bluuebunny/crossref_metadata_2025 huggingface dataset:
Toll-like receptor 3 upregulation in macrophages participates in the initiation and maintenance of pristane-induced arthritis in rats
Authors: Meng Liesu , Zhu Wenhua , Jiang Congshan , He Xiaojing , Hou Weikun , Zheng Fang , Holmdahl Rikard , Lu Shemin
Published: May 2010

Introduction

Toll-like receptors (TLRs) are involved in both innate and adaptive immune responses and are likely to play a complex role in the pathogenesis of human rheumatoid arthritis (RA) and experimental arthritis. The objective of this study was to identify the key TLR in pristane-induced arthritis (PIA), a rat model for RA, and to clarify its roles in the initiation and maintenance of arthritis.

Methods

Arthritis in DA rats was induced by pristane and the severity was evaluated by macroscopic and microscopic score systems. Spleen TLR and cytokine expression was detected at different time points by real-time polymerase chain reaction (PCR) and flow cytometry. Polyinosine-polycytidylic acid (polyI:C, a ligand of TLR3) or TLR3 specific short-hairpin RNA plasmid for RNA interference was administrated to PIA rats in vivo. Serum nitrogen oxide concentration was determined by Griess method, and tumor necrosis factor alpha (TNF-α) was determined by L929 biotest. In splenic macrophages, TLR3 expression was measured by flow cytometry. A rat macrophage cell line (NR8383) was stimulated by pristane, and anti-TLR3 antibody were used to block TLR3 pathway. TLR3 and cytokine expression in NR8383 were detected by real-time PCR.

Results

By screening the TLR expression profile in spleen of DA rats after pristane injection, we found that TLR3 was the most early and prominently upregulated TLR. Both TLR3 mRNA and protein expression of spleen were upregulated at 6 and 26 days after pristane injection. Furthermore, administration of polyI:C exacerbated, whereas RNA interference targeting TLR3 ameliorated, the arthritis. Particularly, TLR3 expression was induced in splenic macrophages of PIA rats, and also in the NR8383 cell line after pristane stimulation in a dose- and time- dependent manner. Upregulation of interferon beta (IFN-β) and TNF-α by pristane stimulation was blocked by anti-TLR3 antibody in NR8383.

Conclusions

TLR3 plays a pivotal role in the initiation and development of PIA which may dependent on macrophage. These findings are useful to understand the pathogenesis of RA and may provide an intriguing therapeutic opportunity for RA.
Anemia and blood transfusion in a surgical intensive care unit
Authors: Sakr Yasser , Lobo Suzana , Knuepfer Stefanie , Esser Elizabeth , Bauer Michael , Settmacher Utz , Barz Dagmar , Reinhart Konrad
Published: May 2010

Introduction

Studies in intensive care unit (ICU) patients have suggested that anemia and blood transfusions can influence outcomes, but these effects have not been widely investigated specifically in surgical ICU patients.

Methods

We retrospectively analyzed the prospectively collected data from all adult patients (>18 years old) admitted to a 50-bed surgical ICU between 1st March 2004 and 30th July 2006.

Results

Of the 5925 patients admitted during the study period, 1833 (30.9%) received a blood transfusion in the ICU. Hemoglobin concentrations were < 9 g/dl on at least one occasion in 57.6% of patients. Lower hemoglobin concentrations were associated with a higher Simplified Acute Physiology Score II and Sequential Organ Failure Assessment score, greater mortality rates, and longer ICU and hospital lengths of stay. Transfused patients had higher ICU (12.5 vs. 3.2%) and hospital (18.3 vs. 6.5%) mortality rates (both p < 0.001) than non-transfused patients. However, ICU and in-hospital mortality rates were similar among transfused and non-transfused matched pairs according to a propensity score (n = 1184 pairs), and after adjustment for possible confounders in a multivariable analysis, higher hemoglobin concentrations (RR 0.97[0.95-0.98], per 1 g/dl, p < 0.001) and blood transfusions (RR 0.96[0.92-0.99], p = 0.031) were independently associated with a lower risk of in-hospital death, especially in patients aged from 66 to 80 years, in patients admitted to the ICU after non-cardiovascular surgery, in patients with higher severity scores, and in patients with severe sepsis.

Conclusions

In this group of surgical ICU patients, anemia was common and was associated with higher morbidity and mortality. Higher hemoglobin concentrations and receipt of a blood transfusion were independently associated with a lower risk of in-hospital death. Randomized control studies are warranted to confirm the potential benefit of blood transfusions in these subpopulations.
Pharyngeal oxygen administration increases the time to serious desaturation at intubation in acute lung injury: an experimental study
Authors: Engström Joakim , Hedenstierna Göran , Larsson Anders
Published: May 2010

Introduction

Endotracheal intubation in critically ill patients is associated with severe life-threatening complications in about 20%, mainly due to hypoxemia. We hypothesized that apneic oxygenation via a pharyngeal catheter during the endotracheal intubation procedure would prevent or increase the time to life-threatening hypoxemia and tested this hypothesis in an acute lung injury animal model.

Methods

Eight anesthetized piglets with collapse-prone lungs induced by lung lavage were ventilated with a fraction of inspired oxygen of 1.0 and a positive end-expiratory pressure of 5 cmH2O. The shunt fraction was calculated after obtaining arterial and mixed venous blood gases. The trachea was extubated, and in randomized order each animal received either 10 L oxygen per minute or no oxygen via a pharyngeal catheter, and the time to desaturation to pulse oximeter saturation (SpO2) 60% was measured. If SpO2 was maintained at over 60%, the experiment ended when 10 minutes had elapsed.

Results

Without pharyngeal oxygen, the animals desaturated after 103 (88-111) seconds (median and interquartile range), whereas with pharyngeal oxygen five animals had a SpO2 > 60% for the 10-minute experimental period, one animal desaturated after 7 minutes, and two animals desaturated within 90 seconds (P < 0.016, Wilcoxon signed rank test). The time to desaturation was related to shunt fraction (R2 = 0.81, P = 0.002, linear regression); the animals that desaturated within 90 seconds had shunt fractions >40%, whereas the others had shunt fractions <25%.

Conclusions

In this experimental acute lung injury model, pharyngeal oxygen administration markedly prolonged the time to severe desaturation during apnea, suggesting that this technique might be useful when intubating critically ill patients with acute respiratory failure.
Regulation and prognostic relevance of serum ghrelin concentrations in critical illness and sepsis
Authors: Koch Alexander , Sanson Edouard , Helm Anita , Voigt Sebastian , Trautwein Christian , Tacke Frank
Published: May 2010

Introduction

Ghrelin has been recently identified as a mediator of various beneficial effects in animal models of sepsis. At present, no data are available concerning specific properties of ghrelin in critically ill patients from large cohorts. In order to identify possible pathogenic functions of ghrelin in critically ill patients and human sepsis from a clinical point of view, we aimed at analyzing ghrelin serum concentrations in a large cohort of well characterized patients with critical illness.

Methods

A total of 170 critically ill patients (122 with sepsis, 48 without sepsis) were studied prospectively on admission to the Medical intensive care unit (ICU) and compared to 60 healthy controls. Careful assessment of clinical data, various laboratory parameters, metabolic and endocrine functions as well as investigational inflammatory cytokine profiles have been performed, and patients were followed for approximately three years.

Results

Ghrelin serum concentrations are elevated in critically ill patients as compared to healthy controls, but do not differ between sepsis and non-sepsis patients. The underlying etiologies of critical diseases are not associated with ghrelin serum levels. Neither pre-existing diabetes mellitus nor body mass index is correlated to serum ghrelin concentrations. Ghrelin is not correlated to markers of inflammation or hepatic function in critically ill patients. In the subgroup of non-sepsis patients, ghrelin correlates inversely with renal function and markers of carbohydrate metabolism. High ghrelin levels are an indicator for a favourable prognosis concerning mortality at the ICU in sepsis patients. Furthermore, ghrelin is significantly associated with the necessity of ventilation in critically ill patients.

Conclusions

Ghrelin serum concentrations are elevated in all circumstances of critical disease, including sepsis and non-sepsis patients. High ghrelin levels are a positive predictor of ICU-survival in sepsis patients, matching previous results from animal models. Future experimental and clinical studies are needed to evaluate ghrelin as a novel prognostic tool in ICU patients and its potential therapeutic use in sepsis.
Transpulmonary thermodilution using femoral indicator injection: a prospective trial in patients with a femoral and a jugular central venous catheter
Authors: Saugel Bernd , Umgelter Andreas , Schuster Tibor , Phillip Veit , Schmid Roland M , Huber Wolfgang
Published: May 2010

Introduction

Advanced hemodynamic monitoring using transpulmonary thermodilution (TPTD) is established for measurement of cardiac index (CI), global end-diastolic volume index (GEDVI) and extra-vascular lung water index (EVLWI). TPTD requires indicator injection via a central venous catheter (usually placed via the jugular or subclavian vein). However, superior vena cava access is often not feasible due to the clinical situation. This study investigates the conformity of TPTD using femoral access.

Methods

This prospective study involved an 18-month trial at a medical intensive care unit at a university hospital. Twenty-four patients with both a superior and an inferior vena cava catheter at the same time were enrolled in the study.

Results

TPTD-variables were calculated from TPTD curves after injection of the indicator bolus via jugular access (TPTDjug) and femoral access (TPTDfem). GEDVIfem and GEDVIjug were significantly correlated (rm = 0.88; P < 0.001), but significantly different (1,034 ± 275 vs. 793 ± 180 mL/m2; P < 0.001). Bland-Altman analysis demonstrated a bias of +241 mL/m2 (limits of agreement: -9 and +491 mL/m2). GEDVIfem, CIfem and ideal body weight were independently associated with the bias (GEDVIfem-GEDVIjug). A correction formula of GEDVIjug after femoral TPTD, was calculated. EVLWIfem and EVLWIjug were significantly correlated (rm = 0.93; P < 0.001). Bland-Altman analysis revealed a bias of +0.83 mL/kg (limits of agreement: -2.61 and +4.28 mL/kg). Furthermore, CIfem and CIjug were significantly correlated (rm = 0.95; P < 0.001). Bland-Altman analysis demonstrated a bias of +0.29 L/min/m2 (limits of agreement -0.40 and +0.97 L/min/m2; percentage-error 16%).

Conclusions

TPTD after femoral injection of the thermo-bolus provides precise data on GEDVI with a high correlation, but a self-evident significant bias related to the augmented TPTD-volume. After correction of GEDVIfem using a correction formula, GEDVIfem shows high predictive capabilities for GEDVIjug. Regarding CI and EVLWI, accurate TPTD-data is obtained using femoral access.
Pegylated Liposomal Doxorubicin and Carboplatin Compared With Paclitaxel and Carboplatin for Patients With Platinum-Sensitive Ovarian Cancer in Late Relapse
Authors: Pujade-Lauraine Eric , Wagner Uwe , Aavall-Lundqvist Elisabeth , Gebski Val , Heywood Mark , Vasey Paul A. , Volgger Birgit , Vergote Ignace , Pignata Sandro , Ferrero Annamaria , Sehouli Jalid , Lortholary Alain , Kristensen Gunnar , Jackisch Christian , Joly Florence , Brown Chris , Le Fur Nathalie , du Bois Andreas
Published: May 2010

Purpose

This randomized, multicenter, phase III noninferiority trial was designed to test the efficacy and safety of the combination of pegylated liposomal doxorubicin (PLD) with carboplatin (CD) compared with standard carboplatin and paclitaxel (CP) in patients with platinum-sensitive relapsed/recurrent ovarian cancer (ROC).

Patients and Methods

Patients with histologically proven ovarian cancer with recurrence more than 6 months after first- or second-line platinum and taxane-based therapies were randomly assigned by stratified blocks to CD (carboplatin area under the curve [AUC] 5 plus PLD 30 mg/m2) every 4 weeks or CP (carboplatin AUC 5 plus paclitaxel 175 mg/m2) every 3 weeks for at least 6 cycles. Primary end point was progression-free survival (PFS); secondary end points were toxicity, quality of life, and overall survival.

Results

Overall 976 patients were recruited. With median follow-up of 22 months, PFS for the CD arm was statistically superior to the CP arm (hazard ratio, 0.821; 95% CI, 0.72 to 0.94; P = .005); median PFS was 11.3 versus 9.4 months, respectively. Although overall survival data are immature for final analysis, we report here a total of 334 deaths. Overall severe nonhematologic toxicity (36.8% v 28.4%; P < .01) leading to early discontinuation (15% v 6%; P < .001) occurred more frequently in the CP arm. More frequent grade 2 or greater alopecia (83.6% v 7%), hypersensitivity reactions (18.8% v 5.6%), and sensory neuropathy (26.9% v 4.9%) were observed in the CP arm; more hand-foot syndrome (grade 2 to 3, 12.0% v 2.2%), nausea (35.2% v 24.2%), and mucositis (grade 2-3, 13.9% v 7%) in the CD arm.

Conclusion

To our knowledge, this trial is the largest in recurrent ovarian cancer and has demonstrated superiority in PFS and better therapeutic index of CD over standard CP.
Metastatic Behavior of Breast Cancer Subtypes
Authors: Kennecke Hagen , Yerushalmi Rinat , Woods Ryan , Cheang Maggie Chon U. , Voduc David , Speers Caroline H. , Nielsen Torsten O. , Gelmon Karen
Published: May 2010

Purpose

Prognostic and predictive factors are well established in early-stage breast cancer, but less is known about which metastatic sites will be affected.

Methods

Patients with early-stage breast cancer diagnosed between 1986 and 1992 with archival tissue were included. Subtypes were defined as luminal A, luminal B, luminal/human epidermal growth factor receptor 2 (HER2), HER2 enriched, basal-like, and triple negative (TN) nonbasal. Distant sites were classified as brain, liver, lung, bone, distant nodal, pleural/peritoneal, and other. Cumulative incidence curves were estimated for each site according to competing risks methods. Association between the site of relapse and subtype was assessed in multivariate models using logistic regression.

Results

Median follow-up time among 3,726 eligible patients was 14.8 years. Median durations of survival with distant metastasis were 2.2 (luminal A), 1.6 (luminal B), 1.3 (luminal/HER2), 0.7 (HER2 enriched), and 0.5 years (basal-like; P < .001). Bone was the most common metastatic site in all subtypes except basal-like tumors. In multivariate analysis, compared with luminal A tumors, luminal/HER2 and HER2-enriched tumors were associated with a significantly higher rate of brain, liver, and lung metastases. Basal-like tumors had a higher rate of brain, lung, and distant nodal metastases but a significantly lower rate of liver and bone metastases. TN nonbasal tumors demonstrated a similar pattern but were not associated with fewer liver metastases.

Conclusion

Breast cancer subtypes are associated with distinct patterns of metastatic spread with notable differences in survival after relapse.
Phase III, Placebo-Controlled Trial of Three Doses of Citalopram for the Treatment of Hot Flashes: NCCTG Trial N05C9
Authors: Barton Debra L. , LaVasseur Beth I. , Sloan Jeff A. , Stawis Allen N. , Flynn Kathleen A. , Dyar Missy , Johnson David B. , Atherton Pamela J. , Diekmann Brent , Loprinzi Charles L.
Published: May 2010

Purpose

Up to 75% of women experience hot flashes, which can negatively impact quality of life. As hot flash physiology is not definitively understood, it cannot be assumed that effective agents represent class effects. Therefore, there is a continued need for rigorous evaluation to identify effective nonhormonal options for hot flash relief.

Methods

A randomized, double-blind trial evaluated citalopram at target doses of 10, 20, or 30 mg/d versus placebo for 6 weeks. Postmenopausal women with at least 14 bothersome hot flashes per week recorded hot flashes for 7 days before starting treatment and were then titrated to their target doses. The primary end point was the change from baseline to 6 weeks in hot flash score.

Results

Two hundred fifty-four women were randomly assigned onto this study. Data for hot flash scores and frequencies showed significant improvement in hot flashes with citalopram over placebo, with no significant differences among doses. Reductions in mean hot flash scores were 2.0 (23%), 7.0 (49%), 7.7 (50%), and 10.7 (55%) for placebo and 10, 20, and 30 mg of citalopram, respectively (P ≤ .002). Improvement in secondary outcomes, such as the Hot Flash Related Daily Interference Scale, was statistically superior in the 20-mg arm. Citalopram was well-tolerated, with no significant negative adverse effects.

Conclusion

Citalopram is an effective, well-tolerated agent in managing hot flashes. There does not appear to be a significant dose response above 10 mg/d, but broader helpful effects of the agent appear to be more evident at 20 mg/d.
Decision Making by Parents of Children With Incurable Cancer Who Opt for Enrollment on a Phase I Trial Compared With Choosing a Do Not Resuscitate/Terminal Care Option
Authors: Maurer Scott H. , Hinds Pamela S. , Spunt Sheri L. , Furman Wayne L. , Kane Javier R. , Baker Justin N.
Published: May 2010

Purpose

Parents of children with incurable cancer make complex and difficult decisions about remaining treatment options. We compared the self-reported rationale, good parent definition, and desired clinical staff behaviors of parents who recently decided for phase I (P1) chemotherapy with parents who chose a do not resuscitate (DNR) or terminal care (TC) option.

Patients and Methods

Sixty-two parents of 58 children were asked for the basis of their decision, their definition of a good parent, and what staff behaviors supported their good parent role. After semantic content analysis, results were compared in the P1 versus DNR/TC groups. These categories were mutually exclusive but did not necessarily represent an either/or decision.

Results

Thirty-one decisions were for P1 chemotherapy and 27 for DNR/TC. Median survival time after study enrollment was greater in the P1 group (0.4 v 0.1 years). Most P1 group parents reported having felt compelled to continue cancer-directed therapy (71% v 7%), whereas those who opted for DNR/TC cited quality of life (QOL; 74% v 3%) and patient wishes (67% v 13%). Decision factors common to both groups were medical facts, doing right, and others’ opinions. Both groups believed that a good parent did right, provided support and presence, and sacrificed for the child. The groups desired similar support from clinicians and expressed gratitude.

Conclusion

Despite similar definitions of a good parent and desired staff behaviors, parents in the P1 group reported having felt compelled to continue cancer-directed therapy, whereas QOL and patient wishes were emphasized in decisions for DNR/TC.
Soluble Mesothelin-Related Peptide and Osteopontin As Markers of Response in Malignant Mesothelioma
Authors: Wheatley-Price Paul , Yang Boming , Patsios Demetris , Patel Devalben , Ma Clement , Xu Wei , Leighl Natasha , Feld Ronald , Cho B.C. John , O'Sullivan Brenda , Roberts Heidi , Tsao Ming Sound , Tammemagi Martin , Anraku Masaki , Chen Zhuo , de Perrot Marc , Liu Geoffrey
Published: May 2010

Purpose

In malignant mesothelioma (MM), radiologic assessment of disease status is difficult. Both soluble mesothelin-related peptide (SMRP) and osteopontin (OP) have utility in distinguishing MM from benign pleural disease. We evaluated whether SMRP and OP also correlated with the disease course of MM.

Patients and Methods

Serial plasma samples from patients with MM were prospectively collected, and SMRP and OP levels were measured. Radiologic tests across time periods showing disease progression, stability, or shrinkage were compared with corresponding changes in SMRP/OP levels.

Results

From 41 patients, 165 samples were collected (range, 2 to 10; median 4). At study entry, 37 of 41 patients had measurable disease, of whom 92% (34 of 37) had elevated baseline SMRP levels; four of 41 patients had no evidence of recurrence and each had normal baseline SMRP levels. In 21 patients receiving systemic therapy, percentage change in SMRP more than 10% correlated with the radiologic assessment by a trained thoracic radiologist (P < .001), by formal Response Evaluation Criteria in Solid Tumors (RECIST; P = .008), or by modified RECIST (P < .001). All seven patients who underwent surgical resection with negative margins had elevated preoperative SMRP levels that fell to normal postoperatively. Rising SMRP was observed in all patients with radiologic disease progression. No associations were found with OP.

Conclusion

Percentage changes in SMRP levels, but not changes in OP levels, are a potentially useful marker of disease course. These findings should be validated prospectively for a role as an objective adjunctive measure of disease course in both clinical trials and clinical practice.
Leaping into Space: The Two Aesthetics ofTo the Lighthouse
Authors: Caracciolo Marco
Published: May 2010

This essay argues against the prevalent view of the aesthetics implicit in Virginia Woolf's To the Lighthouse. It is an aesthetics of closure, an attempt to make “of the moment something permanent” (Woolf 2000a [1927]: 176), which is usually associated (as are Woolf's own theoretical statements) with the novel. This “formalism,” no doubt related to Roger Fry's art criticism, takes fictional shape in the character of Mrs. Ramsay. In fact, it is by bringing life to a standstill, enclosing it in crystalline “moments of being” (Woolf 1976), that Mrs. Ramsay struggles against the grasp of time. However, this aesthetics is shown to be illusory and self-deceptive: the very opposition between humanity and nature stems from the human desire to comprehend and thus reduce to reason (and language) what the text constructs as irreducible. Mrs. Ramsay's aesthetics gives way to the aesthetics of virtuality enacted by Lily Briscoe's painting. Only by reformulating the problem of time in spatial terms can Lily overthrow the limitations of the formalist framework: her art—a hybrid image/text—hinges on the blanks of aesthetic communication (which I define by reference to the work of Wolfgang Iser and Louis Marin). Lily's painting qualifies as the only viable alternative to Mrs. Ramsay's self-contained crystals of shape. Finally, I show how Woolf herself tried to (p)reenact Lily's painting in the central section of the novel, “Time Passes.” Apparently built on the humanity/nature opposition, this baffling segment revolves in fact around a blank (the absence of any perceiving consciousness internal to the fictional world) and encourages the reader to fill it in by imaginatively moving into the fictional world with a virtual body (as defined by Maurice Merleau-Ponty).
Moving away from the midline: new developments for Slit and Robo
Authors: Ypsilanti Athena R. , Zagar Yvrick , Chédotal Alain
Published: May 2010

In most tissues, the precise control of cell migration and cell-cell interaction is of paramount importance to the development of a functional structure. Several families of secreted molecules have been implicated in regulating these aspects of development, including the Slits and their Robo receptors. These proteins have well described roles in axon guidance but by influencing cell polarity and adhesion, they participate in many developmental processes in diverse cell types. We review recent progress in understanding both the molecular mechanisms that modulate Slit/Robo expression and their functions in neural and non-neural tissue.
The leading edge during dorsal closure as a model for epithelial plasticity: Pak is required for recruitment of the Scribble complex and septate junction formation
Authors: Bahri Sami , Wang Simon , Conder Ryan , Choy Juliana , Vlachos Stephanie , Dong Kevin , Merino Carlos , Sigrist Stephan , Molnar Cristina , Yang Xiaohang , Manser Edward , Harden Nicholas
Published: May 2010

Dorsal closure (DC) of the Drosophila embryo is a model for the study of wound healing and developmental epithelial fusions, and involves the sealing of a hole in the epidermis through the migration of the epidermal flanks over the tissue occupying the hole, the amnioserosa. During DC, the cells at the edge of the migrating epidermis extend Rac- and Cdc42-dependent actin-based lamellipodia and filopodia from their leading edge (LE), which exhibits a breakdown in apicobasal polarity as adhesions are severed with the neighbouring amnioserosa cells. Studies using mammalian cells have demonstrated that Scribble (Scrib), an important determinant of apicobasal polarity that functions in a protein complex, controls polarized cell migration through recruitment of Rac, Cdc42 and the serine/threonine kinase Pak, an effector for Rac and Cdc42, to the LE. We have used DC and the follicular epithelium to study the relationship between Pak and the Scrib complex at epithelial membranes undergoing changes in apicobasal polarity and adhesion during development. We propose that, during DC, the LE membrane undergoes an epithelial-to-mesenchymal-like transition to initiate epithelial sheet migration, followed by a mesenchymal-to-epithelial-like transition as the epithelial sheets meet up and restore cell-cell adhesion. This latter event requires integrin-localized Pak, which recruits the Scrib complex in septate junction formation. We conclude that there are bidirectional interactions between Pak and the Scrib complex modulating epithelial plasticity. Scrib can recruit Pak to the LE for polarized cell migration but, as migratory cells meet up, Pak can recruit the Scrib complex to restore apicobasal polarity and cell-cell adhesion.
The cell-surface proteins Dally-like and Ihog differentially regulate Hedgehog signaling strength and range during development
Authors: Yan Dong , Wu Yihui , Yang Yongfei , Belenkaya Tatyana Y. , Tang Xiaofang , Lin Xinhua
Published: May 2010

Hedgehog (Hh) acts as a morphogen in various developmental contexts to specify distinct cell fates in a concentration-dependent manner. Hh signaling is regulated by two conserved cell-surface proteins: Ig/fibronectin superfamily member Interference hedgehog (Ihog) and Dally-like (Dlp), a glypican that comprises a core protein and heparan sulfate glycosaminoglycan (GAG) chains. Here, we show in Drosophila that the Dlp core protein can interact with Hh and is essential for its function in Hh signaling. In wing discs, overexpression of Dlp increases short-range Hh signaling while reducing long-range signaling. By contrast, Ihog has biphasic activity in Hh signaling in cultured cells: low levels of Ihog increase Hh signaling, whereas high levels decrease it. In wing discs, overexpression of Ihog represses high-threshold targets, while extending the range of low-threshold targets, thus showing opposite effects to Dlp. We further show that Ihog and its family member Boi are required to maintain Hh on the cell surface. Finally, Ihog and Dlp have complementary expression patterns in discs. These data led us to propose that Dlp acts as a signaling co-receptor. However, Ihog might not act as a classic co-receptor; rather, it may act as an exchange factor by retaining Hh on the cell surface, but also compete with the receptor for Hh binding.
Dynamic shape changes of ECM-producing cells drive morphogenesis of ball-and-socket joints in the fly leg
Authors: Tajiri Reiko , Misaki Kazuyo , Yonemura Shigenobu , Hayashi Shigeo
Published: May 2010

Animal body shape is framed by the skeleton, which is composed of extracellular matrix (ECM). Although how the body plan manifests in skeletal morphology has been studied intensively, cellular mechanisms that directly control skeletal ECM morphology remain elusive. In particular, how dynamic behaviors of ECM-secreting cells, such as shape changes and movements, contribute to ECM morphogenesis is unclear. Strict control of ECM morphology is crucial in the joints, where opposing sides of the skeleton must have precisely reciprocal shapes to fit each other. Here we found that, in the development of ball-and-socket joints in the Drosophila leg, the two sides of ECM form sequentially. We show that distinct cell populations produce the ‘ball’ and the ‘socket’, and that these cells undergo extensive shape changes while depositing ECM. We propose that shape changes of ECM-producing cells enable the sequential ECM formation to allow the morphological coupling of adjacent components. Our results highlight the importance of dynamic cell behaviors in precise shaping of skeletal ECM architecture.
An interview with Kate Storey and Silvia Marino
Authors: Amsen Eva
Published: May 2010

In February 2010, in the beautiful setting of Wiston House, nestled at the foot of the hilly South Downs in Sussex, UK, The Company of Biologists, the not-for-profit organisation that publishes Development, held the inaugural meeting of their new workshop series dedicated to biological research (for more information on these meetings, please go to http://workshops.biologists.com/). The meeting was titled ‘Neural Stem Cells in Development and Disease’, and was organised by Kate Storey, Professor of Neural Development at the College of Life Sciences of the University of Dundee, and Silvia Marino, Professor of Neuropathology at Barts and The London School of Medicine and Dentistry. They were also assisted by the workshop chairman, François Guillemot, Programme Leader of the Division of Molecular Neurobiology at the National Institute for Medical Research in London. The scientific scope and themes of this workshop are covered in more detail in a meeting review published in this issue (see p. 1933) but, to get a glimpse behind the scenes, we talked to Kate Storey and Silvia Marino and asked them about the organisation of the ‘Neural Stem Cells in Development and Disease’ workshop.
Incompetence of the gastrocnemius vein
Authors: Hobbs J T , Vandendriessche M A W
Published: May 2010

The veins of the popliteal fossa are more complex than is generally realised. It is frequently taught that the short saphenous vein need only be divided deep to the popliteal fascia. However, the pattern and level of termination of the short saphenous vein shows wide variation. Sometimes, the short saphenous vein is normal and the pathology involves other veins. The 'vein of the popliteal fossa' may sometimes be present as a large tortuous varicosity and pierce the fascia to become superficial at the back of the knee.

Incompetence of a gastrocnemius vein, usually the medial, may cause swelling and discomfort within the calf yet nothing is apparent. Awareness may be precipitated by attempting to wear tight fitting boots or trousers when the difference in calf circumference is recognised yet there is no ankle oedema. Next a venous flare or dilated venules appear over a perforator site, usually the mid-calf perforator, but sometimes the Boyd's perforator, filling the posterior arch tributary of the greater saphenous vein. Incompetence of a gastrocnemius vein is suggested by the history and clinical examination. Reflux is demonstrated by Doppler ultrasound and accurately localized by duplex ultrasound with colour-flow imaging. The anatomy is clearly visualized by venography.Large gastrocnemius veins are seen in athletes and ballerinas with well-developed calf muscles and such veins are physiological and should not be interrupted. It is imperative that reflux is demonstrated before surgical treatment is offered.

Treatment involves ligating the incompetent gastrocnemius vein through a small incision over the popliteal fossa. If the mid-calf perforator is also incompetent it is divided deep to the fascia through a small vertical incision and the fascial defect closed. The distal short saphenous vein may be removed by partial stripping and any tributaries removed by phlebectomies using Oesch hooks. Strong below-knee stockings are worn for a month following this surgery.
Value of the Trendelenburg tourniquet test in the assessment of primary varicose veins
Authors: Hoffmann W H , Toonder I M , Wittens C H A
Published: May 2010

Objective: Trendelenburg tourniquet tests should determine long saphenous vein (LSV), short saphenous vein (SSV) or perforating vein incompetence. This study analyses the inter-observer variability of the Trendelenburg test and the results are compared with duplex scanning - the standard for venous incompetence analysis.

Methods: A total of 54 legs of 43 patients with varicose veins were investigated (36 female and seven male patients; mean age 47 years [range: 17-75]). All legs were evaluated for valvular incompetence by Trendelenburg tourniquet tests performed by three different investigators. A duplex scan was also performed in all legs. The inter-observer variability of the tourniquet test was expressed in Kappa (κ <0.5 indicated poor agreement). The sensitivity and specificity of the tourniquet tests are determined using the duplex scan as standard.

Results: The inter-observer variability of the Trendelenburg test in detecting valvular incompetence of the LSV, SSV, perforating veins in the upper leg (PVU) and lower leg (PVL), expressed in Kappa, were: 0.39, 0.42, 0.14 and 0.49, respectively. The sensitivity of the tourniquet test in detecting valvular incompetence of the LSV, SSV, PVU and PVL, in relation to duplex scanning was: 50, 35, 52 and 35% respectively, and the specificity was 59, 72, 46 and 80%, respectively.

Conclusions: The evaluation of patients with varicose veins with the Trendelenburg tourniquet test is unreliable and therefore obsolete. In order to manage patients with varicose veins properly duplex investigation is mandatory.
Microcirculatory changes parallel the clinical deterioration of chronic venous insufficiency
Authors: Labropoulos N , Wierks C , Golts E , Volteas S K , Leon M , Volteas N , Nicolaides A N
Published: May 2010

Objective: This study was designed to determine microcirculatory changes in patients belonging to different chronic venous insufficiency (CVI) classes.

Methods: A total of 80 patients from all CVI classes and 15 symptom-free volunteers were studied prospectively. Venous reflux was verified with duplex scanning. Patients with conditions that may have affected the local microcirculation were excluded. Skin blood flux (SBF) was measured using a laser Doppler flowmeter in the supine position in a constant room temperature of 22°C and after 10 minutes acclimatization. The veno-arteriolar response (VAR) was estimated from the SBF change from supine to dependent position. The vasomotor activity (VMA) was determined from the baseline SBF.The amplitude of cycles (AC) and SBF during heat stress at 45°C were also measured.

Results: Mean age, duration of disease and prevalence of deep vein thrombosis were greater in classes 4-6 compared with classes 1-3 ( P <0.02). Although there was an increase in SBF and AC in classes 2 and 3 compared with the controls this was not significant. Values for SBF and AC were higher in classes 4-6 than classes 1-3 ( P <0.01), and higher in class 6 than class 4 ( P <0.01). Upon heating, the SBF increased more in classes 1-3 than in classes 4-6 ( P <0.01), and in class 4 more than in class 6 ( P <0.01). Values for VAR and VMA decreased with worsening of CVI, but these changes were not significant.

Conclusions: Deterioration of the microcirculation is largely responsible for the clinical symptoms and signs seen in patients with CVI classes 4-6.
Quality of life in a trial of short stretch versus four-layer bandaging in the management of chronic venous ulceration
Authors: Franks P J , Moody M , Moffatt C J , Patton J , Bradley L , Chaloner D , Stevens J ,   C Lewis on behalf of the Wound Healing Nursing Research Group C.
Published: May 2010

Objective: To evaluate health-related quality of life (HRQoL) in a prospective randomized trial of patients suffering from venous ulceration comparing a generic four-layer elastic bandage (4LB) with a new cohesive short stretch bandage system (CSSB).

Methods: Randomized prospective open parallel groups trial in community leg ulcer clinics within twelve trusts in England and Northern Ireland. Patients newly presenting for treatment suffering from chronic venous ulceration, with ankle brachial pressure index (ABPI) >0.8 were entered into the trial. Patients were asked to complete the Nottingham Health Profile (NHP) at entry, at end of trial period (withdrawal or healing), and at 24 weeks. Principal analysis was the comparison of final NHP scores using linear regression with baseline scores entered as a covariate.

Results: In all, 154 of the 156 patients who entered the trial completed the initial questionnaire, with 139/154 (90.2%) patients completing at least one follow-up questionnaire. Improvements were noted for all scores after 24 weeks. The improvements were significantly greater in the 114 patients whose ulcers had healed compared with the 40 whose ulcers remained open in the domains of bodily pain (mean difference [d]=13.2, 95% CI 3.6-22.9, P =0.008), emotional reactions (d=10.5, 95% CI 2.8-18.1, P =0.007) and social isolation (d=8.5, 95% CI 1.2-15.9, P =0.024). There were similar mean scores between the 72 patients treated with the 4LB and the 82 patients treated with CSSB for all domains of the NHP, the largest adjusted difference favoured CSSB for energy (d=3.6, 95% CI-4.3-11.4, P =0.37).

Conclusions: Patients suffering from leg ulceration show improvements in perceived health following effective ulcer management. The two bandage systems achieved similar improvements in perceived health over 24 weeks.
On the significance of an RNA tertiary structure prediction
Authors: Hajdin Christine E. , Ding Feng , Dokholyan Nikolay V. , Weeks Kevin M.
Published: May 2010

Tertiary structure prediction is important for understanding structure–function relationships for RNAs whose structures are unknown and for characterizing RNA states recalcitrant to direct analysis. However, it is unknown what root-mean-square deviation (RMSD) corresponds to a statistically significant RNA tertiary structure prediction. We use discrete molecular dynamics to generate RNA-like folds for structures up to 161 nucleotides (nt) that have complex tertiary interactions and then determine the RMSD distribution between these decoys. These distributions are Gaussian-like. The mean RMSD increases with RNA length and is smaller if secondary structure constraints are imposed while generating decoys. The compactness of RNA molecules with true tertiary folds is intermediate between closely packed spheres and a freely jointed chain. We use this scaling relationship to define an expression relating RMSD with the confidence that a structure prediction is better than that expected by chance. This is the prediction significance, and corresponds to a P-value. For a 100-nt RNA, the RMSD of predicted structures should be within 25 Å of the accepted structure to reach the P ≤ 0.01 level if the secondary structure is predicted de novo and within 14 Å if secondary structure information is used as a constraint. This significance approach should be useful for evaluating diverse RNA structure prediction and molecular modeling algorithms.
Efficient mRNA detection from human archival paraffin-embedded tissue: An update: FIGURE 1.
Authors: Illig Romana , Fritsch Helga , Schwarzer Christoph
Published: May 2010

We recently published an in situ hybridization protocol for archival tissue using a commercial hybridization buffer. This buffer is no more available. Therefore, we have developed an improved protocol with a defined hybridization buffer.
Capacity Management on Long-Distance Passenger Trains of Indian Railways
Authors: Gopalakrishnan Raja , Rangaraj Narayan
Published: May 2010

In this paper, we discuss a model to allocate train capacity among multiple travel segments on an Indian Railways train route with several stops. We use a linear programming model and data preprocessing and postprocessing to determine the optimal capacity allocation on multiple travel legs. The model uses a simple, effective capacity management tool. For historical and social reasons, Indian Railways splits its train capacity based on user and type of travel. Determining the optimal split of such capacity is nontrivial. We deal with the specific issue of the spatial split of seats in an end-to-end travel segment within a given travel class. This addresses the needs of end-to-end and en route travelers. When we applied our model to 17 Indian Railways trains, we achieved increases of 2.6 to 29.3 percent in revenue, 6.7 to 30.8 percent in load factors, and 8.4 to 29 percent in passengers carried.
How to do a meta‐analysis
Authors: Field Andy P. , Gillett Raphael
Published: May 2010

Meta‐analysis is a statistical tool for estimating the mean and variance of underlying population effects from a collection of empirical studies addressing ostensibly the same research question. Meta‐analysis has become an increasing popular and valuable tool in psychological research, and major review articles typically employ these methods. This article describes the process of conducting meta‐analysis: selecting articles, developing inclusion criteria, calculating effect sizes, conducting the actual analysis (including information on how to do the analysis on popular computer packages such as IBM SPSS and R) and estimating the effects of publication bias. Guidance is also given on how to write up a meta‐analysis.
Widespread Expression of PICOT in Mouse and Human Tissues With Predominant Localization to Epithelium
Authors: Ohayon Ariel , Babichev Yael , Galperin Moran , Altman Amnon , Isakov Noah
Published: May 2010

The protein kinase C-interacting cousin of thioredoxin (PICOT; also termed glutaredoxin 3) protein was discovered a decade ago as a protein kinase C θ (PKCθ)-binding protein in human T lymphocytes. PICOT possesses an amino-terminal monothiol thioredoxin-like domain and a carboxy-terminal tandem repeat of a monothiol glutaredoxin-like domain. Nevertheless, the enzymatic activities of PICOT and its potential substrates have not yet been characterized and its biological importance is unknown. Earlier studies reported the presence of PICOT in several different cell lines and tissues, but its expression pattern has not been thoroughly investigated. We performed Northern blot analysis of 19 different human organs and tissues and found the expression of PICOT mRNA in all organs and tissues tested. Western blot analysis confirmed the expression of PICOT at the protein level in all organs and tissues tested and showed, in addition, that PICOT and PKCθ expression in different tissues only partially overlap. These findings support the involvement of PICOT in biological functions that are independent of PKCθ. To analyze the in vivo expression pattern of PICOT within cells of different human organs, we performed immunohistochemical staining using PICOT-specific antibodies. Analysis of breast, pituitary, adrenal, pancreas, and kidney sections demonstrated a differential expression of PICOT in various cell types, with a predominant cytosolic staining of epithelial cells and low or undetectable levels of PICOT in the Stroma.
Sudanese Perspectives on Resettlement in Australia
Authors: Murray Kate E.
Published: May 2010

Resettlement programs for people from a refugee background must respond to a variety of concerns as people from diverse backgrounds and often longstanding periods of upheaval and hardship enter their new resettlement communities. Host countries approach the demands of resettlement through varying programs and policies and those differences across countries can profoundly affect the newcomers' experiences. The current study employs quantitative and qualitative methods to examine the individual and contextual factors that influence the resettlement experience for adults from Sudan being resettled in Queensland, Australia. Ninety Sudanese adults were recruited through snowball sampling techniques for the quantitative study, with 10 individuals purposefully selected to complete the semistructured qualitative interview. In the quantitative sample, 25 to 30% of participants reported significant symptoms of psychological distress and frequent experiences of discrimination, and the majority of participants reported integration (identifying with both Australian and Sudanese cultures) as their method of acculturation. Participants reported feeling initially welcomed into Australia, with positive influences including bonding and bridging capital, which helped them in their adaptation, and negative influences including problems with the resettlement programs and experiences of discrimination. The findings underscore the importance of sociopolitical context on refugee experiences of the resettlement process.
Serbian Stories of Translocation: Factors Influencing the Refugee Journey Arising from the Balkan Conflicts of the 1990s
Authors: King Svetlana M. , Welch Neil , Owens Larry
Published: May 2010

This qualitative study highlights the experiences of ten Serbian refugees who migrated to South Australia from former Yugoslavia as a result of the Balkan conflicts of the 1990s. Multiple semi-structured interviews were employed to examine participants' experiences before, during and after the conflicts. Eight stages of the refugee journey were identified: prewar peaceful co-existence, outbreak of war, fleeing towards refuge in Serbian-held territory, realisation that the pre-war life cannot be regained, dissatisfaction with the family's transition situation, decision and application to emigrate, migration and resettlement in Australia, and adaptation to life in Australia. A number of factors were found to influence each stage of the refugee journey (e.g., social, practical and health challenges, age, and negative Serbian stereotypes). From these findings, three adaptation patterns — active integration, passive integration, and segregation — were identified as specific to the participants in the current study.
Refugee Without Refuge: Wasim, Phillip Adams, and a Nation Divided
Authors: Pedersen Anne , Fozdar Farida
Published: May 2010

This study follows on from previous work (Pedersen et al., 2008) that examined the situation of the stateless asylum seeker, Wasim. In the present study, a blog discussion stemming from an editorial about Wasim (Adams, 2008) was analysed. Participants were identified as ‘Do-Gooders’ and ‘Do-Badders’; categories that indicate their orientation to asylum seeker debates (labels originated from the blog itself). We identified several features of the blog discussion. While similar themes and discursive devices were used by the two groups, they were used very differently. The Do-Gooders were more likely to offer accurate information about asylum seekers or Wasim and to show humanitarian concerns for Wasim and others like him. The Do-Badders were more likely to display emotion, show the ‘Phillip Adams Effect’ (addressing the author of the editorial, Phillip Adams, in their submissions) and name-call. However, there was no significant difference with respect to whether participants addressed Wasim's situation specifically rather than focusing on the general issue of asylum seekers. The blog demonstrates, in microcosm, the divided orientation of Australians regarding asylum seekers.