bluuebunny/crossref_metadata_2025 huggingface dataset:
Phosphate Limitation Induces Drastic Physiological Changes, Virulence-Related Gene Expression, and Secondary Metabolite Production in Pseudovibrio sp. Strain FO-BEG1
Authors: Romano Stefano , Schulz-Vogt Heide N. , González José M. , Bondarev Vladimir
Published: March 2015

Phosphorus is a vital nutrient for living organisms and is obtained by bacteria primarily via phosphate uptake. However, phosphate is often scarcely accessible in nature, and there is evidence that in many areas of the ocean, its concentration limits bacterial growth. Surprisingly, the phosphate starvation response has been extensively investigated in different model organisms (e.g.,
Escherichia coli
), but there is a dearth of studies on heterotrophic marine bacteria. In this work, we describe the response of
Pseudovibrio
sp. strain FO-BEG1, a metabolically versatile alphaproteobacterium and potential symbiont of marine sponges, to phosphate limitation. We compared the physiology, protein expression, and secondary metabolite production under phosphate-limited conditions to those under phosphate surplus conditions. We observed that phosphate limitation had a pleiotropic effect on the physiology of the strain, triggering cell elongation, the accumulation of polyhydroxyalkanoate, the degradation of polyphosphate, and the exchange of membrane lipids in favor of phosphorus-free lipids such as sulfoquinovosyl diacylglycerols. Many proteins involved in the uptake and degradation of phospho-organic compounds were upregulated, together with subunits of the ABC transport system for phosphate. Under conditions of phosphate limitation, FO-BEG1 secreted compounds into the medium that conferred an intense yellow coloration to the cultures. Among these compounds, we identified the potent antibiotic tropodithietic acid. Finally, toxin-like proteins and other proteins likely involved in the interaction with the eukaryotic host were also upregulated. Altogether, our data suggest that phosphate limitation leads to a pronounced reorganization of FO-BEG1 physiology, involving phosphorus, carbon, and sulfur metabolism; cell morphology; secondary metabolite production; and the expression of virulence-related genes.
Efficient Production of 2,5-Diketo-
d
-Gluconate via Heterologous Expression of 2-Ketogluconate Dehydrogenase in Gluconobacter japonicus
Authors: Kataoka Naoya , Matsutani Minenosuke , Yakushi Toshiharu , Matsushita Kazunobu
Published: March 2015

2,5-Diketo-
d
-gluconate (2,5DKG) is a compound that can be the intermediate for
d
-tartrate and also vitamin C production. Although
Gluconobacter oxydans
NBRC3293 produces 2,5DKG from
d
-glucose via
d
-gluconate and 2-keto-
d
-gluconate (2KG), with accumulation of the product in the culture medium, the efficiency of 2,5DKG production is unsatisfactory because there is a large amount of residual
d
-gluconate at the end of the biotransformation process. Oxidation of 2KG to 2,5DKG is catalyzed by a membrane-bound flavoprotein-cytochrome
c
complex: 2-keto-gluconate dehydrogenase (2KGDH). Here, we studied the
kgdSLC
genes encoding 2KGDH in
G. oxydans
NBRC3293 to improve 2,5DKG production by
Gluconobacter
spp. The
kgdS
,
kgdL
, and
kgdC
genes correspond to the small, large, and cytochrome subunits of 2KGDH, respectively. The
kgdSLC
genes were cloned into a broad-host-range vector carrying a DNA fragment of the putative promoter region of the membrane-bound alcohol dehydrogenase gene of
G. oxydans
for expression in
Gluconobacter
spp. According to our results, 2KGDH that was purified from the recombinant
Gluconobacter
cells showed characteristics nearly the same as those reported previously. We also expressed the
kgdSLC
genes in a mutant strain of
Gluconobacter japonicus
NBRC3271 (formerly
Gluconobacter dioxyacetonicus
IFO3271) engineered to produce 2KG efficiently from a mixture of
d
-glucose and
d
-gluconate. This mutant strain consumed almost all of the starting materials (
d
-glucose and
d
-gluconate) to produce 2,5DKG quantitatively as a seemingly unique metabolite. To our knowledge, this is the first report of a
Gluconobacter
strain that produces 2,5DKG efficiently and homogeneously.
Ca
2+
Regulation of Trypanosoma brucei Phosphoinositide Phospholipase C
Authors: King-Keller Sharon , Moore Christina A. , Docampo Roberto , Moreno Silvia N. J.
Published: March 2015

We characterized a phosphoinositide phospholipase C (PI-PLC) from the procyclic form (PCF) of
Trypanosoma brucei
. The protein contains a domain organization characteristic of typical PI-PLCs, such as X and Y catalytic domains, an EF-hand calcium-binding motif, and a C2 domain, but it lacks a pleckstrin homology (PH) domain. In addition, the
T. brucei
PI-PLC (TbPI-PLC) contains an N-terminal myristoylation consensus sequence found only in trypanosomatid PI-PLCs. A peptide containing this N-terminal domain fused to green fluorescent protein (GFP) was targeted to the plasma membrane. TbPI-PLC enzymatic activity was stimulated by Ca
2+
concentrations below the cytosolic levels in the parasite, suggesting that the enzyme is constitutively active. TbPI-PLC hydrolyzes both phosphatidylinositol (PI) and phosphatidylinositol 4,5-bisphosphate (PIP
2
), with a higher affinity for PIP
2
. We found that modification of a single amino acid in the EF-hand motif greatly affected the protein's Ca
2+
sensitivity and substrate preference, demonstrating the role of this motif in Ca
2+
regulation of TbPI-PLC. Endogenous TbPI-PLC localizes to intracellular vesicles and might be using an intracellular source of PIP
2
. Knockdown of
TbPI-PLC
expression by RNA interference (RNAi) did not result in growth inhibition, although enzymatic activity was still present in parasites, resulting in hydrolysis of PIP
2
and a contribution to the inositol 1,4,5-trisphosphate (IP
3
)/diacylglycerol (DAG) pathway.
Understanding the causes of intravenous medication administration errors in hospitals: a qualitative critical incident study
Authors: Keers Richard N , Williams Steven D , Cooke Jonathan , Ashcroft Darren M
Published: March 2015

Objectives

To investigate the underlying causes of intravenous medication administration errors (MAEs) in National Health Service (NHS) hospitals.

Setting

Two NHS teaching hospitals in the North West of England.

Participants

Twenty nurses working in a range of inpatient clinical environments were identified and recruited using purposive sampling at each study site.

Primary outcome measures

Semistructured interviews were conducted with nurse participants using the critical incident technique, where they were asked to discuss perceived causes of intravenous MAEs that they had been directly involved with. Transcribed interviews were analysed using the Framework approach and emerging themes were categorised according to Reason's model of accident causation.

Results

In total, 21 intravenous MAEs were discussed containing 23 individual active failures which included slips and lapses (n=11), mistakes (n=8) and deliberate violations of policy (n=4). Each active failure was associated with a range of error and violation provoking conditions. The working environment was implicated when nurses lacked healthcare team support and/or were exposed to a perceived increased workload during ward rounds, shift changes or emergencies. Nurses frequently reported that the quality of intravenous dose-checking activities was compromised due to high perceived workload and working relationships. Nurses described using approaches such as subconscious functioning and prioritising to manage their duties, which at times contributed to errors.

Conclusions

Complex interactions between active and latent failures can lead to intravenous MAEs in hospitals. Future interventions may need to be multimodal in design in order to mitigate these risks and reduce the burden of intravenous MAEs.
Increasing the value of health research in the WHO African Region beyond 2015—reflecting on the past, celebrating the present and building the future: a bibliometric analysis
Authors: Uthman Olalekan A , Wiysonge Charles Shey , Ota Martin O , Nicol Mark , Hussey Gregory D , Ndumbe Peter M , Mayosi Bongani M
Published: March 2015

Objective

To assess the profile and determinants of health research productivity in Africa since the onset of the new millennium.

Design

Bibliometric analysis.

Data collection and synthesis

In November 2014, we searched PubMed for articles published between 2000 and 2014 from the WHO African Region, and obtained country-level indicators from World Bank data. We used Poisson regression to examine time trends in research publications and negative binomial regression to explore determinants of research publications.

Results

We identified 107 662 publications, with a median of 727 per country (range 25–31 757). Three countries (South Africa, Nigeria and Kenya) contributed 52% of the publications. The number of publications increased from 3623 in 2000 to 12 709 in 2014 (relative growth 251%). Similarly, the per cent share of worldwide research publications per year increased from 0.7% in 2000 to 1.3% in 2014. The trend analysis was also significant to confirm a continuous increase in health research publications from Africa, with productivity increasing by 10.3% per year (95% CIs +10.1% to +10.5%). The only independent predictor of publication outputs was national gross domestic product. For every one log US$ billion increase in gross domestic product, research publications rose by 105%: incidence rate ratio (IRR=2.05, 95% CI 1.39 to 3.04). The association of private health expenditure with publications was only marginally significant (IRR=1.86, 95% CI 1.00 to 3.47).

Conclusions

There has been a significant improvement in health research in the WHO African Region since 2000, with some individual countries already having strong research profiles. Countries of the region should implement the WHO Strategy on Research for Health: reinforcing the research culture (organisation); focusing research on key health challenges (priorities); strengthening national health research systems (capacity); encouraging good research practice (standards); and consolidating linkages between health research and action (translation).
Application of a tool for the evaluation of public and patient involvement in research
Authors: Stocks Susan Jill , Giles Sally J , Cheraghi-Sohi Sudeh , Campbell Stephen M
Published: March 2015

Objectives

Public and patient involvement (PPI) is required at all stages of research by many funding bodies such as the National Institute for Health Research (NIHR). Given the high priority of PPI within NIHR programmes and the associated costs, it is important that the process of involvement and impact of PPI on health services research is evaluated. We aimed to develop a tool to quantitatively evaluate the quality of PPI in research from a PPI participant's perspective in order to inform the researchers about absolute level of quality (cross-sectional aspect) and changes in quality over time (longitudinal aspect).

Setting

A primary care patient safety translational research centre.

Participants

The 12 members of the Research User Group (RUG) of Greater Manchester Primary Care Patient Safety Translational Research Centre.

Interventions

By their own choice each RUG member supported a specific research theme. The level of involvement varied from commenting on documents through to designing their own research projects.

Primary and secondary outcome measures planned

Measure absolute score and change in score over time in a nine-point Likert score within individuals. Compare Likert scores before undertaking PPI with scores after PPI activities. Evaluate the usefulness of a questionnaire based on a theoretical framework of personal and research factors.

Results

The questionnaire had an acceptable to good level of internal consistency (Cronbach's α 0.74–0.81). The majority of the individuals met their initial expectations (11/12) and scored high across all factors. There was no significant change over time in the aggregate score over all factors and all individuals, but there were differences within individuals and factors. A ceiling effect limited the questionnaire's usefulness to measure increasing scores.

Conclusions

The questionnaire has been useful in evaluating the early stages of a PPI group and may be generalisable to another setting.
Surgical learning curves and operative efficiency: a cross-specialty observational study
Authors: Maruthappu Mahiben , Duclos Antoine , Lipsitz Stuart R , Orgill Dennis , Carty Matthew J
Published: March 2015

Objectives

To evaluate the learning curves of three high-volume procedures, from distinct surgical specialties.

Setting

Tertiary care academic hospital.

Participants

A prospectively collected database comprising all medical records of patients undergoing isolated coronary artery bypass grafting (CABG), total knee replacement (TKR) and bilateral reduction mammoplasty (BRM) at the Brigham and Women's Hospital, USA, 1996–2010. Multivariate generalised estimating equation (GEE) regression models were used to adjust for patient risk and clustering of procedures by surgeon.

Primary outcome measure

Operative efficiency.

Results

A total of 1052 BRMs, 3254 CABGs and 3325 TKRs performed by 30 surgeons were analysed. Median number of procedures per surgeon was 61 (range 11–502), 290 (52–973) and 99 (10–1871) for BRM, CABG and TKR, respectively. Mean operative times were 134.4 (SD 34.5), 180.9 (62.3) and 101.9 (30.3) minutes, respectively. For each procedure, attending surgeon experience was associated with significant reductions in operative time (p<0.05). After 15 years of experience, BRM operative time decreased by 69.8 min (38.3%), CABG operative time decreased by 17.5 min (7.8%) and TKR operative time decreased by 94.4 min (48.4%).

Conclusions

Common trends in surgical learning exist. Dependent on the procedure, experience can serve as a powerful driver of improvement or have clinically insignificant impacts on operative time.
Barriers to early diagnosis of symptomatic breast cancer: a qualitative study of Black African, Black Caribbean and White British women living in the UK
Authors: Jones Claire E L , Maben Jill , Lucas Grace , Davies Elizabeth A , Jack Ruth H , Ream Emma
Published: March 2015

Objectives

Understanding barriers to early diagnosis of symptomatic breast cancer among Black African, Black Caribbean and White British women in the UK.

Design

In-depth qualitative interviews using grounded theory methods to identify themes. Findings validated through focus groups.

Participants

94 women aged 33–91 years; 20 Black African, 20 Black Caribbean and 20 White British women diagnosed with symptomatic breast cancer were interviewed. Fourteen Black African and 20 Black Caribbean women with (n=19) and without (n=15) breast cancer participated in six focus groups.

Setting

Eight cancer centres/hospital trusts in London (n=5), Somerset (n=1), West Midlands (n=1) and Greater Manchester (n=1) during 2012–2013.

Results

There are important differences and similarities in barriers to early diagnosis of breast cancer between Black African, Black Caribbean and White British women in the UK. Differences were influenced by country of birth, time spent in UK and age. First generation Black African women experienced most barriers and longest delays. Second generation Black Caribbean and White British women were similar and experienced fewest barriers. Absence of pain was a barrier for Black African and Black Caribbean women. Older White British women (≥70 years) and first generation Black African and Black Caribbean women shared conservative attitudes and taboos about breast awareness. All women viewed themselves at low risk of the disease, and voiced uncertainty over breast awareness and appraising non-lump symptoms. Focus group findings validated and expanded themes identified in interviews.

Conclusions

Findings challenged reporting of Black women homogenously in breast cancer research. This can mask distinctions within and between ethnic groups. Current media and health promotion messages need reframing to promote early presentation with breast symptoms. Working with communities and developing culturally appropriate materials may lessen taboos and stigma, raise awareness, increase discussion of breast cancer and promote prompt help-seeking for breast symptoms among women with low cancer awareness.
Synergistic effect of interaction between perceived health and social activity on depressive symptoms in the middle-aged and elderly: a population-based longitudinal study
Authors: Chun Sung-Youn , Han Kyu-Tae , Lee Seo Yoon , Kim Chan Ok , Park Eun-Cheol
Published: March 2015

Objective

To examine the synergistic effect of interaction between perceived health and social activity on depressive symptoms.

Methods

We investigated whether the interaction between perceived health and social activity has a synergistic effect on depressive symptoms in the middle-aged and elderly using data from 6590 respondents aged 45 and older in the Korean Longitudinal Study on Aging (KLoSA), 2006–2012. A generalised linear mixed-effects model was used to investigate the association in a longitudinal data form. Depressive symptoms were measured using the Center for Epidemiological Studies Depression 10 Scale (CES-D10). Perceived health and level of social activity were categorical variables with three values. Participation in six social activities was assessed.

Results

Interactions between perceived health status and social activity were statistically significant for almost all social activity/perceived health combinations. Addition of the interaction term significantly decreased CES-D10 scores, confirming the synergistic effect of the interaction between perceived health status and social activity (‘normal×moderate’, β=−0.1826; ‘poor×moderate’, β=−0.5739; ‘poor×active’, β=−0.8935). In addition, we performed stratified analyses by region: urban or rural. In urban respondents, the additional effect of the interaction term decreased CES-D10 scores and all social activity/perceived health combinations were statistically significant (‘normal×moderate’, β=−0.2578; ‘normal×active’, β=−0.3945; ‘poor×moderate’, β=−0.5739; ‘poor×active’, β=−0.8935). In rural respondents, only one social activity/perceived health combination was statistically significant, and the additional effect of the interaction term showed no consistent trend on CES-D10 scores.

Conclusions

The interaction between perceived health and social activity has a synergistic effect on depressive symptoms; the additional effect of the interaction term significantly decreased CES-D10 scores in our models.
Expression of CD133 in differentiated thyroid cancer of young patients
Authors: Decaussin-Petrucci Myriam , Deladoëy Johnny , Hafdi-Nejjari Zakia , Sassolas Geneviève , Borson-Chazot Françoise , Abu-Khudir Rasha , Fusco Alfredo , Descotes Francoise , Cournoyer Sonia , Sartelet Hervé ,   and the group of Pathologists of the Rhône Alpes Region
Published: March 2015

Aims

CD133 expression in cancer is frequently associated with poor outcome. Thyroid carcinomas are rare in childhood and adolescence and are associated with a higher risk of recurrence and more metastases than the adult tumours. The aim of the study was to assess whether the expression of CD133 in thyroid carcinomas of children, adolescents and young adults was correlated with clinical prognostic factors.

Methods

Tissue microarrays were constructed with 235 tumours coming from 208 young adults with a median age of 28 years and 27 children with a median age of 13 years. An immunohistochemical study was performed with anti-CD133 antibody. CD133 expression was evaluated, using a semiquantitative score based on the percentage of positive cells. The mutation status of tumours was evaluated by reverse transcriptase PCR. Three cell lines were used to confirm CD133 expression by western blot.

Results

CD133 expression was found in 43% of adult and 37% of child tumours and was confirmed by western blot in cell lines. In young adults, the expression of CD133 was significantly more frequent in patients with tumours >3 cm (p=0.04) and in patients with lymph node metastases (p=0.02). The expression of CD133 was more frequent in patients in whom the tumour presented aBRAF  mutation (p=0.03).

Conclusions

CD133 expression is correlated with tumour size, lymph nodes metastases andBRAFmutations in young adults. The presence of these cancer stem cells could offer new therapeutic alternatives for aggressive thyroid cancers.
Genetic variations in the SOCS3 gene in patients with Graves’ ophthalmopathy
Authors: Yan Ruijia , Yang Junjie , Jiang Ping , Jin Ling , Ma Jing , Huang Rong , Ma Nan , Jiang Fagang
Published: March 2015

Aims

To explore the role of the suppressor of cytokine signalling 3 (SOCS3) gene in Graves’ ophthalmopathy (GO) patients.

Methods

A case–control study was conducted in a Chinese Han population by recruiting 114 Graves’ disease (GD) patients with GO and 156 GD patients without GO. We determined SOCS3 mRNA and protein levels in Epstein–Barr virus-transformed lymphoblastoid cell lines (EBV-LCLs) from peripheral blood mononuclear cells (PBMCs) by quantitative real-time (QRT)-PCR analysis and western blot analysis. We also genotyped five single nucleotide polymorphisms (SNPs) in the SOCS3 locus (SOCS3 rs12952093, rs4969170, rs4969168, rs4969169 and rs2280148) in all 270 GD patients using ligase detection reaction and multiplex PCR analyses. QRT-PCR and western blot assays were then performed to compare SOCS3 mRNA and protein levels between the rs4969170 AA and GG genotype groups from 20 GO patients.

Results

Basal SOCS3 mRNA and protein expression levels were significantly increased in patients with GO (p<0.05). The SOCS3 rs4969170 AA genotype was strongly associated with GO (OR=3.5, 95% CI 1.6 to 7.5, p=0.001). The AA genotype carriers had significantly higher SOCS3 mRNA and protein levels than those with the GG genotype (p<0.05).

Conclusions

Patients with GD who carry the AA genotype of the rs4969170 SNP in SOCS3 are more susceptible to the development of GO.
Physico-mechanical properties and durability performance of natural building and decorative carbonate stones from Cyprus
Authors: Modestou S. , Theodoridou M. , Fournari R. , Ioannou I.
Published: March 2015

Natural stone was the primary building material in Cyprus in the past. Nowadays, its use is mostly confined to decorative purposes and restoration projects. This study represents the first thorough and systematic investigation of the characteristics of local carbonate stone. The variety of the results recorded highlights the complexity of this natural geomaterial and, hence, the particular attention needed before selecting the appropriate lithotype in construction practice. Stones coming from the same geological formation exhibit significant variations in their physico-mechanical properties. The materials’ durability against salt crystallization is explained with reference to their pore structure and flexural strength, revealing that, in many cases, small differences may have a significant impact on stone performance. The study also investigates the use of novel microdestructive techniques in the prediction of the mechanical properties of the stones under study. These techniques can be especially useful in the characterization of monumental stone, where sampling is limited, or when
in situ
characterization of stone is required.
Angiotensin II type I receptor blockade attenuates reflex cutaneous vasoconstriction in aged but not young skin
Authors: Lang James A. , Kolb Kelsey E.
Published: March 2015

Stimulation of angiotensin II type I receptors (AT1R) elicits vasoconstriction (VC) that may be occurring through the activation of a pathogenic vascular pathway such as Rho kinase (ROCK). We hypothesize that reflex cutaneous VC to whole body cooling (mean skin temperature = 30.5°C) in older humans relies in part on AT1R activation, which may explain greater ROCK activity attendant with aging. Two microdialysis (MD) fibers were placed in the forearm skin of 10 young (Y; 24 ± 1 yr) and 10 older (O; 70 ± 2 yr) individuals for infusion of 1) lactated Ringer's solution (switched to fasudil, a ROCK antagonist, after cooling); and 2) AT1R blockade with losartan. Laser Doppler flux (LDF) was measured over each MD site and cutaneous vascular conductance (CVC) was calculated (CVC = LDF/mean arterial pressure) and expressed as percent change from baseline (%ΔCVCBASELINE). In older individuals the VC response to whole body cooling was blunted (Y = −34 ± 2, O = −17 ± 3%ΔCVC) and was further attenuated at the losartan site (Y = −34 ± 3, O = −9 ± 3%ΔCVC; P < 0.05). The VC response to an exogenous 10-μM dose of angiotensin II (Y = −27 ± 3, O = −42 ± 5%ΔCVC) was completely blocked in sites pretreated with losartan or with fasudil. These data suggest that AT1R activation contributes to the reflex VC response in aged but not young skin. Furthermore, the angiotensin II component of the VC response appears to occur primarily through a ROCK-mediated mechanism.
Kinetic profiling of in vivo lung cellular inflammatory responses to mechanical ventilation
Authors: Woods Samantha J. , Waite Alicia A. C. , O'Dea Kieran P. , Halford Paul , Takata Masao , Wilson Michael R.
Published: March 2015

Mechanical ventilation, through overdistension of the lung, induces substantial inflammation that is thought to increase mortality among critically ill patients. The mechanotransduction processes involved in converting lung distension into inflammation during this ventilator-induced lung injury (VILI) remain unclear, although many cell types have been shown to be involved in its pathogenesis. This study aimed to identify the profile of in vivo lung cellular activation that occurs during the initiation of VILI. This was achieved using a flow cytometry-based method to quantify the phosphorylation of several markers (p38, ERK1/2, MAPK-activated protein kinase 2, and NF-κB) of inflammatory pathway activation within individual cell types. Anesthetized C57BL/6 mice were ventilated with low (7 ml/kg), intermediate (30 ml/kg), or high (40 ml/kg) tidal volumes for 1, 5, or 15 min followed by immediate fixing and processing of the lungs. Surprisingly, the pulmonary endothelium was the cell type most responsive to in vivo high-tidal-volume ventilation, demonstrating activation within just 1 min, followed by the alveolar epithelium. Alveolar macrophages were the slowest to respond, although they still demonstrated activation within 5 min. This order of activation was specific to VILI, since intratracheal lipopolysaccharide induced a very different pattern. These results suggest that alveolar macrophages may become activated via a secondary mechanism that occurs subsequent to activation of the parenchyma and that the lung cellular activation mechanism may be different between VILI and lipopolysaccharide. Our data also demonstrate that even very short periods of high stretch can promote inflammatory activation, and, importantly, this injury may be immediately manifested within the pulmonary vasculature.
Association between early airway damage-associated molecular patterns and subsequent bacterial infection in patients with inhalational and burn injury
Authors: Maile Robert , Jones Samuel , Pan Yinghao , Zhou Haibo , Jaspers Ilona , Peden David B. , Cairns Bruce A. , Noah Terry L.
Published: March 2015

Bacterial infection is a major cause of morbidity affecting outcome following burn and inhalation injury. While experimental burn and inhalation injury animal models have suggested that mediators of cell damage and inflammation increase the risk of infection, few studies have been done on humans. This is a prospective, observational study of patients admitted to the North Carolina Jaycee Burn Center at the University of North Carolina who were intubated and on mechanical ventilation for treatment of burn and inhalational injury. Subjects were enrolled over a 2-yr period and followed till discharge or death. Serial bronchial washings from clinically indicated bronchoscopies were collected and analyzed for markers of tissue injury and inflammation. These include damage-associated molecular patterns (DAMPs) such as hyaluronic acid (HA), double-stranded DNA (dsDNA), heat-shock protein 70 (HSP-70), and high-mobility group protein B-1 (HMGB-1). The study population was comprised of 72 patients who had bacterial cultures obtained for clinical indications. Elevated HA, dsDNA, and IL-10 levels in bronchial washings obtained early (the first 72 h after injury) were significantly associated with positive bacterial respiratory cultures obtained during the first 14 days postinjury. Independent of initial inhalation injury severity and extent of surface burn, elevated levels of HA dsDNA and IL-10 in the central airways obtained early after injury are associated with subsequent positive bacterial respiratory cultures in patients intubated after acute burn/inhalation injury.
miR-21 Inhibition Reduces Liver Fibrosis and Prevents Tumor Development by Inducing Apoptosis of CD24+ Progenitor Cells
Authors: Zhang Jing , Jiao Jingjing , Cermelli Silvia , Muir Kyle , Jung Kwang Hwa , Zou Ruhai , Rashid Asif , Gagea Mihai , Zabludoff Sonya , Kalluri Raghu , Beretta Laura
Published: March 2015

miR-21 is upregulated in hepatocellular carcinoma and intrahepatic cholangiocarcinoma, where it is associated with poor prognosis. Here, we offer preclinical evidence that miR-21 offers a therapeutic and chemopreventive target in these liver cancers. In mice with hepatic deletion of Pten, anti-miR-21 treatment reduced liver tumor growth and prevented tumor development. These effects were accompanied with a decrease in liver fibrosis and a concomitant reduction of CD24+ liver progenitor cells and S100A4+ cancer-associated stromal cells. Notch2 inhibition also occurred in tumors following anti-miR-21 treatment. We further showed that miR-21 is necessary for the survival of CD24+ progenitor cells, a cellular phenotype mediated by Notch2, osteopontin, and integrin αv. Our results identify miR-21 as a key regulator of tumor-initiating cell survival, malignant development, and growth in liver cancer, highlighting the role of CD24+ cells in the expansion of S100A4+ cancer-associated stromal cells and associated liver fibrosis. Cancer Res; 75(9); 1859–67. ©2015 AACR.
Induction of Vasculogenic Mimicry Overrides VEGF-A Silencing and Enriches Stem-like Cancer Cells in Melanoma
Authors: Schnegg Caroline I. , Yang Moon Hee , Ghosh Subrata K. , Hsu Mei-Yu
Published: March 2015

The basis for resistance to VEGF inhibition is not fully understood despite its clinical importance. In this study, we examined the adaptive response to VEGF-A inhibition by a loss-of-function analysis using plasmid-based shRNA. Tumor xenografts that initially responded to VEGF-A inhibition underwent an adaptation in vivo, leading to acquired resistance. VEGF-A blockade in tumors was associated with HIF1α expression and an increase in CD144+ vasculogenic mimicry (VM), leading to formation of channels displaying Tie-1 and MMP-2 upregulation. CD133+ and CD271+ melanoma stem-like cells (MSLC) accumulated in the perivascular niche. Tumor xenografts of melanoma cell populations that were intrinsically resistant to VEGF-A blockade did not exhibit any of these features, compared with nontarget control counterparts. Thus, melanomas that are initially sensitive to VEGF-A blockade acquire adaptive resistance by adopting VM as an alternate angiogenic strategy, thereby enriching for deposition of MSLC in the perivascular niche through an HIF1α-dependent process. Conversely, melanomas that are intrinsically resistant to VEGF-A blockade do not show any evidence of compensatory survival mechanisms that promote MSLC accumulation. Our work highlights the potential risk of anti-VEGF treatments owing to a selective pressure for an adaptive resistance mechanism that empowers the development of stem-like cancer cells, with implications for how to design combination therapies that can improve outcomes in patients. Cancer Res; 75(8); 1682–90. ©2015 AACR.
Paracrine WNT5A Signaling Inhibits Expansion of Tumor-Initiating Cells
Authors: Borcherding Nicholas , Kusner David , Kolb Ryan , Xie Qing , Li Wei , Yuan Fang , Velez Gabriel , Askeland Ryan , Weigel Ronald J. , Zhang Weizhou
Published: March 2015

It is not well understood how paracrine communication between basal and luminal cell populations in the mammary gland affects tumorigenesis. During ErbB2-induced mammary tumorigenesis, enriched mammary stem cells that represent a subpopulation of basal cells exhibit enhanced tumorigenic capacity compared with the corresponding luminal progenitors. Transcript profiling of tumors derived from basal and luminal tumor-initiating cells (TIC) revealed preferential loss of the noncanonical Wnt ligand WNT5A in basal TIC-derived tumors. Heterozygous loss of WNT5A was correlated with shorter survival of breast cancer patients. In a mouse model of ErbB2-induced breast cancer, Wnt5a heterozygosity promoted tumor multiplicity and pulmonary metastasis. As a TGFβ substrate, luminal cell-produced WNT5A induced a feed-forward loop to activate SMAD2 in a RYK and TGFβR1-dependent manner to limit the expansion of basal TIC in a paracrine fashion, a potential explanation for the suppressive effect of WNT5A in mammary tumorigenesis. Our results identify the WNT5A/RYK module as a spatial regulator of the TGFβ–SMAD signaling pathway in the context of mammary gland development and carcinogenesis, offering a new perspective on tumor suppression provided by basal–luminal cross-talk in normal mammary tissue. Cancer Res; 75(10); 1972–82. ©2015 AACR.
Ex Vivo Antibody-Dependent Cellular Cytotoxicity Inducibility Predicts Efficacy of Cetuximab
Authors: Taylor Rodney J. , Saloura Vassiliki , Jain Ajay , Goloubeva Olga , Wong Stuart , Kronsberg Shari , Nagilla Madhavi , Silpino Lorna , de Souza Jonas , Seiwert Tanguy , Vokes Everett , Villaflor Victoria , Cohen Ezra E.W.
Published: March 2015

We conducted in vitro studies and a clinical trial for patients with squamous cell carcinoma of the head and neck (SCCHN) to study the relationship between FcγRIIIa polymorphisms and antibody-dependent cellular cytotoxicity (ADCC). In vitro, FcγRIIIa genotype was correlated with ADCC and innate cytotoxicity using natural killer (NK) cells harvested from healthy donors. In the phase II study, patients with recurrent or metastatic SCCHN were treated with cetuximab (500 mg/m2 i.v. every 2 weeks) and lenalidomide (25 mg daily). FcγRIIIa genotype and ex vivo ADCC were correlated with clinical response, progression-free survival (PFS), and overall survival (OS). In vitro, healthy donors with a FcγRIIIa 158-V allele demonstrated more effective ADCC against two colon cancer cell lines HT29 and SW480, mean cytotoxicity: FF 16.1%, VF/VV 24.3% (P = 0.015) and FF 11.7%, VF/VV 21.0% (P = 0.008), respectively. We observed a linear relationship between ADCC response and innate cytotoxicity. In the phase II trial, 40 patients received cetuximab and lenalidomide with median PFS of 7.2 weeks and OS of 16.4 weeks. Thirty-six patients had FcγRIIIa genotype: VV (2), VF (20), and FF (14), and 25 patients had sufficient NK-cell yield to perform ex vivo ADCC. FcγRIIIa genotype was not associated with any clinical outcomes. Patients mounting ex vivo ADCC response had a higher likelihood of stable disease (P = 0.01) and showed a trend toward increased PFS: 14 weeks versus 6.8 weeks, respectively (P = 0.13). Enhanced ex vivo ADCC and innate immunity responses were more predictive of clinical response than FcγRIIIa and may offer a functional assay to select patients suitable for cetuximab therapy. Cancer Immunol Res; 3(5); 567–74. ©2015 AACR.
Long-Term Outcomes of Secondary Atrial Fibrillation in the Community
Authors: Lubitz Steven A. , Yin Xiaoyan , Rienstra Michiel , Schnabel Renate B. , Walkey Allan J. , Magnani Jared W. , Rahman Faisal , McManus David D. , Tadros Thomas M. , Levy Daniel , Vasan Ramachandran S. , Larson Martin G. , Ellinor Patrick T. , Benjamin Emelia J.
Published: March 2015

Background—

Guidelines have proposed that atrial fibrillation (AF) can occur as an isolated event, particularly when precipitated by a secondary, or reversible, condition. However, knowledge of long-term AF outcomes after diagnosis during a secondary precipitant is limited.

Methods and Results—

In 1409 Framingham Heart Study participants with new-onset AF, we examined associations between first-detected AF episodes occurring with and without a secondary precipitant and both long-term AF recurrence and morbidity. We selected secondary precipitants based on guidelines (surgery, infection, acute myocardial infarction, thyrotoxicosis, acute alcohol consumption, acute pericardial disease, pulmonary embolism, or other acute pulmonary disease). Among 439 patients (31%) with AF diagnosed during a secondary precipitant, cardiothoracic surgery (n=131 [30%]), infection (n=102 [23%]), noncardiothoracic surgery (n=87 [20%]), and acute myocardial infarction (n=78 [18%]) were most common. AF recurred in 544 of 846 eligible individuals without permanent AF (5-, 10-, and 15-year recurrences of 42%, 56%, and 62% with versus 59%, 69%, and 71% without secondary precipitants; multivariable-adjusted hazard ratio, 0.65 [95% confidence interval, 0.54–0.78]). Stroke risk (n=209/1262 at risk; hazard ratio, 1.13 [95% confidence interval, 0.82–1.57]) and mortality (n=1098/1409 at risk; hazard ratio, 1.00 [95% confidence interval, 0.87–1.15]) were similar between those with and without secondary precipitants, although heart failure risk was reduced (n=294/1107 at risk; hazard ratio, 0.74 [95% confidence interval, 0.56–0.97]).

Conclusions—

AF recurs in most individuals, including those diagnosed with secondary precipitants. Long-term AF-related stroke and mortality risks were similar between individuals with and without secondary AF precipitants. Future studies may determine whether increased arrhythmia surveillance or adherence to general AF management principles in patients with reversible AF precipitants will reduce morbidity.
Coping with fallout: The influence of radioactive fallout on Canadian decision-making on the Distant Early Warning (DEW) Line
Authors: Trudgen Matthew
Published: March 2015

During the 1950s, Canada and the United States worked together to develop a North American air defence system. While the military cooperation generally worked well, some difficulties did occur. These problems in the relationship were almost always the result of concerns from within the Canadian government and the Department of External Affairs that the air defence measures posed political problems and were a threat to Canada’s sovereignty. In the fall of 1954, opposition to further improvements to the continental air defence system emerged from a different source: General Charles Foulkes, the chairman of the Chiefs of Staff Committee. He believed that radioactive fallout from ground bursts of thermonuclear weapons in a war with the Soviet Union would pose insurmountable problems for the air defence effort. Thus, the countries needed to conduct a joint reappraisal of the air defence problem. This article will explore Foulkes’ position and examine what lessons can be drawn from this experience.
Mental health of internally displaced persons in Jalozai camp, Pakistan
Authors: Mujeeb Arooj
Published: March 2015

Background:

Internal displacement has been a distressing issue of Pakistan for last one decade. Few research works have been conducted on the psychological issues of internally displaced persons in Pakistan.

Aims:

The current research was aimed at determining the psychological effects of internal displacement, that is, psychological well-being, depression, anxiety and stress (internalizing problems) of the individuals who were displaced as a result of an armed conflict in Swat.

Method:

A sample of 126 internally displaced persons was taken from Jalozai camp which included females ( n = 65) and males ( n = 61). Age of the sample ranged from 20 to 75 years with a mean of 47.5 years. Translated and adapted versions of Well-Being Affectometer-2 Scale and Depression Anxiety Stress Scale were used in the current research.

Results:

Results of the study indicated differences between males and females, females being higher on internalizing problems and lower on psychological well-being, whereas family loss during displacement affected the results in the same way. Well-being, gender and family loss emerged as significant predictors of internalizing problems, and gender moderated the relationship between well-being and internalizing problems.

Conclusion:

Internal displacement may bring psychological issues for internally displaced persons, that is, their well-being may decrease and depression, anxiety and stress may increase during displacement. Limitations and implications of the study were discussed further.
Applying the CHIME recovery framework in two culturally diverse Australian communities: Qualitative results
Authors: Brijnath Bianca
Published: March 2015

Background:

CHIME (connectedness, hope and optimism about the future, identity, meaning in life and empowerment) is a framework for conceptualising personal recovery from mental illness. To date, there has been limited research on its cross-cultural applicability.

Aims:

To apply CHIME to two culturally diverse groups’ conceptualisation of recovery from depression.

Method:

Qualitative interviews with 30 Anglo-Australians and 28 Indian-Australians living with depression in Melbourne, Australia. Data were thematically analysed.

Results:

Both groups valued connectedness but experienced stigma and struggled to broker family support. Identity, hope and optimism for the future were associated with positive thinking, being ‘cured’ and discontinuing treatment. Spirituality gave Indian participants meaning in life; Anglos derived meaning from the illness experience itself. Feeling empowered, for both groups, was related to improved socio-economic status and being ‘settled’ (e.g. having gainful employment, a home and family).

Conclusions:

CHIME was applicable in both groups, but culture mediated how cross-cutting issues (e.g. stigma) and sub-components of CHIME were operationalised. Recovery was also influenced by participant’s socio-economic context. Research, policy and practice implications are discussed.
The attributable burden of panic disorder in the impairment of quality of life in a national survey in Italy
Authors: Carta Mauro Giovanni , Moro Maria Francesca , Aguglia Eugenio , Balestrieri Matteo , Caraci Filippo , Dell’Osso Liliana , Di Sciascio Guido , Drago Filippo , Hardoy Maria Carolina , D’Aloja Ernesto , Machado Sergio , Roncone Rita , Faravelli Carlo
Published: March 2015

Introduction/Objective:

The aim was to measure the lifetime prevalence of panic disorder (PD) in an Italian community sample, and to estimate the burden attributable to PD in compromising the quality of life (QoL) of people diagnosed with it.

Methods:

Community survey was conducted on a sample of 4,999 randomly selected adult subjects. Instruments used were semi-structured clinical interview Advanced Neuropsychiatric Tools and Assessment Schedule (ANTAS), administered by clinicians and allowing diagnosis according to Diagnostic and Statistical Manual of Mental Disorder (4th ed.; DSM-IV); Short Form Health Survey (SF-12).

Results:

The lifetime prevalence of PD was 3.6% (4.4% in females, 2.5% in males; p = .002). People with PD had a lower SF-12 score than the standardized community sample (35.5 ± 6.5 vs. 38.4 ± 5.9; p < .0001) with a mean difference (attributable burden) of 2.9 ± 0.7, that is, lower than PD with agoraphobia (AP; 4.2 ± 2.4). Wilson Disease (WD), Multiple Sclerosis, Major Depressive Disorder and Eating Disorders (ED) show a higher attributable burden in impaired QoL than PD, while the attributable burden of PD with AP is not lower than in ED and WD.

Conclusions:

The burden attributable to the impairment of QoL following a lifetime diagnosis of PD was found to be not so great compared to the impairment caused by Major Depressive Disorder (MDD) or neurological conditions. The comorbidity of PD with AP worsens QoL significantly.
Homogenization of elastic properties of short-fiber reinforced composites based on measured microstructure data
Authors: Müller Viktor , Brylka Barthel , Dillenberger Felix , Glöckner Robert , Kolling Stefan , Böhlke Thomas
Published: March 2015

Mechanical properties of short-fiber reinforced composites are crucially influenced by their microstructure. The microstructure itself is mainly governed by the manufacturing process like injection or compression molding. The main contribution of this paper lies in the homogenization of linear elastic properties using experimental microstructural information. For this purpose, the microstructure of injection-molded specimens made of polypropylene reinforced with 30wt.% of short glass fibers are analyzed through micro-computer tomography ( μCT) measurements. Applying a recently developed segmentation algorithm, the spatial position, the orientation distribution and the length of the fibers are determined. This data is evaluated in terms of orientation tensors and length distribution, and is used within three mean field approaches: a self-consistent homogenization method, the interaction direct derivative estimate, which is based on the three-phase model, and a two-step bounding method. All methods account for the orientation, the length and the diameter distribution. The numerical results are compared to experimental tensile tests.
Application of the dual integrated force method to the analysis of the off-axis three-point flexure test of unidirectional composites
Authors: Adarraga I , Romera JM , Cantera MA , Insausti N , Mujika F
Published: March 2015

This paper shows the use of the dual integrated force method in the finite element method and its application to unidirectional composite laminates. This method was developed by SN Patnaik for isotropic materials, considering not only the equilibrium equations but also the compatibility conditions. The method is applied to obtain the stiffness matrix of a four-node rectangular plate element. Then, a three-point flexure test of a unidirectional off-axis composite has been analyzed. The results obtained with this method have been compared with those obtained from a previous analytic approach and with those obtained by commercial software of finite element method, which is based on the stiffness method.
Assessing Organizational Efficiency and Workforce Diversity
Authors: Guajardo Salomon Alcocer
Published: March 2015

This study applied an output-oriented variable returns-to-scale (VRS) data envelopment analysis (DEA) technique to New York City (NYC) agencies to illustrate its usefulness in assessing and estimating organizational efficiency with respect to workforce diversity. Financial, personnel, and labor inputs of 38 agencies were analyzed in relation to the level of workforce diversity achieved by each decision-making unit (DMU). The Simpson index of diversity (D = 1 − Σ p2) was used to measure the level of age, ethnic, and gender diversity in each agency. The findings suggest that the majority of the agencies have inefficient human resource (HR) recruiting and hiring processes (constant returns-to-scale [CRS] > 1.000 and Σλ > 1.000). The findings also suggest that the inefficient agencies would exhibit decreasing returns-to-scale (DRS) if the level of inputs were to be increased.
Credentialing Structures, Pedagogies, Practices, and Curriculum Goals
Authors: Ayers David F.
Published: March 2015

Objective:

To examine the discursive strategies deployed by community colleges to sustain legitimacy in an evolving and contradictory institutional environment.

Method:

Using corpus linguistics software, I compared 1,009 mission statements from 2012-2013 with a reference corpus of 427 mission statements from 2004.

Results:

Keywords analysis, collocation analysis, and concordance analysis suggest that mission statements have changed along four discourse trajectories: credentialing structures, pedagogies, practices, and curriculum goals.

Contributions:

These findings situate the community college as a point of entry into understanding the relations among institutional legitimacy and a changing cultural, political, and economic milieu.