bluuebunny/crossref_metadata_2025 huggingface dataset:
Simultaneous activation of p53 and inhibition of XIAP enhance the activation of apoptosis signaling pathways in AML
Authors: Carter Bing Z. , Mak Duncan H. , Schober Wendy D. , Koller Erich , Pinilla Clemencia , Vassilev Lyubomir T. , Reed John C. , Andreeff Michael
Published: November 2009

Activation of p53 by murine double minute (MDM2) antagonist nutlin-3a or inhibition of X-linked inhibitor of apoptosis (XIAP) induces apoptosis in acute myeloid leukemia (AML) cells. We demonstrate that concomitant inhibition of MDM2 by nutlin-3a and of XIAP by small molecule antagonists synergistically induced apoptosis in p53 wild-type OCI-AML3 and Molm13 cells. Knockdown of p53 by shRNA blunted the synergy, and down-regulation of XIAP by antisense oligonucleotide (ASO) enhanced nutlin-3a–induced apoptosis, suggesting that the synergy was mediated by p53 activation and XIAP inhibition. This is supported by data showing that inhibition of both MDM2 and XIAP by their respective ASOs induced significantly more cell death than either ASO alone. Importantly, p53 activation and XIAP inhibition enhanced apoptosis in blasts from patients with primary AML, even when the cells were protected by stromal cells. Mechanistic studies demonstrated that XIAP inhibition potentiates p53-induced apoptosis by decreasing p53-induced p21 and that p53 activation enhances XIAP inhibition-induced cell death by promoting mitochondrial release of second mitochondria-derived activator of caspases (SMAC) and by inducing the expression of caspase-6. Because both XIAP and p53 are presently being targeted in ongoing clinical trials in leukemia, the combination strategy holds promise for expedited translation into the clinic.
Combination immunosuppressant therapy for patients with chronic refractory immune thrombocytopenic purpura
Authors: Arnold Donald M. , Nazi Ishac , Santos Aurelio , Chan Howard , Heddle Nancy M. , Warkentin Theodore E. , Kelton John G.
Published: November 2009

Treatment options for patients with chronic refractory immune thrombocytopenic purpura (ITP) are limited. Because combination immunosuppressant therapy appeared to be effective in ITP and other disorders, we used this approach in patients with particularly severe and refractory ITP. In this retrospective, observational study, we determined the response (platelet count above 30 × 109/L and doubling of baseline) among 19 refractory ITP patients. Treatment consisted of azathioprine, mycophenolate mofetil, and cyclosporine. The patients had failed a median of 6 prior treatments, including splenectomy (in all except 1). Of 19 patients, 14 (73.7%) achieved a response lasting a median of 24 months, after which time 8 (57.1%) relapsed. Of the 8 relapsing patients, 6 responded to additional treatments. Of the 14 patients who achieved an initial response, 2 (14.3%) remained in remission after eventually stopping all medications. Severe adverse events did not occur. Combination immunosuppressant therapy can produce a rise in the platelet count that is sometimes sustained in refractory ITP patients.
Identification of multidrug resistance protein 1 (MRP1/ABCC1) as a molecular gate for cellular export of cobalamin
Authors: Beedholm-Ebsen Rasmus , van de Wetering Koen , Hardlei Tore , Nexø Ebba , Borst Piet , Moestrup Søren K.
Published: November 2009

Cobalamin (Cbl, vitamin B12) deficiency in humans is a cause of hematologic and neurologic disorders. We show here that the cellular export of Cbl, in contrast to the carrier- and receptor-dependent cellular import of Cbl, occurs by transmembrane transport of “free” Cbl. Screening of candidate transporters by cellular gene silencing showed a role in cellular Cbl efflux of the ATP-binding cassette (ABC)–drug transporter, ABCC1, alias multidrug resistance protein 1 (MRP1), which is present in the basolateral membrane of intestinal epithelium and in other cells. The ability of MRP1 to mediate ATP-dependent Cbl transport was confirmed by vesicular transport experiments, and a physiologic role of MRP1 in mammalian Cbl homeostasis is indicated by the phenotype of knockout mice with targeted disruption of MRP1. These animals have a reduced concentration of Cbl in plasma and in the storage organs liver and kidney. In contrast, Cbl accumulates in the terminal part of the intestine of these mice, suggesting a functional malabsorption because of a lower epithelial basolateral Cbl efflux. The identification of this Cbl export mechanism now allows the delineation of a coherent pathway for Cbl trafficking from food to the body cells.
Rapid activation of endothelial cells enables Plasmodium falciparum adhesion to platelet-decorated von Willebrand factor strings
Authors: Bridges Daniel J. , Bunn James , van Mourik Jan A. , Grau Georges , Preston Roger J.S. , Molyneux Malcolm , Combes Valery , O'Donnell James S. , de Laat Bas , Craig Alister
Published: November 2009

During Plasmodium falciparum malaria infections, von Willebrand factor (VWF) levels are elevated, postmortem studies show platelets colocalized with sequestered infected erythrocytes (IEs) at brain microvascular sites, whereas in vitro studies have demonstrated platelet-mediated IE adhesion to tumor necrosis factor-activated brain endothelium via a bridging mechanism. This current study demonstrates how all these observations could be linked through a completely novel mechanism whereby IEs adhere via platelet decorated ultra-large VWF strings on activated endothelium. Using an in vitro laminar flow model, we have demonstrated tethering and firm adhesion of IEs to the endothelium specifically at sites of platelet accumulation. We also show that an IE pro-adhesive state, capable of supporting high levels of binding within minutes of induction, can be removed through the action of the VWF protease ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13). We propose that this new mechanism contributes to sequestration both independently of and in concert with current adhesion mechanisms.
Defective macrophage phagocytosis of bacteria in COPD
Authors: Taylor A. E. , Finney-Hayward T. K. , Quint J. K. , Thomas C. M. R. , Tudhope S. J. , Wedzicha J. A. , Barnes P. J. , Donnelly L. E.
Published: November 2009

Exacerbations of chronic obstructive pulmonary disease (COPD) are an increasing cause of hospitalisations and are associated with accelerated progression of airflow obstruction. Approximately half of COPD exacerbations are associated with bacteria and many patients have lower airways colonisation. This suggests that bacterial infection in COPD could be due to reduced pathogen removal. This study investigated whether bacterial clearance by macrophages is defective in COPD.

Phagocytosis of fluorescently labelled polystyrene beads andHaemophillus influenzaeandStreptococcus pneumoniaeby alveolar macrophages and monocyte-derived macrophages (MDM) was assessed by fluorimetry and flow cytometry. Receptor expression was measured by flow cytometry.

Alveolar macrophages and MDM phagocytosed polystyrene beads similarly. There was no difference in phagocytosis of beads by MDM from COPD patients compared with cells from smokers and nonsmokers. MDM from COPD patients showed reduced phagocytic responses toS. pneumoniaeandH. influenzaecompared with nonsmokers and smokers. This was not associated with alterations in cell surface receptor expression of toll-like receptor (TLR)2, TLR4, macrophage receptor with collagenous structure, cluster of differentiation (CD)163, CD36 or mannose receptor. Budesonide, formoterol or azithromycin did not suppress phagocytosis suggesting that reduced responses in COPD MDM were not due to medications.

COPD macrophage innate responses are suppressed and may lead to bacterial colonisation and increased exacerbation frequency.
Inhibition of neutrophil elastase-induced goblet cell metaplasia by tiotropium in mice
Authors: Arai N. , Kondo M. , Izumo T. , Tamaoki J. , Nagai A.
Published: November 2009

Airway occlusion by mucus in chronic obstructive disease (COPD) is associated with a poor prognosis. We hypothesised that tiotropium has the ability to inhibit neutrophil elastase (NE)-induced goblet cell metaplasia in mice and mucin productionin vitro.

On days 1, 4, and 7, tiotropium or vehicle was administered to C57BL/6 mice by inhalation and they were allowed to intranasally aspirate human NE. Bronchoalveolar lavage fluid (BALF) and lung sections were analysed on days 8, 11 and 14. The effect of late administration of tiotropium on the goblet cell metaplasia by NE aspiration was also assessed. NE-induced MUC5AC production by NCI-H292 cells was measured with ELISA.

Repeated NE aspiration induced marked goblet cell metaplasia. The grading of goblet cell metaplasia, neutrophil count and eosinophil count in BALF, keratinocyte-derived chemokine level and leukotriene B4level in BALF, and M3receptor expression by immunohistochemistry, were lower in the tiotropium group than in the vehicle group. Late administration of tiotropium inhibited the established goblet cell metaplasia. Tiotropium inhibited NE-induced MUC5AC production.

Tiotropium inhibited NE-induced goblet cell metaplasia and mucin production, probably mediated by suppression of inflammation and a direct action on epithelial cells. This result suggests that tiotropium may be useful for the treatment of mucus overproduction in COPD.
Aerobic training reverses airway inflammation and remodelling in an asthma murine model
Authors: Silva R. A. , Vieira R. P. , Duarte A. C. S. , Lopes F. D. T. Q. S. , Perini A. , Mauad T. , Martins M. A. , Carvalho C. R. F.
Published: November 2009

Aerobic training (AT) decreases dyspnoea and exercise-induced bronchospasm, and improves aerobic capacity and quality of life; however, the mechanisms for such benefits remain poorly understood. The aim of the present study was to evaluate the AT effects in a chronic model of allergic lung inflammation in mice after the establishment of airway inflammation and remodelling.

Mice were divided into the control group, AT group, ovalbumin (OVA) group or OVA+AT group and exposed to saline or OVA. AT was started on day 28 for 60 min five times per week for 4 weeks. Respiratory mechanics, specific immunoglobulin (Ig)E and IgG1, collagen and elastic fibres deposition, smooth muscle thickness, epithelial mucus, and peribronchial density of eosinophils, CD3+ and CD4+, IL-4, IL-5, IL-13, interferon-γ, IL-2, IL-1ra, IL-10, nuclear factor (NF)-κB and Foxp3 were evaluated.

The OVA group showed an increase in IgE and IgG1, eosinophils, CD3+, CD4+, IL-4, IL-5, IL-13, NF-κB, collagen and elastic, mucus synthesis, smooth muscle thickness and lung tissue resistance and elastance. The OVA+AT group demonstrated an increase of IgE and IgG1, and reduction of eosinophils, CD3+, CD4+, IL-4, IL-5, IL-13, NF-κB, airway remodelling, mucus synthesis, smooth muscle thickness and tissue resistance and elastance compared with the OVA group (p<0.05). The OVA+AT group also showed an increase in IL-10 and IL-1ra (p<0.05), independently of Foxp3.

AT reversed airway inflammation and remodelling and T-helper cell 2 response, and improved respiratory mechanics. These results seem to occur due to an increase in the expression of IL-10 and IL-1ra and a decrease of NF-κB.
EIA and GC/MS analysis of 8-isoprostane in EBC of children with problematic asthma
Authors: Carraro S. , Cogo P. E. , Isak I. , Simonato M. , Corradi M. , Carnielli V. P. , Baraldi E.
Published: November 2009

Asthmatic airways are characterised by enhanced oxidative stress, which can be studied by measuring biomarkers, such as 8-isoprostane. The aims of the present study were: 1) to measure the concentrations of 8-isoprostane in exhaled breath condensate (EBC) and urine of children with problematic and well-controlled asthma; 2) to compare the concentrations of 8-isoprostane measured by gas chromatographic/negative ion chemical ionisation mass spectrometry (GC/NICI-MS) and by an enzymatic immunoassay (EIA).

We recruited 20 asthmatic allergic children, 13 with well-controlled asthma and seven with problematic asthma. They underwent exhaled nitric oxide measurements and spirometry, and both EBC and urine samples were collected. 8-isoprostane was measured in EBC by GC/NICI-MS and EIA.

8-isoprostane concentrations in EBC were significantly higher in children with problematic asthma than in children with well-controlled asthma (p = 0.01). An acceptable reproducibility emerged between GC/NICI-MS and EIA (coefficient of reproducibility 11.5 pg·mL−1). 8-isoprostane levels measured in urine did not correlate with those measured in EBC.

We showed that 8-isoprostane in EBC was significantly increased in children with problematic asthma, suggesting a role for oxidative stress in this asthma phenotype. In addition we found an acceptable reproducibility of EIA compared to GC/NICI-MS, even if the latter method had higher accuracy.
The prevalence of quadriceps weakness in COPD and the relationship with disease severity
Authors: Seymour J.M. , Spruit M.A. , Hopkinson N.S. , Natanek S.A. , Man W.D-C. , Jackson A. , Gosker H.R. , Schols A.M.W.J. , Moxham J. , Polkey M.I. , Wouters E.F.M.
Published: November 2009

Quadriceps strength relates to exercise capacity and prognosis in chronic obstructive pulmonary disease (COPD). We wanted to quantify the prevalence of quadriceps weakness in COPD and hypothesised that it would not be restricted to patients with severe airflow obstruction or dyspnoea.

Predicted quadriceps strength was calculated using a regression equation (incorporating age, sex, height and fat-free mass), based on measurements from 212 healthy subjects. The prevalence of weakness (defined as observed values 1.645 standardised residuals below predicted) was related to Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage and Medical Research Council (MRC) dyspnoea score in two cohorts of stable COPD outpatients recruited from the UK (n = 240) and the Netherlands (n = 351).

32% and 33% of UK and Dutch COPD patients had quadriceps weakness. A significant proportion of patients in GOLD stages 1 and 2, or with an MRC dyspnoea score of 1 or 2, had quadriceps weakness (28 and 26%, respectively). These values rose to 38% in GOLD stage 4, and 43% in patients with an MRC Score of 4 or 5.

Quadriceps weakness was demonstrable in one-third of COPD patients attending hospital respiratory outpatient services. Quadriceps weakness exists in the absence of severe airflow obstruction or breathlessness.
The value of endoscopic ultrasound after bronchoscopy to diagnose thoracic sarcoidosis
Authors: Tournoy K. G. , Bolly A. , Aerts J. G. , Pierard P. , De Pauw R. , Leduc D. , Leloup A. , Pieters T. , Slabbynck H. , Janssens A. , Carron K. , Schrevens L. , Pat K. , De Keukeleire T. , Dooms C.
Published: November 2009

A clinicoradiological presentation of thoracic sarcoidosis requires histopathology in order to establish the diagnosis. Flexible bronchoscopy has a reasonable diagnostic yield and is the procedure of first choice for diagnosis. Endoscopic ultrasound (endoscopic ultrasound-guided fine needle aspiration/endobronchial ultrasound-guided transbronchial needle aspiration) can help in the diagnosis of sarcoidosis.

An implementation strategy of endoscopic ultrasound for the diagnosis of sarcoidosis following negative flexible bronchoscopy results was examined prospectively in 15 clinics.

A total of 137 patients (92 males; median age 43 yrs) were included, and sarcoidosis was found in 115 (84%). Alternative diagnoses were tuberculosis, lymphangitis carcinomatosa, pneumoconiosis and alveolitis. All patients were sent for flexible bronchoscopy, which was performed in 121 (88%), resulting in a definite diagnosis in 57 (42%). A total of 80 patients were sent for endoscopic ultrasound, which could be performed in 72 (90%), yielding a definite diagnosis in 47 (59%). Endoscopic ultrasound following negative flexible bronchoscopy avoided a surgical procedure in 47 out of 80 patients. The sensitivity of flexible bronchoscopy for sarcoidosis was 45% (95% confidence interval 35–54%), but 62% (50–72%) if biopsy specimens were taken. The sensitivity of endoscopic ultrasound following negative flexible bronchoscopy results was 71% (58–82%). With this strategy, 97 out of 115 (84% (76–90%)) of proven sarcoidosis was diagnosed using endoscopy.

This large prospective implementation study (trial numberNCT00888212; ClinicalTrials.gov) shows that endoscopic ultrasound is valuable for diagnosing sarcoidosis after negative flexible bronchoscopy results.
Noncardiothoracic nonobstetric surgery in mild-to-moderate pulmonary hypertension
Authors: Price L. C. , Montani D. , Jaïs X. , Dick J. R. , Simonneau G. , Sitbon O. , Mercier F. J. , Humbert M.
Published: November 2009

The anaesthetic management and follow-up of well-characterised patients with pulmonary arterial hypertension presenting for noncardiothoracic nonobstetric surgery has rarely been described.

The details of consecutive patients and perioperative complications during the period January 2000 to December 2007 were reviewed. Repeat procedures in duplicate patients were excluded. Longer term outcomes included New York Heart Association (NYHA) functional class, 6-min walking distance and invasive haemodynamics.

A total of 28 patients were identified as having undergone major (57%) or minor surgery under general (50%) and regional anaesthesia. At the time of surgery, 75% of patients were in NYHA functional class I–II. Perioperative deaths occurred in 7%. Perioperative complications, all related to pulmonary hypertension, occurred in 29% of all patients and in 17% of those with no deaths during scheduled procedures. Most (n = 11, 92%) of the complications occurred in the first 48 h following surgery. In emergencies (n = 4), perioperative complication and death rates were higher (100 and 50%, respectively; p<0.005). Risk factors for complications were greater for emergency surgery (p<0.001), major surgery (p = 0.008) and a long operative time (193versus112 min; p = 0.003). No significant clinical or haemodynamic deterioration was seen in survivors at 3–6 or 12 months of post-operative follow-up.

Despite optimal management in this mostly nonsevere pulmonary hypertension population, perioperative complications were common, although survivors remained stable. Emergency procedures, major surgery and long operations were associated with increased risk.
RETRACTED ARTICLE: Urachal tumour: case report of a poorly understood carcinoma
Authors: Scabini Stefano , Rimini Edoardo , Romairone Emanuele , Scordamaglia Renato , Vallarino Luigi , Giasotto Veronica , Ferro Carlo , Ferrando Valter
Published: November 2009

Background

Urachal carcinoma is an uncommon neoplasm associated with poor prognosis.

Case presentation

A 45-year-old man was admitted with complaints of abdominal pain and pollakisuria. A soft mass was palpable under his navel. TC-scan revealed a 11 × 6 cm tumor, which was composed of a cystic lesion arising from the urachus and a solid mass component at the urinary bladder dome. The tumor was removed surgically. Histological examination detected poor-differentiated adenocarcinoma, which had invaded the urinary bladder. The patient has been followed up without recurrence for 6 months.

Conclusion

The urachus is the embryological remnant of urogenital sinus and allantois. Involution usually happens before birth and urachus is present as a median umbilical ligament. The pathogenesis of urachal tumours is not fully understood. Surgery is the treatment of choice and role of adjuvant treatment is not clearly understood.
Repair of injured right inferior pulmonary vein during mitral valve replacement
Authors: Apostolakis Efstratios , Leivaditis Vassilios N , Kallikourdis Antonios , Dedeilias Panagiotis
Published: November 2009

During mitral valve surgery right pulmonary veins injury, subsequent to excessive traction (for better exposure of the mitral apparatus), is often unavoidable. This is more likely in patients with small left atrium. This common complication may cause severe intraoperative bleeding, while its surgical repair may lead to complications such as late stenosis or obstruction of the pulmonary veins. This injury should be early detected, before left atriotomy closing, and it is suggested to be repaired using a patch so as to avoid any possible late constriction.

We describe a case -to our knowledge, the first reported in the literature- of intraoperatively injured right inferior pulmonary vein in a patient who underwent mitral valve replacement. As outlined we propose that the ostium of the right inferior pulmonary vein can be repaired by using autologous pericardial patch, incorporated in the completion of left atriotomy closure.
Mesenchymal stem cells respond to TNF but do not produce TNF
Authors: van den Berk Lieke C J , Jansen Bastiaan J H , Siebers-Vermeulen Kim G C , Roelofs Helene , Figdor Carl G , Adema Gosse J , Torensma Ruurd
Published: November 2009

The TNF promoter is silenced in mesenchymal stem cells able to respond to LPS by NFκB translocation and cytokine production yet without TNF.

Previously, we demonstrated that several TLRs are expressed on cord blood-derived USSC. Stimulation of USSC with TLR agonists resulted in a marked increase of IL-6 and IL-8 production. Interestingly, TNF was undetectable after TLR stimulation, which appeared to be a result of an inactivated TNF promoter in USSC. Here, we elaborate this study by demonstrating that although USSC do not produce TNF, they are susceptible to TNF stimulation, resulting in NF-κB translocation and cytokine production. Additionally, we compared different stem cell sources for their ability to produce TNF. Interestingly, we found that the TNF promoter in BM-MSC is inactivated as well. Like USSC, they are able to respond to TNF stimulation, but they are not able to produce TNF, even not after LPS stimulation. This limited cytokine response in combination with the well-studied immunosuppressive properties of MSC makes these cells ideal for immune-suppressive treatment modalities such as graft-versus-host disease.
Bone Mineral Density and Serum Levels of Soluble Tumor Necrosis Factors, Estradiol, and Osteoprotegerin in Postmenopausal Women with Cirrhosis after Viral Hepatitis
Authors: González-Calvin Jorge L. , Mundi Jose L. , Casado-Caballero Francisco J. , Abadia Ana C. , Martin-Ibañez Jose J.
Published: November 2009

Context: Cirrhosis after viral hepatitis has been identified as a risk factor for osteoporosis in men. However, in postmenopausal women, most studies have evaluated the effect of primary biliary cirrhosis, but little is known about the effect of viral cirrhosis on bone mass [bone mineral density (BMD)] and bone metabolism.

Objective: Our objective was to assess the effect of viral cirrhosis on BMD and bone metabolism in postmenopausal women.

Design: We conducted a cross-sectional descriptive study.

Setting and Patients: We studied 84 postmenopausal female outpatients with viral cirrhosis and 96 healthy postmenopausal women from the general community. BMD was measured by dual-energy x-ray absorptiometry at lumbar spine (LS) and femoral neck (FN).

Results: The percentage with osteoporosis did not significantly differ between patients (LS, 43.1%; FN, 32.2%) and controls (LS, 41.2%; FN, 29.4%), and there was no difference in BMD (z-score) between groups. Serum concentrations of soluble TNF receptors, estradiol, and osteoprotegerin (OPG) were significantly higher in patients vs. controls (P < 0.001, P < 0.05, and P < 0.05, respectively). No significant difference was observed in urinary deoxypyridinoline. Serum OPG levels were positively correlated with soluble TNF receptors (r = 0.35; P < 0.02) and deoxypyridinoline (r = 0.37; P < 0.05).

Conclusions: This study shows that bone mass and bone resorption rates do not differ between postmenopausal women with viral cirrhosis and healthy postmenopausal controls and suggests that viral cirrhosis does not appear to increase the risk of osteoporosis in these women. High serum estradiol and OPG concentrations may contribute to preventing the bone loss associated with viral cirrhosis in postmenopausal women.

High serum estradiol and osteoprotegerin concentrations may contribute to preventing the bone loss associated with viral cirrhosis in postmenopausal women.
Multifunctional Enhancers Regulate Mouse and Human Vitamin D Receptor Gene Transcription
Authors: Zella Lee A. , Meyer Mark B. , Nerenz Robert D. , Lee Seong Min , Martowicz Melissa L. , Pike J. Wesley
Published: November 2009

The vitamin D receptor (VDR) mediates the endocrine actions of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and autoregulates the expression of its own gene in target cells. In studies herein, we used chromatin immunoprecipitation-chip analyses to examine further the activities of 1,25(OH)2D3 and to assess the consequences of VDR/retinoid X receptor heterodimer binding at the VDR gene locus. We also explored mechanisms underlying the ability of retinoic acid, dexamethasone, and the protein kinase A activator forskolin to induce VDR up-regulation as well. We confirmed two previously identified intronic 1,25(OH)2D3-inducible enhancers and discovered two additional regions, one located 6 kb upstream of the VDR transcription start site. Although RNA polymerase II was present at the transcription start site in the absence of 1,25(OH)2D3, it was strikingly up-regulated at both this site and at individual enhancers in its presence. 1,25(OH)2D3 also increased basal levels of H4 acetylation at these enhancers as well. Surprisingly, many of these enhancers were targets for CCAAT enhancer-binding protein-β and runt-related transcription factor 2; a subset also bound cAMP response element binding protein, retinoic acid receptor, and glucocorticoid receptor. Unexpectedly, many of these factors were resident at the Vdr gene locus in the absence of inducer, suggesting that they might contribute to basal Vdr gene expression. Indeed, small interfering RNA down-regulation of CCAAT enhancer-binding protein-β suppressed basal VDR expression. These regulatory activities of 1,25(OH)2D3, forskolin, and dexamethasone were recapitulated in MC3T3-E1 cells stably transfected with a full-length VDR bacterial artificial chromosome (BAC) clone-luciferase reporter gene. Finally, 1,25(OH)2D3 also induced accumulation of VDR and up-regulated H4 acetylation at conserved regions in the human VDR gene. These data provide important new insights into VDR gene regulation in bone cells.
SCF, BDNF, and Gas6 Are Regulators of Growth Plate Chondrocyte Proliferation and Differentiation
Authors: Hutchison Michele R. , Bassett Mary H. , White Perrin C.
Published: November 2009

We previously demonstrated that bovine epiphyseal chondrocytes separated by density gradient centrifugation differ in proliferative response to IGF-I and IGF-I receptor number. To identify novel modifiers of IGF-I action at the growth plate, we used microarray analyses to compare bovine hypertrophic and reserve zones and identified several receptors differentially expressed across the growth plate: NTRK2 [receptor for brain-derived neurotrophic factor (BDNF)], KIT [receptor for stem cell factor (SCF)], and MER and AXL [two receptors for growth arrest-specific 6 (Gas6)]. The corresponding ligands were tested for their ability to stimulate either proliferation of isolated chondrocytes or differentiation in ATDC5 cells. Each factor inhibited IGF-I-mediated proliferation in isolated chondrocytes by attenuating ERK1/2 activation. SCF, BDNF, Gas6, and C-type natriuretic peptide promoted differentiation in ATDC5 cells, each factor producing different expression patterns for collagen X, collagen 2, aggrecan, and lysyl oxidase. Whereas multiple factors stimulated ATDC5 differentiation, only IGF-I and high-dose insulin, out of several factors implicated in chondrocyte maturation, stimulated proliferation of isolated chondrocytes. IGF-I appears to be the primary proliferative signal in growth plate chondrocytes, whereas multiple factors including SCF, BDNF, and Gas6 regulate the pace of differentiation at the growth plate.
Pricing Rule in a Clock Auction
Authors: Cramton Peter , Sujarittanonta Pacharasut
Published: November 2009

We analyze a discrete clock auction with lowest-accepted-bid (LAB) pricing and provisional winners, as adopted by India for its 3G spectrum auction. In a perfect Bayesian equilibrium, the provisional winner shades her bid, whereas provisional losers do not. Such differential shading leads to inefficiency. An auction with highest-rejected-bid (HRB) pricing and exit bids is strategically simple, has no bid shading, and is fully efficient. In addition, it has higher revenues than the LAB auction, assuming profit-maximizing bidders. The bid shading in the LAB auction exposes a bidder to the possibility of losing the auction at a price below the bidder's value. Thus, a fear of losing at profitable prices may cause bidders in the LAB auction to bid more aggressively than predicted, assuming profit-maximizing bidders. We extend the model by adding an anticipated loser's regret to the payoff function. Revenue from the LAB auction yields higher expected revenue than the HRB auction when bidders' fear of losing at profitable prices is sufficiently strong. This would provide one explanation why India, with an expressed objective of revenue maximization, adopted the LAB auction for its upcoming 3G spectrum auction, rather than the seemingly superior HRB auction.
A Quantitative Measurement of Regret Theory
Authors: Bleichrodt Han , Cillo Alessandra , Diecidue Enrico
Published: November 2009

This paper introduces a method to measure regret theory, a popular theory of decision under uncertainty. Regret theory allows for violations of transitivity, and it may seem paradoxical to quantitatively measure an intransitive theory. We adopt the trade-off method and show that it is robust to violations of transitivity. Our method makes no assumptions about the shape of the functions reflecting utility and regret. It can be performed at the individual level, taking account of preference heterogeneity. Our data support the main assumption of regret theory, that people are disproportionately averse to large regrets, even when event-splitting effects are controlled for. The findings are robust: similar results were obtained in two measurements using different stimuli. The data support the reliability of the trade-off method: its measurements could be replicated using different stimuli and were not susceptible to strategic responding.
Inventory Dynamics and Supply Chain Coordination
Authors: Krishnan Harish , Winter Ralph A.
Published: November 2009

This paper extends the theory of supply chain incentive contracts from the static newsvendor framework of the existing literature to the simplest dynamic setting. A manufacturer distributes a product through retailers who compete on both price and fill rates. We show that inventory durability is the key factor in determining the underlying nature of incentive distortions and their contractual resolutions. When the product is highly perishable, retailers are biased toward excessive price competition and inadequate inventories. Vertical price floors or inventory buybacks (subsidies for unsold inventory) can coordinate incentives in both pricing and inventory decisions. When the product is less perishable, the distortion is reversed and vertical price ceilings or inventory penalties can coordinate incentives.
Generalizability of career orientations: A comparative study in Switzerland and Great Britain
Authors: Gerber Marius , Wittekind Anette , Grote Gudela , Conway Neil , Guest David
Published: November 2009

This study examined the generalizability of types of career orientation. Exploratory latent class analyses were used to examine whether structurally the same career orientations can be found across a large sample of Swiss German (N=737), Swiss French (N=319), and British (N=1,002) employees. The finding showed that the generalizability of career orientations was not supported across the two countries and not even between the German‐ and French‐speaking parts of Switzerland. At least four career orientations were found in all samples. Country‐specific inspection of these four career orientations showed that they differed in terms of their combinations of specific components (boundaryless, protean, advancement, and time orientation). Mixtures of types of career orientations exist and make it difficult to identify fully the same type of career orientation across different cultural contexts. Explanations for differences in career orientation are discussed focusing on the cultural and economic context of Switzerland and Great Britain. Implications for organizational career management practices as well as theory of the career orientation concept are discussed.
Career transitions and their causes: A country‐comparative perspective
Authors: Chudzikowski Katharina , Demel Barbara , Mayrhofer Wolfgang , Briscoe Jon P. , Unite Julie , Bogićević Milikić Biljana , Hall Douglas T. (Tim) , Heras Mireia Las , Shen Yan , Zikic Jelena
Published: November 2009

This empirical paper investigates how individuals conceptualize causes of career transitions, focusing on the three European countries of Austria, Serbia, and Spain in comparison to the USA and China. Collectively, these countries represent four separate cultural regions according to Schwartz. Semi‐structured interviews were conducted with members of three occupational groups: business people, nurses, and blue‐collar workers. Analysis of the data generates greater insight about the existence of both region‐specific patterns as well as potentially universalistic tendencies regarding perceived causes of career transitions. Perceptions of internal (to the person) drivers of career transitions as activating forces are evident in all five countries. The overall results support contemporary notions of occupational careers that are highly individualized, a characterization strongly emphasized in the current career literature. In the European culture clusters, causes of career transitions are attributed internally and externally. China, representing the Confucian cultural region, stresses external causes for career transitions. By contrast, in the USA only internal attributions of causes are reported.
What is a Good Plan? Cultural Variations in Expert Planners'Concepts of Plan Quality
Authors: Rasmussen Louise J. , Sieck Winston R. , Smart Paul
Published: November 2009

This article presents the results of a field research study examining commonalities and differences between American and British operational planners' mental models of planning. We conducted cultural network analysis interviews with 14 experienced operational planners in the United States and the United Kingdom. Our results demonstrate the existence of fundamental differences between the ways American and British expert planners conceive of a high-quality plan. Our results revealed that the American planners' model focused on specification of action to achieve synchronization, providing little autonomy at the level of execution, and included the belief that increasing contingencies reduces risk. The British planners' model stressed the internal coherence of the plan to support shared situational awareness and thereby flexibility at the level of execution. The British model also emphasized the belief that reducing the number of assumptions decreases risk. Overall, the American ideal plan serves a controlling function, whereas the British ideal plan supports an enabling function. Interestingly, both the U.S. and UK planners viewed the other's ideal plan as riskier than their own. The implications of cultural models of plans and planning are described for establishing performance measures and designing systems to support multinational planning teams.
System Dynamics Modeling of the Time Course of the Recognition-Primed Decision Model
Authors: Patterson Robert , Fournier Lisa , Pierce Byron J. , Winterbottom Marc D. , Tripp Lisa M.
Published: November 2009

Two types of decision-making processes have been identified in the literature: an analytical process and an intuitive process. One conceptual model of the latter is the recognition-primed decision (RPD) model (e.g., Klein, 2008). According to this model, decision making in naturalistic contexts entails a situational pattern-recognition process that, if subsequent expectancies are confirmed, leads the decision maker to render a decision to engage in a given course of action. In this paper, we describe a system dynamics model of Klein's RPD framework that focuses upon the dynamics of the decision-making process. The structure of our RPD model is based on a model of a set of laboratory phenomena called conjunction benefits and costs (e.g., L. R. Fournier, Patterson, Dyre, Wiediger, & Winters, 2007), which was extended to encompass the RPD framework. The results of our simulations suggest that decision priming (a bias toward rendering a given decision based on prior information) is a phenomenon that should occur in many naturalistic settings.
Autosomal recessive familial neurohypophyseal diabetes insipidus: onset in early infancy
Authors: Abu Libdeh Abdulsalam , Levy-Khademi Floris , Abdulhadi-Atwan Maha , Bosin Emily , Korner Mira , White Perrin C , Zangen David H
Published: November 2009

Background

Familial neurohypophyseal diabetes insipidus (FNDI), usually an autosomal dominant disorder, is caused by mutations in the arginine vasopressin (AVP)–neurophysin II preprohormone leading to aberrant preprohormone processing and gradual destruction of AVP-secreting cells. Patients typically present between 1 and 6 years of age with polyuria and polydipsia.

Objective

Clinical, biochemical, and genetic studies of three new cases of autosomal recessive FNDI presenting in early infancy.

Patients

Three Palestinian cousins presented with failure to thrive, vomiting, irritability, and fever. The parents were asymptomatic. Patients developed hypernatremia (154–163 mmol/l) and serum hyperosmolality (>320 mOsm/kg), while urine osmolality remained between 73 and 229 mOsm/kg. Plasma AVP levels were low, and the posterior pituitary bright spot was absent on magnetic resonance imaging (MRI). All patients responded to desmopressin.

Results

Patients were homozygous and parents were heterozygous for microsatellite markers flanking the AVP gene. All patients were homozygous for the P26L (proline to leucine) substitution affecting mature AVP. A founder effect with the single original kindred carrying the P26L mutation was confirmed by microsatellite analysis, but patients in that family presented only at 2 years of age. In microsatellite analysis, the new kindred patients were not homozygous and did not share a single allele at the aquaporin 2 and vasopressin receptor-2 genes locuses.

Conclusion

This is the first description of autosomal recessive FNDI presenting in the neonatal period. The unusual early clinical and radiological (MRI) presentation argues against gradual destruction of AVP-secreting neurons as the pathophysiological mechanism. Factors beside allelism of AVP-related genes must influence the age of FNDI presentation given the founder effect demonstrated for the P26L mutation.
Serum glucose and insulin are associated with QTc and RR intervals in nondiabetic elderly
Authors: van Noord Charlotte , Sturkenboom Miriam C J M , Straus Sabine M J M , Hofman Albert , Kors Jan A , Witteman Jacqueline C M , Stricker Bruno H Ch
Published: November 2009

Aims

To study whether nondiabetic persons with impaired fasting serum glucose and hyperinsulinemia have QTc/QT interval prolongation and RR interval shortening in the electrocardiogram (ECG), and whether these were associated with an increased risk of sudden cardiac death.

Methods

This study consisted of two analyses. First, a cross-sectional analysis was used as part of the population-based Rotterdam Study including 1050 men and 1520 women (≥55 years) without diabetes mellitus. Participants in round 3 of the Rotterdam Study for whom an ECG and fasting serum glucose and fasting insulin measurements were available were eligible for the study. Participants using digoxin or QTc-prolonging drugs and participants with left ventricular hypertrophy and left and right bundle branch block were excluded. The endpoints of the study were the lengths of the QTc, QT, and RR intervals. The associations were examined by means of linear regression analysis. Secondly, in all 6020 participants of the Rotterdam Study with an ECG, the associations between the QTc, QT, and RR intervals and sudden cardiac death were examined by means of Cox regression analysis.

Results

Overall, there was a significant association between impaired fasting serum glucose and the QTc interval with an increase of 2.6 ms (95% confidence interval (CI): 0.3; 5.0) in those with fasting glucose >6 mmol/l. Hyperinsulinemia was also associated with QTc prolongation (3.0 ms (0.8; 5.3)) in those with fasting insulin ≥100 pmol/l. Impaired fasting glucose (IFG) and hyperinsulinemia were significantly associated with a decrease of the RR interval (−33.7 ms (−48.8; −18.6) and −44.4 ms (−58.7; −30.0) respectively). Participants in the fourth quartile of the QTc and QT intervals had a significantly increased risk of sudden cardiac death compared to participants in the first quartile (hazard ratio (HR) 2.87 (95% CI: 2.02–4.06); HR 3.05 (1.99–4.67) respectively). Furthermore, there was a significant inverse association between the fourth quartile of the RR interval compared to the first quartile and the risk of sudden cardiac death (HR 0.49 (0.34–0.80)).

Conclusion

In this population-based study, we demonstrated that IFG and hyperinsulinemia are associated with a significantly increased QTc interval and with significant shortening of the RR interval, the latter probably due to an increased sympathetic activity. In addition, we demonstrated that both a prolonged QTc interval and a shortened RR interval are associated with an increased risk of sudden cardiac death.
Excision of an Active CACTA-Like Transposable Element From DFR2 Causes Variegated Flowers in Soybean [Glycine max (L.) Merr.]
Authors: Xu Min , Brar Hargeet K , Grosic Sehiza , Palmer Reid G , Bhattacharyya Madan K
Published: November 2009

Active endogenous transposable elements, useful tools for gene isolation, have not been reported from any legume species. An active transposable element was suggested to reside in the W4 locus that governs flower color in soybean. Through biochemical and molecular analyses of several revertants of the w4-m allele, we have shown that the W4 locus encodes dihydroflavonol-4-reductase 2 (DFR2). w4-m has arisen through insertion of Tgm9, a 20,548-bp CACTA-like transposable element, into the second intron of DFR2. Tgm9 showed high nucleic acid sequence identity to Tgmt*. Its 5′ and 3′ terminal inverted repeats start with conserved CACTA sequence. The 3′ subterminal region is highly repetitive. Tgm9 carries TNP1- and TNP2-like transposase genes that are expressed in the mutable line, T322 (w4-m). The element excises at a high frequency from both somatic and germinal tissues. Following excision, reinsertions of Tgm9 into the DFR2 promoter generated novel stable alleles, w4-dp (dilute purple flowers) and w4-p (pale flowers). We hypothesize that the element is fractured during transposition, and truncated versions of the element in new insertion sites cause stable mutations. The highly active endogenous transposon, Tgm9, should facilitate genomics studies specifically that relate to legume biology.
Recurrent Selection on the Winters sex-ratio Genes in Drosophila simulans
Authors: Kingan Sarah B , Garrigan Daniel , Hartl Daniel L
Published: November 2009

Selfish genes, such as meiotic drive elements, propagate themselves through a population without increasing the fitness of host organisms. X-linked (or Y-linked) meiotic drive elements reduce the transmission of the Y (X) chromosome and skew progeny and population sex ratios, leading to intense conflict among genomic compartments. Drosophila simulans is unusual in having a least three distinct systems of X chromosome meiotic drive. Here, we characterize naturally occurring genetic variation at the Winters sex-ratio driver (Distorter on the X or Dox), its progenitor gene (Mother of Dox or MDox), and its suppressor gene (Not Much Yang or Nmy), which have been previously mapped and characterized. We survey three North American populations as well as 13 globally distributed strains and present molecular polymorphism data at the three loci. We find that all three genes show signatures of selection in North America, judging from levels of polymorphism and skews in the site-frequency spectrum. These signatures likely result from the biased transmission of the driver and selection on the suppressor for the maintenance of equal sex ratios. Coalescent modeling indicates that the timing of selection is more recent than the age of the alleles, suggesting that the driver and suppressor are coevolving under an evolutionary “arms race.” None of the Winters sex-ratio genes are fixed in D. simulans, and at all loci we find ancestral alleles, which lack the gene insertions and exhibit high levels of nucleotide polymorphism compared to the derived alleles. In addition, we find several “null” alleles that have mutations on the derived Dox background, which result in loss of drive function. We discuss the possible causes of the maintenance of presence–absence polymorphism in the Winters sex-ratio genes.
Healing of Euchromatic Chromosome Breaks by Efficient de novo Telomere Addition in Drosophila melanogaster
Authors: Titen Simon W A , Golic Kent G
Published: November 2009

Previously, we observed that heterochromatic 4 and Y chromosomes that had experienced breakage in the male germline were frequently transmitted to progeny. Their behavior suggested that they carried functional telomeres. Here we show that efficient healing by de novo telomere addition is not unique to heterochromatic breaks.
Expression of the claudin-4 molecule in benign and malignant canine hepatoid gland tumours
Authors: Jakab Csaba , Rusvai Miklós , Szabó Zoltán , Szabára Ágnes , Kulka Janina
Published: November 2009

Claudins are integral membrane proteins of the tight junction structures expressed by epithelial and endothelial cells. The present study has evaluated the expression of claudin-4 in 10 normal canine hepatoid glands and in 67 hepatoid glands with hyperplastic and neoplastic lesions. The lesions studied included normal hepatoid glands (n = 10), nodular hyperplasias (n = 10), adenomas (n = 12), epitheliomas (n = 15), differentiated carcinomas (n = 15) and anaplastic carcinomas (n = 15). There was an intensive expression of claudin-4 in normal canine hepatoid glands as well as in hyperplasias and adenomas. Claudin-4 was detected as a well-localised linear circumferential membranous staining pattern of epithelial cells (mature hepatoid cells) in normal hepatoid glands, perianal gland hyperplasias and adenomas. In nodular hyperplasia and adenoma, the reserve cells showed membrane positivity for the claudin-4 molecule. There was a weaker expression in hepatoid gland epitheliomas. In the epitheliomas, the basaloid reserve cells never expressed the claudin-4 molecule. The multiple small parts of epitheliomas in which the cells exhibited typical hepatoid features showed a well-localised linear circumferential membranous staining pattern for claudin-4. The numerical score for cellular expression of claudin-4 was higher in differentiated carcinomas than in epitheliomas, but moderately lower than in adenomas. The anaplastic, poorly differentiated hepatoid gland carcinomas showed an overexpression of claudin-4. These results suggest that low claudin-4 expression in epitheliomas is a molecular characteristic indicative of increasing cellular disorientation, detachment motility and invasion by tumour cells, and claudin-4 seems to be helpful in distinguishing undifferentiated carcinomas from differentiated carcinomas and epitheliomas of the hepatoid gland. In addition, claudin-4 can help distinguish epithelioma from differentiated carcinoma of the canine hepatoid gland.