bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Antimalarial Activities of Methylene Blue and the 1,4-Naphthoquinone 3-[4-(Trifluoromethyl)Benzyl]-Menadione Are Not Due to Inhibition of the Mitochondrial Electron Transport Chain
Authors: Ehrhardt Katharina , Davioud-Charvet Elisabeth , Ke Hangjun , Vaidya Akhil B. , Lanzer Michael , Deponte Marcel 
Published: February 2013

ABSTRACT

Methylene blue and a series of recently developed 1,4-naphthoquinones, including 3-[4-(substituted)benzyl]-menadiones, are potent antimalarial agents
in vitro
and
in vivo
. The activity of these structurally diverse compounds against the human malaria parasite
Plasmodium falciparum
might involve their peculiar redox properties. According to the current theory, redox-active methylene blue and 3-[4-(trifluoromethyl)benzyl]-menadione are “subversive substrates.” These agents are thought to shuttle electrons from reduced flavoproteins to acceptors such as hemoglobin-associated or free Fe(III)-protoporphyrin IX. The reduction of Fe(III)-protoporphyrin IX could subsequently prevent essential hemoglobin digestion and heme detoxification in the parasite. Alternatively, owing to their structures and redox properties, methylene blue and 1,4-naphthoquinones might also affect the mitochondrial electron transport chain. Here, we tested the latter hypothesis using an established system of transgenic
P. falciparum
cell lines and the antimalarial agents atovaquone and chloroquine as controls. In contrast to atovaquone, methylene blue and 3-[4-(trifluoromethyl)benzyl]-menadione do not inhibit the mitochondrial electron transport chain. A systematic comparison of the morphologies of drug-treated parasites furthermore suggests that the three drugs do not share a mechanism of action. Our findings support the idea that methylene blue and 3-[4-(trifluoromethyl)benzyl]-menadione exert their antimalarial activity as redox-active subversive substrates.
Effectiveness of a Double-Carbapenem Regimen for Infections in Humans Due to Carbapenemase-Producing Pandrug-Resistant Klebsiella pneumoniae
Authors: Giamarellou Helen , Galani Lambrini , Baziaka Fotini , Karaiskos Ilias 
Published: February 2013

ABSTRACT

Ertapenem plus doripenem or meropenem were given in three patients suffering from pandrug-resistant, KPC-2-positive
Klebsiella pneumoniae
bacteremia (2 patients) and urinary tract infection (1 patient), respectively. All responded successfully, without relapse at follow-up. The results obtained should probably be attributed to ertapenem's increased affinity for the carbapenemases hindering doripenem/meropenem degradation in the environment of the microorganism.
OXA-235, a Novel Class D β-Lactamase Involved in Resistance to Carbapenems in Acinetobacter baumannii
Authors: Higgins Paul G. , Pérez-Llarena Francisco J. , Zander Esther , Fernández Ana , Bou Germán , Seifert Harald 
Published: February 2013

ABSTRACT

We investigated the mechanism of carbapenem resistance in 10
Acinetobacter baumannii
strains isolated from the United States and Mexico between 2005 and 2009. The detection of known metallo-β-lactamase or carbapenem-hydrolyzing oxacillinase (OXA) genes by PCR was negative. The presence of plasmid-encoded carbapenem resistance genes was investigated by transformation of
A. baumannii
ATCC 17978. Shotgun cloning experiments and sequencing were performed, followed by the expression of a novel β-lactamase in
A. baumannii
. Three novel OXA enzymes were identified, OXA-235 in 8 isolates and the amino acid variants OXA-236 (Glu173-Val) and OXA-237 (Asp208-Gly) in 1 isolate each. The deduced amino acid sequences shared 85% identity with OXA-134, 54% to 57% identities with the acquired OXA-23, OXA-24, OXA-58, and OXA-143, and 56% identity with the intrinsic OXA-51 and, thus, represent a novel subclass of OXA. The expression of OXA-235 in
A. baumannii
led to reduced carbapenem susceptibility, while cephalosporin MICs were unaffected. Genetic analysis revealed that
bla
OXA-235
,
bla
OXA-236
, and
bla
OXA-237
were bracketed between two IS
Aba1
insertion sequences. In addition, the presence of these acquired β-lactamase genes might result from a transposition-mediated mechanism. This highlights the propensity of
A. baumannii
to acquire multiple carbapenem resistance determinants.
A Heterologous Prime-Boost Vaccination Strategy Comprising the Francisella tularensis Live Vaccine StraincapBMutant and Recombinant Attenuated Listeria monocytogenes Expressing F. tularensis IglC Induces Potent Protective Immunity in Mice against Virulent F. tularensis Aerosol Challenge
Authors: Jia Qingmei , Bowen Richard , Sahakian Jacob , Dillon Barbara Jane , Horwitz Marcus A. 
Published: February 2013

ABSTRACTFrancisella tularensis, the causative agent of tularemia, is a category A bioterrorism agent. A vaccine that is safer and more effective than the currently available unlicensedF. tularensislive vaccine strain (LVS) is needed to protect against intentional release of aerosolizedF. tularensis, the most dangerous type of exposure. In this study, we employed a heterologous prime-boost vaccination strategy comprising intradermally administered LVS ΔcapB(highly attenuatedcapB-deficient LVS mutant) as the primer vaccine and rLm/iglC (recombinant attenuatedListeria monocytogenesexpressing theF. tularensisimmunoprotective antigen IglC) as the booster vaccine. Boosting LVS ΔcapB-primed mice with rLm/iglC significantly enhanced T cell immunity; their splenic T cells secreted significantly more gamma interferon (IFN-γ) and had significantly more cytokine (IFN-γ and/or tumor necrosis factor [TNF] and/or interleukin-2 [IL-2])-producing CD4+and CD8+T cells uponin vitroIglC stimulation. Importantly, mice primed with LVS ΔcapBor rLVS ΔcapB/IglC, boosted with rLm/iglC, and subsequently challenged with 10 50% lethal doses (LD50) of aerosolized highly virulentF. tularensisSchu S4 had a significantly higher survival rate and mean survival time than mice immunized with only LVS ΔcapB(P< 0.0001); moreover, compared with mice immunized once with LVS, primed-boosted mice had a higher survival rate (75% versus 62.5%) and mean survival time during the first 21 days postchallenge (19 and 20 days for mice boosted after being primed with LVS ΔcapBand rLVS ΔcapB/IglC, respectively, versus 17 days for mice immunized with LVS) and maintained their weight significantly better (P< 0.01). Thus, the LVS ΔcapB-rLm/iglC prime-boost vaccination strategy holds substantial promise for a vaccine that is safer and at least as potent as LVS.
Hepatocarcinogenesis Driven by GSNOR Deficiency Is Prevented by iNOS Inhibition
Authors: Tang Chi-Hui , Wei Wei , Hanes Martha A. , Liu Limin 
Published: February 2013

Abstract
Hepatocellular carcinoma (HCC) is one of the most common and deadly human cancers and it remains poorly managed. Human HCC development is often associated both with elevated expression of inducible nitric oxide synthase (iNOS) and with genetic deletion of the major denitrosylase S-nitrosoglutathione reductase (GSNOR/ADH5). However, their causal involvement in human HCC is not established. In mice, GSNOR deficiency causes S-nitrosylation and depletion of the DNA repair protein O6-alkylguanine-DNA-alkyltransferase (AGT) and increases rates of both spontaneous and DEN carcinogen-induced HCC. Here, we report that administration of 1400W, a potent and highly selective inhibitor of iNOS, blocked AGT depletion and rescued the repair of mutagenic O6-ethyldeoxyguanosines following DEN challenge in livers of GSNOR-deficient (GSNOR−/−) mice. Notably, short-term iNOS inhibition following DEN treatment had little effect on carcinogenesis in wild-type mice, but was sufficient to reduce HCC multiplicity, maximal size, and burden in GSNOR−/− mice to levels comparable with wild-type controls. Furthermore, increased HCC susceptibility in GSNOR−/− mice was not associated with an increase in interleukin 6, tumor necrosis factor-α, oxidative stress, or hepatocellular proliferation. These results suggested that GSNOR deficiency linked to defective DNA damage repair likely acts at the tumor initiation stage to promote HCC carcinogenesis. Together, our findings provide the first proof of principle that HCC development in the context of uncontrolled nitrosative stress can be blocked by pharmacologic inhibition of iNOS, possibly providing an effective therapy for patients with HCC. Cancer Res; 73(9); 2897–904. ©2013 AACR.
Vascular Normalization as an Emerging Strategy to Enhance Cancer Immunotherapy
Authors: Huang Yuhui , Goel Shom , Duda Dan G. , Fukumura Dai , Jain Rakesh K. 
Published: February 2013

Abstract
The recent approval of Provenge has brought new hope for anticancer vaccine therapies. However, the immunosuppressive tumor microenvironment seems to impair the efficacy of vaccine therapies. The abnormal tumor vasculature creates a hypoxic microenvironment that polarizes inflammatory cells toward immune suppression. Moreover, tumors systemically alter immune cells' proliferation, differentiation, and function via secretion of growth factors and cytokines. For example, VEGF, a major proangiogenic cytokine induced by hypoxia, plays a critical role in immunosuppression via these mechanisms. Hence, antiangiogenic treatment may be an effective modality to potentiate immunotherapy. Here, we discuss the local and systemic effects of VEGF on tumor immunity and propose a potentially translatable strategy to re-engineer the tumor–immune microenvironment and improve cancer immunotherapy by using lower “vascular normalizing” doses of antiangiogenic agents. Cancer Res; 73(10); 2943–8. ©2013 AACR.
Using Genetic Proxies for Lifecourse Sun Exposure to Assess the Causal Relationship of Sun Exposure with Circulating Vitamin D and Prostate Cancer Risk
Authors: Bonilla Carolina , Gilbert Rebecca , Kemp John P. , Timpson Nicholas J. , Evans David M. , Donovan Jenny L. , Hamdy Freddie C. , Neal David E. , Fraser William D. , Davey Smith George , Lewis Sarah J. , Lathrop Mark , Martin Richard M. 
Published: February 2013

Abstract
Background: Ecological and epidemiological studies have identified an inverse association of intensity and duration of sunlight exposure with prostate cancer, which may be explained by a reduction in vitamin D synthesis. Pigmentation traits influence sun exposure and therefore may affect prostate cancer risk. Because observational studies are vulnerable to confounding and measurement error, we used Mendelian randomization to examine the relationship of sun exposure with both prostate cancer risk and the intermediate phenotype, plasma levels of vitamin D.
Methods: We created a tanning, a skin color, and a freckling score as combinations of single nucleotide polymorphisms that have been previously associated with these phenotypes. A higher score indicates propensity to burn, have a lighter skin color and freckles. The scores were tested for association with vitamin D levels (25-hydroxyvitamin-D and 1,25-dihydroxyvitamin-D) and prostate-specific antigen detected prostate cancer in 3,123 White British individuals enrolled in the Prostate Testing for cancer and Treatment (ProtecT) study.
Results: The freckling score was inversely associated with 25(OH)D levels [change in 25(OH)D per score unit −0.27; 95% CI, −0.52% to −0.01%], and the tanning score was positively associated with prostate cancer risk (OR = 1.05; 95% CI, 1.02–1.09), after adjustment for population stratification and potential confounders.
Conclusions: Individuals who tend to burn are more likely to spend less time in the sun and consequently have lower plasma vitamin D levels and higher susceptibility to prostate cancer.
Impact: The use of pigmentation-related genetic scores is valuable for the assessment of the potential benefits of sun exposure with respect to prostate cancer risk. Cancer Epidemiol Biomarkers Prev; 22(4); 597–606. ©2013 AACR.
(In)visibility and the Process of Public Theology
Authors: Stoddart Eric 
Published: February 2013

Abstract
In this article the notion of (in)visibility as a skill and an analytical device is brought into the field of public theology, and, using political and sociological insights from Andrea Brighenti and Pierre Bourdieu, a theoretical basis is established. Further, a liturgical and eschatological hermeneutic is applied to relativize (in)visibility and to locate its development as a skill in a Christian narrative context. The article argues that (in)visibility offers a complementary paradigm to the auditory that otherwise attends predominantly to the substantive content of public theological interventions; hence, it contends, the process and consequences for others (not necessarily acting as public theologians) are to be encompassed in a model of public theology. In addition, a case study on a recent statement by a Roman Catholic bishop in Scotland is presented.
Overcoming the triad of rural health disparities: How local culture, lack of economic opportunity, and geographic location instigate health disparities
Authors: Thomas Tami L , DiClemente Ralph , Snell Samuel 
Published: February 2013

Objective: To discuss how the effects of culture, economy, and geographical location intersect to form a gestalt triad determining health-related disparities in rural areas. Methods: We critically profile each component of the deterministic triad in shaping current health-related disparities in rural areas; evaluate the uniquely composed intersections of these disparities in relation to Human Papillomavirus (HPV)-related cancer prevention in three isolated rural Georgia counties; and develop implications for future leadership in rural healthcare research, policy, and practice. Results: The deterministic triad of culture, economy, and geographical location is unique to a rural community, and even if two rural communities experience the same health disparity, each community is likely to have a discretely different composition of cultural, economic, and geographic determinants. Conclusion: The deterministic triad presents a challenge for health policymakers, researchers, and practitioners trying to develop health-related interventions that are equitable, efficacious, and practical in low-resource rural communities. The situation is worsened by the limited opportunities for employment, which leads to greater disparities and creates propagating cultural norms that further reduce access to healthcare and opportunities for sustainable health promotion.
Migraine with aura: A predictor of patent foramen ovale in children and adolescents
Authors: Choi Deok Young , Shin Dong Hoon , Cho Kang Ho , Lee Sang Pyo , Park Sanghui 
Published: February 2013

Background The prevalence of patent foramen ovale (PFO) is higher among adult migraine patients. The purpose of this study was to determine the frequency of PFO in children and adolescent migraine patients. Methods and results A total of 32 patients with migraine (divided into two subgroups, the migraine with aura subgroup and the migraine without aura subgroup) and 31 normal control subjects were enrolled in this study. All of the participants underwent transthoracic echocardiography with an agitated saline test. We compared the prevalence of PFO and the severity of right-to-left shunt (RLS) in each group. No statistical difference in age and sex ratio was observed in either group. The prevalence of PFO was higher in the migraine group than in the control group, but without statistical significance (46.9% vs. 25.8%, p = 0.084). The prevalence of PFO was significantly higher in the migraine with aura subgroup than in the migraine without aura subgroup ( p = 0.031) and the normal control group ( p = 0.0074). Migraine with aura was the only significant factor showing an association with PFO (<0.01). RLS size did not have an influence on migraine. Conclusions Considering the significantly high prevalence of PFO in pediatric migraine with aura patients, migraine with aura is a clear predictor of PFO among children and adolescents.
Use of serotonergic antidepressants and St John’s wort in older Australians: a population-based cohort study
Authors: Rahman Syed Ziaur , Basilakis Jim , Rahmadi Anton , Lujic Sanja , Musgrave Ian , Jorm Louisa , Hay Phillipa , Münch Gerald 
Published: February 2013

Objective: The study investigated the use of serotonergic antidepressants (SSRIs: selective serotonin reuptake inhibitors; SNRIs: serotonin–norepinephrine reuptake inhibitors) and St John’s wort in a large NSW-based community sample, and sought to identify a potentially dangerous concomitant use of these medications. Methods: Cross-sectional data from 266,848 participants from the ‘45 and Up’ study were used. The questionnaire captures self-reported treatment for depression or anxiety and antidepressant medications in the last four weeks. Results: 5.8% of participants received treatment for depression or anxiety, with 4.7% taking an SSRI and 1.3% an SNRI. St John’s wort was taken by 0.3% of the participants. Use of SSRIs and SNRIs was reported more frequently by females than males (respectively, 64.1% vs 35.9%, 66.9% vs 33.1%). The gender difference was even more pronounced for St John’s wort (75.6% vs. 24.4%). Use of antidepressants decreased after the age of 65 years. One hundred and forty people reported concurrent use of an SSRI and an SNRI, and 11 people of an SSRI with St John’s wort. Conclusions: Around 7% of the study population aged 45–65 years reported the use of SSRIs or SNRIs, decreasing to 5% above 70 years of age. It is of concern that some individuals used an SSRI concurrently with St John’s wort.
Cerebrospinal fluid fetuin-A is a biomarker of active multiple sclerosis
Authors: Harris Violaine K , Donelan Nicola , Yan Qi Jiang , Clark Kristi , Touray Amir , Rammal Mustapha , Sadiq Saud A 
Published: February 2013

Background: There is an urgent need for biomarkers in multiple sclerosis (MS) that can reliably measure ongoing disease activity relative to inflammation, neurodegeneration, and demyelination/remyelination. Fetuin-A was recently identified as a potential biomarker in MS cerebrospinal fluid (CSF). Fetuin-A has diverse functions, including a role in immune pathways. Objective: The objective of this research is to investigate whether fetuin-A is a direct indicator of disease activity. Methods: We measured fetuin-A in CSF and plasma of patients with MS and correlated these findings to clinical disease activity and natalizumab response. Fetuin-A expression was characterized in MS brain tissue and in experimental autoimmune encephalomyelitis (EAE) mice. We also examined the pathogenic role of fetuin-A in EAE using fetuin-A-deficient mice. Results: Elevated CSF fetuin-A correlated with disease activity in MS. In natalizumab-treated patients, CSF fetuin-A levels were reduced one year post-treatment, correlating with therapeutic response. Fetuin-A was markedly elevated in demyelinated lesions and in gray matter within MS brain tissue. Similarly, fetuin-A was elevated in degenerating neurons around demyelinated lesions in EAE. Fetuin-A-deficient mice demonstrated delayed onset and reduced severity of EAE symptoms. Conclusions: Our results show that CSF fetuin-A is a biomarker of disease activity and natalizumab response in MS. Neuronal expression of fetuin-A suggests that fetuin-A may play a pathological role in the disease process.
Mycobacterium avium subsp. paratuberculosis and multiple sclerosis in Sardinian patients: epidemiology and clinical features
Authors: Frau J , Cossu D , Coghe G , Lorefice L , Fenu G , Melis M , Paccagnini D , Sardu C , Murru MR , Tranquilli S , Marrosu MG , Sechi LA , Cocco E 
Published: February 2013

Background: Mycobacterium avium subspecies paratuberculosis (MAP) is an infectious factor recently found in association with multiple sclerosis (MS) in Sardinia. Objectives: The objectives of this study were to confirm this association and evaluate its role in clinical features. Methods: A total of 436 patients and 264 healthy controls (HCs) were included. We examined the blood of each individual for MAPDNA and MAP2694 antibodies using IS900-specific PCR and ELISA, respectively. Differences in MAP presence between the MS group and HCs were evaluated. In MS patients, we considered: gender, age, age at onset, duration of disease, course, EDSS, therapy, relapse/steroids at study time, and oligoclonal bands (OBs). Results: MAPDNA and MAP2694 antibodies were detected in 68 MS and six HCs ( p = 1.14 × 10−11), and 123 MS and 10 HCs ( p = 2.59 × 10−23), respectively. OBs were found with reduced frequency in MAP-positive patients (OR = 0.52; p = 0.02). MAP2694 antibodies were detected more in patients receiving MS treatments (OR = 2.26; p = 0.01), and MAPDNA in subjects on steroids (OR = 2.65; p = 0.02). Conclusion: Our study confirmed the association of MAP and MS in Sardinia. The low OB frequency in MAP patients suggests a peripheral role as a trigger in autoimmunity. MAP positivity might be influenced by steroids and MS therapy. Studies in other populations are needed to confirm the role of MAP in MS.
The balance between human maternal plasma angiotensin II and angiotensin 1-7 levels in early gestation pregnancy is influenced by fetal sex
Authors: Sykes Shane D , Pringle Kirsty G , Zhou Ang , Dekker Gustaaf A , Roberts Claire T , Lumbers Eugenie R ,   on behalf of the SCOPE Consortium
Published: February 2013

Hypothesis: There are fetal sex-associated differences in the circulating maternal renin–angiotensin system (RAS) in early pregnancy. Methods: Plasma prorenin, angiotensin (Ang) II, Ang 1-7 and angiotensin-converting enzyme (ACE) concentrations were measured at 15 weeks’ gestation in 131 women with uncomplicated pregnancies from the Adelaide SCOPE cohort. Uterine and umbilical artery Doppler sonography was performed at 20 weeks’ gestation. Results: At 15 weeks, women bearing female fetuses had higher maternal Ang II concentrations ( p = 0.017) and lower Ang 1-7 to Ang II ratios ( p = 0.016) than women bearing males. In women with male fetuses, Ang II positively correlated with birth weight ( p = 0.028) and prorenin negatively correlated with placental weight ( p = 0.014). Female fetuses had higher umbilical artery resistance indices ( p = 0.019) that were related to maternal prorenin concentrations ( p = 0.007). Conclusions: In early human pregnancy, the maternal RAS is influenced by fetal sex. The lower Ang 1-7 to Ang II ratios in women with female fetuses may contribute to the lower maternal peripheral microvascular flow as described previously and the lack of any positive effect of Ang II on fetal growth, as seen in women with male fetuses.
Benzopyrene Serum Concentration After Endovenous Laser Ablation of the Great Saphenous Vein
Authors: Klem T.M.A.L. , Stok M. , Grotenhuis B.A. , Faber M.J. , Leeuwen S.P.J. van , Janssen H. , Vrijland W.W. 
Published: February 2013

Background: During endovenous laser ablation (EVLA) of the great saphenous vein, patients often involuntarily mention an uncomfortable “burnt” smell and taste. When applying intense heat to proteins and carbohydrates, it is inevitable that polycyclic aromatic hydrocarbons (PAHs) are formed. This group of PAH includes the human carcinogen benzo[a]pyrene (B[a]P). This study determined the serum concentration of B[a]P just before and after EVLA. Methods: A total of 20 patients were included. The B[a]P serum concentration was determined just before and directly after EVLA. Results: In 18 patients, B[a]P was determined before and after EVLA. In 2 patients, EVLA was not possible. In this study, no elevated serum concentration of B[a]P was found before and after EVLA. Conclusion: It remains to be established which heat products cause the burnt smell and taste sensation in patients during EVLA. Further research is needed to determine whether EVLA can be considered as a safe procedure.