised fibular grafting has provided more consistently successful results than any other joint-preserving method. It supports the collapsing subchondral plate by primary callus formation, reduces intra-osseous pressure, removes and replaces the necrotic segment, and adds viable cortical bone graft plus fresh cancellous graft, which has osseoinductive and osseoconductive potential. Factors predisposing to success are the aetiology, stage and size of the lesion. Furthermore, it is a hip-salvaging procedure in early pre-collapse stages, and a time-buying one when the femoral head has collapsed.
The effects of social support and negative appraisals on acute stress symptoms and depression in children and adolescents
Authors: Ellis Alicia A. , Nixon Reginald D. V. , Williamson Paul
Published: March 2009

Objectives. To investigate the impact of social support on both acute stress symptoms and depression in children and adolescents following a single‐incident trauma as well as the potential mediating effects of negative appraisals.

Design. A cross‐sectional concurrent design was used.

Method. Ninety‐seven children (aged 7–17 years) and a parent of each were recruited through the emergency department or in‐patient ward of two metropolitan hospitals. Negative appraisals, child perception of social support, parent availability to provide social support, prior trauma and psychological difficulties, depression and acute stress symptoms were measured within 4 weeks of trauma.

Results. Negative appraisals about the trauma were highly correlated with both acute stress and depression symptoms. Social support was negatively correlated with depression symptoms, but not acute stress symptoms. There was a trend for social support to be negatively correlated with negative appraisals. There was no evidence that negative appraisals mediated the social support–symptoms relationships.

Conclusions. The findings lend support to recent cognitive and developmental models of the aetiology of post‐traumatic stress disorder, and the possible shared cognitive vulnerability between trauma symptoms and depression. Clinically, the results indicate that, appraisals, social support, and depression symptoms should be assessed in addition to trauma symptoms following single‐incident traumatic events. The findings also suggest that when depression symptoms are present following trauma exposure, it may be useful to ensure children have adequate social support. Future research should also develop trauma specific measures of social support.
Ministry orientation and ministry outcomes: Evaluation of a new multidimensional model of clergy burnout and job satisfaction
Authors: Miner Maureen H. , Dowson Martin , Sterland Sam
Published: March 2009

In secularized countries, where the authority of religious institutions has declined, church ministers face pressures that may precipitate burnout and threaten ministry satisfaction. This study examined the relationship of ministry orientation to burnout and ministry satisfaction in a large sample of Australian clergy. The sample comprised 2,132 church leaders surveyed as part of the 2001 National Church Life Survey in Australia. They completed brief, alternative measures of ministry orientation, burnout, and ministry satisfaction. Data were analysed by means of confirmatory factor analysis, a multiple indicator multiple cause model, and structural equation modelling. Results supported the validity of three‐factor models of ministry orientation and burnout as applied to clergy, with burnout mediating the relationship between an internal orientation to ministry and satisfaction in ministry. The independence of personal accomplishment from satisfaction in ministry was also established. The usefulness of ministry orientation as predictive of ministry outcomes in the context of secularization is discussed.
Affective evaluation and cognitive structure of respiratory sensations in healthy individuals
Authors: Petersen Sibylle , Morenings Matthias , von Leupoldt Andreas , Ritz Thomas
Published: March 2009

Objective Dyspnea is defined as an uncomfortable awareness of the need to breathe. Verbal report of dyspnea can be a valuable source of diagnostic information. However, little is known about the cognitive representation of respiratory sensations and about their affective evaluation in individuals not suffering from respiratory disease. Such knowledge would be important in evaluating the comparability of respiratory sensation report between healthy controls and patient groups.

Method Five hundred and eighty‐two healthy individuals rated 20 descriptors of respiratory sensation with regard to frequency, valence, and situational incidence. Ratings were analysed on the level of subgroups of items found with cluster analysis and Multidimensional Scaling (MDS).

Results Not all respiratory sensations commonly subsumed under dyspnea are perceived to be uncomfortable by healthy individuals. Two higher‐order clusters were found, interpreted as (1) compensation of dyspnea and (2) breathing deficiencies. Breathing deficiencies were unknown by approximately 50% of participants and rated to be less frequent and more uncomfortable than compensation of dyspnea. Furthermore, three dimensions of respiratory sensations were found using MDS interpreted as (1) fit between need for air and actual breathing, (2) effort, and (3) attempt of voluntary control.

Conclusion The extent to which respiratory sensation ratings can be compared between patients and healthy individuals is limited. Latent dimensions of dyspnea might be less affected by differences in interpretation and evaluation of language descriptors of dyspnea and could help to assess comparability of sensation report between groups with different experiential background regarding breathlessness.
Indirect measurement of dysfunctional attitudes in bipolar affective disorder
Authors: Thomas Justin , Bentall Richard P. , Knowles Rebecca , Tai Sara
Published: March 2009

Objective. The present study uses an indirect measure to explore whether dysfunctional attitudes are characteristic of all phases of bipolar disorder. Previous studies with bipolar patients using indirect measurements have uncovered depression‐like responses that were otherwise undetected.

Design. A cross‐sectional study design was adopted to explore the presence of dysfunctional attitudes within each phase of the illness.

Method. Manic patients, depressed bipolar patients, remitted bipolar patients, and healthy controls were compared on a sentence stem completion task designed to implicitly assess dysfunctional attitudes.

Results. The manic, depressed, and remitted patients all exceeded the controls on implicit measures of dysfunctional attitudes.

Conclusions. The findings are consistent with the hypothesis that all phases of bipolar disorder are associated with depressogenic dysfunctional attitudes.
Perspective: Assessing the Clinical Utility of Serum CTX in Postmenopausal Osteoporosis and Its Use in Predicting Risk of Osteonecrosis of the Jaw
Authors: Baim Sanford , Miller Paul D
Published: March 2009

Bone turnover markers (BTMs) have become increasingly important in the management of postmenopausal osteoporosis (PMO). In bisphosphonate-treated women with PMO, BTMs can provide early indications of treatment efficacy, are predictors of BMD response and fracture risk reduction, and are potentially useful for monitoring patient compliance. The bone resorption marker serum C-telopeptide cross-link of type 1 collagen (sCTX) has shown high sensitivity and specificity for the detection of increased bone resorption. Recently, sCTX has been singled out as a potential indicator of risk of osteonecrosis of the jaw (ONJ) in patients receiving oral bisphosphonates who require oral surgery. However, whether BTMs are capable of predicting ONJ risk and whether sCTX is usable for this purpose are controversial questions. This article presents an overview of the current literature regarding critical issues affecting the clinical utility of BTMs (including variability and reference ranges) and the current applications of BTMs in PMO management, with a focus on sCTX. Last, the appropriateness of using sCTX to predict ONJ risk in women receiving oral bisphosphonates for PMO is evaluated.
Hip Fracture Patients at Risk of Second Hip Fracture: A Nationwide Population-Based Cohort Study of 169,145 Cases During 1977–2001
Authors: Ryg Jesper , Rejnmark Lars , Overgaard Soren , Brixen Kim , Vestergaard Peter
Published: March 2009

In patients with prior hip fracture (HFx), little is known about time frame and risk factors of second HFx, as well as the ensuing mortality. The aim of the study was to elucidate the incidence of second HFx and subsequent mortality. All 169,145 patients with a first HFx in Denmark during 1977–2001 were followed for up to 25 yr and compared with the background population. Data on fractures, vital status, comorbidity, redeemed prescriptions, and socio-demographic variables were retrieved from national registers. Median follow-up was 3.8 yr, corresponding to 1,041,177 patient-years. A total of 27,834 patients had a second HFx. The cumulative incidence was 9% after 1 yr and 20% after 5 yr, being significantly higher than expected (2% and 12%, respectively; p < 0.05). The RR of second HFx was 2.2 (95% CI: 2.0–2.5) at 1 yr and did not normalize until 15 yr (RR = 1.01, 95% CI: 1.0–1.02). Risk factors for a second HFx were female sex (HR = 1.36, 95% CI: 1.32–1.40), age (HR = 1.68, 95% CI: 1.60–1.76 in patients >85 yr), alcoholism (HR = 1.61, 95% CI: 1.51–1.72), any prior fracture (HR = 1.08, 95%CI :1.04–1.11), and living alone (HR = 1.06, 95% CI: 1.04–1.09). Both sexes had higher mortality at 1 and 5 yr after a second HFx compared with the background population (men—1 yr: 27% versus 9%, p < 0.05; 5 yr: 64% versus 40%, p < 0.05; women—1 yr: 21% versus 10%, p < 0.05; 5 yr: 58% versus 41%, p < 0.05). Patients with HFx are at 2-fold risk of further HFx and the subsequent mortality is highly increased. We propose that programs for secondary prevention should be developed and tested.
Elevated Aromatase Expression in Osteoblasts Leads to Increased Bone Mass Without Systemic Adverse Effects
Authors: Sjögren Klara , Lagerquist Marie , Moverare-Skrtic Sofia , Andersson Niklas , Windahl Sara H , Swanson Charlotte , Mohan Subburaman , Poutanen Matti , Ohlsson Claes
Published: March 2009

The stimulatory effects of testosterone (T) on bone can either be through a direct activation of the androgen receptor (AR) or mediated through aromatization of T to estradiol (E2), followed by activation of estrogen receptors (ERs) in bone. Aromatase expression in osteoblasts and reproductive tissues is dependent on different promoters, which are differentially regulated. To study the effect of elevated local aromatization of T to E2 in bone, we developed a transgenic mouse model (Coll-1α1-Arom) that overexpresses the human aromatase gene under the control of the osteoblast specific rat type I α I procollagen promoter. The Coll-1α1-Arom mice expressed human aromatase mRNA specifically in bone and had unaffected serum E2 and T levels. Male Coll-1α1-Arom mice had clearly increased total body BMD, trabecular BMD, cortical BMD, and cortical thickness associated with elevated osteoprotegerin mRNA levels and reduced number of osteoclasts (p < 0.01). Treatment of ovariectomized mice with T increased cortical and trabecular thickness in the Coll-1α1-Arom mice (p < 0.001) but not in the wildtype mice. In conclusion, elevated aromatase expression specifically in osteoblasts results in stimulatory estrogenic effects in bone without increasing serum E2 levels. Because osteoblast-specific aromatase expression results in an increased ER to AR activation ratio in bone, we propose that activation of ERs results in a more pronounced increase in bone mass than what is seen after activation of the AR. Development of osteoblast-specific inducers of aromatase expression might identify substances with stimulatory effects on bone without systemic adverse effects.
Antifracture Efficacy and Reduction of Mortality in Relation to Timing of the First Dose of Zoledronic Acid After Hip Fracture
Authors: Eriksen Erik Fink , Lyles Kenneth W , Colón-Emeric Cathleen S , Pieper Carl F , Magaziner Jay S , Adachi Jonathan D , Hyldstrup Lars , Recknor Chris , Nordsletten Lars , Lavecchia Catherine , Hu Huilin , Boonen Steven , Mesenbrink Peter
Published: March 2009

Annual infusions of zoledronic acid (5 mg) significantly reduced the risk of vertebral, hip, and nonvertebral fractures in a study of postmenopausal women with osteoporosis and significantly reduced clinical fractures and all-cause mortality in another study of women and men who had recently undergone surgical repair of hip fracture. In this analysis, we examined whether timing of the first infusion of zoledronic acid study drug after hip fracture repair influenced the antifracture efficacy and mortality benefit observed in the study. A total of 2127 patients (1065 on active treatment and 1062 on placebo; mean age, 75 yr; 76% women and 24% men) were administered zoledronic acid or placebo within 90 days after surgical repair of an osteoporotic hip fracture and annually thereafter, with a median follow-up time of 1.9 yr. Median time to first dose after the incident hip fracture surgery was ∼6 wk. Posthoc analyses were performed by dividing the study population into 2-wk intervals (calculated from time of first infusion in relation to surgical repair) to examine effects on BMD, fracture, and mortality. Analysis by 2-wk intervals showed a significant total hip BMD response and a consistent reduction of overall clinical fractures and mortality in patients receiving the first dose 2-wk or later after surgical repair. Clinical fracture subgroups (vertebral, nonvertebral, and hip) were also reduced, albeit with more variation and 95% CIs crossing 1 at most time points. We concluded that administration of zoledronic acid to patients suffering a low-trauma hip fracture 2 wk or later after surgical repair increases hip BMD, induces significant reductions in the risk of subsequent clinical vertebral, nonvertebral, and hip fractures, and reduces mortality.
Calcium-Sensing Receptor Expression Is Regulated by Glial Cells Missing-2 in Human Parathyroid Cells
Authors: Mizobuchi Masahide , Ritter Cynthia S , Krits Irina , Slatopolsky Eduardo , Sicard Gregorio , Brown Alex J
Published: March 2009

Glial cells missing-2 (Gcm2) is the key regulating transcription factor for parathyroid gland development. The continued expression of high levels of Gcm2 in mature parathyroid glands suggests that it is required for maintenance of parathyroid cell differentiation. The role of Gcm2 in parathyroid cell physiology, however, has not been fully studied. In this study, we examined the effects of Gcm2 silencing on cultured human parathyroid cells. Collagenase-dispersed human parathyroid cells from patients with chronic kidney disease were placed in monolayer cultures and infected with lentivirus expressing shRNA for human Gcm2. Seventy-two hours after infection, mRNA was processed and analyzed for Gcm2, PTH, vitamin D receptor (VDR), calcium-sensing receptor (CaR), 25-hydroxyvitamin D3 1-α-hydroxylase (1-OHase), and proliferating cell nuclear antigen (PCNA) by real-time PCR (qPCR). Protein expression of affected genes was analyzed by immunoblot 72 h after infection. Gcm2 mRNA and protein were decreased by 74.2 ± 12.2% (SD; n = 3 experiments; p < 0.01) and 67.5 ± 15.7% (n = 2; p < 0.01), respectively. CaR mRNA and protein were reduced by 47.8 ± 21.1% (n = 3; p < 0.01) and 48.1 ± 4.3% (n = 3; p < 0.01), respectively. However, VDR, PTH, 1-OHase, and PCNA were not significantly affected by Gcm2 silencing. Further analysis of CaR mRNA indicated that transcripts containing exon 1B, derived by transcription from CaR promoter 2, were downregulated (58.8 ± 19.27%; n = 3; p < 0.05) by Gcm2 silencing. Exon 1A–containing transcripts from promoter 1 were expressed at very low levels in the cultures. These results indicate that one function of Gcm2 is to maintain high levels of CaR expression in parathyroid cells.
Risedronate in the Treatment of Mild Pediatric Osteogenesis Imperfecta: A Randomized Placebo-Controlled Study
Authors: Rauch Frank , Munns Craig F , Land Christof , Cheung Moira , Glorieux Francis H
Published: March 2009

Intravenous pamidronate is the most widely used treatment for moderate to severe osteogenesis imperfecta (OI). Currently, there is no medical treatment for patients with mild OI. We conducted a single-center randomized double-blind placebo-controlled trial to examine the efficacy and safety of oral risedronate in the treatment of pediatric patients with mild OI. A total of 26 children and adolescents (age, 6.1–17.7 yr; 11 girls) with OI type I were randomized to either placebo (N = 13) or risedronate (N = 13) for 2 yr. Risedronate doses were 15 mg once per week in patients weighing <40 kg and 30 mg once per week in patients weighing >40 kg. After 2 yr of treatment, risedronate decreased serum levels of the bone resorption marker collagen type I N-telopeptide by 35% compared with a 6% reduction with placebo (p = 0.003). Risedronate increased lumbar spine areal BMD Z-scores by 0.65, whereas patients receiving placebo experienced a decrease of 0.15 (p = 0.002). In contrast, no significant treatment differences in bone mass and density were found at the radial metaphysis and diaphysis, the hip, and the total body. Histomorphometric analysis of transiliac bone biopsies at the end of the study period did not show a significant treatment difference in cortical width, trabecular bone volume, or parameters of bone turnover. Similarly, there was no detectable treatment effect on vertebral morphometry, second metacarpal cortical width, grip force, bone pain, or number of new fractures. Regarding safety, risedronate was generally well tolerated, and the incidence of clinical or laboratory adverse experiences was similar among treatment groups. These results suggest that the skeletal effects of oral risedronate are weaker than those that are commonly observed with intravenous pamidronate treatment but still lead to an increase in lumbar spine areal BMD. Future studies should investigate whether oral risedronate is effective in reducing fracture rates in children and adolescents with mild OI type I.
Sequestosome 1 Mutations in Paget's Disease of Bone in Australia: Prevalence, Genotype/Phenotype Correlation, and a Novel Non-UBA Domain Mutation (P364S) Associated With Increased NF-κB Signaling Without Loss of Ubiquitin Binding
Authors: Rea Sarah L , Walsh John P , Ward Lynley , Magno Aaron L , Ward Bryan K , Shaw Barry , Layfield Robert , Kent G Neil , Xu Jiake , Ratajczak Thomas
Published: March 2009

Previously reported Sequestosome 1(SQSTM1)/p62 gene mutations associated with Paget's disease of bone (PDB) cluster in, or cause deletion of, the ubiquitin-associated (UBA) domain. The aims of this study were to examine the prevalence of SQSTM1 mutations in Australian patients, genotype/phenotype correlations and the functional consequences of a novel point mutation (P364S) located upstream of the UBA. Mutation screening of the SQSTM1 gene was conducted on 49 kindreds with PDB. In addition, 194 subjects with apparently sporadic PDB were screened for the common P392L mutation by restriction enzyme digestion. HEK293 cells stably expressing RANK were co-transfected with expression plasmids for SQSTM1 (wildtype or mutant) or empty vector and a NF-κB luciferase reporter gene. GST-SQSTM1 (wildtype and mutant) proteins were used in pull-down assays to compare monoubiquitin-binding ability. We identified SQSTM1 mutations in 12 of 49 families screened (24.5%), comprising 9 families with the P392L mutation and 1 family each with the following mutations: K378X, 390X, and a novel P364S mutation in exon 7, upstream of the UBA. The P392L mutation was found in 9 of 194 (4.6%) patients with sporadic disease. Subjects with SQSTM1 mutations had more extensive disease, but not earlier onset, compared with subjects without mutations. In functional studies, the P364S mutation increased NF-κB activation compared with wildtype SQSTM1 but did not reduce ubiquitin binding. This suggests that increased NF-κB signaling, but not the impairment of ubiquitin binding, may be essential in the pathogenesis of PDB associated with SQSTM1 mutations.
One Year of Transgenic Overexpression of Osteoprotegerin in Rats Suppressed Bone Resorption and Increased Vertebral Bone Volume, Density, and Strength
Authors: Ominsky Michael S , Stolina Marina , Li Xiaodong , Corbin Timothy J , Asuncion Franklin J , Barrero Mauricio , Niu Qing-Tian , Dwyer Denise , Adamu Steven , Warmington Kelly S , Grisanti Mario , Tan Hong L , Ke Hua Z , Simonet William S , Kostenuik Paul J
Published: March 2009

RANKL is an essential mediator of bone resorption, and its activity is inhibited by osteoprotegerin (OPG). Transgenic (Tg) rats were engineered to continuously overexpress OPG to study the effects of continuous long-term RANKL inhibition on bone volume, density, and strength. Lumbar vertebrae, femurs, and blood were obtained from 1-yr-old female OPG-Tg rats (n = 32) and from age-matched wildtype (WT) controls (n = 23). OPG-Tg rats had significantly greater serum OPG (up to 260-fold) and significantly lower serum TRACP5b and osteocalcin compared with WT controls. Vertebral histomorphometry showed significant reductions in osteoclasts and bone turnover parameters in OPG-Tg rats versus WT controls, and these reductions were associated with significantly greater peak load in vertebrae tested through compression. No apparent differences in bone material properties were observed in OPG-Tg rat vertebrae, based on their unchanged intrinsic strength parameters and their normal linear relationship between vertebral bone mass and strength. Femurs from OPG-Tg rats were of normal length but showed mild osteopetrotic changes, including reduced periosteal perimeter (−6%) and an associated reduction in bending strength. Serum OPG levels in WT rats showed no correlations with any measured parameter of bone turnover, mass, or strength, whereas the supraphysiological serum OPG levels in OPG-Tg rats correlated negatively with bone turnover parameters and positively with vertebral bone mass and strength parameters. In summary, low bone turnover after 1 yr of OPG overexpression in rats was associated with increased vertebral bone mass and proportional increases in bone strength, with no evidence for deleterious effects on vertebral material properties.
Evaluation of Pharmaceuticals With a Novel 50-Hour Animal Model of Bone Loss
Authors: Tomimori Yoshiya , Mori Kaoru , Koide Masanori , Nakamichi Yuko , Ninomiya Tadashi , Udagawa Nobuyuki , Yasuda Hisataka
Published: March 2009

Osteoporosis remains a major public health problem through its associated fragility fractures. Several animal models for the study of osteoporotic bone loss, such as ovariectomy (OVX) and denervation, require surgical skills and several weeks to establish. Osteoclast differentiation and activation is mediated by RANKL. Here we report the establishment of a novel and rapid bone loss model by the administration of soluble RANKL (sRANKL) to mice. Mice were injected intraperitoneally with sRANKL and used to evaluate existing anti-osteoporosis drugs. sRANKL decreased BMD within 50 h in a dose-dependent manner. The marked decrease in femoral trabecular BMD shown by pQCT and the 3D images obtained by μCT were indistinguishable from those observed in the OVX model. Histomorphometry showed that osteoclastic activity was significantly increased in the sRANKL-injected mice. In addition, serum biochemical markers of bone turnover such as Ca, C-telopeptide of type 1 collagen (CTX), and TRACP5b were also significantly increased in the sRANKL-injected mice in a dose-dependent manner. Bisphosphonates (BPs), selective estrogen receptor modulators (SERMs), and PTH are commonly used for the treatment of osteoporosis. We successfully evaluated the effects of anti–bone-resorbing agents such as BPs, a SERM, and anti–RANKL-neutralizing antibody on bone resorption in a couple of weeks. We also evaluated the effects of PTH on bone formation in 2 wk. A combination of sRANKL injections and OVX made it possible to evaluate a SERM. The sRANKL model is the simplest, fastest, and easiest of all osteoporosis models and could be useful in the evaluation of drug candidates for osteoporosis.