bluuebunny/crossref_metadata_2025 huggingface dataset:
CD19‐Chimeric Antigen Receptor T Cells for Treatment of Chronic Lymphocytic Leukaemia and Acute Lymphoblastic Leukaemia
Authors: Lorentzen C. L. , Straten P. T.
Published: June 2015

Adoptive cell therapy (ACT) for cancer represents a promising new treatment modality. ACT based on the administration of cytotoxic T cells genetically engineered to express a chimeric antigen receptor (CAR) recognizing CD19 expressed by B cell malignancies has been shown to induce complete lasting responses in patients with chronic lymphocytic leukaemia (CLL) and acute lymphoblastic leukaemia (ALL). So far, eleven clinical trials including 99 CLL and ALL patients treated with CAR T cells targeting CD19 have been published, and the results from these trials are promising with impressive clinical responses in heavily pretreated patients. Thus, CAR T cell therapy has induced complete responses in both CLL and ALL, and surprisingly, current results indicate that patients with ALL are more prone to respond than are CLL patients. Importantly, the majority of CAR cell studies have observed severe therapy‐associated toxicities, which needs attention. Herein we review current data and discuss key aspects of this powerful approach to treat and potentially cure B cell malignancies.
Inclusion of human immunodeficiency virus Type 2 (HIV‐2) in a multiplex transcription‐mediated amplification assay does not affect detection of HIV‐1 and hepatitis B and C virus genotypes: a multicenter performance evaluation study
Authors: Grabarczyk Piotr , Koppelman Marco , Boland Fiona , Sauleda Silvia , Fabra Cécile , Cambie Giuseppe , Kopacz Aneta , O'Riordan Karen , van Drimmelen Harry , O'Riordan Joan , Lelie Nico
Published: June 2015

BACKGROUND

The Ultrio Elite assay (Hologic/Grifols) runs on the Panther blood screening system and is comparable to the Ultrio Plus assay apart from the addition of oligonucleotides for human immunodeficiency virus Type 2 (HIV‐2) detection. In this multicenter evaluation study the analytical sensitivity and genotype detection efficiency of the two assay versions were compared.

STUDY DESIGN AND METHODS

The analytical sensitivity and genotype detection efficiency were analyzed by replicate (18‐303) testing of 27 hepatitis B virus (HBV), hepatitis C virus (HCV), HIV‐1, and HIV‐2 standard dilution panels calibrated in international units (IUs) and copies/mL. A wider range of subgenotypes was tested at 25 copies/mL. Specificity was evaluated in 30,756 donor samples.

RESULTS

The 95% lower limits of detection (LODs) in Ultrio Elite assay on WHO standards were 4.6, 7.3, 23.5, and 23.3 IU/mL for HBV, HCV, HIV‐1, and HIV‐2, respectively, and ranged from 13 to 44, 7 to 23, 6 to 15, and 9 copies/mL on genotype panels of the respective viruses. Comparable LODs had been previously found on the same panels with the Ultrio Plus assay. The specificity was 99.95% on initial test and 100% in the repeat test algorithm.

CONCLUSION

The change in the oligonucleotide design of the Ultrio Elite assay to enable HIV‐2 detection has not affected the analytical sensitivity for the other viruses regardless of the genotype. Genotype reference panels are instrumental to compare the sensitivity of nucleic acid test assay versions and could serve as an alternative to seroconversion panels.
Local infusion of ascorbate augments NO‐dependent cutaneous vasodilatation during intense exercise in the heat
Authors: Meade Robert D. , Fujii Naoto , Alexander Lacy M. , Paull Gabrielle , Louie Jeffrey C. , Flouris Andreas D. , Kenny Glen P.
Published: June 2015

Key points

Recent work demonstrates that nitric oxide (NO) contributes to cutaneous vasodilatation during moderate (400 W of metabolic heat production) but not high (700 W of metabolic heat production) intensity exercise bouts performed in the heat (35°C).

The present study evaluated whether the impairment in NO‐dependent cutaneous vasodilatation was the result of a greater accumulation of reactive oxygen species during high (700 W of metabolic heat production) relative to moderate (500 W of metabolic heat production) intensity exercise.

It was shown that local infusion of ascorbate (an anti‐oxidant) improves NO‐dependent forearm cutaneous vasodilatation during high intensity exercise in the heat.

These findings provide novel insight into the physiological mechanisms governing cutaneous blood flow during exercise‐induced heat stress and provide direction for future research exploring whether oxidative stress underlies the impairments in heat dissipation that may occur in older adults, as well as in individuals with pathophysiological conditions such as type 2 diabetes.

Nitric oxide (NO)‐dependent cutaneous vasodilatation is reportedly diminished during exercise performed at a high (700 W) relative to moderate (400 W) rate of metabolic heat production. The present study evaluated whether this impairment results from increased oxidative stress associated with an accumuluation of reactive oxygen species (ROS) during high intensity exercise. On two separate days, 11 young (mean ± SD, 24 ± 4 years) males cycled in the heat (35°C) at a moderate (500 W) or high (700 W) rate of metabolic heat production. Each session included two 30 min exercise bouts followed by 20 and 40 min of recovery, respectively. Cutaneous vascular conductance (CVC) was monitored at four forearm skin sites continuously perfused via intradermal microdialysis with: (1) lactated Ringer solution (Control); (2) 10 mm ascorbate (Ascorbate); (3) 10 mm l‐NAME; or (4) 10 mm ascorbate + 10 mm l‐NAME (Ascorbate + l‐NAME). At the end of each 500 W exercise bout, CVC was attenuated with l‐NAME (∼35% CVCmax) and Ascorbate + l‐NAME (∼43% CVCmax) compared to Control (∼60% CVCmax; all P < 0.04); however, Ascorbate did not modulate CVC during exercise (∼60% CVCmax; both P > 0.87). Conversely, CVC was elevated with Ascorbate (∼72% CVCmax; both P < 0.03) but remained similar to Control (∼59% CVCmax) with l‐NAME (∼50% CVCmax) and Ascorbate + l‐NAME (∼47% CVCmax; all P > 0.05) at the end of both 700 W exercise bouts. We conclude that oxidative stress associated with an accumulation of ascorbate‐sensitive ROS impairs NO‐dependent cutaneous vasodilatation during intense exercise.
Adaptive Complex Function Projective Synchronization of Uncertain Complex Chaotic Systems
Authors: Zhang Fangfang , Liu Shutang
Published: June 2015

Complex function projective synchronization (CFPS) is the most general synchronization and it enhances the security of communication. However, there always exist unknown parameters for chaotic systems in the real world. Considering all possible cases of unknown parameters of two complex chaotic systems, we design adaptive CFPS schemes and parameters update laws based on speed-gradient (SG) method. The convergence factors and pseudogradient condition are added to regulate the convergence speed and increase robustness. SG method is extended from real field to complex field. Numerical simulations are performed to demonstrate the effectiveness and feasibility of the proposed schemes.
Characteristics of WNxCy films deposited using remote plasma atomic layer deposition with (MeCp)W(CO)2(NO) for Cu diffusion barrier
Authors: Kim Hyunjung , Park Jingyu , Jeon Heeyoung , Jang Woochool , Jeon Hyeongtag , Yuh Junhan
Published: June 2015

Diffusion barrier characteristics of tungsten–nitride–carbide (WNxCy) thin films interposed between Cu and SiO2 layers were studied. The WNxCy films were deposited by remote plasma atomic layer deposition (RPALD) using a metal organic source, (MeCp)W(CO)2(NO), and ammonia. Auger electron spectroscopy analysis indicated the WNxCy films consisted of tungsten, nitrogen, carbon, and oxygen. X-ray diffraction (XRD) analysis showed that the film deposited at 350 °C was nanocrystalline. The resistivity of WNxCy film deposited by RPALD was very low compared to that in previous research because of the lower nitrogen content and different crystal structures of the WNxCy. To verify the diffusion barrier characteristics of the WNxCy film, Cu films were deposited by physical vapor deposition after WNxCy film was formed by RPALD on Si substrate. The Cu/WNxCy/Si film stack was annealed in a vacuum by rapid thermal annealing at 500 °C. Cu diffusion through the barrier layer was verified by XRD. Stable film properties were observed up to 500 °C, confirming that WNxCy film is suitable as a Cu diffusion barrier in microelectronic circuits.
Single‐frequency excitation wideband MRI (SE‐WMRI)
Authors: Wu Edzer L. , Huang Yun‐An , Chiueh Tzi‐Dar , Chen Jyh‐Horng
Published: June 2015

Purpose:

In this study, single‐frequency excitation wideband magnetic resonance imaging (MRI) (SE‐WMRI) was proposed to obtain high‐quality accelerated images by reducing phase‐encoding steps while applying separation gradients.

Methods:

A zig‐zag k‐space trajectory with reduced phase‐encoding steps and an increased readout sampling rate was proposed. A unique gradient design with buffer intervals near the trajectory turns was employed to avoid undersampling and image artifacts. A gridding method and Fourier transform were used for image reconstruction. Quantitative analysis was performed on phantom images to investigate the characteristics of the acceleration method.

Results:

The proposed method showed evident improvements in the accelerated phantom images, substantially reducing the ringing and blurring artifacts found using previous methods. Furthermore, the accelerated images exhibited the same signal‐to‐noise ratio as standard imaging. The accelerated in vivo experiment also produced the same quality as standard imaging.

Conclusions:

The proposed SE‐WMRI method can effectively remove image artifacts and acquire images of higher temporal or spatial resolutions with less compromise.
An empirical study of the effect of granting multiple tries for online homework
Authors: Kortemeyer Gerd
Published: June 2015

When deploying online homework in physics courses, an important consideration is how many tries learners should be allowed to solve numerical free-response problems. While on the one hand, this number should be large enough to allow learners mastery of concepts and avoid copying, on the other hand, granting too many allowed tries encourages counter-productive behavior. We investigate data from an introductory calculus-based physics course that allowed different numbers of tries in different semesters. It turns out that the probabilities for successfully completing or abandoning problems during a particular try are independent of the number of tries already made, which indicates that students do not learn from their earlier tries. We also find that the probability for successfully completing a problem during a particular try decreases with the number of allowed tries, likely due to increased carelessness or guessing, while the probability to give up on a problem after a particular try is largely independent of the number of allowed tries. These findings lead to a mathematical model for learner usage of multiple tries, which predicts an optimum number of five allowed tries.
Are Cancer Survivors Physically Active? A Comparison by US States
Authors: Tannenbaum Stacey L. , McClure Laura A. , Asfar Taghrid , Sherman Recinda L. , LeBlanc William G. , Lee David J.
Published: June 2015

Background:

Cancer survivors who engage in physical activity (PA) have improved quality of life, reduced fatigue, and lower mortality rates. We compare the percentage of cancer survivors meeting PA recommendations for US states, stratified by age and gender, to identify the need for PA education and intervention among cancer survivors.

Methods:

Pooled data from the 1997–2010 National Health Interview Survey were used to determine and rank age-adjusted PA by state. American Cancer Society guidelines (≥150 min/wk of PA) were used to compare prevalence by state, stratified by age group (< 65 and ≥65) and gender.

Results:

Thirty-three percent of cancer survivors met PA recommendations. The highest age-adjusted compliance to PA recommendations was in Vermont (59.9%, 95% confidence interval [CI], 40.8–76.3) and the lowest was in Louisiana (14.8%, 95% CI, 9.6–22.1) and Mississippi (15.5%, 95% CI, 10.4–22.3). The lowest percentages meeting recommendations were in Arkansas for males (8.6%, 95% CI, 7.0–10.6), Louisiana for females (12.5%, 95% CI, 6.8–21.9), Louisiana for survivors < 65 (15.6%, 95% CI, 10.5–22.6), and West Virginia for those ≥65 years (12.7%, 95% CI, 7.6–20.6).

Conclusions:

Meeting PA recommendations by cancer survivors varies markedly by state of residence. Future efforts should target states with low percentages, tailoring interventions to the special needs of this high-risk population. The importance of PA should be incorporated within cancer survivorship care plans.
Variety, Enjoyment, and Physical Activity Participation Among High School Students
Authors: Michael Shannon L. , Coffield Edward , Lee Sarah M. , Fulton Janet E.
Published: June 2015

Background:

Federal guidelines state that youth should participate in a variety of physical activity (PA) they find enjoyable. Little is known, however, about how variety and enjoyment are associated with PA participation among adolescents.

Methods:

Data came from the 2010 National Youth Physical Activity and Nutrition Survey, a nationally representative survey of adolescents. Path analysis was used to examine the association of a variety of self-reported PA, defined as the number of activities and activity types (ie, team sports/weightlifting, individual activities, and other competitive/recreational sports), on self-reported PA enjoyment and participation. The analysis also examined whether enjoyment mediates the association between a variety of PA and participation. Separate models were estimated for boys and girls.

Results:

Number of activities was associated with increased PA enjoyment and participation. For boys and girls, team sports/weightlifting was associated with increased participation, and individual activities were indirectly associated with increased participation through enjoyment. For boys, team sports/weightlifting was indirectly related with participation.

Conclusions:

These findings suggest that participation in a variety of PA is associated with increased PA enjoyment and participation. Providing opportunities for adolescents to engage in a variety of activities might help them identify PA they enjoy and facilitate lifelong PA habits.
Findings From the EASY Minds Cluster Randomized Controlled Trial: Evaluation of a Physical Activity Integration Program for Mathematics in Primary Schools
Authors: Riley Nicholas , Lubans David R. , Holmes Kathryn , Morgan Philip J
Published: June 2015

Background:

To evaluate the impact of a primary school-based physical activity (PA) integration program delivered by teachers on objectively measured PA and key educational outcomes.

Methods:

Ten classes from 8 Australian public schools were randomly allocated to treatment conditions. Teachers from the intervention group were taught to embed movement-based learning in their students’ (n = 142) daily mathematics program in 3 lessons per week for 6 weeks. The control group (n = 98) continued its regular mathematics program. The primary outcome was accelerometer-determined PA across the school day. Linear mixed models were used to analyze treatment effects.

Results:

Significant intervention effects were found for PA across the school day (adjusted mean difference 103 counts per minute [CPM], 95% confidence interval [CI], 36.5–169.7, P = .008). Intervention effects were also found for PA (168 CPM, 95% CI, 90.1–247.4, P = .008) and moderate-to-vigorous PA (2.6%, 95% CI, 0.9–4.4, P = .009) in mathematics lessons, sedentary time across the school day (–3.5%, 95% CI, –7.0 to –0.13, P = .044) and during mathematics (–8.2%, CI, –13.0 to –2.0, P = .010) and on-task behavior (13.8%, 95% CI, 4.0–23.6, P = .011)—but not for mathematics performance or attitude.

Conclusion:

Integrating movement across the primary mathematics syllabus is feasible and efficacious.
Identification of small-molecule inhibitors of calcineurin-NFATc signaling that mimic the PxIxIT motif of calcineurin binding partners
Authors: Matsoukas Minos-Timotheos , Aranguren-Ibáñez Álvaro , Lozano Teresa , Nunes Virginia , Lasarte Juan José , Pardo Leonardo , Pérez-Riba Mercè
Published: June 2015

Finding compounds that target a specific phosphatase-substrate interaction may yield immunosuppressive drugs with fewer side effects.
Multicenter Retrospective Study of Cefmetazole and Flomoxef for Treatment of Extended-Spectrum-β-Lactamase-Producing Escherichia coli Bacteremia
Authors: Matsumura Yasufumi , Yamamoto Masaki , Nagao Miki , Komori Toshiaki , Fujita Naohisa , Hayashi Akihiko , Shimizu Tsunehiro , Watanabe Harumi , Doi Shoichi , Tanaka Michio , Takakura Shunji , Ichiyama Satoshi
Published: June 2015

The efficacy of cefmetazole and flomoxef (CF) for the treatment of patients with extended-spectrum β-lactamase-producing
Escherichia coli
(ESBL-EC) bacteremia (ESBL-CF group) was compared with that of carbapenem treatment for ESBL-EC patients (ESBL-carbapenem group) and with that of CF treatment in patients with non-ESBL-EC bacteremia (non-ESBL-CF group). Adult patients treated for
E. coli
bacteremia in four hospitals were retrospectively evaluated. The 30-day mortality rates in patients belonging to the ESBL-CF, ESBL-carbapenem, and non-ESBL-CF groups were compared as 2 (empirical and definitive therapy) cohorts. The adjusted hazard ratios (aHRs) for mortality were calculated using Cox regression models with weighting according to the inverse probability of propensity scores for receiving CF or carbapenem treatment. The empirical-therapy cohort included 104 patients (ESBL-CF, 26; ESBL-carbapenem, 45; non-ESBL-CF, 33), and the definitive-therapy cohort included 133 patients (ESBL-CF, 59; ESBL-carbapenem, 54; non-ESBL-CF, 20). The crude 30-day mortality rates for patients in the ESBL-CF, ESBL-carbapenem, and non-ESBL-CF groups were, respectively, 7.7%, 8.9%, and 3.0% in the empirical-therapy cohort and 5.1%, 9.3%, and 5.0% in the definitve-therapy cohort. In patients without hematological malignancy and neutropenia, CF treatment for ESBL-EC patients was not associated with mortality compared with carbapenem treatment (empirical-therapy cohort: aHR, 0.87; 95% confidence interval [CI], 0.11 to 6.52; definitive therapy cohort: aHR, 1.04; CI, 0.24 to 4.49). CF therapy may represent an effective alternative to carbapenem treatment for patients with ESBL-EC bacteremia for empirical and definitive therapy in adult patients who do not have hematological malignancy and neutropenia.
Interactions between QnrB, QnrB Mutants, and DNA Gyrase
Authors: Kim Eu Suk , Chen Chunhui , Braun Molly , Kim Hyo Youl , Okumura Ryo , Wang Yin , Jacoby George A. , Hooper David C.
Published: June 2015

Plasmid-encoded protein QnrB1 protects DNA gyrase from ciprofloxacin inhibition. Using a bacterial two-hybrid system, we evaluated the physical interactions between wild-type and mutant QnrB1, the GyrA and GyrB gyrase subunits, and a GyrBA fusion protein. The interaction of QnrB1 with GyrB and GyrBA was approximately 10-fold higher than that with GyrA, suggesting that domains of GyrB are important for stabilizing QnrB1 interaction with the holoenzyme. Sub-MICs of ciprofloxacin or nalidixic acid reduced the interactions between QnrB1 and GyrA or GyrBA but produced no reduction in the interaction with GyrB or a quinolone-resistant GyrA:S83L (GyrA with S83L substitution) mutant, suggesting that quinolones and QnrB1 compete for binding to gyrase. Of QnrB1 mutants that reduced quinolone resistance, deletions in the C or N terminus of QnrB1 resulted in a marked decrease in interactions with GyrA but limited or no effect on interactions with GyrB and an intermediate effect on interactions with GyrBA. While deletion of loop B and both loops moderately reduced the interaction signal with GyrA, deletion of loop A resulted in only a small reduction in the interaction with GyrB. The loop A deletion also caused a substantial reduction in interaction with GyrBA, with little effect of loop B and dual-loop deletions. Single-amino-acid loop mutations had little effect on physical interactions except for a Δ105I mutant. Therefore, loops A and B may play key roles in the proper positioning of QnrB1 rather than as determinants of the physical interaction of QnrB1 with gyrase.
Prolonged Entecavir Therapy Is Not Effective for HBeAg Seroconversion in Treatment-Naive Chronic Hepatitis B Patients with a Partial Virological Response
Authors: Lee Hyun Woong , Kwon Jae-Cheol , Oh In Soo , Chang Hye Young , Cha Young Joo , Choi Ik-Seong , Kim Hyung Joon
Published: June 2015

The aims of this study were to investigate the efficacy of prolonged entecavir (ETV) therapy in treatment-naive chronic hepatitis B (CHB) patients and to determine whether continuous ETV therapy is feasible to achieve HBeAg seroconversion, particularly in patients with partial virological response (PVR). A total of 142 treatment-naive patients with CHB were enrolled. The mean duration of treatment was 65 (range, 26 to 90) months, and 86 patients (60.6%) were HBeAg positive. PVR was defined as detectable hepatitis B virus (HBV) DNA (>116 copies/ml) at year 1. The cumulative incidence of virological response (VR) increased from 54.9% at year 1 to 98.2% at year 7. HBeAg positivity (odds ratio [OR], 4.146;
P
= 0.001) and initial alanine aminotransferase (ALT) (OR, 0.997;
P
= 0.004) were independent risk factors for PVR. Among the 64 patients with PVR, 47 patients (73.4%) achieved VR within 4 years after prolonged ETV therapy without treatment adaptation. Three patients (2.1%) experienced virological breakthrough and HBV variants with genotypic resistance. The cumulative rate of HBeAg seroconversion was significantly higher in the patients with VR than in the patients with PVR (
P
= 0.018). None of the PVR patients with HBV DNA at ≥5,000 copies/ml at year 1 ever experienced HBeAg seroconversion. Multivariate analysis identified VR at year 1 as the only determinant of HBeAg seroconversion (hazard ratio [HR], 3.009;
P
= 0.010). In conclusion, although there were patients with PVR, prolonged ETV therapy showed excellent VR, with only 2.1% emergence of viral resistance during a 7-year follow-up. However, to achieve HBeAg seroconversion, drug modification is needed for HBeAg-positive patients with PVR (especially those with HBV DNA at ≥5,000 copies/ml at year 1).
Moraxella catarrhalis Binds Plasminogen To Evade Host Innate Immunity
Authors: Singh Birendra , Al-Jubair Tamim , Voraganti Chandrashekar , Andersson Tobias , Mukherjee Oindrilla , Su Yu-Ching , Zipfel Peter , Riesbeck Kristian
Published: June 2015

Several bacterial species recruit the complement regulators C4b-binding protein, factor H, and vitronectin, resulting in resistance against the bactericidal activity of human serum. It was recently demonstrated that bacteria also bind plasminogen, which is converted to plasmin that degrades C3b and C5. In this study, we found that a series of clinical isolates (
n
= 58) of the respiratory pathogen
Moraxella catarrhalis
, which is commonly isolated from preschool children and adults with chronic obstructive pulmonary disease (COPD), significantly binds human plasminogen. Ubiquitous surface protein A2 (UspA2) and hybrid UspA2 (UspA2H) were identified as the plasminogen-binding factors in the outer membrane proteome of
Moraxella
. Furthermore, expression of a series of truncated recombinant UspA2 and UspA2H proteins followed by a detailed analysis of protein-protein interactions suggested that the N-terminal head domains bound to the kringle domains of plasminogen. The binding affinity constant (

K
D

) values of full-length UspA2
30–539
(amino acids 30 to 539 of UspA2) and full-length UspA2H
50–720
for immobilized plasminogen were 4.8 × 10
−8
M and 3.13 × 10
−8
M, respectively, as measured by biolayer interferometry. Plasminogen bound to intact
M. catarrhalis
or to recombinant UspA2/UspA2H was readily accessible for a urokinase plasminogen activator that converted the zymogen into active plasmin, as verified by the specific substrate S-2251 and a degradation assay with fibrinogen. Importantly, plasmin bound at the bacterial surface also degraded C3b and C5, which consequently may contribute to reduced bacterial killing. Our findings suggest that binding of plasminogen to
M. catarrhalis
may lead to increased virulence and, hence, more efficient colonization of the host.
Multiple Functions of Glutamate Uptake via Meningococcal GltT-GltM
l
-Glutamate ABC Transporter in Neisseria meningitidis Internalization into Human Brain Microvascular Endothelial Cells
Authors: Takahashi Hideyuki , Yanagisawa Tatsuo , Kim Kwang Sik , Yokoyama Shigeyuki , Ohnishi Makoto
Published: June 2015

We previously reported that
Neisseria meningitidis
internalization into human brain microvasocular endothelial cells (HBMEC) was triggered by the influx of extracellular
l
-glutamate via the GltT-GltM
l
-glutamate ABC transporter, but the underlying mechanism remained unclear. We found that the Δ
gltT
Δ
gltM
invasion defect in assay medium (AM) was alleviated in AM without 10% fetal bovine serum (FBS) [AM(−S)]. The alleviation disappeared again in AM(−S) supplemented with 500 μM glutamate. Glutamate uptake by the Δ
gltT
Δ
gltM
mutant was less efficient than that by the wild-type strain, but only upon HBMEC infection. We also observed that both GltT-GltM-dependent invasion and accumulation of ezrin, a key membrane-cytoskeleton linker, were more pronounced when
N. meningitidis
formed larger colonies on HBMEC under physiological glutamate conditions. These results suggested that GltT-GltM-dependent meningococcal internalization into HBMEC might be induced by the reduced environmental glutamate concentration upon infection. Furthermore, we found that the amount of glutathione within the Δ
gltT
Δ
gltM
mutant was much lower than that within the wild-type
N. meningitidis
strain only upon HBMEC infection and was correlated with intracellular survival. Considering that the
l
-glutamate obtained via GltT-GltM is utilized as a nutrient in host cells,
l
-glutamate uptake via GltT-GltM plays multiple roles in
N. meningitidis
internalization into HBMEC.
Aminoimidazole Carboxamide Ribotide Exerts Opposing Effects on Thiamine Synthesis in Salmonella enterica
Authors: Bazurto Jannell V. , Heitman Nicholas J. , Downs Diana M.
Published: June 2015

In
Salmonella enterica
, the thiamine biosynthetic intermediate 5-aminoimidazole ribotide (AIR) can be synthesized
de novo
independently of the early purine biosynthetic reactions. This secondary route to AIR synthesis is dependent on (i) 5-amino-4-imidazolecarboxamide ribotide (AICAR) accumulation, (ii) a functional phosphoribosylaminoimidazole-succinocarboxamide (SAICAR) synthetase (PurC; EC 6.3.2.6), and (iii) methionine and lysine in the growth medium. Studies presented here show that AICAR is a direct precursor to AIR
in vivo
. PurC-dependent conversion of AICAR to AIR was recreated
in vitro
. Physiological studies showed that exogenous nutrients (e.g., methionine and lysine) antagonize the inhibitory effects of AICAR on the ThiC reaction and decreased the cellular thiamine requirement. Finally, genetic results identified multiple loci that impacted the effect of AICAR on thiamine synthesis and implicated cellular aspartate levels in AICAR-dependent AIR synthesis. Together, the data here clarify the mechanism that allows conditional growth of a strain lacking the first five biosynthetic enzymes, and they provide additional insights into the complexity of the metabolic network and its plasticity.

IMPORTANCE
In bacteria, the pyrimidine moiety of thiamine is derived from aminoimidazole ribotide (AIR), an intermediate in purine biosynthesis. A previous study described conditions under which AIR synthesis is independent of purine biosynthesis. This work is an extension of that previous study and describes a new synthetic pathway to thiamine that depends on a novel thiamine precursor and a secondary activity of the biosynthetic enzyme PurC. These findings provide mechanistic details of redundancy in the synthesis of a metabolite that is essential for nucleotide and coenzyme biosynthesis. Metabolic modifications that allow the new pathway to function or enhance it are also described.
Identification of the Final Two Genes Functioning in Methanofuran Biosynthesis in Methanocaldococcus jannaschii
Authors: Wang Yu , Xu Huimin , Jones Michael K. , White Robert H.
Published: June 2015

All methanofuran structural variants contain a basic core structure of 4-[
N
-(γ-
l
-glutamyl)-
p
-(β-aminoethyl)phenoxymethyl]-(aminomethyl)furan (APMF-Glu) but have different side chains depending on the source organism. Recently, we identified four genes (MfnA, MfnB, MfnC, and MfnD) that are responsible for the biosynthesis of the methanofuran precursor γ-glutamyltyramine and 5-(aminomethyl)-3-furanmethanol-phosphate (F1-P) from tyrosine, glutamate, glyceraldehyde-3-P, and alanine in
Methanocaldococcus jannaschii
. How γ-glutamyltyramine and F1-P couple together to form the core structure of methanofuran was previously unknown. Here, we report the identification of two enzymes encoded by the genes
mj0458
and
mj0840
that catalyze the formation of F1-PP from ATP and F1-P and the condensation of F1-PP with γ-glutamyltyramine, respectively, to form APMF-Glu. We have annotated these enzymes as MfnE and MfnF, respectively, representing the fifth and sixth enzymes in the methanofuran biosynthetic pathway to be identified. Although MfnE was previously reported as an archaeal adenylate kinase, our present results show that MfnE is a promiscuous enzyme and that its possible physiological role is to produce F1-PP. Unlike other enzymes catalyzing coupling reactions involving pyrophosphate as the leaving group, MfnF exhibits a distinctive α/β two-layer sandwich structure. By comparing MfnF with thiamine synthase and dihydropteroate synthase, a substitution nucleophilic unimolecular (S
N
-1) reaction mechanism is proposed for MfnF. With the identification of MfnE and MfnF, the biosynthetic pathway for the methanofuran core structure APMF-Glu is complete.

IMPORTANCE
This work describes the identification of the final two enzymes responsible for catalyzing the biosynthesis of the core structure of methanofuran. The gene products of
mj0458
and
mj0840
catalyze the formation of F1-PP and the coupling of F1-PP with γ-glutamyltyramine, respectively, to form APMF-Glu. Although the chemistry of such a coupling reaction is widespread in biochemistry, we provide here the first evidence that such a mechanism is used in methanofuran biosynthesis. MfnF belongs to the hydantoinase A family (PF01968) and exhibits a unique α/β two-layer sandwich structure that is different from the enzymes catalyzing similar reactions. Our results show that MfnF catalyzes the formation of an ether bond during methanofuran biosynthesis. Therefore, this work further expands the functionality of this enzyme family.
Broncholithiasis presenting as bronchiectasis and recurrent pneumonias
Authors: Dakkak Melissa , Siddiqi Furqan , Cury James Davis
Published: June 2015

A broncholith is defined as the presence of calcified material within a bronchus or within a cavity communicating with a bronchus. It is most frequently caused byHistoplasmosisor tuberculosis (TB) spp. Bronchial distortion, irritation and erosion by broncholiths can cause bronchiectasis, recurrent pneumonias and haemoptysis. We present a case of recurrent pneumonia due to a broncholith, which resolved conservatively with antibiotics. Owing to recurrent fevers and post obstructive pneumonias, a lobectomy or rigid bronchoscopic removal were considered but the patient was deemed not to be a candidate for general anaesthesia due to her comorbidities. Broncholiths are an uncommon cause of bronchiectasis and recurrent pneumonias. However, the wide range of symptoms and low clinical suspicion are the main reasons why a diagnosis can be delayed. Various treatment options are available and the choice of therapy should be made depending on the broncholith's size, mobility, location and local surgical expertise.
Successful living donor liver transplantation of fulminant liver failure due to isoniazid prophylaxis
Authors: Çakır Tuğrul , Ara Cengiz , Soyer Hacı Vural , Koc Suleyman
Published: June 2015

Progressive liver failure is rarely seen in tuberculosis chemoprophylaxis with isoniazid. We present a case of a 32-year-old woman admitted to our clinic reporting abdominal pain, nausea and vomiting for 2 days. The initial diagnosis was fulminant toxic hepatitis due to isoniazid chemoprophylaxis, which was treated successfully with living donor transplantation. Tuberculosis continues to be a significant public health problem. Isoniazid-related hepatotoxicity is extremely rare in adults. The only treatment in cases of fulminant liver failure is orthotopic liver transplantation from a deceased or living donor. If a deceased donor is not available or the patient refuses this treatment, living donor transplantation is the only choice. Although rare, isoniazid used as protective therapy for pulmonary tuberculosis can lead to fulminant liver failure. When cadaveric liver transplantation is not available, living donor liver transplantation is vital.
Bony non-union in a patient receiving androgen deprivation therapy for prostate cancer
Authors: Ikram Adeel , Singh Jagwant , Ali Ahmad
Published: June 2015

We present a case of a 76-year-old man who underwent a corrective femoral osteotomy for a varus deformity and stress fractures. The patient was on androgen deprivation therapy (ADT) for prostate cancer and the osteotomy failed to heal. At 13 months, the ADT was stopped and bony union was achieved in 3 months. Orthopaedic surgeons treating fractures in this patient population need to aware of the problems associated with ADT and closely liaise with oncologists and urologists to stop ADT or start alternative treatment until bony union has been achieved.
From a fish tank injury to hospital haemodialysis: the serious consequences of drug interactions
Authors: Hill Fay Joanne , McCloskey Sarah Jane , Sheerin Neil
Published: June 2015

We present the case of a 68-year-old man admitted to hospital with severe acute kidney injury secondary to statin-induced rhabdomyolysis. Five weeks previously, the patient started a course of clarithromycin for infection of a finger wound withMycobacterium marinum. His current medications included simvastatin, which he continued along with clarithromycin. The severity of the acute kidney injury necessitated initial continuous venovenous haemofiltration followed by 12 haemodialysis sessions before a spontaneous improvement in renal function occurred. Statins are widely prescribed and we report this case to encourage increased vigilance in avoiding drug interactions known to increase the risk of statin-induced myopathy, including macrolide antibiotics, calcium channel antagonists and amiodarone. The authors would also like to highlight recent guidance on atorvastatin as the statin of choice in patients with chronic kidney disease, and of the need for dose adjustment in those with an estimated glomerular filtration rate less than 30 mLs/min/1.73 m².
Postpartum onset and subsequent relapse of eosinophilic granulomatosis with polyangiitis
Authors: Edwards Mark Hiley , Curtis Elizabeth Mary , Ledingham Joanna Mary
Published: June 2015

Eosinophilic granulomatosis with polyangiitis (EGPA) can affect women of childbearing age. However, reports of the disease in the postpartum period are limited. We present a case of postpartum-onset EGPA that went into clinical remission before relapsing in the subsequent postpartum period. Our patient presented with dyspnoea, arthralgia and rash, shown to be eosinophilic vasculitis, 3 days following the birth of her second child. CT of the thorax showed alveolar shadowing and mediastinal lymphadenopathy. She was treated successfully for EGPA with glucocorticoid therapy. She declined maintenance treatment during remission. Off treatment, she remained disease free throughout her next pregnancy. In the postpartum period she relapsed in an almost identical manner, requiring prolonged glucocorticoid therapy, cyclophosphamide and rituximab. This case highlights the importance of maintenance therapy around pregnancy in individuals with EGPA, and the need for careful monitoring of women with a history of EGPA in the postpartum period.
Predictors of hepatic decompensation after TACE for hepatocellular carcinoma
Authors: Kohla Mohamed A S , Abu Zeid Mai I , Al-Warraky Mohamed , Taha Hossam , Gish Robert G
Published: June 2015

Aim

To study predictive factors for hepatic decompensation after transarterial chemoembolisation (TACE) for hepatocellular carcinoma (HCC).

Methods

Between November 2009 and August 2010, of 254 patients with HCC who presented to our multidisciplinary HCC clinic for evaluation, 102 (40%) were amenable for TACE. In this prospective study, there were 102 patients with compensated cirrhosis with HCC and Child-Pugh Class A cirrhosis who underwent TACE at the National Liver Institute, Menoufiya University, Egypt. We excluded all patients with prior locoregional therapy, systemic therapy and/or surgical intervention. At baseline and at 1 month postprocedure, laboratory criteria, tumour criteria (size, number) and Child-Pugh score were recorded. Patients were classified into group 1 (no Child-Pugh point increase after TACE) and group 2 (one or more added Child-Pugh points after TACE, defining hepatic decompensation). Univariate and multivariate analyses were performed to identify factors predictive of hepatic decompensation.

Results

Patients were mostly males (82.4%) of mean age 58.4±8.1 years. The only significant changes in laboratory findings at 1 month after TACE were increased international normalised ratio, serum total bilirubin, alanine transaminase and aspartate transaminase and decreased serum albumin and α-fetoprotein (AFP). The statistically significant predictive factors for hepatic decompensation using univariate analysis were found to be baseline lower serum albumin, higher serum α-fetoprotein, more advanced Barcelona Clinic Liver Cancer (BCLC) stage, larger tumour size and a greater number of tumour nodules; with logistic regression, multivariate analysis found that at baseline larger tumour size (p=0.004 at 95% CI), higher serum AFP (p=0.046 at 95% CI) and lower serum albumin (p=0.033 at 95% CI) predicted decompensation; BCLC stage, number of tumour nodules and pre-TACE bilirubin did not predict changes in liver function.

Conclusions

Lower serum albumin and increased tumour burden (larger tumour size/more nodules and higher α-fetoprotein) at baseline may help predict post-TACE decompensation.
A stepped wedge, cluster controlled trial of an intervention to improve safety and quality on medical wards: the HEADS-UP study protocol
Authors: Pannick Samuel , Beveridge Iain , Ashrafian Hutan , Long Susannah J , Athanasiou Thanos , Sevdalis Nick
Published: June 2015

Introduction

The majority of preventable deaths in healthcare are due to errors on general wards. Staff perceptions of safety correlate with patient survival, but effectively translating ward teams’ concerns into tangibly improved care remains problematic. The Hospital Event Analysis Describing Significant Unanticipated Problems (HEADS-UP) trial evaluates a structured, multidisciplinary team briefing, capturing safety threats and adverse events, with rapid feedback to clinicians and service managers. This is the first study to rigorously assess a simpler intervention for general medical units, alongside an implementation model applicable to routine clinical practice.

Methods/analysis

7 wards from 2 hospitals will progressively incorporate the intervention into daily practice over 14 months. Wards will adopt HEADS-UP in a pragmatic sequence, guided by local clinical enthusiasm. Initial implementation will be facilitated by a research lead, but rapidly delegated to clinical teams. The primary outcome is excess length of stay (a surplus stay of 24 h or more, compared to peer institutions’ Healthcare Resource Groups-predicted length of stay). Secondary outcomes are 30-day readmission or excess length of stay; in-hospital death or death/readmission within 30 days; healthcare-acquired infections; processes of escalation of care; use of traditional incident-reporting systems; and patient safety and teamwork climates. HEADS-UP will be analysed as a stepped wedge cluster controlled trial. With 7840 patients, using best and worst case predictions, the study would achieve between 75% and 100% power to detect a 2–14% absolute risk reduction in excess length of stay (two-sided p<0.05). Regression analysis will use generalised linear mixed models or generalised estimating equations, and a time-to-event regression model. A qualitative analysis will evaluate facilitators and barriers to HEADS-UP implementation and impact.

Ethics and dissemination

Participating institutions’ Research and Governance departments approved the study. Results will be published in peer-reviewed journals and at conference presentations.

Trial registration number

ISRCTN34806867.
Do women seeking termination of pregnancy need pre-abortion counselling?
Authors: Baron Charlotte , Cameron Sharon , Johnstone Anne
Published: June 2015

Background

Pre-termination counselling is currently voluntary in the UK; however, there has been political debate regarding the introduction of mandatory pre-termination counselling as well as who should be providing the abortion counselling services.

Objective

To quantify the proportion of women who use pre-termination counselling services and to evaluate their experience.

Method

An anonymous self-administered questionnaire of women requesting an abortion at Chalmers Sexual Health Centre and the Royal Infirmary of Edinburgh NHS Lothian from 6 October to 2 December 2014.

Results

Only 18 (9%) of the 201 women surveyed reported using pre-termination counselling. The majority of women did not feel counselling was necessary because they were already certain of their decision. Nearly a quarter (22%) of women claimed to not know counselling was available. Women who did use counselling were satisfied with the services they received. The majority of counselling services were provided by the National Health Service and only one woman used a ‘pro-life’ charity. Women stated that they would prefer face-to-face counselling rather than telephone or Internet-based counselling.

Conclusions

Most women do not seem to want or need pre-termination counselling therefore policies aimed at mandatory counselling, would be contrary to women's wishes. Counselling should be targeted at women with risk factors for psychological complications post-termination.
Numerical simulations of seismic and post-seismic behavior of tailings
Authors: Ferdosi Behnam , James Michael , Aubertin Michel
Published: June 2015

Several tailings impoundments have failed as a result of earthquakes in the last few decades. A majority of these failures were due to direct seismic loading, tailings liquefaction during shaking, or the post-seismic behavior of the tailings as it relates to the dissipation of excess pore-water pressures that were generated during shaking. Previous work has indicated that the UBCSAND model developed by Byrne et al. in 1995 is capable of simulating the cyclic simple shear testing response of low-plasticity tailings over a range of consolidation stresses and cyclic shear ratios. However, the ability of the model to simulate the dynamic and subsequent behavior of such tailings for other conditions, such those induced by shaking table tests, has not yet been evaluated. In this regard, previous work has shown that the main components of the UBCSAND model cannot realistically simulate some specific responses, including the post-seismic volumetric strains related to excess pore-water pressure dissipation. This paper presents numerical modeling results of the dynamic behavior of tailings from hard rock mines. It introduces a method for simulating their post-seismic behavior by including an updating scheme for the elastic moduli into the UBCSAND model. The results of cyclic simple shear testing, seismic table testing, and complementary experimental relationships were used to calibrate and validate the model with its new component. The simulated response of tailings during cyclic simple shear testing and for a complete seismic table test shows that the proposed approach simulates the experimental observations well. Level-ground, seismically induced liquefaction and post-seismic behavior of a 15 m thick tailings deposit are also simulated, leading to post-liquefaction settlements that are in agreement with empirical relationships.
Analyzing the anti-ischemia–reperfusion injury effects of ginsenoside Rb1 mediated through the inhibition of p38α MAPK
Authors: Li Gonghao , Qian Wenhao , Zhao Changyun
Published: June 2015

Recent studies have demonstrated that ginsenoside Rb1 protects the myocardium from ischemia–reperfusion (I/R) injury. However, the precise mechanisms for this protection have not been determined. This study aimed to determine whether the attenuation of I/R-induced myocardial injury by ginsenoside Rb1 (GS Rb1) is due to inhibition of p38α mitogen-activated protein kinase (MAPK). Sprague–Dawley rats were distributed among 6 treatment groups: sham group; I/R group; p38 MAPK inhibitor SB203580 group (SB + I/R); GS Rb1 group (GS + I/R); p38 MAPK agonist anisomycin group (Ani + I/R); and the GS Rb1 + Ani group (GS + Ani + I/R). All of the anaesthetized rats, except those in the sham group, underwent an open-chest procedure that involved 30 min of myocardial ischemia followed by 2 h of reperfusion. Myocardial infarction size (MIS), caspase-3 activity, and levels of the cytokine tumor necrosis factor alpha (TNF-α) in the myocardium were monitored. The expressions of p38α MAPK, caspase-3, and TNF-α in the myocardium were assayed. GS Rb1 reduced MIS and attenuated caspase-3 activity and the levels of TNF-α in the myocardium. Protein expression of total p38α MAPK was not significantly altered. In the Ani + I/R and I/R groups, the levels of phospho-p38α MAPK were significantly increased compared with the sham group, and these increased levels were reduced with GS Rb1. Hemodynamic parameters were not significantly different between the GS + I/R and SB + I/R groups. GS Rb1 exerts an anti-apoptotic effect that protects against I/R injury by inhibiting p38α MAPK phosphorylation, suggesting that GS Rb1-mediated protection requires the inhibition of p38α MAPK.
2-Killing vector fields on warped product manifolds
Authors: Shenawy Sameh , Ünal Bülent
Published: June 2015

This paper provides a study of 2-Killing vector fields on warped product manifolds as well as characterization of this structure on standard static and generalized Robertson–Walker space-times. Some conditions for a 2-Killing vector field on a warped product manifold to be parallel are obtained. Moreover, some results on the curvature of a warped product manifolds in terms of 2-Killing vector fields are derived. Finally, we apply our results to describe 2-Killing vector fields of some well-known warped product space-time models.
HOW CONTRACTS AND CULTURE MEDIATE JOINT TRANSACTIONS OF INNOVATION PARTNERSHIPS
Authors: SCHWEITZER JOCHEN
Published: June 2015

Although the literature suggests that matters of contracting and governance in strategic innovation partnerships are interrelated and that governance of partnerships generally occurs with contractual heterogeneity, our understanding about the specific relationships between contracting and the partnership culture that facilitates joint transactions is rather vague. In this study, we clarify how the complexity of contractual agreements between partners in conjunction with the alignment of their innovation objectives and the ambiguity inherent in their mutual contributions to the partnership can be used to predict the culture of the partnership. We find that innovation partnerships result to be one of four types: bureaucratic, market, clan, or adhocracy. Our result emphasises the central role of contractual complexity as a suitable and relevant concept to capture the nature of inter-organisational innovation partnerships.