bluuebunny/crossref_metadata_2025 huggingface dataset:
A Tumorigenic Factor Interactome Connected through Tumor Suppressor MicroRNA-198 in Human Pancreatic Cancer
Authors: Marin-Muller Christian , Li Dali , Bharadwaj Uddalak , Li Min , Chen Changyi , Hodges Sally E. , Fisher William E. , Mo Qianxing , Hung Mien-Chie , Yao Qizhi
Published: August 2013

Purpose: The majority of pancreatic cancers overexpress mesothelin (MSLN), which contributes to enhanced proliferation, invasion, and migration. However, the MSLN regulatory network is still unclear. Here, we investigated the regulation of a panel of tumorigenic factors and explored the potential of MSLN-regulated miR-198 treatment in vivo.

Experimental Design: The expression and functional regulation of the tumorigenic factors MSLN, NF-κB, and the homeobox transcription factors (TF) POU2F2 (OCT-2), Pre-B-cell leukemia homeobox factor 1 (PBX-1), valosin-containing protein (VCP), and miR-198 were studied in pancreatic cancer cell lines, patient tumor samples, and xenograft pancreatic cancer mouse models.

Results: We found that miR-198 is downregulated in pancreatic cancer and is involved in an intricate reciprocal regulatory loop with MSLN, which represses miR-198 through NF-κB–mediated OCT-2 induction. Furthermore, miR-198 repression leads to overexpression of PBX-1 and VCP. The dysregulated PBX-1/VCP axis leads to increased tumorigenicity. Reconstitution of miR-198 in pancreatic cancer cells results in reduced tumor growth, metastasis, and increased survival through direct targeting MSLN, PBX-1, and VCP. Most interestingly, reduced levels of miR-198 in human tissue samples are associated with upregulation of these tumorigenic factors (MSLN, OCT-2, PBX-1, VCP) and predict poor survival. Reduced miR-198 expression links this tumor network signature and prognosticates poor patient outcome. High miR-198 disrupts the network and predicts better prognosis and increased survival.

Conclusions: miR-198 acts as a central tumor suppressor and modulates the molecular makeup of a critical interactome in pancreatic cancer, indicating a potential prognostic marker signature and the therapeutic potential of attacking this tumorigenic network through a central vantage point. Clin Cancer Res; 19(21); 5901–13. ©2013 AACR.
Inhibition of Hedgehog and Androgen Receptor Signaling Pathways Produced Synergistic Suppression of Castration-Resistant Prostate Cancer Progression
Authors: Gowda Pramod S. , Deng Jianhong D. , Mishra Sweta , Bandyopadhyay Abhik , Liang Sitai , Lin Shu , Mahalingam Devalingam , Sun Lu-Zhe
Published: August 2013

Metastatic prostate cancer is initially treated with androgen ablation therapy, which causes regression of androgen-dependent tumors. However, these tumors eventually relapse resulting in recurrent castration-resistant prostate cancer (CRPC). Currently, there is no effective therapy for CRPC and the molecular mechanisms that lead to the development of CRPC are not well understood. Here, we evaluated the hypothesis that combined inhibition of Hedgehog (Hh) and androgen receptor (AR) signaling will synergistically attenuate the growth of CRPC in vitro and in vivo. Androgen deprivation induced full-length androgen receptor protein levels in CRPC cells, but decreased its nuclear localization and transcriptional activity. However, androgen deprivation also increased a truncated form of androgen receptor (lacking ligand-binding domain) that possessed transcriptional activity in CRPC cells. Androgen deprivation also promoted the expression of Hh signaling components in CRPC cells, xenograft tumors, and the prostate glands of castrated mice. Importantly, although inhibition of either Hh or androgen receptor signaling alone was only moderately effective in blocking CRPC cell growth, combination of an Hh pathway inhibitor and a noncompetitive androgen receptor inhibitor synergistically suppressed the growth of CRPC cells in vitro and in vivo. Finally, noncompetitive inhibition of androgen receptor, but not competitive inhibition, was effective at limiting the activity of truncated androgen receptor leading to the inhibition of CRPC.

Implications: Combined therapy using Hh inhibitors and a non-competitive AR inhibitor may limit CRPC growth. Mol Cancer Res; 11(11); 1448–61. ©2013 AACR.
Inverse Association between Programmed Death Ligand 1 and Genes in the VEGF Pathway in Primary Clear Cell Renal Cell Carcinoma
Authors: Joseph Richard W. , Parasramka Mansi , Eckel-Passow Jeanette E. , Serie Dan , Wu Kevin , Jiang Liuyan , Kalari Krishna , Thompson R. Houston , Huu Ho Thai , Castle Erik P. , Cheville John , Kwon Eugene D. , Thompson E. Aubrey , Parker Alexander
Published: August 2013

Increased angiogenesis and tumor-induced immune evasion are two mechanisms by which clear cell renal cell carcinoma (ccRCC) proliferate and metastasize; however, the relationship between these pathways in human ccRCC is poorly understood. We conducted a nested case–control study using 98 archived tumor samples from patients diagnosed with primary ccRCC between 1990 and 2006, half of which were identified by immunohistochemistry (IHC) as either programmed death ligand 1 (PDL-1)–positive or PDL-1–negative. RNAs were extracted from the formalin-fixed paraffin-embedded tumor slides and the expression of the VEGFA, VEGFR1, VEGFR2, and PDL-1 genes was quantified. We assessed the presence of tumor-infiltrating lymphocytes (TIL) by IHC for CD3, and then analyzed the relationship among VEGFA, VEGFR1, VEGFR2, CD3, and PDL-1. When analyzed as a continuous variable, PDL-1 protein expression by IHC inversely correlates with the expression of the three VEGF-related genes: VEGFA (r = −0.23; P = 0.01), VEGFR1 (r = −0.34; P < 0.001), and VEGFR2 (r = −0.23; P = 0.01). When dichotomized, the PDL-1–positive cohort trended toward a lower expression of VEGFA (fold change = 0.72; P = 0.056) and VEGFR1 (fold change = 0.69; P = 0.057). In addition, there was a significant and positive relationship between the presence of TIL as assessed by IHC for CD3 and PDL-1 by IHC (r = 0.25; P = 0.015), and there was a trend toward an inverse relationship between TIL and VEGFA gene expression (r = −0.18; P = 0.089). In conclusion, this is the first demonstration of an inverse association between the angiogenesis and PDL-1 pathways in tumor samples from primary ccRCC, and this relationship may be related to the immunosuppressive effects of VEGF signaling. Cancer Immunol Res; 1(6); 378–85. ©2013 AACR.
Epigenetics in Neurodevelopmental and Mental Disorders
Authors: Kubota Takeo , Miyake Kunio , Hirasawa Takae
Published: August 2013

Epigenetic mechanisms are essential for normal development during embryogenesis and for differentiation of neural cells. Thus, precise understanding of epigenetic mechanisms, including DNA methylation and histone modification, is important to elucidate the pathogenic pathways in neurodevelopmental disorders. These include various congenital disorders caused by failures of genomic imprinting, X chromosome inactivation, and mutations of the proteins associated with epigenetic gene regulation. Several lines of evidence have suggested that various environmental factors, including insufficient nutrition, drugs, and mental stress, can alter epigenetic gene regulation in the brain, which potentially cause autism and adult mental disorders. However, epigenetic mechanisms are reversible mechanisms based on the attachment and detachment of modification factors onto DNA and histone proteins. Furthermore, recent studies indicate that epigenetic proteins, such as MeCP2, act as ‘lubricants' rather than essential parts that make up the brain structure, which works at a relatively later period of brain development. Therefore, making use of this epigenetic reversibility, the correction of abnormal epigenomic patterns and the administration or upregulation of epigenetic molecules will potentially be useful therapies for neurodevelopmental and mental disorders caused by epigenetic abnormalities.
Test Accuracy of Short Screening Tests for Diagnosis of Delirium or Cognitive Impairment in an Acute Stroke Unit Setting
Authors: Lees Rosalind , Corbet Sinead , Johnston Christina , Moffitt Emma , Shaw Grahame , Quinn Terence J.
Published: August 2013

Background and Purpose—

Guidelines recommend cognitive screening in acute stroke. Various instruments are available, with no consensus on a preferred tool. We aimed to describe test accuracy of brief screening tools for diagnosis of cognitive impairment and delirium in acute stroke.

Methods—

We collected data on sequential stroke unit admission in a single center. Four assessors trained in cognitive testing independently performed screening and reference tests. Brief assessments comprised the following: 10- and 4-point Abbreviated Mental Test (AMT-10; AMT-4); 4-A Test (4AT); Clock Drawing Test (CDT); Cog-4; and Glasgow Coma Scale (GCS). We also recorded the multidisciplinary team’s informal review using single question (SQ). We compared against reference standards of Montreal Cognitive Assessment (MoCA) and Confusion Assessment Method for delirium using usual diagnostic cutpoints. For MoCA, we described effects of lowering the diagnostic threshold to MoCA <24 and MoCA <20. We described sensitivity, specificity, and positive and negative predictive values.

Results—

Over a 10-week period, 111 subjects had cognitive assessment data. Subjects were 50% male (n=55), and median age was 74 years (interquartile range, 64–85). AMT-4, AMT-10, and SQ all had excellent (1.00) specificity for detection of cognitive impairment, although sensitivity was poor (all <0.60). The 4AT had greatest sensitivity for detecting delirium (1.00 [confidence interval [CI], 0.74–1.00]) and reasonable specificity (0.82 [CI, 0.72–0.89]). Properties of 4AT for detection of cognitive impairment, at the traditional MoCA threshold, were also good (sensitivity, 0.86; specificity, 0.78). Using diagnostic thresholds of MoCA ≤26, <24, and <20 gave proportions with cognitive impairments of 86%, 61%, and 49%, respectively, with resulting changes in screening test properties. At lower MoCA thresholds, CDT had favorable sensitivity and specificity (MoCA <20: sensitivity, 0.93, specificity, 0.66; MoCA <24: sensitivity, 0.85, specificity, 0.77).

Conclusions—

Many brief screening assessments are specific but not sensitive for detection of cognitive impairment in acute stroke. Our primary analysis suggests that 4AT is a reasonable choice for delirium and cognitive screening in this setting. However, these data are based on standard MoCA diagnostic threshold and may not be suited for an acute stroke population.
Quantitative Analysis of Hypoperfusion in Acute Stroke
Authors: Nael Kambiz , Meshksar Arash , Liebeskind David S. , Coull Bruce M. , Krupinski Elizabeth A. , Villablanca J. Pablo
Published: August 2013

Background and Purpose—

This study compares the concordance between arterial spin labeling (ASL) and dynamic susceptibility contrast (DSC) for the identification of regional hypoperfusion and diffusion-perfusion mismatch tissue classification using a quantitative method.

Methods—

The inclusion criteria for this retrospective study were as follows: patients with acute ischemic syndrome with symptom onset <24 hours and acquisition of both ASL and DSC MR perfusion. The volumes of infarction and hypoperfused lesions were calculated on ASL and DSC multi-parametric maps. Patients were classified into reperfused, matched, or mismatch groups using time to maximum >6 sec as the reference. In a subset of patients who were successfully recanalized, the identical analysis was performed and the infarction and hypoperfused lesion volumes were used for paired pre- and posttreatment comparisons.

Results—

Forty-one patients met our inclusion criteria. Twenty patients underwent successful endovascular revascularization (TICI>2a), resulting in a total of 61 ASL-DSC data pairs for comparison. The hypoperfusion volume on ASL-cerebral blood flow best approximated the DSC-time to peak volume (
r
=0.83) in pretreatment group and time to maximum (
r
=0.46) after recanalization. Both ASL-cerebral blood flow and DSC-TTP overestimated the hypoperfusion volume compared with time to maximum volume in pretreatment (
F
=27.41,
P
<0.0001) and recanalized patients (
F
=8.78,
P
<0.0001).

Conclusions—

ASL-cerebral blood flow overestimates the DSC time to maximum hypoperfusion volume and mismatch classification in patients with acute ischemic syndrome. Continued overestimation of hypoperfused volume after recanalization suggests flow pattern and velocity changes in addition to arterial transit delay can affects the performance of ASL.
Sports Diplomacy: The Chinese Experience and Perspective
Authors: Qingmin Zhang
Published: August 2013

Summary

Sport is a political and diplomatic arena where politics parodies sport and vice versa. When relations between two nations are poor, sport can be employed as a tool to heighten confrontation or, if relations start to improve, sport can also create and accelerate diplomatic momentum. In both cases, sport is politicized, but in the Chinese perspective only the latter instance can be considered as sports diplomacy. Sport itself is neither sufficient for diplomatic breakthrough, nor sufficient for diplomatic breakdown. The increasing importance of sports diplomacy also validates the transformation of traditional to new diplomacy.
Ikaros limits basophil development by suppressing C/EBP-α expression
Authors: Rao Kavitha N. , Smuda Craig , Gregory Gregory D. , Min Booki , Brown Melissa A.
Published: August 2013

Key Points

Ik−/− mice overproduce basophils and their precursors in the absence of extrinsic inflammatory signals. Ikaros restrains development of basophils by regulating histone modifications at lineage-specifying genes, including Cebpa and Hes1.
Are concomitant treatments confounding factors in randomized controlled trials on intensive blood-glucose control in type 2 diabetes? a systematic review
Authors: Boussageon Rémy , Supper Irène , Erpeldinger Sylvie , Cucherat Michel , Bejan-Angoulvant Theodora , Kassai Behrouz , Cornu Catherine , Gueyffier François
Published: August 2013

Background

Open-label, randomized controlled trials (RCTs) are subject to observer bias. If patient management is conducted without blinding, a difference between groups may be explained by other factors than study treatment. One factor may come from taking concomitant treatments with an efficacy on the studied outcomes. In type 2 diabetes, some antihypertensive or lipid-lowering drugs are effective against diabetic complications. We wanted to determine if these concomitant treatments were correctly reported in articles of RCTs on type 2 diabetes and if they might have influenced the outcome.

Methods

We performed a systematic review using Medline, Embase, and the Cochrane Library (from January 1950 to July 2010). Open-label RCTs assessing the effectiveness of intensive blood-glucose control in type 2 diabetes were included. We chose five therapeutic classes with proven efficacy against diabetes complications: angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor antagonists (AIIRAs), fibrates, statins, and aspirin. Differences between concomitant treatments were considered statistically significant when p < 0.05.

Results

A total of eight open-label RCTs were included, but only three (37.5%) of them published concomitant treatments. In two studies (ACCORD and ADVANCE), a statistically significant difference was observed between the two groups for aspirin (p = 0.02) and ACEIs (p = 0.02).

Conclusions

Few concomitant treatments were published in this sample of open-label RCTs. We cannot completely eliminate an observer bias for these studies. This bias probably influenced the results to an extent that has yet to be determined.
Geriatric assessment in undergraduate geriatric education – a structured interpretation guide improves the quantity and accuracy of the results: a cohort comparison
Authors: Igenbergs Elisabeth , Deutsch Tobias , Frese Thomas , Sandholzer Hagen
Published: August 2013

Background

With regard to the growing proportion of elderly multimorbid patients, a sound undergraduate geriatric education becomes more important. Therefore we included the execution and interpretation of a comprehensive geriatric assessment (CGA) into a mandatory two-week clerkship at a general practitioner's office. The present study examined the effect of a guide structuring the students’ considerations when interpreting a CGA on the quantity and accuracy of the documented findings and conclusions.

Methods

We compared random samples out of two cohorts of fourth-year medical students (interpreting the CGA with and without using the structured interpretation guide) completing their clerkship between April 2006 and March 2008 with regard to the content of the CGA interpretation and the grades the students achieved for their clerkship documentation, which were substantially determined by the quantity and accuracy of the documentation and interpretation of the CGA.

Results

The structured interpretation guide led to significantly more mentions of aspects that have to be considered in geriatric patient care and to a higher documentation rate of respective positive results. Furthermore, students who analysed the CGA by using the interpretation guide achieved significantly better grades.

Conclusions

An additional tool structuring medical students’ considerations when interpreting a CGA increases the quantity and the accuracy of the documented findings and conclusions. This may enhance the students’ learning gain.
Mahanine restores RASSF1A expression by down-regulating DNMT1 and DNMT3B in prostate cancer cells
Authors: Agarwal Soumik , Amin Karishma S , Jagadeesh Shankar , Baishay Gokul , Rao Paruchuri G , Barua Nabin C , Bhattacharya Samir , Banerjee Partha P
Published: August 2013

Background

Hypermethylation of the promoter of the tumor suppressor gene RASSF1A silences its expression and has been found to be associated with advanced grade prostatic tumors. The DNA methyltransferase (DNMT) family of enzymes are known to be involved in the epigenetic silencing of gene expression, including RASSF1A, and are often overexpressed in prostate cancer. The present study demonstrates how mahanine, a plant-derived carbazole alkaloid, restores RASSF1A expression by down-regulating specific members of the DNMT family of proteins in prostate cancer cells.

Results

Using methylation-specific PCR we establish that mahanine restores the expression of RASSF1A by inducing the demethylation of its promoter in prostate cancer cells. Furthermore, we show that mahanine treatment induces the degradation of DNMT1 and DNMT3B, but not DNMT3A, via the ubiquitin-proteasome pathway; an effect which is rescued in the presence of a proteasome inhibitor, MG132. The inactivation of Akt by wortmannin, a PI3K inhibitor, results in a similar down-regulation in the levels DNMT1 and DNMT3B. Mahanine treatment results in a decline in phospho-Akt levels and a disruption in the interaction of Akt with DNMT1 and DNMT3B. Conversely, the exogenous expression of constitutively active Akt inhibits the ability of mahanine to down-regulate these DNMTs, suggesting that the degradation of DNMT1 and DNMT3B by mahanine occurs via Akt inactivation.

Conclusions

Taken together, we show that mahanine treatment induces the proteasomal degradation of DNMT1 and DNMT3B via the inactivation of Akt, which facilitates the demethylation of the RASSF1A promoter and restores its expression in prostate cancer cells. Therefore, mahanine could be a potential therapeutic agent for advanced prostate cancer in men when RASSF1A expression is silenced.
Improving activity of minicellulosomes by integration of intra- and intermolecular synergies
Authors: Xu Qi , Ding Shi-You , Brunecky Roman , Bomble Yannick J , Himmel Michael E , Baker John O
Published: August 2013

Background

Complete hydrolysis of cellulose to glucose requires the synergistic action of three general types of glycoside hydrolases; endoglucanases, exoglucanases, and cellobiases. Cellulases that are found in Nature vary considerably in their modular diversity and architecture. They include: non-complexed enzymes with single catalytic domains, independent single peptide chains incorporating multiple catalytic modules, and complexed, scaffolded structures, such as the cellulosome. The discovery of the latter two enzyme architectures has led to a generally held hypothesis that these systems take advantage of intramolecular and intermolecular proximity synergies, respectively, to enhance cellulose degradation. We use domain engineering to exploit both of these concepts to improve cellulase activity relative to the activity of mixtures of the separate catalytic domains.

Results

We show that engineered minicellulosomes can achieve high levels of cellulose conversion on crystalline cellulose by taking advantage of three types of synergism; (1) a complementary synergy produced by interaction of endo- and exo-cellulases, (2) an intramolecular synergy of multiple catalytic modules in a single gene product (this type of synergism being introduced for the first time to minicellulosomes targeting crystalline cellulose), and (3) an intermolecular proximity synergy from the assembly of these cellulases into larger multi-molecular structures called minicellulosomes. The binary minicellulosome constructed in this study consists of an artificial multicatalytic cellulase (CBM4-Ig-GH9-X11-X12-GH8-Doc) and one cellulase with a single catalytic domain (a modified Cel48S with the structure CBM4-Ig-GH48-Doc), connected by a non-catalytic scaffoldin protein. The high level endo-exo synergy and intramolecular synergies within the artificial multifunctional cellulase have been combined with an additional proximity-dependent synergy produced by incorporation into a minicellulosome demonstrating high conversion of crystalline cellulose (Avicel). Our minicellulosome is the first engineered enzyme system confirmed by test to be capable of both operating at temperatures as high as 60°C and converting over 60% of crystalline cellulose to fermentable sugars.

Conclusion

When compared to previously reported minicellulosomes assembled from cellulases containing only one catalytic module each, our novel minicellulosome demonstrates a method for substantial reduction in the number of peptide chains required, permitting improved heterologous expression of minicellulosomes in microbial hosts. In addition, it has been shown to be capable of substantial conversion of actual crystalline cellulose, as well as of the less-well-ordered and more easily digestible fraction of nominally crystalline cellulose.
Beyond malignancy: the role of carbohydrate antigen 125 in heart failure
Authors: Hung Chung-Lieh , Hung Ta-Chuan , Lai Yau-Hui , Lu Chi-Sheng , Wu Yih-Jer , Yeh Hung-I
Published: August 2013

Carbohydrate antigen 125 (CA-125), traditionally a tumor marker for screening, diagnosis, and monitoring in ovarian malignancy, had recently been shown increasing evidence and more extensively recognized/explored as a novel surrogate of heart failure (HF). The exact mechanisms underlying the pathophysiologic link between elevated serum CA-125 concentration and HF may be multi-factorial, with both mechanical and inflammatory process including numerous potential cytokines involved. Accumulating data had consistently indicated its diagnostic and prognostic role in HF patients in various clinical settings, however, there is limited clinical information regarding the incremental value or head-to-head comparison of such marker to other well-established HF markers. In this brief review, we aimed to discuss the biosynthesis, and potential insights of underlying pathophysiologies associated with CA-125 secretion in the scenarios of cardiac structural/functional alterations and HF, and further explored its current usage and roles in several recent reports.
Measuring cell-type specific differential methylation in human brain tissue
Authors: Montaño Carolina M , Irizarry Rafael A , Kaufmann Walter E , Talbot Konrad , Gur Raquel E , Feinberg Andrew P , Taub Margaret A
Published: August 2013

The behavior of epigenetic mechanisms in the brain is obscured by tissue heterogeneity and disease-related histological changes. Not accounting for these confounders leads to biased results. We develop a statistical methodology that estimates and adjusts for celltype composition by decomposing neuronal and non-neuronal differential signal. This method provides a conceptual framework for deconvolving heterogeneous epigenetic data from postmortem brain studies. We apply it to find cell-specific differentially methylated regions between prefrontal cortex and hippocampus. We demonstrate the utility of the method on both Infinium 450k and CHARM data.
The informational stance: Philosophy and logic. Part II. From physics to society
Authors: Kun Wu , Brenner Joseph E.
Published: August 2013

In Part I of our joint paper [WuB13], we outlined our respective theories, The Basic Theory of the Philosophy of Information (BTPI) and Logic in Reality (LIR) and showed their synergy for the understanding of complex informational processes. In this part, we develop Wu’s fundamental philosophical insight of the origin of the values of information in the interactions of complex information processing. A key concept in our work is that of a logical isomorphism between human individual and social value and the natural laws of the physical world. On the basis of Wu’s concept of Informational Thinking, we propose an Informational Stance, a philosophical stance that is most appropriate for, and not separated nor isolated from, the emerging unified theory of information. We propose our metaphilosophy and metalogic of information as further support for the ethical development of the Information Society.
The influence of comorbidity scores on re-operations following primary total hip replacement
Authors: Gordon M. , Stark A. , Sköldenberg O. G. , Kärrholm J. , Garellick G.
Published: August 2013

While an increasing amount of arthroplasty articles report comorbidity measures, none have been validated for outcomes. In this study, we compared commonly used International Classification of Diseases-based comorbidity measures with re-operation rates after total hip replacement (THR). Scores used included the Charlson, the Royal College of Surgeons Charlson, and the Elixhauser comorbidity score. We identified a nationwide cohort of 134 423 THRs from the Swedish Hip Arthroplasty Register. Re-operations were registered post-operatively for up to 12 years. The hazard ratio was estimated by Cox’s proportional hazards regression, and we used C-statistics to assess each measure’s ability to predict re-operation. Confounding variables were age, gender, type of implant fixation, hospital category, hospital implant volume and year of surgery.

In the first two years only the Elixhauser score showed any significant relationship with increased risk of re-operation, with increased scores for both one to two and three or more comorbidities. However, the predictive C-statistic in this period for the Elixhauser score was poor (0.52). None of the measures proved to be of any value between two and 12 years. They might be of value in large cohort or registry studies, but not for the individual patient.

Cite this article: Bone Joint J 2013;95-B:1184–91.
Total hip replacement for developmental dysplasia of the hip with more than 30% lateral uncoverage of uncemented acetabular components
Authors: Li H. , Mao Y. , Oni J. K. , Dai K. , Zhu Z.
Published: August 2013

In developmental dysplasia of the hip (DDH), a bone defect is often observed superior to the acetabulum after the reconstruction at the level of the true acetabulum during total hip replacement (THR). However, the essential amount of uncemented acetabular component coverage required for a satisfactory outcome remains controversial. The purpose of this study was to assess the stability and function of acetabular components with a lack of coverage > 30% (31% to 50%). A total of 760 DDH patients underwent THR with acetabular reconstruction at the level of the true floor. Lack of coverage above the acetabular component of > 30% occurred in 56 patients. Intra-operatively, autogenous morcellised bone grafts were used to fill the uncovered portion. Other than two screws inserted through the acetabular shell, no additional structural supports were used in these hips. In all, four patients were lost to follow-up. Therefore, 52 patients (52 hips, 41 women and 11 men) with a mean age of 60.1 years (42 to 78) were available for this study at a mean of 4.8 years (3 to 7). There were no instances of prosthesis revision or marked loosening during the follow-up. The Harris hip score improved from a mean of 40.7 points (sd 12.2) pre-operatively to 91.1 (sd 5.0) at the last follow-up. Radiological analysis with medical imaging software allowed us to calculate the extent of the uncoverage in terms of the uncovered arc of the implant as viewed on the anteroposterior pelvic radiograph. From this we propose that up to 17 mm of lateral undercoverage in the presence of a stable initial implantation in the presence of bone autografting, with an inclination angle of the acetabular component between 40° and 55°, is acceptable. This represents undercoverage of ≤ 50%.

Cite this article: Bone Joint J 2013;95-B:1178–83.
Hemicortical resection and reconstruction using pasteurised autograft for parosteal osteosarcoma of the distal femur
Authors: Liu T. , Liu Z-Y. , Zhang Q. , Zhang X-S.
Published: August 2013

The aim of this study was to assess a specific protocol for the treatment of patients with a parosteal osteosarcoma of the distal femur with limb salvage involving hemicortical resection and reconstruction using recycled pasteurised autograft and internal fixation. Between January 2000 and January 2010, 13 patients with a mean age of 26.5 years (17 to 39) underwent this procedure. All the tumours were staged according to Enneking’s criteria: there were eight stage IA tumours and five stage IB tumours. The mean follow-up was 101.6 months (58 to 142), and mean post-operative Musculoskeletal Tumour Society functional score was 88.6% (80% to 100%) at the final follow-up. All the patients had achieved bony union; the mean time to union was 11.2 months (6 to 18). Local recurrence occurred in one patient 27 months post-operatively. No patient had a pulmonary metastasis.

A hemicortical procedure for the treatment of a parosteal osteosarcoma is safe and effective. Precise pre-operative planning using MRI is essential in order to define the margins of resection. Although it is a technically demanding procedure, gratifying results make it worthwhile for selected patients.

Cite this article: Bone Joint J 2013;95-B:1275–9.
Femoral head deformity and severity of acetabular dysplasia of the hip
Authors: Okano K. , Yamaguchi K. , Ninomiya Y. , Matsubayashi S. , Osaki M. , Takahashi K.
Published: August 2013

Patients with acetabular dysplasia commonly undergo peri-acetabular osteotomy after skeletal maturity to reduce the risk of the late development of osteoarthritis. Several studies have suggested that deformity of the femoral head influences the long-term outcome. We radiologically examined 224 hips in 112 patients with acetabular dysplasia and early-stage osteoarthritis. There were 103 women and nine men with a mean age of 37.6 years (18 to 49). A total of 201 hips were placed in the acetabular dysplasia group and 23 in a normal group. The centre–edge angle and acetabular head index were significantly smaller (both p < 0.001), and the acetabular angle, acetabular roof angle and roundness index were significantly greater in the acetabular dysplasia group than those in the normal group (all p < 0.001). There were significant correlations between the roundness index and other parameters. Femoral head shape may be influenced by the severity of the acetabular dysplasia.

Cite this article: Bone Joint J 2013;95-B:1192–6.
Supracondylar humeral fractures in children
Authors: Lim K. B. L. , Lim C. T. , Tawng D. K.
Published: August 2013

Supracondylar humeral fractures are common in children, but there are no classification systems or radiological parameters that predict the likelihood of having to perform an open reduction. In a retrospective case–control study we evaluated the use of the medial spike angle and fracture tip–skin distance to predict the mode of reduction (closed or open) and the operating time in fractures with posterolateral displacement. A total of 21 patients (4.35%) with a small medial spike angle (< 45°) were identified from a total of 494 patients, and 42 patients with a medial spike angle of > 45° were randomly selected as controls. The medial spike group had significantly smaller fracture tip–skin distances (p < 0.001), longer operating times (p = 0.004) and more complications (p = 0.033) than the control group. There was no significant difference in the mode of reduction and a composite outcome measure. After adjustments for age and gender, only fracture tip–skin distance remained significantly associated with the operating time (β = -0.724, p = 0.042) and composite outcome (OR 0.863 (95% confidence interval 0.746 to 0.998); p = 0.048).

Paediatric orthopaedic surgeons should have a lower threshold for open reduction when treating patients with a small medial spike angle and a small fracture tip–skin distance.

Cite this article: Bone Joint J 2013;95-B:1290–4.
Institutionalising knowledge brokering as a sustainable knowledge translation solution in healthcare: how can it work in practice?
Authors: Chew Sarah , Armstrong Natalie , Martin Graham
Published: August 2013

In healthcare, translating evidence into changed practice remains challenging. Novel interventions are being used to address these challenges, including the use of ‘knowledge brokers’. But how sustainable these roles might be, and the consequences for the individual of enacting such roles, are unknown. We explore these questions by drawing on qualitative data from case studies of fulltime roles in research-practice collaboration. We suggest that structural issues around professional boundaries, organisational norms and career pathways may make such roles difficult to sustain in the long term, but highlight interventions that might improve their feasibility.
Earth Stewardship of rangelands: coping with ecological, economic, and political marginality
Authors: Sayre Nathan F , McAllister Ryan RJ , Bestelmeyer Brandon T , Moritz Mark , Turner Matthew D
Published: August 2013

Rangelands encompass 30–40% of Earth's land surface and support 1 to 2 billion people. Their predominant use is extensive livestock production by pastoralists and ranchers. But rangelands are characterized by ecological, economic, and political marginality, and higher value, more intensive land uses are impinging on rangelands around the world. Earth Stewardship of rangelands must address both livestock management and the broader socioecological dynamics that promote land‐use changes, fragmentation, and degradation. We identify specific gradients on which human–rangeland systems can be arrayed, including issues of variability, adaptation to disturbance, commercialization, land‐use change, land‐tenure security, and effective governance, and we illustrate the gradients' interactions and effects in sites worldwide. The result is a synthetic framework to help in understanding how rangeland Earth Stewardship can be achieved in the face of marginality, globalization, and climate change.
Promoting Earth Stewardship through urban design experiments
Authors: Felson Alexander J , Bradford Mark A , Terway Timothy M
Published: August 2013

Earth Stewardship requires a repositioning of ecological science in society to promote social–ecological change. This may place ecologists in situations that are largely unfamiliar to them, such as playing a role in the process of urban design. “Designed Experiments” – defined as projects that embed ecological research into urban design to study and shape buildings, landscapes, and the infrastructure of human settlements – are intended to enhance the impact of ecologists working in these new situations. Designed Experiments provide a framework for organizing relationships among ecologists, urban designers, decision makers, and citizens; an opportunity for testing ecological hypotheses; and a platform for experiential learning among multiple participants – all of which have the potential to aid in overcoming barriers to the goals of Earth Stewardship. Here we explore the capacity of Designed Experiments to facilitate progress toward Earth Stewardship through real‐world case studies.
Activating Transcription Factor 4 Links Metabolic Stress to Interleukin-6 Expression in Macrophages
Authors: Iwasaki Yorihiro , Suganami Takayoshi , Hachiya Rumi , Shirakawa Ibuki , Kim-Saijo Misa , Tanaka Miyako , Hamaguchi Miho , Takai-Igarashi Takako , Nakai Michikazu , Miyamoto Yoshihiro , Ogawa Yoshihiro
Published: August 2013

Chronic inflammation is a molecular element of the metabolic syndrome and type 2 diabetes. Saturated fatty acids (SFAs) are considered to be an important proinflammatory factor. However, it is still incompletely understood how SFAs induce proinflammatory cytokine expression. Hereby we report that activating transcription factor (ATF) 4, a transcription factor that is induced downstream of metabolic stresses including endoplasmic reticulum (ER) stress, plays critical roles in SFA-induced interleukin-6 (Il6) expression. DNA microarray analysis using primary macrophages revealed that the ATF4 pathway is activated by SFAs. Haploinsufficiency and short hairpin RNA–based knockdown of ATF4 in macrophages markedly inhibited SFA- and metabolic stress–induced Il6 expression. Conversely, pharmacological activation of the ATF4 pathway and overexpression of ATF4 resulted in enhanced Il6 expression. Moreover, ATF4 acts in synergy with the Toll-like receptor-4 signaling pathway, which is known to be activated by SFAs. At a molecular level, we found that ATF4 exerts its proinflammatory effects through at least two different mechanisms: ATF4 is involved in SFA-induced nuclear factor-κB activation; and ATF4 directly activates the Il6 promoter. These findings provide evidence suggesting that ATF4 links metabolic stress and Il6 expression in macrophages.
Ultrastructural characteristics of the vitellarium of Brandesia turgida (Brandes, 1888) (Digenea: Pleurogenidae) and an examination of the potential usefulness of such vitelline traits in digenean systematics
Authors: Poddubnaya L. , Bruňanská M. , Brázová T. , Zhokhov A. , Gibson D.
Published: August 2013

Transmission electron microscopical observations were made on the vitelline structure of the digenean Brandesia turgida (Brandes, 1888) collected from crypts within the intestinal wall of the frog Pelophylax ridibundus (Pallas, 1771). Ultrastructural details of the vitelline follicles of B. turgida include: (a) the presence within the vitellarium of a single type of cell, i.e. vitellocytes at different stages of their development; (b) a narrow region between the vitellocytes filled with the processes of surrounding parenchymal cells; and (c) the occurrence of the junctional complexes between the vitellocytes and the surrounding parenchymal cells at the periphery of the vitelline follicles. It is shown that the vitelline globules and a few lipid droplets are the main inclusions resulting from vitellocyte synthetic activity. The limited amount of nutritive reserves in the vitellocytes can be explained by the nature of the parasite’s life-cycle, which is characterized by fully-embryonated intrauterine eggs containing a fully-formed miracidium. Despite the small number of digenean species studied in relation to their vitelline cytoarchitecture, two structural patterns of the vitellarium can be elucidated; these are examined in terms of digenean systematic relationships.
CSM 2011 Orthopaedic and Sports Physical Therapy Section Programming
Authors: Simoneau Guy
Published: August 2013

Presented here is the schedule of platform and poster research presentations made by the Orthopaedic Section and Sports Physical Therapy Section of the American Physical Therapy Association (APTA) during APTA's Combined Sections Meeting, February 9–12, 2011, in New Orleans, LA. J Orthop Sports Phys Ther 2011;41(1):A1–A10. doi:10.2519/jospt.2011.41.1.A1
April 2013 Book Reviews
Authors: Neumann Donald
Published: August 2013

JOSPT offers invited reviews of current titles. The April 2013 column includes 5 reviews of the following books: Diagnosis for Physical Therapists: A Symptom-Based Approach; FIMS Sports Medicine Manual: Event Planning and Emergency Care; Brunnstrom's Clinical Kinesiology: 6th Edition; Atlas of Anatomy: 2nd Edition; and Anatomy & Physiology Revealed.

J Orthop Sports Phys Ther 2013;43(4):276–279. doi:10.2519/jospt.2013.43.4.276
Early treatment of coronal synostosis with endoscopy-assisted craniectomy and postoperative cranial orthosis therapy: 16-year experience
Authors: Jimenez David F. , Barone Constance M.
Published: August 2013

Object

The objective of this study was to present the authors' 16-year experience treating coronal craniosynostosis in infants using endoscopy-assisted techniques and postoperative cranial orthoses.

Methods

A total of 128 synostosed coronal sutures in 115 patients were treated between 1996 and 2012 by endoscopically resecting a strip of bone containing the stenosed suture via a 2–3 cm incision made at the ipsilateral stephanion. Data were obtained from a prospective database. Following surgery, patients were fitted with custom cranial orthoses to help correct preoperative craniofacial deformities. All patients were followed closely with cranial anthropometric measurements and photographs.

Results

The estimated mean blood loss was 20 ml (range 5–120 ml) and the estimated mean strip size was 0.6 cm × 10.7 cm. The mean surgical duration was 55 minutes (range 22–150 minutes). One patient underwent an intraoperative blood transfusion and 1 had a postoperative blood transfusion, for a total transfusion rate of 1.7%. Ninety-seven percent of patients were discharged on the first postoperative day. There were no deaths. Vertical dystopia correction of more than 80% from baseline was obtained in almost two-thirds of patients, with 51% achieving 100% correction. Nasal and sagittal craniofacial deviation (vertex-nasion-gnathion) correction greater than 80% was achieved in 80% of patients, with 77% achieving 100% correction. Supraorbital rim advancement of the ipsilateral eye was obtained in 98% of cases, with correction of frontal plagiocephaly the last deformity to achieve correction.

Conclusions

Early treatment of coronal synostosis with endoscopy-assisted craniectomy and postoperative molding helmets leads to significant correction of craniofacial abnormalities, including vertical dystopia, nasal deviation, sagittal misalignment, and ipsilateral proptosis. This treatment method is associated with minimal trauma, blood loss, and transfusion rates, and typically only requires 1 overnight stay. This surgical approach is safe, effective, and associated with excellent results.
Distribution of cerebellar tonsil position: implications for understanding Chiari malformation
Authors: Smith Brandon W. , Strahle Jennifer , Bapuraj J. Rajiv , Muraszko Karin M. , Garton Hugh J. L. , Maher Cormac O.
Published: August 2013

Object

Prior attempts to define normal cerebellar tonsil position have been limited by small numbers of patients precluding analysis of normal distribution by age group. The authors' objective in the present study was to analyze cerebellar tonsil location in every age range.

Methods

Two thousand four hundred patients were randomly selected from a database of 62,533 consecutive patients undergoing MRI and were organized into 8 age groups. Magnetic resonance images were directly examined for tonsil location, morphology, and other features. Patients with a history or imaging findings of posterior fossa abnormalities unrelated to Chiari malformation (CM) were excluded from analysis. The caudal extent of the cerebellar tonsils was measured at the midsagittal and lowest parasagittal positions.

Results

The mean tonsil height decreased slightly with advancing age into young adulthood and increased with advancing age in the adult age range. An increasing age in the adult age range was associated with a decreased likelihood of a tonsil position 5 mm or more below the foramen magnum (p = 0.0004). In general, the lowest tonsil position in each age group was normally distributed. Patients with pegged morphology were more likely to have a tonsil location at least 5 mm below the foramen magnum (85%), as compared with those having intermediate (38%) or rounded (2%) morphology (p < 0.0001). Female sex was associated with a lower mean tonsil position (p < 0.0001). Patients with a lower tonsil position also tended to have an asymmetrical tonsil position, usually lower on the right (p < 0.0001).

Conclusions

Cerebellar tonsil position follows an essentially normal distribution and varies significantly by age. This finding has implications for advancing our understanding of CM.
Expansion of CD133-positive glioma cells in recurrent de novo glioblastomas after radiotherapy and chemotherapy
Authors: Tamura Kaoru , Aoyagi Masaru , Ando Noboru , Ogishima Takahiro , Wakimoto Hiroaki , Yamamoto Masaaki , Ohno Kikuo
Published: August 2013

Object

Recent evidence suggests that a glioma stem cell subpopulation may determine the biological behavior of tumors, including resistance to therapy. To investigate this hypothesis, the authors examined varying grades of gliomas for stem cell marker expressions and histopathological changes between primary and recurrent tumors.

Methods

Tumor samples were collected during surgery from 70 patients with varying grades of gliomas (Grade II in 12 patients, Grade III in 16, and Grade IV in 42) prior to any adjuvant treatment. The samples were subjected to immunohistochemistry for MIB-1, factor VIII, GFAP, and stem cell markers (CD133 and nestin). Histopathological changes were compared between primary and recurrent tumors in 31 patients after radiation treatment and chemotherapy, including high-dose irradiation with additional stereotactic radiosurgery.

Results

CD133 expression on glioma cells was confined to de novo glioblastomas but was not observed in lower-grade gliomas. In de novo glioblastomas, the mean percentage of CD133-positive glioma cells in sections obtained at recurrence was 12.2% ± 10.3%, which was significantly higher than that obtained at the primary surgery (1.08% ± 1.78%). CD133 and Ki 67 dual-positive glioma cells were significantly increased in recurrent de novo glioblastomas as compared with those in primary tumors (14.5% ± 6.67% vs 2.16% ± 2.60%, respectively). In contrast, secondary glioblastomas rarely expressed CD133 antigen even after malignant progression following radiotherapy and chemotherapy.

Conclusions

The authors' results indicate that CD133-positive glioma stem cells could survive, change to a proliferative cancer stem cell phenotype, and cause recurrence in cases with de novo glioblastomas after radiotherapy and chemotherapy.
Stereotactic radiosurgery used to manage a meningioma filling the posterior two-thirds of the superior sagittal sinus
Authors: Deibert Christopher P. , Kondziolka Douglas
Published: August 2013

Intrinsic meningiomas of the superior sagittal sinus pose a significant technical challenge, particularly in the posterior two-thirds of the sinus. Resection is curative but frequently is not possible because of the involvement of critical vascular structures. Here, the authors present the case of a 49-year-old woman with a recurrent meningioma located exclusively in the posterior two-thirds of the sagittal sinus. The patient was treated with a margin dose of 12 Gy and a maximum dose of 24 Gy to the length of the tumor, which measured 16 cm. Five years after treatment, the tumor remains stable and the patient is symptom free. This case demonstrates the unique role that stereotactic radiosurgery can play in the management of meningiomas that are surgically unresectable and have no accepted form of treatment. To the authors' knowledge, 16 cm also represents the longest segment of tumor treated using stereotactic radiosurgery.