bluuebunny/crossref_metadata_2025 huggingface dataset:
BMSCs reduce rat granulosa cell apoptosis induced by cisplatin and perimenopause
Authors: Guo Jun-qi , Gao Xia , Lin Zhi-jie , Wu Wei-zhen , Huang Liang-hu , Dong Hui-yue , Chen Jin , Lu Jun , Fu Yun-fen , Wang Jin , Ma Yu-jie , Chen Xiao-wen , Wu Zhi-xian , He Fu-qiang , Yang Shun-liang , Liao Lian-ming , Zheng Feng , Tan Jian-ming
Published: March 2013

Background

The objective of this study was to evaluate the effect of bone marrow mesenchymal stem cells (BMSCs) on the apoptosis of granulosa cells (GCs) in rats.

BMSCs and GCs were isolated from rats. GCs were separated into one of the following three groups: an untreated control group (control), a cisplatin (5 mg/L) treatment group (cisplatin), and group co-cultured with BMSCs and treated with cisplatin (BMSC). GC apoptosis was analyzed by annexin V staining and real-time PCR analysis for apoptosis-related genes. The effect of BMSCs was also determined in 9 to 10 month-old perimenopausal rats that were separated into the following groups: saline control, BMSC transplantation (1–2 × 106 cells), and estrogen treatment (0.158 mg/kg/d) groups. A young group consisting of 3 to 4 month-old rats that were treated with saline was also evaluated as a control. After 1 and 3 months, GC apoptosis was evaluated by TUNEL analysis.

Results

Cisplatin increased GC apoptosis from 0.59% to 13.04% in the control and cisplatin treatment groups, respectively, which was significantly reduced upon co-culture with BMSCs to 4.84%. Cisplatin treatment increased p21 and bax and decreased c-myc mRNA expression, which was reversed upon co-culture with BMSCs. As compared to young rats, increased apoptosis was observed in the perimenopausal rats (P < 0.001). After 3 months, the apoptosis rate in the BMSC group was significantly lower than that of the control group (P = 0.007).

Conclusions

BMSC therapy may protect against GC apoptosis induced by cisplatin and perimenopause. Further studies are necessary to evaluate therapeutic efficacy of BMSCs.
Evolution of S-domain receptor-like kinases in land plants and origination of S-locus receptor kinases in Brassicaceae
Authors: Xing Shilai , Li Mengya , Liu Pei
Published: March 2013

Background

The S-domain serine/threonine receptor-like kinases (SRLKs) comprise one of the largest and most rapidly expanding subfamilies in the plant receptor-like/Pelle kinase (RLKs) family. The founding member of this subfamily, the S-locus receptor kinase (SRK), functions as the female determinant of specificity in the self-incompatibility (SI) responses of crucifers. Two classes of proteins resembling the extracellular S domain (designated S-domain receptor-like proteins, SRLPs) or the intracellular kinase domain (designated S-domain receptor-like cytoplasmic kinases, SRLCKs) of SRK are also ubiquitous in land plants, indicating that the SRLKs are composite molecules that originated by domain fusion of the two component proteins. Here, we explored the origin and diversification of SRLKs by phylogenomic methods.

Results

Based on the distribution patterns of SRLKs and SRLCKs in a reconciled species-domain tree, a maximum parsimony model was then established for simultaneously inferring and dating gene duplication/loss and fusion /fission events in SRLK evolution. Various SRK alleles from crucifer species were then included in our phylogenetic analyses to infer the origination of SRKs by identifying the proper outgroups.

Conclusions

Two gene fusion events were inferred and the major gene fusion event occurred in the common ancestor of land plants generated almost all of extant SRLKs. The functional diversification of duplicated SRLKs was illustrated by molecular evolution analyses of SRKs. Our findings support that SRKs originated as two ancient haplotypes derived from a pair of tandem duplicate genes through random regulatory neo-/sub- functionalization in the common ancestor of the Brassicaceae.
Meta-analysis: preoperative transcatheter arterial chemoembolization does not improve prognosis of patients with resectable hepatocellular carcinoma
Authors: Zhou Yanming , Zhang Xiaofeng , Wu Lupeng , Ye Feng , Su Xu , Shi Lehua , Li Bin
Published: March 2013

Background

Long-term outcomes of partial liver resection of hepatocellular carcinoma (HCC) remain satisfactory due to high incidences of recurrence. This study was intended to see whether preoperative transcatheter arterial chemoembolization (TACE) reduces postoperative tumor recurrences and prolongs survival of patients with resectable HCC.

Methods

A computerized literature search was performed to identify relevant articles. The quality of nonrandomized comparative studies (NRCTs) was assessed using the methodological index for nonrandomized studies (MINORS). Data synthesis was performed using Review Manager 5.0 software.

Results

Twenty-one studies (4 randomized controlled trials and 17 NRCTs) with a total of 3,210 participants were suitable for analysis. There was no significant difference in disease-free and overall survival at 5-year (32.1% vs. 30.0% and 40.2% vs. 45.2%), and intra- and extra-hepatic recurrence (51.2% vs.53.6% and 12.9% vs.10.3%) between patients with and without preoperative TACE. Postoperative morbidity (28.9% vs. 26.8%) and in-hospital mortality (4.1% vs. 3.1%) were also similar between the two groups.

Conclusions

Preoperative TACE does not seem to improve prognosis and therefore it is prudent to recommend it as a preoperative routine procedure for resectable HCC.
Serum levels and renal deposition of C1q complement component and its antibodies reflect disease activity of lupus nephritis
Authors: Tan Ying , Song Di , Wu Li-hua , Yu Feng , Zhao Ming-hui
Published: March 2013

Background

Lupus nephritis is considered to be a principal cause of morbidity and mortality in SLE. Few studies focus on the association between anti-C1q antibodies in circulation and renal C1q deposition in human lupus nephritis. In this study, we detected the serum levels of C1q, presence of anti-C1q antibodies in circulation, renal C1q deposition and further analyzed their associations with clinical and pathological activity in a large cohort of Chinese lupus nephritis patients.

Methods

Sera and renal biopsies from 218 consecutive patients with lupus nephritis with long-term follow up data were studied. Sera were tested for levels of C1q and anti-C1q autoantibodies. Associations of levels of C1q, anti-C1q autoantibodies with renal deposition of C1q, clinical and histopathological data and renal outcome were further investigated.

Results

The levels of serum C1q were significantly lower in lupus nephritis than that in normal controls [33.81 ± 20.36 v.s. 61.97 ± 10.50 μg/ml (P < 0.001)]. The prevalence of anti-C1q antibodies, ratios of glomerular and vascular deposition of C1q in patients with lupus nephritis were 42.7% (93/218), 71.6% (156/218) and 86.2% (188/218), respectively. The serum C1q levels and anti-C1q antibodies were associated with SLEDAI scores (P < 0.001, P = 0.012, respectively), renal total activity indices scores (P < 0.001,P < 0.001, respectively). Granular positive staining of C1q and IgG by immunofluorescence was co-localized almost completely along the glomerular capillary wall and mesangial areas. Patients with anti-C1q antibodies presented with significantly lower serum C1q levels than those without it (23.82 [0.60, 69.62] μg/ml v.s. 37.36 [0.64, 82.83] μg/ml,P < 0.001). The presence of anti-C1q antibodies was associated with the presence of glomerular C1q deposition (P < 0.001), but not with the presence of renal vascular C1q deposition (P = 0.203).

Conclusion

Anti-C1q autoantibodies were closely associated with serum levels of C1q and glomerular deposition of C1q. Kidney is at least one of the target organs of anti-C1q autoantibodies.
Induction of labour with a Foley catheter or oral misoprostol at term: the PROBAAT-II study, a multicentre randomised controlled trial
Authors: ten Eikelder Mieke LG , Neervoort Femke , Rengerink Katrien Oude , Jozwiak Marta , de Leeuw Jan-Willem , de Graaf Irene , van Pampus Maria G , Franssen Maureen , Oudijk Martijn , van der Salm Paulien , Woiski Mallory , Pernet Paula JM , Feitsma A Hanneke , van Vliet Huib , Porath Martina , Roumen Frans , van Beek Erik , Versendaal Hans , Heres Marion , Mol Ben Willem J , Bloemenkamp Kitty W M
Published: March 2013

Background

Induction of labour is a common obstetric procedure. At present, different methods are used for induction of labour in women with an unfavourable cervix. Recently, we showed that in term women with an unfavorable cervix the use of a Foley catheter in comparison with vaginal Prostaglandin E2 gel, results in a comparable vaginal delivery rate. A meta-analysis on the subject indicated lower rates of hyperstimulation, and probably as a sequel fewer cases of postpartum haemorrhage. Misoprostol (PgE1) is another type of prostaglandin frequently used for labour induction, recommended by the international federation of gynaecology and obstetrics (FIGO). Misoprostol can be administered by vaginal, rectal and oral route. There is evidence that oral administration results in less asphyxia and hyperstimulation than vaginal administration. At present, valid comparisons between oral misoprostol and Foley catheter are lacking. Therefore, we propose a randomised controlled trial comparing Foley catheter to oral misoprostol in order to assess safety and cost-effectiveness.

Methods/Design

We plan a multicentre, randomised, controlled, open-label clinical trial among term pregnant women with a vital singleton in cephalic presentation, unfavorable cervix, intact membranes and an indication for induction of labour. After informed consent, women will be randomly allocated by a webbased randomisation system to transcervical Foley catheter or oral misoprostol (50 mcg every 4 hours). The primary outcome will be a composite of complications of uterine hyperstimulation, i.e. post partum haemorrhage and asphyxia. Secondary outcomes are mode of delivery, maternal and neonatal morbidity, costs and women’s preference. Serious adverse events such as severe maternal or neonatal morbitity or mortality will be monitored and reported to an independent data safety monitory board. With a sample size of 1860 women we will be able to demonstrate a 5% non-inferiority of the Foley catheter as compared to misoprostol for the composite outcome.

Discussion

Worldwide, various methods are being used for labour induction. Results of the proposed trial will contribute to the answer which method of induction of labour is most safe, cost-effective, and patient friendly and will help to construct evidence based guidelines.

Trial registration

The Netherlands Trial Register NTR3466
Progress risk assessment of oral premalignant lesions with saliva miRNA analysis
Authors: Yang Ya , Li Yue-xiu , Yang Xi , Jiang Long , Zhou Zuo-jun , Zhu Ya-qin
Published: March 2013

Background

Oral cancer develops through multi-stages: from normal to mild (low grade) dysplasia (LGD), moderate dysplasia, and severe (high grade) dysplasia (HGD), to carcinoma in situ (CIS) and finally invasive oral squamous cell carcinomas (OSCC). Clinical and histological assessments are not reliable in predicting which precursor lesions will progress. The aim of this study was to assess the potential of a noninvasive approach to assess progress risk of oral precancerous lesions.

Methods

We first used microRNA microarray to profile progressing LGD oral premaligant lesions (OPLs) from non-progressing LGD OPLs in order to explore the possible microRNAs deregulated in low grade OPLs which later progressed to HGD or OSCC. We then used RT-qPCR to detect miRNA targets from the microarray results in saliva samples of these patients.

Results

We identified a specific miRNA signature that is aberrantly expressed in progressing oral LGD leukoplakias. Similar expression patterns were detected in saliva samples from these patients.

Conclusions

These results show promise for using saliva miRNA signature for monitoring of cancer precursor lesions and early detection of disease progression.
Knowledge of, attitudes toward, and preventive practices relating to cholera and oral cholera vaccine among urban high-risk groups: findings of a cross-sectional study in Dhaka, Bangladesh
Authors: Wahed Tasnuva , Kaukab Sheikh Shah Tanvir , Saha Nirod Chandra , Khan Iqbal Ansary , Khanam Farhana , Chowdhury Fahima , Saha Amit , Khan Ashraful Islam , Siddik Ashraf Uddin , Cravioto Alejandro , Qadri Firdausi , Uddin Jasim
Published: March 2013

Background

In endemic countries such as Bangladesh, consequences of cholera place an enormous financial and social burden on patients and their families. Cholera vaccines not only provide health benefits to susceptible populations but also have effects on the earning capabilities and financial stability of the family. Community-based research and evaluations are necessary to understand perceptions about and practices of the community relating to cholera and oral cholera vaccines. This may help identify the ways in which such vaccines may be successfully introduced, and other preventive measures can be implemented. The present study assessed the knowledge of, attitudes toward, and preventive practices relating to cholera and oral cholera vaccine among an urban population residing in a high cholera-prone setting in Dhaka, Bangladesh.

Methods

This cross-sectional study was conducted in an area of high cholera prevalence in 15 randomly-selected clusters in Mirpur, Dhaka city. A study team collected data through a survey and in-depth interviews during December 2010–February 2011.

Results

Of 2,830 families included in the final analysis, 23% could recognize cholera as acute watery diarrhea and 16% had ever heard of oral cholera vaccine. About 54% of the respondents had poor knowledge about cholera-related issues while 97% had a positive attitude toward cholera and oral cholera vaccine. One-third showed poor practice relating to the prevention of cholera.

The findings showed a significant (p < 0.05) association between the respondents’ knowledge and sex, education, occupation, monthly overall household expenditure, attitudes and practice. In the adjusted model, male sex, having a lower monthly overall household expenditure, and having a less positive attitude toward cholera were the significant predictors to having poor knowledge.

Conclusions

The findings suggest the strengthening of health education activities to improve knowledge on cholera, its prevention and treatment and information on cholera vaccination among high-risk populations. The data also underscore the potential of mass cholera vaccination to prevent and control cholera.
Development of a Fur-dependent and tightly regulated expression system in Escherichia colifor toxic protein synthesis
Authors: Guan Lingyu , Liu Qin , Li Chao , Zhang Yuanxing
Published: March 2013

Background

There is a continuous demanding for tightly regulated prokaryotic expression systems, which allow functional synthesis of toxic proteins in Escherichia coli for bioscience or biotechnology application. However, most of the current promoter options either are tightly repressed only with low protein production levels, or produce substantial protein but lacking of the necessary repression to avoid mutations initiated by leaky expression in the absence of inducer. The aim of this study was to develop a tightly regulated, relatively high-efficient expression vector in E. coli based on the principle of iron uptake system.

Results

By using GFP as reporter, PfhuA with the highest relative fluorescence units, but leaky expression, was screened from 23 iron-regulated promoter candidates. PfhuA was repressed by ferric uptake regulator (Fur)-Fe2+ complex binding to Fur box locating at the promoter sequence. Otherwise, PfhuA was activated without Fur-Fe2+ binding in the absence of iron. In order to improve the tightness of PfhuA regulation for toxic gene expression, Fur box in promoter sequence and fur expression were refined through five different approaches. Eventually, through substituting E. coli consensus Fur box for original one of PfhuA, the induction ratio of modified PfhuA (named PfhuA1) was improved from 3 to 101. Under the control of PfhuA1, strong toxic gene E was successfully expressed in high, middle, low copy-number vectors, and other two toxic proteins, Gef and MazF were functionally synthesized without E. coli death before induction.

Conclusions

The features of easy control, tight regulation and relatively high efficiency were combined in the newly engineered PfhuA1. Under this promoter, the toxic genes E, gef and mazF were functionally expressed in E. coli induced by iron chelator in a tightly controllable way. This study provides a tightly regulated expression system that might enable the stable cloning, and functional synthesis of toxic proteins for their function study, bacterial programmed cell death in biological containment system and bacterial vector vaccine development.
LINE-1 and Alu hypomethylation in mucoepidermoid carcinoma
Authors: Sirivanichsuntorn Porntipa , Keelawat Somboon , Danuthai Kittipong , Mutirangura Apiwat , Subbalekha Keskanya , Kitkumthorn Nakarin
Published: March 2013

Background

Mucoepidermoid carcinoma (MEC) can be classified into low-, intermediate-, and high-grade tumors based on its histological features. MEC is mainly composed of three cell types (squamous or epidermoid, mucous and intermediate cells), which correlates with the histological grade and reflects its clinical behavior. Most cancers exhibit reduced methylation of repetitive sequences such as Long INterspersed Element-1 (LINE-1) and Alu elements. However, to date very little information is available on the LINE-1 and Alu methylation status in MEC. The aim of this study was to investigate LINE-1 and Alu element methylation in MEC and compare if key differences in the methylation status exist between the three different cell types, and adjacent normal salivary gland cells, to see if this may reflect the histological grade.

Methods

LINE-1 and Alu element methylation of 24 MEC, and 14 normal salivary gland tissues were compared using Combine Bisulfite Restriction Analysis (COBRA). Furthermore, the three different cell types from MEC samples were isolated for enrichment by laser capture microdissection (LCM), essentially to see if COBRA was likely to increase the predictive value of LINE-1 and Alu element methylation.

Results

LINE-1 and Alu element methylation levels were significantly different (p<0.001) between the cell types, and showed a stepwise decrease from the adjacent normal salivary gland to the intermediate, mucous and squamous cells. The reduced methylation levels of LINE-1 were correlated with a poorer histological grade. In addition, MEC tissue showed a significantly lower level of LINE-1 and Alu element methylation overall compared to normal salivary gland tissue (p<0.001).

Conclusions

Our findings suggest that LINE-1 methylation differed among histological grade mucoepidermoid carcinoma. Hence, this epigenetic event may hold value for MEC diagnosis and prognostic prediction.
Systemic release of high mobility group box 1 (HMGB1) protein is associated with severe and fatal Plasmodium falciparum malaria
Authors: Higgins Sarah J , Xing Katharine , Kim Hani , Kain Dylan C , Wang Feng , Dhabangi Aggrey , Musoke Charles , Cserti-Gazdewich Christine M , Tracey Kevin J , Kain Kevin C , Liles W Conrad
Published: March 2013

Background

Severe falciparum malaria (SM) pathogenesis has been attributed, in part, to deleterious systemic host inflammatory responses to infection. High mobility group box 1 (HMGB1) protein is an important mediator of inflammation implicated in sepsis pathophysiology.

Methods

Plasma levels of HMGB1 were quantified in a cohort of febrile Ugandan children withPlasmodium falciparuminfection, enrolled in a prospective observational case-controlled study, using a commercial enzyme-linked immunosorbent assay. The utility of HMGB1 to distinguish severe malaria (SM; n = 70) from uncomplicated malaria (UM; n = 33) patients and fatal (n = 21)versusnon-fatal (n = 82) malaria, at presentation, was examined. Receiver operating characteristic curve analysis was used to assess the prognostic accuracy of HMGB1. The ability ofP. falciparum-parasitized erythrocytes to induce HMGB1 from peripheral blood mononuclear cells was assessedin vitro. The effect of an anti-HMGB1 neutralizing antibody on disease outcome was assessed in the experimentalPlasmodium bergheiANKA rodent parasite model of SM. Mortality and parasitaemia was assessed daily and compared to isotype antibody-treated controls.

Results

Elevated plasma HMGB1 levels at presentation were significantly associated with SM and a subsequent fatal outcome in paediatric patients withP. falciparuminfection.In vitro, parasitized erythrocytes induced HMGB1 release from human peripheral blood mononuclear cells. Antibody-mediated neutralization of HMGB1 in the experimental murine model of severe malaria failed to reduce mortality.

Conclusion

These data suggest that elevated HMGB1 is an informative prognostic marker of disease severity in human SM, but do not support HMGB1 as a viable target for therapeutic intervention in experimental murine SM.
Effects of partial or complete laser-assisted hatching on the hatching of mouse blastocysts and their cell numbers
Authors: Chailert Chanchai , Sanmee Usanee , Piromlertamorn Waraporn , Samchimchom Sudarat , Vutyavanich Teraporn
Published: March 2013

Background

It is still debatable whether a full-thickness assisted hatching (AH) is better than the partial zona thinning. In this research, we used a mouse model to study the effect of partial and complete laser-AH on the rate of completely hatched blastocyst and their cell numbers.

Methods

In experiment 1, mouse morulae had 0, 1, 2 or 3 full-thickness openings of 10 microns created in the zona pellucida with an infrared laser beam. In the second experiment, 0, 1 and 2 openings of 20 microns were studied. In the third experiment, a full-thickness opening of 20 microns or quarter-thinning of the zonal circumference to a depth of 90% was compared with non-AH controls.

Results

No difference in blastocyst formation was found in laser-treated groups and in the controls. In experiment 1, the rate of completely hatched blastocysts was significantly lower than the controls. In experiment 2 when the size of the opening was increased, blastocysts completely hatched at a significantly higher rate than that in the controls. In experiment 3, the rate of completely hatched blastocysts was the highest in the full-thickness group. Cell numbers in completely hatched blastocysts from both AH groups were significantly fewer than those in the controls.

Conclusions

Full-thickness opening resulted in a higher rate of completely hatched blastocysts than quarter zonal-thinning and controls, but the cell numbers were significantly decreased.
Ghrelin inhibits LPS-induced release of IL-6 from mouse dopaminergic neurones
Authors: Beynon Amy L , Brown M Rowan , Wright Rhiannon , Rees Mark I , Sheldon I Martin , Davies Jeffrey S
Published: March 2013

Background

Ghrelin is an orexigenic stomach hormone that acts centrally to increase mid-brain dopamine neurone activity, amplify dopamine signaling and protect against neurotoxin-induced dopamine cell death in the mouse substantia nigra pars compacta (SNpc). In addition, ghrelin inhibits the lipopolysaccharide (LPS)-induced release of pro-inflammatory cytokines from peripheral macrophages, T-cells and from LPS stimulated microglia. Here we sought to determine whether ghrelin attenuates pro-inflammatory cytokine release from dopaminergic neurones.

Findings

The dopaminergic SN4741 cell-line, which derives from the mouse substantia nigra (SN) and expresses the ghrelin-receptor (growth hormone secretagogue receptor (GHS-R)) and the ghrelin-O-acyl transferase (GOAT) enzyme, was used to determine the neuro-immunomodulatory action of ghrelin. We induced innate immune activation via LPS challenge (1 μg/ml) of SN4741 neurones that had been pre-cultured in the presence or absence of ghrelin (1, 10, 100 nM) for 4 h. After 24 h supernatants were collected for detection of IL-1 beta (IL-1β ), TNF alpha (TNF-α) and IL-6 cytokines via enzyme linked immunosorbent assay (ELISA) analysis. Nuclear translocation of the transcription factor nuclear factor kappa B (NF-κB) was analyzed by Western blotting, and to determine viability of treatments a cell viability assay and caspase-3 immunohistochemistry were performed.

We provide evidence that while IL-1β and TNF-α were not detectable under any conditions, SN4741 neurones constitutively released IL-6 under basal conditions and treatment with LPS significantly increased IL-6 secretion. Pre-treatment of neurones with ghrelin attenuated LPS-mediated IL-6 release at 24 h, an affect that was inhibited by the GHS-R antagonist [D-Lys3]-GHRP-6. However, while ghrelin pre-treatment attenuated the LPS-mediated increase in NF-κB, there was no alteration in its nuclear translocation. Cell viability assay and caspase-3 immunocytochemistry demonstrated that the results were independent from activation of cytotoxic and/or apoptotic mechanisms in the neuronal population, respectively.

Conclusion

Our results provide evidence that the gut-hormone, ghrelin, attenuates IL-6 secretion to LPS challenge in mid-brain dopaminergic neurones. These data suggest that ghrelin may protect against dopaminergic SN nerve cell damage or death via modulation of the innate immune response.
Predictors of poor outcome after both column acetabular fractures: a 30-year retrospective cohort study
Authors: Lichte Philipp , Sellei Richard M , Kobbe Philipp , Dombroski Derek G , Gänsslen Axel , Pape Hans-Christoph
Published: March 2013

Background and Purpose

Acetabular fractures are often combined with associated injuries to the hip joint. Some of these associated injuries seem to be responsible for poor long-term results and these injuries seem to affect the outcome independent of the quality of the acetabular reduction. The aim of our study was to analyze the outcome of both column acetabular fractures and the influence of osseous cofactors such as initial fracture displacement, hip dislocation, femoral head lesions and injuries of the acetabular joint surface.

Methods

A retrospective cohort study in patients with both column acetabular fractures treated over a 30 year period was performed. Patients with a follow-up of more than two years were invited for a clinical and radiological examination. Displacement was analyzed on initial and postoperative radiographs. Contusion and impaction of the femoral head was grouped. Injuries of the acetabular joint surface consisting of impaction, contusion and comminution were recorded. The Merle d’Aubigné Score was documented and radiographs were analysed for arthritis (Helfet classification), femoral head avascular necrosis (Ficat/Arlet classification) and heterotopic ossifications (Brooker classification).

Results

115 patients were included in the follow up examination. Anatomic reduction (malreduction ≤ 1mm) was associated with a significantly better clinical outcome than nonanatomical reduction (p = 0.001). Initial displacement of more than 10mm (p = 0.031) and initial intraarticular fragments (p = 0.041) were associated with worse outcome. Other associated injuries, such as the presence of a femoral head dislocation, femoral head injuries and injuries to the acetabular joint surface showed no significant difference in outcome individually, but in fractures with more than two associated local injuries the risk for joint degeneration was significant higher (p < 0.001) than in cases with less than two of them.

In the subgroup of anatomically reconstructed fractures no significant influence of the analyzed cofactors could be observed.

Conclusion

Anatomical reduction appears to be an important parameter for a good clinical outcome in patients with both column acetabular fractures. Additional fracture characteristics such as the initial displacement and intraarticular fragments seem to influence the results. Patients should also be advised that both column acetabular fractures with more than two additional associated factors have a significantly higher risk of joint degeneration.
The effect of diabetes mellitus on the association between measures of glycaemiccontrol and ICU mortality: a retrospective cohort study
Authors: Sechterberger Marjolein K , Bosman Robert J , Oudemans-van Straaten Heleen M , Siegelaar Sarah E , Hermanides Jeroen , Hoekstra Joost BL , De Vries J Hans
Published: March 2013

Introduction

In critical illness, four measures of glycaemic control are associated with ICUmortality: mean glucose concentration, glucose variability, the incidence ofhypoglycaemia (≤ 2.2 mmol/l) or low glucose (2.3 to 4.7 mmol/l). Underlyingdiabetes mellitus (DM) might affect these associations. Our objective was to studywhether the association between these measures of glycaemic control and ICUmortality differs between patients without and with DM and to explore the cutoffvalue for detrimental low glucose in both cohorts.

Methods

This retrospective database cohort study included patients admitted betweenJanuary 2004 and June 2011 to a 24-bed medical/surgical ICU in a teachinghospital. We analysed glucose and outcome data from 10,320 patients: 8,682 withoutDM and 1,638 with DM. The cohorts were subdivided into quintiles of mean glucoseand quartiles of glucose variability. Multivariable regression models were used toexamine the independent association between the four measures of glycaemic controland ICU mortality, and for defining the cutoff value for detrimental lowglucose.

Results

Regarding mean glucose, a U-shaped relation was observed in the non-DM cohort withan increased ICU mortality in the lowest and highest glucose quintiles (odds ratio= 1.4 and 1.8, P < 0.001). No clear pattern was found in the DMcohort. Glucose variability was related to ICU mortality only in the non-DMcohort, with highest ICU mortality in the upper variability quartile (odds ratio =1.7, P < 0.001). Hypoglycaemia was associated with ICU mortality inboth cohorts (odds ratio non-DM = 2.5, P < 0.001; odds ratio DM = 4.2,P = 0.001), while low-glucose concentrations up to 4.9 mmol/l wereassociated with an increased risk of ICU mortality in the non-DM cohort and up to3.5 mmol/l in the DM cohort.

Conclusion

Mean glucose and high glucose variability are related to ICU mortality in thenon-DM cohort but not in the DM cohort. Hypoglycaemia (≤ 2.2 mmol/l) wasassociated with ICU mortality in both. The cutoff value for detrimental lowglucose is higher in the non-DM cohort (4.9 mmol/l) than in the DM cohort (3.5mmol/l). While hypoglycaemia (≤ 2.2 mmol/l) should be avoided in bothgroups, DM patients seem to tolerate a wider glucose range than non-DMpatients.
Personal genome testing in medical education: student experiences with genotyping in the classroom
Authors: Vernez Simone Lucia , Salari Keyan , Ormond Kelly E , Lee Sandra Soo-Jin
Published: March 2013

Background

Direct-to-consumer (DTC) personal genotyping services are beginning to be adoptedby educational institutions as pedagogical tools for learning about humangenetics. However, there is little known about student reactions to such testing.This study investigated student experiences and attitudes towards DTC personalgenome testing.

Methods

Individual interviews were conducted with students who chose to undergo personalgenotyping in the context of an elective genetics course. Ten medical and graduatestudents were interviewed before genotyping occurred, and at 2 weeks and 6 monthsafter receiving their genotype results. Qualitative analysis of interviewtranscripts assessed the expectations and experiences of students who underwentpersonal genotyping, how they interpreted and applied their results; how thetesting affected the quality of their learning during the course, and what weretheir perceived needs for support.

Results

Students stated that personal genotyping enhanced their engagement with the coursecontent. Although students expressed skepticism over the clinical utility of sometest results, they expressed significant enthusiasm immediately after receivingtheir personal genetic analysis, and were particularly interested in results suchas drug response and carrier testing. However, few reported making behavioralchanges or following up on specific results through a healthcare provider.Students did not report utilizing genetic counseling, despite feeling stronglythat the 'general public' would need these services. In follow-up interviews,students exhibited poor recall on details of the consent and biobankingagreements, but expressed little regret over their decision to undergo genotyping.Students reported mining their raw genetic data, and conveyed a need for furtherconsultation support in their exploration of genetic variants.

Conclusions

Personal genotyping may improve students' self-reported motivation and engagementwith course material. However, consultative support that is different fromtraditional genetic counseling will be necessary to support students. Beforeincorporating personal genotyping into coursework, institutions should leadmulti-disciplinary discussion to anticipate issues and incorporate teachingmechanisms that engage the ethical, legal, and social implications of personalgenotyping, including addressing those found in this study, to go beyond what isoffered by commercial providers.
Development of Therapeutic Combinations Targeting Major Cancer Signaling Pathways
Authors: Yap Timothy A. , Omlin Aurelius , de Bono Johann S.
Published: March 2013

Signaling networks play key homeostatic processes in living organisms but are commonly hijacked in oncogenesis. Prominent examples include genetically altered receptor tyrosine kinases and dysregulated intracellular signaling molecules. The discovery and development of targeted therapies against such oncogenic proteins has imparted clinical benefit. Nevertheless, concerns remain about the limited single-agent efficacy and narrow therapeutic indices of many of these antitumor agents. Moreover, it is apparent that oncogenic proteins comprise complex signaling networks that interact through crosstalk and feedback loops, which modify therapeutic vulnerability. These complexities mandate the study of drug combinations, which will also become necessary to reverse tumor drug resistance. Here, we outline the challenges associated with rational drug codevelopment strategies, with a focus on the importance of analytically validated biomarkers for patient selection and pharmacokinetic-pharmacodynamic (PK-PD) studies. Overall, the most informative clinical studies of novel combinations will have the following characteristics: robust scientific hypotheses leading to their selection; supportive preclinical data from contextually appropriate preclinical model systems; sufficient preclinical PK data to inform on the risk of drug-drug interactions; and detailed PD studies to determine the biologically active dose range for each agent. Toward this end, several novel clinical trial designs may be envisioned to accelerate successful drug combination development while minimizing the risk of late drug combination attrition. Although considerable challenges remain, these efforts may enable important steps to be taken toward more durable therapeutic control of many cancers.
Randomized Trial of Lapatinib Versus Placebo Added to Paclitaxel in the Treatment of Human Epidermal Growth Factor Receptor 2–Overexpressing Metastatic Breast Cancer
Authors: Guan Zhongzhen , Xu Binghe , DeSilvio Michelle L. , Shen Zhenzhou , Arpornwirat Wichit , Tong Zhongsheng , Lorvidhaya Vicharn , Jiang Zefei , Yang Junlan , Makhson Anatoly , Leung Wai Lim , Russo Mark W. , Newstat Beth , Wang Li , Chen George , Oliva Cristina , Gomez Henry
Published: March 2013

Purpose

Lapatinib is an oral small-molecule tyrosine kinase inhibitor of both epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2). This study is designed to test whether the addition of lapatinib to paclitaxel improves overall survival (OS) compared with placebo plus paclitaxel in patients with HER2-overexpressing metastatic breast cancer (MBC).

Patients and Methods

This phase III, randomized, double-blind study assessed the efficacy and safety of lapatinib plus paclitaxel compared with placebo plus paclitaxel in patients with newly diagnosed HER2-positive MBC. The primary end point was OS. Secondary end points included progression-free survival (PFS), overall response rate (ORR), clinical benefit rate, and safety.

Results

The addition of lapatinib to paclitaxel significantly improved OS versus paclitaxel (treatment hazard ratio [HR], 0.74; 95% CI, 0.58 to 0.94; P = .0124); median OS was 27.8 versus 20.5 months, respectively. Median PFS was prolonged by 3.2 months, from 6.5 months with placebo plus paclitaxel to 9.7 months with lapatinib plus paclitaxel (HR, 0.52; 95% CI, 0.42 to 0.64; stratified log-rank P < .001). ORR was significantly higher with lapatinib plus paclitaxel compared with placebo plus paclitaxel (69% v 50%, respectively; P < .001). The incidence of grades 3 and 4 diarrhea and neutropenia was higher in the lapatinib plus paclitaxel arm. Only 4% of patients in this group reported febrile neutropenia. Cardiac events were low grade, asymptomatic, and mostly reversible. The incidence of hepatic events was similar in both arms. There were no fatal adverse events in the lapatinib plus paclitaxel arm.

Conclusion

This trial demonstrated that lapatinib combined with paclitaxel offers a significant and clinically meaningful survival advantage over paclitaxel alone in patients with HER2-positive MBC.
The Play of Living Creation: Time and Finitude in Tagore's Humanism
Authors: Basu Manisha
Published: March 2013

This article examines a selection of Rabindranath Tagore's essays with a view to demonstrating that the Indian Nobel Laureate was distressed about the fact that in the early twentieth century the modern historical sense was eclipsing the place of poetics in the colonial world. In place of the transcendental vision implied by a developmental process of world-history, Tagore proposed that literary language generates a notion of time that is radically finite because it is aligned with the human failure to achieve divine transcendence. More specifically, his essays stage truly secular, historical time as the effect of a notion of rhythm that is bound neither to the imperial authority of history nor to mathematical measures, but rather emerges in the variety and contradictoriness of traces that language impresses upon itself, through the play of shifting economies of meaning, changing image patterns, and the mobility and textile strangeness of syntactic and accentual imports. In order to elaborate the radically finite temporality of such a literary language, this essay draws on Tagore's formulation of jivalila, or the play of living creation, which he opposes to the Western conceptualization of life as a primal struggle against death. Tied to the notion of a joyful union with the Supreme Being as it unfolds in the scriptural Upanishads, jivalila may at first seem like the kernel of yet another transcendental vision of Totality. But in Tagore's hands it becomes instead a recognition of the enduring gap between man and his god, just as death for the radical secularist is the epistemological confrontation of the nothingness between mortality and redemption. It is this enduring gap — rather than a specific mechanics of meter and verse — that Tagore imagines as rhythm, and it is in this gap that the play of literary language as also the play of living creation comes to be, together creating a dense relationship between the human form and its poetic scripting. The essay argues that Tagore offers a different imagining of the modern human condition — one that employs literary thinking to give us a radically secular human unchained from the transcendental process of world-history and from redemption as the conceptual telos of that sovereign process.
The Classical Notion of Competition Revisited
Authors: Salvadori Neri , Signorino Rodolfo
Published: March 2013

This article seeks to fill a lacuna within classical economics concerning the process of market price determination in situations of market disequilibrium. To this aim, first we distinguish the classical notion of free competition from the Walrasian notion of perfect competition and we argue that the latter is beset with some theoretical difficulties alien to the former. Second, we reconstruct in some detail Smith’s and Marx’s views concerning market price determination and show that Marx’s extensive use of metaphors and numerical examples foreshadows the modern taxonomy of buyers’ market, sellers’ market, and mixed strategy equilibrium in the capacity space of a standard Bertrand duopoly model. Finally, we highlight similarities and differences between the classical notion of competition and contemporary Bertrand competition models.
NMR and DFT Study on Onium Ions Derived from Substituted Fluoranthenes and Benzo[k]fluoranthenes
Authors: Okazaki Takao , Adachi Taisuke , Kitagawa Toshikazu
Published: March 2013

Fluoranthene and benzo[k]fluoranthene (3) are nonalternant polyaromatic hydrocarbons. Their derivatives, 3-acetyl, 8-acetyl, 3-nitro, and 3-aminofluoranthenes (4, 5, 7, and 8) were reacted in FSO3H/SO2ClF and the solutions were observed by NMR measurements at low temperatures, which showed the formation of PAH-substituted onium ions. The most deshielded 13C peaks in fluoranthene frames were observed at 155.7 and 148.7 ppm for 4H+, 154.4 ppm for 5H+, 159.1 and 139.6 ppm for 7H+, and 139.7 ppm for 8H+. Distribution of the positive charges were estimated on the basis of changes in 13C NMR chemical shifts between onium ions and their corresponding parent compounds. Only limited delocalization of positive charges into the aromatic rings was found to occur. GIAO-derived NMR chemical shifts calculated by the DFT method were generally consistent with the experimental chemical shifts. DFT calculations suggested that benzo[k]fluoranthene (3) is favored to be protonated at C-3/C-7 positions. GIAO-derived NICS(1)zz were computed to elucidate aromaticity/antiaromaticity, and the results suggested that the five-membered rings are antiaromatic for cations 4H+, 7H+, 8H+, and 3aH+ (3-benzo[k]fluoranthenium ion).
Structural Models of Nonequilibrium Strategic Thinking: Theory, Evidence, and Applications
Authors: Crawford Vincent P , Costa-Gomes Miguel A , Iriberri Nagore
Published: March 2013

Most applications of game theory assume equilibrium, justified by presuming either that learning will have converged to one, or that equilibrium approximates people's strategic thinking even when a learning justification is implausible. Yet several recent experimental and empirical studies suggest that people's initial responses to games often deviate systematically from equilibrium, and that structural nonequilibrium “level-k” or “cognitive hierarchy” models often out-predict equilibrium. Even when learning is possible and converges to equilibrium, such models allow better predictions of history-dependent limiting outcomes. This paper surveys recent theory and evidence on strategic thinking and illustrates the applications of level-k models in economics. (JEL C70, D03, D82, D83)
Mixed Bundling in Two-Sided Markets in the Presence of Installed Base Effects
Authors: Chao Yong , Derdenger Timothy
Published: March 2013

We analyze mixed bundling in two-sided markets where installed base effects are present and find that the pricing structure deviates from traditional bundling as well as the standard two-sided markets literature—we determine prices on both sides fall with bundling. Mixed bundling acts as a price discrimination tool segmenting the market more efficiently. Consequently, as a by-product of this price discrimination, the two sides are better coordinated, and social welfare is enhanced. We show unambiguously that platform participations increase on both sides of the market. After theoretically evaluating the impact mixed bundling has on prices and welfare, we take the model predictions to data from the portable video game console market. We find empirical support for all theoretical predictions.

This paper was accepted by J. Miguel Villas-Boas, marketing.
Organization and Bargaining: Sales Process Choice at Auto Dealerships
Authors: Bennett Victor Manuel
Published: March 2013

This paper examines how firms' organizational form affects prices negotiated. Negotiated prices are one factor determining whether a vendor or customer captures the value from a transaction. Firms that systematically negotiate more effectively capture more value. Research has investigated individual- and market-level determinants of negotiation outcomes, but little has been done on the firm-level determinants of negotiated prices. I present a first look at one feature, sales process: whether salespeople handle the entire sale in parallel or customers begin with less experienced salespeople who can escalate difficult assignments. I model firms' choice of sales process as a biform game and test predictions of the model using a combination of transaction-level data on new car purchases in the United States and a unique survey of dealership management practices. I find that a serial process has implications consistent with improving firms' bargaining power and reducing customers' outside options.

This paper was accepted by Bruno Cassiman, business strategy.
Coinsurance Within Business Groups: Evidence from Related Party Transactions in an Emerging Market
Authors: Jia Nan , Shi Jing , Wang Yongxiang
Published: March 2013

Using novel transaction-level data on Chinese business groups, this study provides the first direct evidence of the coinsurance theory of business groups by investigating when different types of internal resources are transferred within a business group. We find that in Chinese business groups, a credit crunch experienced by the controlling shareholding firm (the “controller”) of a publicly listed firm increases the loan-based related party transactions (RPTs) including loan guarantees and intercorporate loans provided by the listed firm to the controller. In turn, when the listed firm's performance dips, the controller and its son firms provide more support to the listed firm in the form of non-loan-based RPTs. These findings directly show the dynamic interactions of members within business groups.

This paper was accepted by Bruno Cassiman, business strategy.
Some Thoughts on John C. Weaver's The Great Land Rush and the Making of the Modern World, 1650-1900
Authors: Errington E. J.
Published: March 2013

The CHR is publishing the papers presented at the François-Xavier Garneau Prize roundtable, which takes place during the Canadian Historical Association's annual congress. The François-Xavier Garneau Medal, awarded every five years, is the most prestigious of the CHA prizes, honouring an outstanding Canadian contribution to historical research. The roundtable provides the opportunity for historians in the field to discuss the winning study's contribution from multiple perspectives. The 2010 winner was John C. Weaver's The Great Land Rush and the Making of the Modern World, 1650-1900 , published by McGill-Queen's University Press, 2003. La CHR publie les interventions faites lors d'une table ronde organisée pour la remise de la médaille François-Xavier-Garneau, qui s'est tenue lors de la rencontre annuelle de la Société historique du Canada. Attribuée tous les cinq ans, la médaille François-Xavier-Garneau est le plus prestigieux prix de la SHC . Elle honore une contribution canadienne remarquable à la recherche en histoire. La table ronde donne aux historiens spécialistes l'occasion de discuter de la contribution du livre gagnant selon plusieurs perspectives. En 2010, le gagnant fut The Great Land Rush and the Making of the Modern World, 1650-1900 , de John C. Weaver, paru chez McGill-Queen's University Press en 2003.