bluuebunny/crossref_metadata_2025 huggingface dataset:
Ex‐vivo expanded baboon CD4+ CD25Hi Treg cells suppress baboon anti‐pig T and B cell immune response
Authors: Singh Avneesh K. , Seavey Caleb N. , Horvath Keith A. , Mohiuddin Muhammad M.
Published: April 2012

Singh AK, Seavey CN, Horvath KA, Mohiuddin MM. Ex‐vivo expanded baboon CD4+ CD25Hi Treg cells suppress baboon anti‐pig T and B cell immune response. Xenotransplantation 2012; 19: 102–111. © 2012 John Wiley & Sons A/S.

Abstract: Background:  CD4+ CD25+ FoxP3+ regulatory T (Treg) cells play an important role in regulating immune responses. A very small number of Treg cells are present in peripheral blood and lymphoid organs, but due to their ability to suppress the immune response, they have a high potential for immunotherapy in clinics. Successful ex‐vivo expansion of naturally occurring CD4+ CD25+ T cells has been achieved after TCR stimulation in the presence of T cell growth factors. In this study, we evaluated the role of these Treg cells in suppressing proliferative response of baboon T and B cells to pig xenoantigens.

Methods:  Naturally occurring baboon CD4+ CD25+ regulatory T cells (nTreg) were sorted from peripheral blood and expanded in the presence of either anti‐CD3/CD28 beads or irradiated pig peripheral blood mononuclear cells with IL‐2. Treg cells were also enriched directly from CD4+ T cells cultured in the presence of rapamycin (0.1–10 nm). Mixed lymphocyte culture and polyclonal B cell stimulation with ex‐vivo Treg cells were performed to assess the function of ex‐vivo expanded Treg cells.

Results:  The nTreg cells were expanded to more than 200‐fold in 4 weeks and retained all the nTreg cell phenotypic characteristics, including high levels of FoxP3 expression. 2‐fold increase in enrichment of CD4+ CD25+ FoxP3+ Treg cells from CD4+ cells was observed with rapamycin compared to cultures without rapamycin. The ex‐vivo expanded Treg cells obtained from both methods were able to suppress the baboon anti‐porcine xenogeneic T and B cell immune response in‐vitro efficiently (more than 90% suppression at 1 : 1 ratio of T regulatory cells: T effector cells), and their suppression potential was retained even at 1 : 256 ratio. However, freshly isolated nTreg cells had only 70% suppression at 1 : 1 ratio, and their suppressive ability was reduced to ≤50% at 1 : 16 ratio. Furthermore, we have found that ex‐vivo expanded Treg can also suppress the proliferation of B cells after polyclonal stimulation. Forty to 50 percent reduction in B cell proliferation was observed when ex‐vivo expanded Treg cells were added to the culture at a 1 : 1 ratio. The addition of CD4+ CD25Neg cells however induced vigorous proliferation.

Conclusion:  Ex‐vivo expanded CD4+ CD25+ FoxP3+ Treg cells can be used to efficiently suppress xenogeneic immune responses by inhibiting T and B cell proliferation. These ex‐vivo expanded Treg cells may also be used with other immunosuppressive agents to overcome xenograft rejection in preclinical xenotransplantation models.
Prospective randomized controlled trial to compare the effects of omeprazole and famotidine in preventing delayed bleeding and promoting ulcer healing after endoscopic submucosal dissection
Authors: Tomita Toshihiko , Kim Yongmin , Yamasaki Takahisa , Okugawa Takuya , Kondo Takashi , Toyoshima Fumihiko , Sakurai Jun , Tanaka Junji , Morita Tsuyoshi , Oshima Tadayuki , Fukui Hirokazu , Hori Kazutoshi , Watari Jiro , Matsumoto Takayuki , Miwa Hiroto
Published: April 2012

Background and Aims:  Proton pump inhibitors (PPIs) are generally used to prevent delayed bleeding after endoscopic submucosal dissection (ESD) and to heal the artificial ulcers. However, it remains controversial whether PPIs or histamine‐2 receptor antagonists (H2RAs) are more effective in preventing delayed bleeding after ESD. We prospectively compared the effects of omeprazole and famotidine in preventing delayed bleeding and promoting artificial ulcer healing after ESD.

Methods:  A total of 158 patients (155 early gastric cancers and three adenomas) were randomly assigned to the PPI group (omeprazole 20 mg/day) or H2RA group (famotidine 40 mg/day) in a prospective randomized controlled trial. The primary end point was the incidence of hematemesis, melena, and/or a decrease in hemoglobin level of 2 g/dL or more requiring endoscopic hemostatic treatment. ESD‐induced ulcer healing and changes in ulcer size were also compared at 6 weeks after ESD as a secondary end point.

Results:  Of the 158 patients, two were excluded from analysis because they had been treated with a PPI before the present study. Accordingly, data from 77 PPI and 79 H2RA subjects were included for analysis. Delayed bleeding after ESD occurred in 6.5% of subjects (PPI group) and in 6.3% (H2RA group); there was no significant difference between the two groups. Likewise, the two groups were not significantly different with respect to ulcer stage or ulcer size reduction rate.

Conclusions:  Proton pump inhibitors are not superior to H2RAs for the prevention of delayed bleeding or the healing of artificially induced ulcers after ESD.
Molecular cloning reveals nearly half of patients with Crohn's disease have an antibody to peroxiredoxin 6‐like protein
Authors: Iizuka Masahiro , Nakagomi Osamu , Nanjo Hiroshi , Chiba Mitsuro , Fukushima Tsuneo , Sugita Akira , Sagara Shiho , Horie Yasuo , Watanabe Sumio
Published: April 2012

Background and Aim:  Crohn's disease (CD) is a chronic inflammatory bowel disease (IBD) of unknown etiology. We aimed to identify the etiological agent of CD using a molecular cloning strategy that was particularly focused on identifying agents causing immune abnormalities and infectious agents.

Methods:  We constructed a cDNA library derived from the inflamed intestinal tissue of a CD patient, and screened 1.5 million clones in this library with the serum from another typical CD patient. The expressed cDNA clones that positively reacted with the serum were then expressed as fusion proteins with glutathione S‐transferase, and western blotting was performed using the sera of 22 CD, 13 ulcerative colitis (UC), and 16 non‐IBD patients.

Results:  We identified nine positive clones that did not contain any viral or bacterial genomic DNA. Of these, we selected one clone (clone 50) with which the typical CD patient's serum most strongly reacted. Clone 50 is highly homologous to the antioxidant protein peroxiredoxin 6. In western blotting, the sera of 47.6% CD patients (small intestine type 80%, large and small intestine type 43%, large intestine type 0%) showed strong reactivity to clone 50, none of the UC patients were reactive to clone 50, and 18.8% of non‐IBD patients were very weakly reactive to it. We also found that the expression of peroxiredoxin 6 was significantly increased in inflamed intestinal epithelia of CD.

Conclusion:  The present study first showed that some CD patients have an antibody against peroxiredoxin 6‐like protein, which may be involved in the pathogenesis of CD.
Selecting a prognostic renal surrogate for patients with hepatocellular carcinoma undergoing transarterial chemoembolization
Authors: Lee Yun‐Hsuan , Hsu Chia‐Yang , Huang Yi‐Hsiang , Su Chien‐Wei , Lin Han‐Chieh , Lee Rheun‐Chuan , Chiou Yi‐You , Huo Teh‐Ia , Lee Shou‐Dong
Published: April 2012

Background and Aim:  Renal insufficiency (RI) often coexists with hepatocellular carcinoma (HCC) and predicts a poor outcome in patients receiving transarterial chemoembolization (TACE). The modification of diet in renal disease (MDRD) and chronic kidney disease epidemiology collaboration (CKD‐EPI) equations are used to provide estimated glomerular filtration rate (eGFR). This study aimed to determine a prognsotic renal surrogate for outcome prediction in HCC patients receiving TACE.

Methods:  A total of 684 patients with HCC undergoing TACE were retrospectively analyzed. The prognostic ability between the MDRD and CKD‐EPI equation was compared by the Akaike information criterion (AIC).

Results:  Patients were categorized by eGFR into > 60, 30–60 and < 30 mL/min per 1.73 m2 (equivalent to CKD stages 1–2, 3, and 4–5, respectively) groups. The eGFR generated by the MDRD equation had a better predictive accuracy by having a lower AIC score (3234.5) compared to the CKD‐EPI equation (3236.7). The adjusted risk ratio for patients with eGFR 30–60 mL/min per 1.73 m2 by the MDRD was 1.313 (P = 0.041) compared with patients with eGFR > 60 mL/min per 1.73 m2 in the multivariate Cox model. The eGFR defined by the MDRD equation consistently had better prognostic ability when patients were stratified by the Child‐Turcotte‐Pugh score of 5 and > 5 and Cancer of the Liver Italian Program score 0 to 1 and > 1.

Conclusions:  The eGFR according the MDRD equation may provide better prognostic accuracy than the CKD‐EPI equation independent of liver functional reserve and tumor staging, and is a more feasible renal surrogate for outcome prediction in CKD stage 1–3 HCC patients receiving TACE.
Common bile duct stones in infancy: A medical approach
Authors: Nordin Nazrul , Alex George , Clarnette Tom , Stephens Nicola , Oliver Mark
Published: April 2012

Abstract:  Symptomatic choledocholithiasis in infancy is not common. It usually presents with jaundice and acholic stools and is diagnosed on abdominal ultrasonography. Favourable outcome of conservative management has been reported, but specific management guidelines are not well defined in the literature. We describe three cases using a combination of ursodeoxycholic acid and antibiotics as a treatment paradigm, which could potentially negate more invasive treatment. All three patients had ultrasonography proven choledocholithiasis with concomitant obstructive liver function test. They were treated with a combination of ursodeoxycolic acid and antibiotics. Patient 1 had an Escherichia coli urinary tract infection and was treated with oral bactrim. Intravenous amoxicillin, gentamicin and metronidazole were used for the other two patients. All three patients responded with a return to normal‐coloured stools within 48 h of combination treatment. Repeat ultrasonography done within 11 days after the first study for all three patients confirmed complete resolution of choledocholithiasis. It is postulated that this improvement is as a result of a reduction in inflammation and oedema, associated with a low‐grade cholangitis, following antibiotic treatment. This is coupled with improved bile flow with ursodeoxycholic acid therapy. The findings suggest the potential application of this safe, non‐invasive therapeutic strategy as initial management in infants with this condition. A follow‐up prospective randomised controlled trial may be an answer to prove the validity of this observation but due to the rarity of this problem, it would be a challenge to recruit sufficient number of patients.
Assessing sub‐seafloor microbial activity by combined stable isotope probing with deuterated water and 13C‐bicarbonate
Authors: Wegener Gunter , Bausch Marlene , Holler Thomas , Thang Nguyen Manh , Prieto Mollar Xavier , Kellermann Matthias Y. , Hinrichs Kai‐Uwe , Boetius Antje
Published: April 2012

Sub‐seafloor sediments are populated by large numbers of microbial cells but not much is known about their metabolic activities, growth rates and carbon assimilation pathways. Here we introduce a new method enabling the sensitive detection of microbial lipid production and the distinction of auto‐ and heterotrophic carbon assimilation. Application of this approach to anoxic sediments from a Swedish fjord allowed to compare the activity of different functional groups, the growth and turnover times of the bacterial and archaeal communities. The assay involves dual stable isotope probing (SIP) with deuterated water (D2O) and 13CDIC (dissolved inorganic carbon). Culture experiments confirmed that the D content in newly synthesized lipids is in equilibrium with the D content in labelled water, independent of whether the culture grew hetero‐ or autotrophically. The ratio of 13CDIC to D2O incorporation enables distinction between these two carbon pathways in studies of microbial cultures and in environmental communities. Furthermore, D2O‐SIP is sufficiently sensitive to detect the formation of few hundred cells per day in a gram of sediment. In anoxic sediments from a Swedish fjord, we found that > 99% of newly formed lipids were attributed to predominantly heterotrophic bacteria. The production rate of bacterial lipids was highest in the top 5 cm and decreased 60‐fold below this depth while the production rate of archaeal lipids was rather low throughout the top meter of seabed. The contrasting patterns in the rates of archaeal and bacterial lipid formation indicate that the factors controlling the presence of these two lipid groups must differ fundamentally.
Electing a candidate: a speculative history of the bacterial phylum OP10
Authors: Dunfield Peter F. , Tamas Ivica , Lee Kevin C. , Morgan Xochitl C. , McDonald Ian R. , Stott Matthew B.
Published: April 2012

In 1998, a cultivation‐independent survey of the microbial community in Obsidian Pool, Yellowstone National Park, detected 12 new phyla within the Domain Bacteria. These were dubbed ‘candidate divisions’ OP1 to OP12. Since that time the OP10 candidate division has been commonly detected in various environments, usually as part of the rare biosphere, but occasionally as a predominant community component. Based on 16S rRNA gene phylogeny, OP10 comprises at least 12 class‐level subdivisions. However, despite this broad ecological and evolutionary diversity, all OP10 bacteria have eluded cultivation until recently. In 2011, two reference species of OP10 were taxonomically validated, removing the phylum from its ‘candidate’ status. Construction of a highly resolved phylogeny based on 29 universally conserved genes verifies its standing as a unique bacterial phylum. In the following paper we summarize what is known and what is suspected about the newest described bacterial phylum, the Armatimonadetes.
Androgen deprivation therapy for volume reduction, lower urinary tract symptom relief and quality of life improvement in patients with prostate cancer: degarelix vs goserelin plus bicalutamide
Authors: Axcrona Karol , Aaltomaa Sirpa , da Silva Carlos Martins , Özen Haluk , Damber Jan‐Erik , Tankó László B. , Colli Enrico , Klarskov Peter
Published: April 2012

Study Type – Therapy (RCT)

Level of Evidence 1b

What's known on the subject? and What does the study add?

Androgen deprivation therapy (ADT) is commonly used as a primary treatment for patients with prostate cancer (PCa) who are not eligible for radical treatment options. ADT is also used in patients with PCa as neo‐adjuvant hormone therapy to reduce prostate volume and down‐stage the disease before radiotherapy with curative intent.

The present study showed that ADT with the gonadotropin hormone‐releasing hormone (GhRH) antagonist degarelix is non‐inferior to combined treatment with the LHRH agonist goserelin and bicalutamide in terms of reducing prostate volume during the treatment period of 3 months. Degarelix treatment evokes, however, significantly better relief of lower urinary tract symptoms in patients having moderate and severe voiding problems.

OBJECTIVE

To assess the efficacy of monthly degarelix treatment for reduction of total prostate volume (TPV), relief of lower urinary tract symptoms (LUTS) and improvement of quality of life (QoL) in patients with prostate cancer (PCa) using monthly goserelin as active control.

METHODS

This was a randomized, parallel‐arm, active‐controlled, open‐label, multicentre trial on 182 patients treated with either monthly degarelix (240/80 mg) or goserelin (3.6 mg) for 12 weeks.

For flare protection, goserelin‐treated patients also received daily bicalutamide (50 mg) during the initial 28 days.

Key trial variables monitored monthly were TPV (primary endpoint), serum testosterone, prostate‐specific antigen (PSA), the International Prostate Symptom Score (IPSS) and the Benign Prostate Hyperplasia Impact Index.

RESULTS

In all, 175 patients completed the trial (96.1%).

At week 12, changes in TPV for degarelix and goserelin were similar (−37.2% vs −39.0%) and met the predefined non‐inferiority criterion.

Decreases in IPSS were greater in degarelix than in goserelin‐treated patients, differences being statistically significant in patients with baseline IPSS > 13 (−6.7 ± 1.8 vs −4.0 ± 1.0; P= 0.02).

The number of patients with an IPSS change of ≥3 over baseline was also significantly higher in patients treated with degarelix (61.0 vs 44.3%, P= 0.02).

Both treatments were safe and well tolerated.

CONCLUSIONS

Medical castration reduces TPV and could also improve LUTS in patients with PCa.

While the short‐term efficacy of degarelix and goserelin + bicalutamide was the same in terms of TPV reduction, degarelix showed superiority in LUTS relief in symptomatic patients, which could highlight the different actions of these drugs on extrapituitary gonadotrophin‐releasing hormone (GnRH) receptors in the bladder and/or the prostate.
Patient‐reported quality of life during radiation treatment for localized prostate cancer: results from a prospective phase II trial
Authors: Chen Ronald C. , Zhang Yuanye , Chen Ming‐Hui , McMahon Elizabeth , Loffredo Marian , McPherson Carol P. , Nguyen Angela U. , Nguyen Paul L. , D'Amico Anthony V.
Published: April 2012

Study Type – Therapy (cohort)

Level of Evidence 2a

What's known on the subject? and What does the study add?

Patient‐reported quality of life (QoL) in prostate cancer is recognized as an important outcome, and has been shown in multiple studies to capture the incidence and timing of patient symptoms more accurately than physician‐graded toxicity reports. Although the long‐term QoL after completing radiation therapy (RT) has been previously studied, patient experience during RT is not well described in the literature.

The present study collected patient‐reported QoL during RT in a prospective phase II clinical trial. The study describes in detail the time course and severity of gastrointestinal and genitourinary symptoms during radiation, providing clinically useful information for patients and physicians considering RT during the treatment decision‐making process.

OBJECTIVE

To evaluate data collected from a phase II trial to describe the time course and trajectory of patient‐reported acute urinary and bowel symptom development during radiation therapy (RT) for prostate cancer.

PATIENTS AND METHODS

In all, 100 patients with intermediate‐ or high‐risk prostate cancer received 72 Gy of RT to the prostate and seminal vesicles, with 6 months of concurrent androgen deprivation therapy; a rectal balloon was used for prostate immobilization.

Patients completed the validated Prostate Cancer Symptom Indices questionnaire every 1–2 weeks, reporting urinary and bowel symptoms on a four‐ or five‐point Likert scale.

A score of ≥3 in a symptom is associated with clinically meaningful distress. Cumulative incidence of each symptom is reported. Bonferroni corrections of P values were used to adjust for multiple comparisons.

RESULTS

Urinary symptoms were frequent at baseline and worsened during treatment. By the end of RT, 28–50% of patients developed clinically meaningful obstructive and irritative urinary symptoms.

Acute bowel symptoms were less frequent. Each bowel symptom increased in frequency by 9–26% from baseline to end of RT.

Urinary incontinence was rare.

Overall, symptom burden at the end of treatment was modest.

CONCLUSIONS

Urinary symptoms were common during RT, and bowel symptoms were less frequent.

These results inform patients and physicians during the decision‐making process about potential patient quality of life experiences during RT, and also provide a benchmark for comparative effectiveness studies against newer treatments and technologies.
Limitations of preoperative biopsy in patients with metastatic renal cell carcinoma: comparison to surgical pathology in 405 cases
Authors: Abel E. Jason , Carrasco Alonso , Culp Stephen H. , Matin Surena F. , Tamboli Pheroze , Tannir Nizar M. , Wood Christopher G.
Published: April 2012

Study Type – Diagnostic (cohort)

Level of Evidence 2b

What's known on the subject? and What does the study add?

Although there have been many investigations of biopsy for small renal masses, there are scant data on the accuracy of biopsy in the setting of metastatic renal cell carcinoma (mRCC). We report a large series of biopsies and compare with nephrectomy pathology in patients with mRCC.

The present study highlights the inaccuracy of biopsy in the setting of metastatic disease, which is related to sampling error because of heterogeneity within the tumour and among metastases. These limitations are important to realize when designing trials that depend on pathological findings from biopsy and not nephrectomy. In addition, we found that biopsy of primary tumours were more likely than biopsy of metastatic sites to be diagnostic of RCC. Future studies with multiquadrant biopsies of primary tumours could yield the most accurate pathological results for future studies.

OBJECTIVE

To evaluate the ability of preoperative biopsy to identify high‐risk pathological features by comparing pathology from preoperative metastatic site and primary tumour biopsies with nephrectomy pathology in patients with metastatic renal cell carcinoma (mRCC).

PATIENTS AND METHODS

We reviewed clinical and pathological data from patients who underwent biopsy before cytoreductive nephrectomy for mRCC at MD Anderson Cancer Center (MDACC) from 1991 to 2007.

Percutaneous biopsy techniques included fine‐needle aspiration, core needle biopsy or a combination of both techniques.

RESULTS

The pathology of 405 preoperative biopsies (239 metastatic site, 166 primary tumour) from 378 patients was reviewed at MDACC before cytoreductive nephrectomy.

The biopsy and nephrectomy specimens had the same histological subtype in 96.0% of clear‐cell renal cell carcinomas (RCCs) and 72.7% of non‐clear‐cell RCCs.

Of 76 nephrectomy specimens where sarcomatoid de‐differentiation was identified, only seven (9.2%) were able to be identified from the preoperative biopsy.

In 38.3% of patients, the same Fuhrman grade was identified in both the biopsy and nephrectomy specimens.

A definitive diagnosis of RCC was more likely to be reported in primary tumour biopsies than in metastatic site biopsies. (P < 0.001).

CONCLUSIONS

Preoperative biopsy has limited ability to identify non‐clear‐cell histological subtype, Fuhrman grade or sarcomatoid features.

When surgical pathology is not available, a biopsy obtaining multiple samples from different sites within the primary tumour should be recommended rather than limited metastatic site biopsy to identify patients for clinical trials.
High insulin‐like growth factor mRNA‐binding protein 3 (IMP3) protein expression is associated with poor survival in muscle‐invasive bladder cancer
Authors: Szarvas Tibor , Dorp Frank vom , Niedworok Christian , Melchior‐Becker Ariane , Fischer Jens W. , Singer Bernhard B. , Reis Henning , Bánkfalvi Ágnes , Schmid Kurt W. , Romics Imre , Ergün Süleyman , Rübben Herbert
Published: April 2012

What's known on the subject? and What does the study add?

Insulin‐like growth factor mRNA‐binding protein 3 (IMP3) is an oncofetal protein found to be re‐expressed in a series of human cancers including bladder cancer. In vitro analyses showed an invasion and proliferation promoting effect for IMP3. Further in vitro studies suggested that IMP3 is able to bind to the mRNAs of CD44 and insulin‐like growth factor 2 (IGF2), enhancing their stability and expression. However, this molecular interaction has not yet been analysed in tumour samples.

In the present study, we identified for the first time high IMP3 tissue protein expression as an independent predictor of poor patients' survival in muscle‐invasive bladder cancer. Furthermore, there was no correlation between IMP3 and its molecular targets in bladder carcinoma specimens and concluded that the tumour‐promoting effect of IMP3 is not related to its regulatory action on IGF2 and CD44.

OBJECTIVE

To assess the prognostic value and molecular actions of the oncofetal protein insulin‐like growth factor mRNA‐binding protein 3 (IMP3) in muscle‐invasive bladder cancer (BC).

PATIENTS AND METHODS

IMP3 expression was analysed by immunohistochemistry, real‐time polymerase chain reaction and Western blot analysis in 224 patients with BC.

The molecular targets of IMP3; CD44, insulin‐like growth factor 2 (IGF2) and its receptor the IGF1 receptor (IGF1‐R) were also investigated.

Expression levels were correlated with clinical follow‐up data by using both univariate and multivariate Cox regression analyses.

RESULTS

IMP3 mRNA and protein levels were significantly elevated in high‐stage and high‐grade muscle‐invasive BC.

In muscle‐invasive BC IMP3 protein but not gene expression proved to be an independent predictor of disease‐specific (hazard ratio [HR] 2.58, 95% confidence interval [CI] 1.28–4.56, P = 0.004) and overall survival (HR 2.07, 95% CI 1.12–3.82, P = 0.020).

The expression levels of IGF2 and CD44 showed no correlation with that of IMP3.

CONCLUSIONS

High IMP3 protein levels may identify patients with BC at high risk of disease progression and may therefore select patients for a more intensive therapy or for a strict follow‐up.

Its high expression in high‐grade bladder carcinoma cells makes IMP3 for an attractive target for therapy.

The tumour promoting effect of IMP3 is independent from its regulatory action on IGF2 and CD44 expression.
The WISERD Geoportal: A Tool for the Discovery, Analysis and Visualization of Socio‐economic (Meta‐) Data for Wales
Authors: Fry Richard , Berry Robert , Higgs Gary , Orford Scott , Jones Sam
Published: April 2012

The Wales Institute of Socio‐Economic Research, Data and Methods (WISERD) is an interdisciplinary, cross‐institutional academic research group based in Wales, UK. One of the key objectives of WISERD is to develop a spatial framework that enhances a researcher's ability to discover socio‐economic research data relating to Wales with the aim of encouraging collaborative research and re‐use of existing data. This article describes the development of an online geoportal designed to meet this objective. Using free and open‐source software (FOSS) components and services, a range of software tools has been developed to capture standards‐compliant metadata for a variety of data sources. The geoportal is unique in that, in our review of over 120 geoportals worldwide, we have not previously encountered a geoportal dedicated to supporting quantitative and qualitative social science academic and policy research. A particularly innovative aspect of the geoportal has involved the building of a rich meta‐database of government surveys, geo‐referenced semantically‐tagged qualitative data (generated from primary research), ‘grey’ data (e.g. from transcripts, journal publications, books, PhD theses) and Government administrative data. This article describes the challenges faced during the development of the WISERD Geoportal which can be accessed via http://www.wiserd.ac.uk/geoportal/.
Who's Watching Your Food? A Flexible Framework for Public Health Monitoring1
Authors: Supak Stacy , Luo Huan , Tateosian Laura , Fang Kunsheng , Harrell Julia , Harrelson Cris , Bailey Andrew D. , Devine Hugh
Published: April 2012

By responding to potentially life‐threatening emergencies such as foodborne illnesses and water contamination, U.S. public health agencies play a vital role in promoting human health and protecting the environment. Local, state, and federal partners must collaborate to strategically plan initiatives, allocate resources, and evaluate emergency response activities. These collaborative decision‐making processes can be improved by using web‐based mapping applications for visualization and analysis. We developed a web‐based GIS framework which is applied to public health data for North Carolina's (NC) Department of Health and Human Services. The application visualizes all state‐regulated food service facilities and supports query and analysis tools crucial for food recalls or radiation contamination tracking. Built with PostgreSQL/PostGIS, GeoServer, and a customized GeoExplorer map viewer, the framework delivers a web‐based mapping tool that is flexible and Open Source. The flexibility of the framework is an important dimension of its scalability, allowing it to be customizable, modular, and portable so that it is easily configurable to support additional research and education initiatives. This approach reverses a trend toward application‐specific web mapping development in Open Source GIS. To demonstrate flexibility, we configured an additional website for forest landowner management to be used by another state agency, the NC Forest Service.
Advancing Global Marine Biogeography Research with Open‐source GIS Software and Cloud Computing
Authors: Fujioka Ei , Berghe Edward Vanden , Donnelly Ben , Castillo Julio , Cleary Jesse , Holmes Chris , McKnight Sean , Halpin Patrick
Published: April 2012

Across many scientific domains, the ability to aggregate disparate datasets enables more meaningful global analyses. Within marine biology, the Census of Marine Life served as the catalyst for such a global data aggregation effort. Under the Census framework, the Ocean Biogeographic Information System was established to coordinate an unprecedented aggregation of global marine biogeography data. The OBIS data system now contains 31.3 million observations, freely accessible through a geospatial portal. The challenges of storing, querying, disseminating, and mapping a global data collection of this complexity and magnitude are significant. In the face of declining performance and expanding feature requests, a redevelopment of the OBIS data system was undertaken. Following an Open Source philosophy, the OBIS technology stack was rebuilt using PostgreSQL, PostGIS, GeoServer and OpenLayers. This approach has markedly improved the performance and online user experience while maintaining a standards‐compliant and interoperable framework. Due to the distributed nature of the project and increasing needs for storage, scalability and deployment flexibility, the entire hardware and software stack was built on a Cloud Computing environment. The flexibility of the platform, combined with the power of the application stack, enabled rapid re‐development of the OBIS infrastructure, and ensured complete standards‐compliance.
Using GRASS GIS to Model Solar Irradiation on North Carolina Aquatic Habitats with Canopy Data
Authors: Newcomb Doug
Published: April 2012

Sunlight can have a significant impact on freshwater aquatic communities. Using 64‐ bit GRASS, a previously generated 18.2 m resolution forest canopy height grid for the State of North Carolina was used as a base elevation layer for calculation of 18.2 m resolution total irradiance (Watt‐hours/square meter/day) grids for 365 days of the year. Daily calculations were aggregated annually and overlaid on rasterized 1:24,000‐scale USGS hydrology with canopy type and seasonal filters to quantify annual solar irradiation input to streams and rivers in North Carolina. Bare earth calculations of solar irradiation for the aquatic habitats were compared to the canopy filtered calculations. There was substantially less solar irradiation in aquatic habitats under the canopy filtered model. Total solar irradiation for subbasins created from point locations of occurrences of Dwarf wedgemussel (Alasmidonta heterodon) were compared with total solar irradiation for watersheds created from locations with no mussels for the full subbasin, 1 km, and 500 m upstream from the sampling point. There was no significant difference in the amount of total solar irradiation modeled for the subbasins with Dwarf wedgemussel and watersheds with no mussels.
GIS‐based Calibration of MassMov2D
Authors: Molinari Monia Elisa , Cannata Massimiliano , Begueria Santiago , Ambrosi Christian
Published: April 2012

MassMov2D is a numerical model for simulating runout and deposition of landslide phenomena over a complex topography that is implemented in the free GIS PCRaster. This research aims at improving the mechanism of MassMov2D calibration and verifying its capability of representing complex landslides. In this article the authors present the enhancement of the MassMov2D code due to the introduction of the Nash‐Sutcliffe coefficient for model efficiency calculation; this enables the replacement of the inefficient ‘trial and error’ approach used for sensitivity analysis and calibration with a semi‐automatic procedure. During this research the improved code was tested in a case study located on the Canaria Valley (Switzerland) where a complex landslide occurred. An optimal set of parameters were calculated for evaluating the effects of a possible further slope failure.

The availability of a unique dataset of high resolution digital elevation models just before and after the collapse allowed precise evaluation of the sensitivity and calibration of the model with the new procedure. The results demonstrate that this model is capable of reproducing the observed deposits even though some model limitations were identified in steep slope areas. Finally the study presents the expected scenario due to a future landslide.
Monteverdi'sEarlySeventeenth‐Century‘HarmonicProgressions’
Authors: KANG YOUYOUNG
Published: April 2012

The seemingly tonal harmonic markers in Monteverdi's music, identified by many previous analytical investigations, appear side by side with tonally unconventional progressions in Monteverdi's oeuvre, particularly the sacred polyphony composed for San Marco. These unique ‘harmonic progressions’ which so clearly distinguish Monteverdi's music sonorously from that of both his contemporaries and his successors exhibit instead a peculiarly seventeenth‐century experimentation with counterpoint. Monteverdi's harmonic practice, like that of his contemporaries, is firmly embedded in a few basic contrapuntal principles: using the bass as the fundamental part, always preferring the fifth (rather than the sixth) and third above the bass, creating sequences of melodic motives to give impetus for harmonic motion and employing diminished note values to mask consecutive perfect consonances. Consequently, the counterpoint against a melodic bass line which moves by step or by thirds also creates sequential harmonic motion by those intervals, often resulting in juxtapositions of unrelated harmonies. In theSelva Morale(1640) andMessa et Salmi(1650) collections, these adventurous progressions help express affect and provide dramatic contrast to the harmonically static and conventional sections for solo voice or small ensembles.
Left Atrial Function Assessed by Tissue Doppler Imaging as a New Predictor of Cardiac Events after Non‐ST‐Elevation Acute Coronary Syndrome
Authors: Liu Yong‐Tai , Li Rui‐Jie , Fang Fang , Zhang Qing , Yan Bryan Ping‐Yen , Lam Yat‐Yin , Lee Alex Pui‐Wai , Yu Cheuk‐Man
Published: April 2012

Aims: Left ventricular (LV) function is a predictor for future cardiac events in patients with non‐ST‐elevation acute coronary syndrome (NSTE‐ACS). The aim of this study was to assess whether left atrium (LA) function has additional predictive value for the prognosis of NSTE‐ACS patients, especially when assessed by tissue Doppler imaging (TDI). Methods and Results: This study prospectively recruited 164 patients with NSTE‐ACS where clinical and echocardiographic parameters were collected within the first 72 hours of admission. Primary end point was assessed during the 6‐month follow‐up period which included cardiac mortality and/or rehospitalization for recurrent ACS or heart failure. Atrial function was assessed by conventional echocardiographic parameters and by TDI that measured the mean atrial contraction velocity at the midsegments of interatrial septum, anterior, inferior, and lateral wall of LA (mLA‐V). The primary end point occurred in 33 (20.1%) patients who had lower mLV‐A (5.4 ± 1.6 vs 6.5 ± 1.4 cm/sec, P < 0.01). Patients with mLA‐V <6.3 cm/sec had more cardiac events (30.9% vs 9.6%, P < 0.01). By multivariate logistic regression analysis, mLA‐V <6.3 cm/sec was an independent predictor for cardiac events (odds ratio: 2.79, 95% confidence interval: 1.07–7.30, P = 0.04). Furthermore, mLA‐V<6.3 cm/sec had an incremental predictive value for cardiac events to clinical data, LV ejection fraction, and LV diastolic function (E/E’) (P = 0.02). Conclusions: In patients with NSTE‐ACS, early assessment of LA function by TDI appears useful to predict the midterm cardiac events, which adds prognostic information in addition to that of LV function.
Systolic Myocardial Mechanics in Patients with Anderson–Fabry Disease with and without Left Ventricular Hypertrophy and in Comparison to Nonobstructive Hypertrophic Cardiomyopathy
Authors: Gruner Christiane , Verocai Flavia , Carasso Shemy , Vannan Mani A. , Jamorski Michael , Clarke Joe T.R. , Care Melanie , Iwanochko Robert M. , Rakowski Harry
Published: April 2012

Objectives: Anderson–Fabry disease (AFD) is a lysosomal storage disease, which can involve the heart, mimicking hypertrophic cardiomyopathy (HCM). The underlying mechanism of disease in AFD is an infiltrative, diffuse process, whereas HCM is a primary heart muscle condition with patchy distribution, which may prompt differences in myocardial mechanics. The aim of this study was to assess myocardial mechanics in AFD according to the presence of left ventricular hypertrophy (LVH) compared to nonobstructive HCM (NHCM) and healthy controls. Methods and Results: We carried out a single‐center, retrospective study in a small, genetically confirmed AFD cohort, which was divided into a subgroup with LVH (LVH+, n = 19), and without LVH (LVH–, n = 21). Comparison groups were healthy controls (n = 40) and NHCM patients (n = 19). Vector Velocity Imaging was applied to two‐dimensional echocardiography studies for assessment of longitudinal strain (LS), circumferential strain (CS), and base‐to‐apex CS gradients. AFD LVH+ patients had lower global LS than AFD LVH– patients (–14 ± 4% vs –17 ± 3%, P < 0.05), but similarly lowered global CS (–24 ± 5% vs –22 ± 5%, P = ns). AFD LVH+ and NHCM had similarly lowered global LS compared to normals, but significantly lower global CS was observed in AFD LVH+ (–24 ± 5% vs –28 ± 4%, P < 0.05), whereas it was significantly increased in NHCM (–31 ± 2% vs –28 ± 4%, P < 0.05). Unlike NHCM, in both AFD subgroups, patients lost their normal base‐to‐apex CS gradient. Conclusions: AFD patients without LVH already show abnormal systolic myocardial mechanics. Relevant differences in myocardial mechanics between AFD patients with LVH compared to NHCM reflect the different underlying mechanisms of disease.
The diverse roles of IRF4 in late germinal center B‐cell differentiation
Authors: De Silva Nilushi S. , Simonetti Giorgia , Heise Nicole , Klein Ulf
Published: April 2012

Summary:  Interferon regulatory factor 4 (IRF4) is a member of the IRF family of transcription factors and is expressed in most cell types of the immune system. Within the B‐cell lineage, IRF4 is expressed in all developmental stages except during the germinal center (GC) reaction. IRF4 expression, however, is upregulated during exit from the GC reaction and has been demonstrated to have critical functions in at least three key developmental processes: the termination of the GC B‐cell transcriptional program, immunoglobulin (Ig) class switch recombination (CSR), and plasma cell development. Herein, we attempt to reconcile the often contradictory findings regarding IRF4 into a model to explain the role of IRF4 in the transcription factor networks that operate within exiting GC B cells. In addition, a deregulation of the biological programs controlled by IRF4 has recently been implicated in the pathogenesis of various B‐cell–derived malignancies. Determining the specific functions of IRF4 in the markedly diverse developmental processes that coordinate B‐cell development is therefore likely to have important implications for understanding these malignancies and devising therapeutic interventions.
S1PR2 links germinal center confinement and growth regulation
Authors: Green Jesse A. , Cyster Jason G.
Published: April 2012

Summary:  Germinal centers (GCs) are sites of rapid B‐cell proliferation and somatic mutation. These ovoid structures develop within the center of follicles and grow to a stereotypic size. The cell migration and interaction dynamics underlying GC B‐cell selection events are currently under intense scrutiny. In recent study, we identified a role for a migration inhibitory receptor, S1PR2, in promoting GC B‐cell confinement to GCs. S1PR2 also dampens Akt activation and deficiency in S1PR2 or components of its signaling pathway result in a loss of growth control in chronically stimulated mucosal GCs. Herein, we detail present understanding of S1PR2 and S1P biology as it pertains to GC B cells and place this information in the context of a current model of GC function.
The 1‐1‐1 fallacy
Authors: Crotty Shane
Published: April 2012

Summary:  T‐cell help to B cells is a fundamental aspect of adaptive immunity and the generation of B‐cell memory (memory B cells and plasma cells). Follicular helper CD4+ T (Tfh) cells are the specialized providers of B‐cell help, and Tfh cells depend on Bcl6 for their differentiation. This review discusses Tfh cell functions, transcription factors, and induction signals, with particular focus on the richness of the underlying biology and assessing the simplicity or complexity of each of these processes.
From SAP‐less T cells to helpless B cells and back: dynamic T–B cell interactions underlie germinal center development and function
Authors: Qi Hai
Published: April 2012

Summary:  Operation of the immune system critically depends on intercellular communication among multiple cell types, frequently in the form of physical cell–cell interactions. Germinal centers (GCs) are highly organized tissue microdomains in which high affinity, class‐switched, antibody‐producing cells and humoral immune memory are generated. Critical underlying cell–cell interaction events include at the minimum binary interactions between CD4+ T‐helper cells and antigen‐presenting dendritic cells (DCs), which ensure proper T‐cell activation and acquisition of effecter potentials, and those between T‐helper cells and antigen‐activated B cells whereby the latter cells receive helper signals (e.g. CD40L) important for their proliferation, survival, and differentiation. How these critical cellular interaction events are molecularly regulated and dynamically orchestrated to support GC formation and function is still a study in progress. Signaling lymphocytic activation molecule (SLAM)‐associated protein (SAP) has recently been defined as a pivotal molecule that controls cognate T–B interactions and GC formation. Detailed analysis of interaction and migration dynamics of SAP‐deficient T cells has raised the interesting possibility that T cell:antigen‐presenting cell interactions underlying GC development and function are regulated in a cell type‐ and spatiotemporal stage‐specific manner. This has important implications for our understanding of synapse formation, helper signal delivery to B cells, follicular helper T‐cell differentiation, and quality control of the GC reaction in general. A model of selective T–B interactions involving bi‐directional feedback and feed‐forward logic is proposed to underlie GC development and function.
T cells that promote B‐Cell maturation in systemic autoimmunity
Authors: Weinstein Jason S. , Hernandez Sairy G. , Craft Joe
Published: April 2012

Summary:  Follicular helper T (Tfh) cells play an essential role in helping B cells generate antibodies upon pathogen encounters. Such T‐cell help classically occurs in germinal centers (GCs) located in B‐cell follicles of secondary lymphoid organs, a site of immunoglobulin affinity maturation and isotype switching. B‐cell maturation also occurs extrafollicularly, in the red pulp of the spleen and medullary cords in lymph nodes, with plasma cell formation and antibody production. Development of extrafollicular foci (EF) in T‐cell‐dependent (TD) immune responses is reliant upon CD4+ T cells with characteristics of Tfh cells. Pathogenic autoantibodies, arising from self‐reactive B cells having undergone somatic hypermutation with affinity selection and class switching within GCs and EF, are major contributors to the end‐organ injury in systemic autoimmunity. B cells maturing to produce autoantibodies in systemic autoimmune diseases, like those in normal immune responses, largely require T‐helper cells. This review highlights Tfh cell development as an introduction to a more in‐depth discussion of human Tfh cells and blood borne cells with similar features and the role of these cells in promotion of systemic autoimmunity.
Early Primaries, Viability and Changing Preferences for Presidential Candidates
Authors: COLLINGWOOD LOREN , BARRETO MATT A. , DONOVAN TODD
Published: April 2012

Given the fluid context of primaries and observed swings in national polls, many Democratic voters likely switched candidate support over the course of the 2008 primary campaign. We examine how perceptions of early caucus and primary outcomes subsequently affected voter choice and candidate momentum. Although the 2008 calendar left many voters with a brief window to assess candidates, it nonetheless allowed a non–front‐runner to benefit from momentum and win the Democratic nomination. This article employs a panel study of voters surveyed at two time points during the nomination contest to assess individual‐level change in candidate support. Results from the earlier states sent signals about candidate viability to people who had not yet voted. We find that voters deciding after results were in from early states changed their perceptions of candidate viability and that this changed whom they intended to support. We conclude that momentum remains an important factor in presidential nominations.
Circumventing Adversity: Executive Orders and Divided Government
Authors: FINE JEFFREY A. , WARBER ADAM L.
Published: April 2012

Scholars of the unilateral presidency are left with an empirical puzzle regarding whether and how divided government influences presidential use of executive orders. While the strategic model suggests that presidents should issue more executive orders when faced with an adverse situation vis‐à‐vis Congress, most of the research finds just the opposite. We offer a more appropriate test of the strategic model by examining how presidential‐congressional adversity influences presidential decisions to issue symbolic, routine, and major policy executive orders. We find support for the strategic model and present new findings to demonstrate that presidents behave differently with respect to distinct types of executive orders during periods of unified and divided government.
Presidential Leverage and the Politics of Policy Formulation
Authors: PONDER DANIEL E.
Published: April 2012

This article applies a concept of “presidential leverage” to the inner workings of the White House, specifically decisions regarding the location of policy formulation. The guiding question addresses how a president's leverage in the political system influences decisions regarding policy making. Findings support the propositions that (1) leverage has a systematic impact on presidential policy formation, (2) divided government has little or no impact on policy making location, and (3) presidents who are ideologically compatible with Congress are less likely to centralize. I conclude with some general thoughts on the current state of presidential leverage.