bluuebunny/crossref_metadata_2025 huggingface dataset:
From the Billboard to the School Board
Authors: Campbell Christine , DeArmond Michael
Published: November 2011

This case covers the period 1993 to 2003. It tells the story of the challenges the Fort Worth Independent School District board faced when the state accountability system revealed extremely poor student achievement and a stark achievement gap. To address the problem, the board hired a dynamic superintendent, Dr. Tom Tocco, who initiated aggressive instructional changes, particularly around reading instruction. Throughout this time, Tocco worked closely with Gary Manny, longtime president of the school board, to maintain district and community support. Manny’s death in March 2002 led to internal board turmoil and questions about the role of the board president and how board leadership should be selected.
Collective leadership with power symmetry: Lessons from Aboriginal prehistory
Authors: Sveiby Karl-Erik
Published: November 2011

This article draws upon Australian Aboriginal knowledge in traditional law stories and anthropological studies of contemporary African bands. It applies the DAC ontology ( Drath et al., 2008 ) to analyse two collective leadership models developed by forager peoples: one egalitarian ‘upside-down hierarchy’ and one power-symmetric model. Their existence has several implications for leadership research. Firstly, it encourages shared/distributed leadership scholars to shift their current reactive stage toward building theory of collective leadership on its own terms. This may require exploration of alternatives outside the mainstream both in terms of ontology and cases, and this article attempts to show the value in doing so. Secondly, it highlights the importance of power; the concept needs to be considered more explicitly in collective leadership theory. Finally, it shows that collective leadership is not a recent phenomenon confined to modern organizations – but rather a form for achieving conjoint action in human groups, developed by the first peoples on Earth, and still practised.
Targeting the insulin-like growth factor receptor pathway in lung cancer: problems and pitfalls
Authors: Fidler Mary Jo , Shersher David D. , Borgia Jeffrey A. , Bonomi Philip
Published: November 2011

The insulin-like growth factor (IGF) pathway is a complex pathway involving interactions between membrane-bound receptors, ligands, binding proteins, downstream effectors, and other receptor tyrosine kinase signaling cascades. The IGF pathway has been identified as a potential therapeutic target in non-small cell lung cancer (NSCLC) based on the following provocative factors. Preclinical observations in NSCLC have shown that this pathway is involved in tumor cell proliferation, survival, and invasiveness. In addition, IGF-1R protein expression is found in a significant number of non-small cell tumor specimens. Initial therapeutic efforts involved the development of monoclonal antibodies and tyrosine kinase inhibitors that target IGF-1R, a transmembrane receptor tyrosine kinase. Enthusiasm for targeting this pathway increased when a randomized phase II study showed that combining an anti-IGF-1R monoclonal antibody (figitumumab) with a platinum doublet resulted in a higher response rate and trends for superior progression-free survival and overall survival. Subsequently, a phase III study failed to confirm the promising results observed in the phase II trial. Currently, investigators are studying different monoclonal antibodies and tyrosine kinases targeting IGF-1R. In unselected patients, results presented thus far do not suggest efficacy of this agent. However, retrospective subgroup analyses suggest that circulating IGF-1 levels might identify patients who could benefit from treatment with an IGF-1R monoclonal antibody and may warrant further exploratory studies for predictive molecular markers. The purpose of this paper is to briefly discuss the IGF pathway and its relationship with other signaling pathways in lung cancer and to review the ongoing IGF clinical trials and efforts to identify predictive molecular markers.
Topologies of practice
Authors: Coleman Mat
Published: November 2011

Allen’s (2011) provocative argument on the difference between topographic and topologic ontologies in human geography offers human geographers an important opportunity to re-engage with other similarly spirited arguments about the limitations of the topographic. For example, debate over Marston et al.’s (2005) argument for a ‘site ontology’ has tended to sidestep the question of topological space and has instead dwelled on whether or not their representation of human geography research on scale is accurate. However, if Allen’s research gives human geographers another opportunity to take up the question of sociospatial practice as contingent, site-specific, and self-structuring, it also poses at least two problems. On the one hand, Allen characterizes the topographic and topologic according to a too neat calendar of sociospatial relations. On the other hand, Allen overlooks a long-standing appreciation for the topologic in human geography by drawing a strong distinction between past and newer intellectual approaches to power and space.
Blocking IL-21 signaling ameliorates xenogeneic GVHD induced by human lymphocytes
Authors: Hippen Keli L. , Bucher Christoph , Schirm Dawn K. , Bearl Amanda M. , Brender Ty , Mink Kathy A. , Waggie Kimberly S. , Peffault de Latour Regis , Janin Anne , Curtsinger Julie M. , Dillon Stacey R. , Miller Jeffrey S. , Socie Gerard , Blazar Bruce R.
Published: November 2011

In rodent graft-versus-host disease (GVHD) models, anti–IL-21 neutralizing mAb treatment ameliorates lethality and is associated with decreases in Th1 cytokine production and gastrointestinal tract injury. GVHD prevention was dependent on the in vivo generation of donor-inducible regulatory T cells (Tregs). To determine whether the IL-21 pathway might be targeted for GVHD prevention, skin and colon samples obtained from patients with no GVHD or grade 2 to 4 GVHD were analyzed for IL-21 protein expression. By immunohistochemistry staining, IL-21 protein-producing cells were present in all gastrointestinal tract samples and 54% of skin samples obtained from GVHD patients but not GVHD-free controls. In a human xenogeneic GVHD model, human IL-21–secreting cells were present in the colon of GVHD recipients and were associated with elevated serum IL-21 levels. A neutralizing anti–human IL-21 mAb given prophylactically significantly reduced GVHD-associated weight loss and mortality, resulting in a concomitant increase in Tregs and a decrease in T cells secreting IFN-γ or granzyme B. Based on these findings, anti–IL-21 mAb could be considered for GVHD prevention in the clinic.
Bronchoscopic thermal vapour ablation therapy in the management of heterogeneous emphysema
Authors: Snell Gregory , Herth Felix J.F. , Hopkins Peter , Baker Kimberley M. , Witt Christian , Gotfried Mark H. , Valipour Arschang , Wagner Manfred , Stanzel Franz , Egan Jim J. , Kesten Steven , Ernst Armin
Published: November 2011

The need for a less invasive procedure than surgical lung volume reduction that can produce consistent improvements with reduced morbidity remains a medical goal in patients with emphysema. We sought to determine the effect of bronchoscopic thermal vapour ablation (BTVA) on lung volumes and outcomes in patients with emphysema.

44 patients with upper lobe-predominant emphysema were treated unilaterally with BTVA. Entry criteria included: age 40–75 yrs, forced expiratory volume in 1 s (FEV1) 15–45% predicted, previous pulmonary rehabilitation and a heterogeneity index (tissue/air ratio of lower lobe/upper lobe) from high-resolution computed tomography (HRCT) ≥1.2. Changes in FEV1, St George's Respiratory Questionnaire (SGRQ), 6-min walk distance (6MWD), modified Medical Research Council (mMRC) dyspnoea score, and hyperinflation were measured at baseline, and 3 and 6 months post-BTVA.

At 6 months, mean±seFEV1improved by 141±26 mL (p<0.001) and residual volume was reduced by 406±113 mL (p<0.0001). SGRQ total score improved by 14.0±2.4 points (p<0.001), with 73% improving by ≥4 points. Improvements were observed in 6MWD (46.5±10.6 m) and mMRC dyspnoea score (0.9±0.2) (p<0.001 for both). Lower respiratory events (n=11) were the most common adverse event and occurred most often during the initial 30 days.

BTVA therapy results in clinically relevant improvements in lung function, quality of life and exercise tolerance in upper lobe predominant emphysema.
Clonality of multifocal nonsmall cell lung cancer: implications for staging and therapy
Authors: Warth Arne , Macher-Goeppinger Stephan , Muley Thomas , Thomas Michael , Hoffmann Hans , Schnabel Philipp A. , Penzel Roland , Schirmacher Peter , Aulmann Sebastian
Published: November 2011

Nonsmall cell lung cancers (NSCLCs) display a variety of morphological and molecular features. Accurate subtyping of NSCLC has been shown to predict patient survival as well as response rates and toxicities of specific drugs. Assessment of multifocal lung tumours and the distinction of synchronous primary tumours from intrapulmonary metastases represent an important problem as this decision significantly influences tumour staging and subsequent treatment strategies.

In order to provide a basis for evidence-based treatment decisions in these patients, we analysed the clonal relationship of multifocal NSCLC with indistinguishable histomorphology in a series of 78 patients by allelotyping (using polymorphic short tandem repeat markers) as well asKRASand epidermal growth factor receptor (EGFR) mutation testing.

Our data demonstrate a common clonal origin indicative of intrapulmonary metastases in almost two-thirds (∼62%) of the cases, while ∼36% of multifocal NSCLC displayed unique molecular profiles suggesting separate primary tumours. DivergentKRASand/orEGFRmutations were observed in ∼8% of all cases.

With the increased availability of EGFR-targeted therapy options, nonresectable, multifocal NSCLC with divergingKRASand/orEGFRmutations are likely to show different treatment responses, underlining the need to separately analyse multifocal tumours. Obviously, this also holds true for further, novel molecular predictors of targeted therapies.
Do adjunct tuberculosis tests, when combined with Xpert MTB/RIF, improve accuracy and the cost of diagnosis in a resource-poor setting?
Authors: Theron Grant , Pooran Anil , Peter Jonny , van Zyl-Smit Richard , Kumar Mishra Hridesh , Meldau Richard , Calligaro Greg , Allwood Brian , Sharma Surendra Kumar , Dawson Rod , Dheda Keertan
Published: November 2011

Information regarding the utility of adjunct diagnostic tests in combination with Xpert MTB/RIF (Cepheid, Sunnyvale, CA, USA) is limited. We hypothesised adjunct tests could enhance accuracy and/or reduce the cost of tuberculosis (TB) diagnosis prior to MTB/RIF testing, and rule-in or rule-out TB in MTB/RIF-negative individuals.

We assessed the accuracy and/or laboratory-associated cost of diagnosis of smear microscopy, chest radiography (CXR) and interferon-γ release assays (IGRAs; T-SPOT-TB (Oxford Immunotec, Oxford, UK) and QuantiFERON-TB Gold In-Tube (Cellestis, Chadstone, Australia)) combined with MTB/RIF for TB in 480 patients in South Africa.

When conducted prior to MTB/RIF: 1) smear microscopy followed by MTB/RIF (if smear negative) had the lowest cost of diagnosis of any strategy investigated; 2) a combination of smear microscopy, CXR (if smear negative) and MTB/RIF (if imaging compatible with active TB) did not further reduce the cost per TB case diagnosed; and 3) a normal CXR ruled out TB in 18% of patients (57 out of 324; negative predictive value (NPV) 100%). When downstream adjunct tests were applied to MTB/RIF-negative individuals, radiology ruled out TB in 24% (56 out of 234; NPV 100%), smear microscopy ruled in TB in 21% (seven out of 24) of culture-positive individuals and IGRAs were not useful in either context.

In resource-poor settings, smear microscopy combined with MTB/RIF had the highest accuracy and lowest cost of diagnosis compared to either technique alone. In MTB/RIF-negative individuals, CXR has poor rule-in value but can reliably rule out TB in approximately one in four cases. These data inform upon the programmatic utility of MTB/RIF in high-burden settings.
Characterization of the genome of bald cypress
Authors: Liu Wenxuan , Thummasuwan Supaphan , Sehgal Sunish K , Chouvarine Philippe , Peterson Daniel G
Published: November 2011

Background

Bald cypress (Taxodium distichum var. distichum) is a coniferous tree of tremendous ecological and economic importance. It is a member of the family Cupressaceae which also includes cypresses, redwoods, sequoias, thujas, and junipers. While the bald cypress genome is more than three times the size of the human genome, its 1C DNA content is amongst the smallest of any conifer. To learn more about the genome of bald cypress and gain insight into the evolution of Cupressaceae genomes, we performed a Cot analysis and used Cot filtration to study Taxodium DNA. Additionally, we constructed a 6.7 genome-equivalent BAC library that we screened with known Taxodium genes and select repeats.

Results

The bald cypress genome is composed of 90% repetitive DNA with most sequences being found in low to mid copy numbers. The most abundant repeats are found in fewer than 25,000 copies per genome. Approximately 7.4% of the genome is single/low-copy DNA (i.e., sequences found in 1 to 5 copies). Sequencing of highly repetitive Cot clones indicates that most Taxodium repeats are highly diverged from previously characterized plant repeat sequences. The bald cypress BAC library consists of 606,336 clones (average insert size of 113 kb) and collectively provides 6.7-fold genome equivalent coverage of the bald cypress genome. Macroarray screening with known genes produced, on average, about 1.5 positive clones per probe per genome-equivalent. Library screening with Cot-1 DNA revealed that approximately 83% of BAC clones contain repetitive sequences iterated 103 to 104 times per genome.

Conclusions

The BAC library for bald cypress is the first to be generated for a conifer species outside of the family Pinaceae. The Taxodium BAC library was shown to be useful in gene isolation and genome characterization and should be an important tool in gymnosperm comparative genomics, physical mapping, genome sequencing, and gene/polymorphism discovery. The single/low-copy (SL) component of bald cypress is 4.6 times the size of the Arabidopsis genome. As suggested for other gymnosperms, the large amount of SL DNA in Taxodium is likely the result of divergence among ancient repeat copies and gene/pseudogene duplication.
Preventing preterm birth with progesterone: costs and effects of screening low risk women with a singleton pregnancy for short cervical length, the Triple P study
Authors: van Os Melanie A , van der Ven Jeanine A , Kleinrouweler C Emily , Pajkrt Eva , de Miranda Esteriek , van Wassenaer Aleid , Porath Martina , Bossuyt Patrick M , Bloemenkamp Kitty WM , Willekes Christine , Woiski Mallory , Oudijk Martijn A , Bilardo Katia M , Sikkema Marko J , Duvekot Johannes J , Veersema Diederik , Laudy Jacqueline , Kuiper Petra , de Groot Christianne JM , Mol Ben Willem J , Haak Monique C
Published: November 2011

Background

Women with a short cervical length in mid-trimester pregnancy have a higher risk of preterm birth and therefore a higher rate of neonatal mortality and morbidity. Progesterone can potentially decrease the number of preterm births and lower neonatal mortality and morbidity. Previous studies showed good results of progesterone in women with either a history of preterm birth or a short cervix. However, it is unknown whether screening for a short cervix and subsequent treatment in mid trimester pregnancy is effective in low risk women.

Methods/Design

We plan a combined screen and treat study among women with a singleton pregnancy without a previous preterm birth. In these women, we will measure cervical length at the standard anomaly scan performed between 18 and 22 weeks. Women with cervical length ≤ 30 mm at two independent measurements will be randomly allocated to receive either vaginal progesterone tablets or placebo between 22 and 34 weeks. The primary outcome of this trial is adverse neonatal condition, defined as a composite outcome of neonatal mortality and severe morbidity. Secondary outcomes are time to delivery, preterm birth rate before 32, 34 and 37 weeks, days of admission in neonatal intensive care unit, maternal morbidity, maternal admission days for preterm labour and costs. We will assess growth, physical condition and neurodevelopmental outcome of the children at two years of age.

Discussion

This study will provide evidence for the usefulness and cost-effectiveness of screening for short cervical length at the 18-22 weeks and subsequent progesterone treatment among low risk women.

Trial registration

Netherlands Trial Register (NTR): NTR207
Hepatitis B virus core promoter mutations G1613A and C1653T are significantly associated with hepatocellular carcinoma in genotype C HBV-infected patients
Authors: Tatsukawa Masashi , Takaki Akinobu , Shiraha Hidenori , Koike Kazuko , Iwasaki Yoshiaki , Kobashi Haruhiko , Fujioka Shin-Ichi , Sakaguchi Kohsaku , Yamamoto Kazuhide
Published: November 2011

Background

Hepatitis B virus (HBV) is a major cause of hepatocarcinogenesis.

To identify mutations relevant to hepatocellular carcinoma (HCC) development, we compared the full genome sequences of HBV from the sera of patients with and without HCC.

Methods

We compared the full genome sequences of HBV isolates from 37 HCC patients (HCC group 1) and 38 patients without HCC (non-HCC group 1). We also investigated part of the core promoter region sequences from 40 HCC patients (HCC group 2) and 68 patients without HCC. Of the 68 patients who initially did not have HCC, 52 patients remained HCC-free during the follow-up period (non-HCC group 2), and 16 patients eventually developed HCC (pre-HCC group 2). Serum samples collected from patients were subjected to PCR, and the HBV DNA was directly sequenced.

Results

All patients had genotype C. A comparison of the nucleotide sequences of the HBV genome between HCC group 1 and non-HCC group 1 revealed that the prevalence of G1613A and C1653T mutations in the core promoter region was significantly higher in the HCC group. These mutations tended to occur simultaneously in HCC patients. Multivariate analysis with group 2 revealed that the presence of HCC was associated with aging and the double mutation. Future emergence of HCC was associated with aging and the presence of a single G1613A mutation.

Conclusions

G1613A and C1653T double mutations were frequently found in patients with HCC. A single G1613A mutation was associated with future emergence of HCC. These mutations may serve as useful markers in predicting HCC development.
Can the FAST and ROSIER adult stroke recognition tools be applied to confirmed childhood arterial ischemic stroke?
Authors: Yock-Corrales Adriana , Babl Franz E , Mosley Ian T , Mackay Mark T
Published: November 2011

Background

Stroke recognition tools have been shown to improve diagnostic accuracy in adults. Development of a similar tool in children is needed to reduce lag time to diagnosis. A critical first step is to determine whether adult stoke scales can be applied in childhood stroke.

Our objective was to assess the applicability of adult stroke scales in childhood arterial ischemic stroke (AIS)

Methods

Children aged 1 month to < 18 years with radiologically confirmed acute AIS who presented to a tertiary emergency department (ED) (2003 to 2008) were identified retrospectively. Signs, symptoms, risk factors and initial management were extracted. Two adult stroke recognition tools; ROSIER (Recognition of Stroke in the Emergency Room) and FAST (Face Arm Speech Test) scales were applied retrospectively to all patients to determine test sensitivity.

Results

47 children with AIS were identified. 34 had anterior, 12 had posterior and 1 child had anterior and posterior circulation infarcts. Median age was 9 years and 51% were male. Median time from symptom onset to ED presentation was 21 hours but one third of children presented within 6 hours. The most common presenting stroke symptoms were arm (63%), face (62%), leg weakness (57%), speech disturbance (46%) and headache (46%). The most common signs were arm (61%), face (70%) or leg weakness (57%) and dysarthria (34%). 36 (78%) of children had at least one positive variable on FAST and 38 (81%) had a positive score of ≥1 on the ROSIER scale. Positive scores were less likely in children with posterior circulation stroke.

Conclusion

The presenting features of pediatric stroke appear similar to adult strokes. Two adult stroke recognition tools have fair to good sensitivity in radiologically confirmed childhood AIS but require further development and modification. Specificity of the tools also needs to be determined in a prospective cohort of children with stroke and non-stroke brain attacks.
What stops children with a chronic illness accessing health care: a mixed methods study in children with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME)
Authors: Webb Carly M , Collin Simon M , Deave Toity , Haig-Ferguson Andrew , Spatz Amy , Crawley Esther
Published: November 2011

Background

Paediatric Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is relatively common and disabling with a mean time out of school of more than one academic year. NICE guidelines recommend referral to specialist services immediately if severely affected, within 3 months if moderately affected and within 6 months if mildly affected. However, the median time-to-assessment by a specialist service in the UK is 18 months. This study used a mixed-methods approach to examine factors associated with time taken to access specialist services.

Methods

Time-to-assessment was analysed as a continuous "survival-time" variable in Cox regression models using data from self-completed assessment forms for children attending a regional specialist CFS/ME service between January 2006 and December 2009. Semi-structured interviews about barriers experienced in accessing healthcare for their child were conducted with nine parents of children aged < 17 years (8 individual and one parent couple). Interviews were digitally recorded and analysed using "thematic analysis".

Results

405 children were assessed between 2006 and 2009 and information on school attendance was available on 388. Only 1/125 with severe CFS/ME and 49/263 (19%) with mild to moderate CFS/ME were seen within NICE recommended timeframe. Increased fatigue was associated with shorter time to assessment (HR = 1.15; 95% CI 1.03, 1.29 per unit increase in Chalder fatigue score; P = 0.01). Time-to-assessment was not associated with disability, mood, age or gender. Parents described difficulties accessing specialist services because of their own as well as their GP's and Paediatrician's lack of knowledge. They experienced negative attitudes and beliefs towards the child's condition when they consulted GPs, Paediatricians and Child Psychiatrists. Parents struggled to communicate an invisible illness that their child and not themselves were experiencing.

Conclusions

GPs, Child Psychiatrists and Paediatricians need more knowledge about CFS/ME and the appropriate referral pathways to ensure timeliness in referral to specialist services.
Papillomavirus E5: the smallest oncoprotein with many functions
Authors: Venuti Aldo , Paolini Francesca , Nasir Lubna , Corteggio Annunziata , Roperto Sante , Campo Maria S , Borzacchiello Giuseppe
Published: November 2011

Papillomaviruses (PVs) are established agents of human and animal cancers. They infect cutaneous and mucous epithelia. High Risk (HR) Human PVs (HPVs) are consistently associated with cancer of the uterine cervix, but are also involved in the etiopathogenesis of other cancer types. The early oncoproteins of PVs: E5, E6 and E7 are known to contribute to tumour progression. While the oncogenic activities of E6 and E7 are well characterised, the role of E5 is still rather nebulous. The widespread causal association of PVs with cancer makes their study worthwhile not only in humans but also in animal model systems. The Bovine PV (BPV) system has been the most useful animal model in understanding the oncogenic potential of PVs due to the pivotal role of its E5 oncoprotein in cell transformation. This review will highlight the differences between HPV-16 E5 (16E5) and E5 from other PVs, primarily from BPV. It will discuss the targeting of E5 as a possible therapeutic agent.
Combination therapy of renal cell carcinoma or breast cancer patients with dendritic cell vaccine and IL-2: results from a phase I/II trial
Authors: Baek Soyoung , Kim Choung-Soo , Kim Sung-Bae , Kim Yong-man , Kwon Seog-Woon , Kim YongMan , Kim HyunSoo , Lee Hyunah
Published: November 2011

Background

Ten cancer patients (Six renal cell carcinoma and four breast cancer patients) were treated in a phase I/II study with a vaccine composed of autologous dendritic cells (DCs) and IL-2 to evaluate the DC vaccine-related toxicity and antigen-specific immune alteration.

Methods

Cancer patients were treated twice with autologous CD34+ hematopoietic stem cell-derived, GM-CSF/IFN-γ-differentiated DCs pulsed with autologous tumor lysate and KLH, by 4-week interval. Following each subcutaneous injection of therapeutic DCs, low-dose (200 MIU) IL-2 was introduced for 14 consecutive days as an immune adjuvant. To determine the DC vaccine-induced immunological alterations, the KLH-specific lymphocyte proliferation, number of IFN-γ secreting T cells (ELISPOT assay), NK activity and the cytokine modulation were measured.

Results

Cultured-DCs expressing HLA-DR, CD11c, CD83, and B7.1/B7.2 produced IL-12p70. After vaccination, the patients tolerated it. Clinical response was observed in one RCC patient as stable disease. However DC-vaccine related antigen-specific immune responses including peripheral blood lymphocyte proliferation and the number of IFN-r secreting cells were induced in six patients without clear correlation with clinical responses. Also NK activity was induced significantly in six patients after vaccination. DC vaccine-related decrease of TGF-β level or increase of IL-12p70 level and decline of CD4+CD25+ T cells were observed in three patients. However only in the RCC patient whose disease stabilized, combination of stimulatory as well as inhibitory immune alterations including induction of IFN-γ secreting T cell with reduction of CD4+ CD25+ T cell were correlated with clinical responses.

Conclusion

Data indicated that DC vaccine combined with IL-2 is well tolerated without major side effects. DC vaccine induced the specific immunity against introduced antigen. Combinatorial alterations of immunological parameters indicating antigen-specific immune induction along with reduction of inhibitory immunity were correlated with clinical responses in DC vaccine treated patients.
Rheological non-Newtonian behaviour of ethylene glycol-based Fe2O3 nanofluids
Authors: Pastoriza-Gallego María Jose , Lugo Luis , Legido José Luis , Piñeiro Manuel M
Published: November 2011

The rheological behaviour of ethylene glycol-based nanofluids containing hexagonal scalenohedral-shaped α-Fe2O3 (hematite) nanoparticles at 303.15 K and particle weight concentrations up to 25% has been carried out using a cone-plate Physica MCR rheometer. The tests performed show that the studied nanofluids present non-Newtonian shear-thinning behaviour. In addition, the viscosity at a given shear rate is time dependent, i.e. the fluid is thixotropic. Finally, using strain sweep and frequency sweep tests, the storage modulus G', loss modulus G″ and damping factor were determined as a function of the frequency showing viscoelastic behaviour for all samples.
Contrasting macrophage activation by fine and ultrafine titanium dioxide particles is associated with different uptake mechanisms
Authors: Scherbart Agnes M , Langer Julia , Bushmelev Alexey , van Berlo Damiёn , Haberzettl Petra , van Schooten Frederik-Jan , Schmidt Annette M , Rose Christine R , Schins Roel PF , Albrecht Catrin
Published: November 2011

Inhalation of (nano)particles may lead to pulmonary inflammation. However, the precise mechanisms of particle uptake and generation of inflammatory mediators by alveolar macrophages (AM) are still poorly understood. The aim of this study was to investigate the interactions between particles and AM and their associated pro-inflammatory effects in relation to particle size and physico-chemical properties.

NR8383 rat lung AM were treated with ultrafine (uf), fine (f) TiO2or fine crystalline silica (DQ12 quartz). Physico-chemical particle properties were investigated by transmission electron microscopy, elemental analysis and thermogravimetry. Aggregation and agglomeration tendency of the particles were determined in assay-specific suspensions by means of dynamic light scattering.

All three particle types were rapidly taken up by AM. DQ12 and ufTiO2, but not fTiO2, caused increased extracellular reactive oxygen species (ROS), heme oxygenase 1 (HO-1) mRNA expression and tumor necrosis factor (TNF)-α release. Inducible nitric oxide synthase (iNOS) mRNA expression was increased most strongly by ufTiO2, while DQ12 exclusively triggered interleukin (IL) 1β release. However, oscillations of intracellular calcium concentration and increased intracellular ROS were observed with all three samples. Uptake inhibition experiments with cytochalasin D, chlorpromazine and a Fcγ receptor II (FcγRII) antibody revealed that the endocytosis of fTiO2by the macrophages involves actin-dependent phagocytosis and macropinocytosis as well as clathrin-coated pit formation, whereas the uptake of ufTiO2was dominated by FcγIIR. The uptake of DQ12 was found to be significantly reduced by all three inhibitors. Our findings suggest that the contrasting AM responses to fTiO2, ufTiO2and DQ12 relate to differences in the involvement of specific uptake mechanisms.
Basal progenitor cells in the embryonic mouse thalamus - their molecular characterization and the role of neurogenins and Pax6
Authors: Wang Lynn , Bluske Krista K , Dickel Lauren K , Nakagawa Yasushi
Published: November 2011

Background

The size and cell number of each brain region are influenced by the organization and behavior of neural progenitor cells during embryonic development. Recent studies on developing neocortex have revealed the presence of neural progenitor cells that divide away from the ventricular surface and undergo symmetric divisions to generate either two neurons or two progenitor cells. These 'basal' progenitor cells form the subventricular zone and are responsible for generating the majority of neocortical neurons. However, not much has been studied on similar types of progenitor cells in other brain regions.

Results

We have identified and characterized basal progenitor cells in the embryonic mouse thalamus. The progenitor domain that generates all of the cortex-projecting thalamic nuclei contained a remarkably high proportion of basally dividing cells. Fewer basal progenitor cells were found in other progenitor domains that generate non-cortex projecting nuclei. By using intracellular domain of Notch1 (NICD) as a marker for radial glial cells, we found that basally dividing cells extended outside the lateral limit of radial glial cells, indicating that, similar to the neocortex and ventral telencephalon, the thalamus has a distinct subventricular zone. Neocortical and thalamic basal progenitor cells shared expression of some molecular markers, including Insm1, Neurog1, Neurog2 and NeuroD1. Additionally, basal progenitor cells in each region also expressed exclusive markers, such as Tbr2 in the neocortex and Olig2 and Olig3 in the thalamus. In Neurog1/Neurog2 double mutant mice, the number of basally dividing progenitor cells in the thalamus was significantly reduced, which demonstrates the roles of neurogenins in the generation and/or maintenance of basal progenitor cells. In Pax6 mutant mice, the part of the thalamus that showed reduced Neurog1/2 expression also had reduced basal mitosis.

Conclusions

Our current study establishes the existence of a unique and significant population of basal progenitor cells in the thalamus and their dependence on neurogenins and Pax6. These progenitor cells may have important roles in enhancing the generation of neurons within the thalamus and may also be critical for generating neuronal diversity in this complex brain region.
Identifying cancer biomarkers by network-constrained support vector machines
Authors: Chen Li , Xuan Jianhua , Riggins Rebecca B , Clarke Robert , Wang Yue
Published: November 2011

Background

One of the major goals in gene and protein expression profiling of cancer is to identify biomarkers and build classification models for prediction of disease prognosis or treatment response. Many traditional statistical methods, based on microarray gene expression data alone and individual genes' discriminatory power, often fail to identify biologically meaningful biomarkers thus resulting in poor prediction performance across data sets. Nonetheless, the variables in multivariable classifiers should synergistically interact to produce more effective classifiers than individual biomarkers.

Results

We developed an integrated approach, namely network-constrained support vector machine (netSVM), for cancer biomarker identification with an improved prediction performance. The netSVM approach is specifically designed for network biomarker identification by integrating gene expression data and protein-protein interaction data. We first evaluated the effectiveness of netSVM using simulation studies, demonstrating its improved performance over state-of-the-art network-based methods and gene-based methods for network biomarker identification. We then applied the netSVM approach to two breast cancer data sets to identify prognostic signatures for prediction of breast cancer metastasis. The experimental results show that: (1) network biomarkers identified by netSVM are highly enriched in biological pathways associated with cancer progression; (2) prediction performance is much improved when tested across different data sets. Specifically, many genes related to apoptosis, cell cycle, and cell proliferation, which are hallmark signatures of breast cancer metastasis, were identified by the netSVM approach. More importantly, several novel hub genes, biologically important with many interactions in PPI network but often showing little change in expression as compared with their downstream genes, were also identified as network biomarkers; the genes were enriched in signaling pathways such as TGF-beta signaling pathway, MAPK signaling pathway, and JAK-STAT signaling pathway. These signaling pathways may provide new insight to the underlying mechanism of breast cancer metastasis.

Conclusions

We have developed a network-based approach for cancer biomarker identification, netSVM, resulting in an improved prediction performance with network biomarkers. We have applied the netSVM approach to breast cancer gene expression data to predict metastasis in patients. Network biomarkers identified by netSVM reveal potential signaling pathways associated with breast cancer metastasis, and help improve the prediction performance across independent data sets.
Preventing progression to first-episode psychosis in early initial prodromal states
Authors: Bechdolf A. , Wagner M. , Ruhrmann S. , Harrigan S. , Putzfeld V. , Pukrop R. , Brockhaus-Dumke A. , Berning J. , Janssen B. , Decker P. , Bottlender R. , Maurer K. , Möller H.-J. , Gaebel W. , Häfner H. , Maier W. , Klosterkötter J.
Published: November 2011

Background

Young people with self-experienced cognitive thought and perception deficits (basic symptoms) may present with an early initial prodromal state (EIPS) of psychosis in which most of the disability and neurobiological deficits of schizophrenia have not yet occurred.

Aims

To investigate the effects of an integrated psychological intervention (IPI), combining individual cognitive–behavioural therapy, group skills training, cognitive remediation and multifamily psychoeducation, on the prevention of psychosis in the EIPS.

Method

A randomised controlled, multicentre, parallel group trial of 12 months of IPI v. supportive counselling (trial registration number: NCT00204087). Primary outcome was progression to psychosis at 12- and 24-month follow-up.

Results

A total of 128 help-seeking out-patients in an EIPS were randomised. Integrated psychological intervention was superior to supportive counselling in preventing progression to psychosis at 12-month follow-up (3.2% v. 16.9%; P = 0.008) and at 24-month follow-up (6.3% v. 20.0%; P = 0.019).

Conclusions

Integrated psychological intervention appears effective in delaying the onset of psychosis over a 24-month time period in people in an EIPS.
Implantation of biomaterial as an efficient method to harvest mesenchymal stem cells
Authors: Wu Xiaoyun , Liu Xiaoshuai , Wang Shili
Published: November 2011

Autologous mesenchymal stem cell (MSC) transplants have been used successfully to treat a number of diseases, and patients undergoing cell transplantation must have stem cells collected before transplantation. In this study, we developed a new method to harvest MSCs. Biomaterials were implanted into the spatium intermuscular of mice hind limbs, and a large number of migrating cells (MCs) were isolated from the transplanted biomaterials. The adherent cells in MCs showed the characteristics of MSCs. Further comparative study demonstrated that the characteristics of MC-MSCs were similar to that of bone marrow (BM)-MSCs, including morphology, phenotype, proliferation potential, multilineage differentiation capacity and hematopoiesis-supportive function. The colony-forming unit-ﬁbroblast frequency of the MCs was equivalent to approximately 20-fold of that of the BM. In addition, a BM transplantation experiment demonstrated that MC-MSCs were derived from the peripheral blood. In conclusion, we successfully establish an efficient method to harvest MSCs, and together with the distinct advantages of this method, such as accessibility and possibility for autologous cell therapy, we conclude that our efficient method may be a promising alternative for clinical application.
Modeling and analysis of the migration of HTO and237Np in a fractured granite core at the Äspö hard rock laboratory
Authors: Park Chung-Kyang , Kienzler Bernhard , Vejmelka Peter , Jeong Jong-Tae
Published: November 2011

Migration characteristics of HTO and237Np were analyzed through experiments performed with a fractured granite core in the Chemlab2 probe at the Äspö hard rock laboratory in Sweden. These experimental data covered the elution of HTO and237Np as well as information of retained actinides onto the fracture surfaces. The flow field was simulated with a two-dimensional variable aperture channel model. The mass transport process was described with a random-walk method. Three types of basic migration processes were considered: advection, sorption and matrix diffusion. By a combination of these processes, specific effects of each process on transport were evaluated. The retardation of the neptunium were analysed quantitatively by the model. The results were compared to the experimental findings in terms of the elution curves and of distribution patterns on the fracture surface. The elution curves of HTO were used to determine the hydraulic propert ies in the fractured core such as the extent of a dispersion effect according to the flow rates. After termination of the migration test, the rock core was opened, and the retained radioactivities onto the fracture surfaces were measured to investigate an extend of237Np retardation and the retardation mechanism. A retardation factor was obtained by comparing the simulated results to the distribution of sorbed tracers along the flow path. The validity of sorption data from batch tests was also discussed for estimating migration of sorbing tracers.
The Influence of Induction Therapy for Kidney Transplantation after a Non-Renal Transplant
Authors: Cassuto James R. , Levine Matthew H. , Reese Peter P. , Bloom Roy D. , Goral Simin , Naji Ali , Abt Peter L.
Published: November 2011

Background and objectives

Non-renal transplant recipients who subsequently develop ESRD and undergo kidney transplantation are medically and immunologically complex due to comorbidities, high cumulative exposure to immunosuppressants, and sensitization to alloantigen from the prior transplant. Although prior non-renal transplant recipients are one of the fastest growing segments of the kidney wait list, minimal data exist to guide the use of antibody induction therapy (IT+) at the time of kidney after lung (KALu), heart (KAH), and liver (KALi) transplant.

Design, setting, participants, & measurements

This retrospective cohort study used national registry data to examine IT use and survival after kidney transplantation. Separate multivariate Cox regression models were constructed to assess patient survival for IT+ and IT− KALu (n=232), KAH (n=588), and KALi (n=736) recipients.

Results

Use of IT increased during the study period. The percentage of patients considered highly sensitized (panel reactive antibody ≥20%) was not statistically significant between IT+ and IT− groups. IT+ was not associated with improvement in 1- and 10-year patient survival for KALu (P=0.20 and P=0.22, respectively) or for KAH (P=0.90 and P=0.14, respectively). However, IT+ among KALi was associated with inferior patient survival at 1 and 10 years (P=0.04 and P=0.02, respectively).

Conclusions

Use of IT for kidney transplantation among prior non-renal transplant recipients may not offer a survival advantage in KALu or KAH. However, due to limited power, these findings should be interpreted cautiously. IT+ was associated with inferior outcomes for KALi. Use of IT should be judicially reconsidered in this complex group of recipients.
Improving Ascertainment of Sudden Cardiac Death in Patients with End Stage Renal Disease
Authors: Pun Patrick H. , Herzog Charles A. , Middleton John P.
Published: November 2011

Background and objectives

Data collected by the US Renal Data System (USRDS) identify sudden cardiac death (SCD) as the leading cause of death among hemodialysis patients. However, evidence suggests that clinical events captured on the USRDS death notification form may be inaccurate. A new method for classifying SCD was recently developed to enhance the accuracy of SCD classification. This study examined the performance characteristics of this refined definition using a cohort of hemodialysis patients who experienced a witnessed SCD as the reference standard.

Design, setting, participants, & measurements

This is a retrospective cohort study of 363 patients who experienced a witnessed SCD in US Gambro (DaVita) outpatient dialysis clinics. Sensitivity of SCD defined by death notification forms and SCD defined using additional administrative sources was compared. Clinical data recorded near time of death were also examined.

Results

Existing USRDS death notification forms reported 70.8% of witnessed SCD as “cardiac arrest/cause unknown” or “arrhythmia.” The refined definition significantly improved identification to 83.8% of witnessed SCD events (P<0.001). Verified SCD cases that were not identified by either definition were more likely to be reported on the death notification form as death due to myocardial infarction, hyperkalemia, sepsis, malignancy, or unknown cause.

Conclusions

Compared with the death notification form alone, the refined SCD definition significantly improves the sensitivity of reporting of witnessed SCD occurring within outpatient hemodialysis clinics. More accurate reporting of cardiac events by clinicians and refinements to existing death notification forms may further improve recognition and understanding of SCD.
Serum Fibroblast Growth Factor-23 and Risk of Incident Chronic Kidney Disease in Older Community-Dwelling Women
Authors: Semba Richard D. , Fink Jeffrey C. , Sun Kai , Cappola Anne R. , Dalal Mansi , Crasto Candace , Ferrucci Luigi , Fried Linda P.
Published: November 2011

Background and objectives

Elevated circulating fibroblast growth factor 23 (FGF23) predicts progression of CKD, but it is unknown whether circulating FGF23 independently predicts incident CKD. This study aimed to determine whether circulating FGF23 predicts incident CKD in community-dwelling women.

Design, setting, participants, & measurements

This study examined the relationship of intact serum FGF23, 1,25-dihydroxyvitamin D3 (1,25[OH]2D), 25-hydroxyvitamin D (25[OH]D), parathyroid hormone, calcium, and phosphate with prevalent and incident CKD in 701 disabled women, ≥65 years of age, from the Women’s Health and Aging Study I in Baltimore, Maryland, from 1993 to 1997. Incident CKD was defined as a low estimated GFR (eGFR) <60 ml/min per 1.73 m2 only, low eGFR <60 ml/min per 1.73 m2 and a ≥25% decline in eGFR from baseline, and an increase in serum creatinine (≥0.4 mg/dl) at follow-up.

Results

At baseline, 381 women (54.3%) had stage 3 CKD. Of 307 women without CKD at baseline, 63 (20.5%) developed stage 3 CKD over 24 months of follow-up. After excluding prevalent cases of CKD, FGF23 (per 1 SD increase) was associated with incident stage 3 CKD (hazard ratio [HR], 1.51; 95% confidence interval [95% CI], 1.06, 2.16; P=0.02), low and declining eGFR (HR, 3.69; 95% CI, 1.68, 8.11; P=0.001), and increase in serum creatinine (HR, 5.35; 95% CI, 1.27, 22.54; P=0.02) in respective multivariable Cox proportional hazards models adjusting for baseline eGFR, age, race, phosphate, 1,25-dihydroxyvitamin D3, parathyroid hormone, and other potential confounders.

Conclusions

Elevated FGF23 is an independent risk factor for incident CKD in older, disabled, community-dwelling women.
Inotuzumab Ozogamicin Murine Analog–Mediated B-Cell Depletion Reduces Anti-islet Allo- and Autoimmune Responses
Authors: Carvello Michele , Petrelli Alessandra , Vergani Andrea , Lee Kang Mi , Tezza Sara , Chin Melissa , Orsenigo Elena , Staudacher Carlo , Secchi Antonio , Dunussi-Joannopoulos Kyri , Sayegh Mohamed H. , Markmann James F. , Fiorina Paolo
Published: November 2011

B cells participate in the priming of the allo- and autoimmune responses, and their depletion can thus be advantageous for islet transplantation. Herein, we provide an extensive study of the effect of B-cell depletion in murine models of islet transplantation. Islet transplantation was performed in hyperglycemic B-cell–deficient(μMT) mice, in a purely alloimmune setting (BALB/c into hyperglycemic C57BL/6), in a purely autoimmune setting (NOD.SCID into hyperglycemic NOD), and in a mixed allo-/autoimmune setting (BALB/c into hyperglycemic NOD). Inotuzumab ozogamicin murine analog (anti-CD22 monoclonal antibody conjugated with calicheamicin [anti-CD22/cal]) efficiently depleted B cells in all three models of islet transplantation examined. Islet graft survival was significantly prolonged in B-cell–depleted mice compared with control groups in transplants of islets from BALB/c into C57BL/6 (mean survival time [MST]: 16.5 vs. 12.0 days; P = 0.004), from NOD.SCID into NOD (MST: 23.5 vs. 14.0 days; P = 0.03), and from BALB/c into NOD (MST: 12.0 vs. 5.5 days; P = 0.003). In the BALB/c into B-cell–deficient mice model, islet survival was prolonged as well (MST: μMT = 32.5 vs. WT = 14 days; P = 0.002). Pathology revealed reduced CD3+ cell islet infiltration and confirmed the absence of B cells in treated mice. Mechanistically, effector T cells were reduced in number, concomitant with a peripheral Th2 profile skewing and ex vivo recipient hyporesponsiveness toward donor-derived antigen as well as islet autoantigens. Finally, an anti-CD22/cal and CTLA4-Ig–based combination therapy displayed remarkable prolongation of graft survival in the stringent model of islet transplantation (BALB/c into NOD). Anti-CD22/cal–mediated B-cell depletion promotes the reduction of the anti-islet immune response in various models of islet transplantation.