bluuebunny/crossref_metadata_2025 huggingface dataset:
Glycine Betaine Catabolism Contributes to Pseudomonas syringae Tolerance to Hyperosmotic Stress by Relieving Betaine-Mediated Suppression of Compatible Solute Synthesis
Authors: Li Shanshan , Yu Xilan , Beattie Gwyn A.
Published: March 2013

Many bacteria can accumulate glycine betaine for osmoprotection and catabolize it as a growth substrate, but how they regulate these opposing roles is poorly understood. InPseudomonas syringaeB728a, expression of the betaine catabolism genes was reduced by an osmotic upshift to an intermediate stress level, consistent with betaine accumulation, but was increased by an upshift to a high stress level, as confirmed by an accompanying increase in degradation of radiolabeled betaine. Deletion of thegbcABbetaine catabolism genes reduced osmotolerance at a high osmolarity, and this reduction was due to the relief of betaine-mediated suppression of compatible solute synthesis. This conclusion was supported by the findings that, at high osmolarity, the ΔgbcABmutant accumulated high betaine levels and low endogenous solutes and exhibited reduced expression of the solute synthesis genes. Moreover, the ΔgbcABmutant and a mutant deficient in the synthesis of the compatible solutes NAGGN and trehalose exhibited similar reductions in osmotolerance and also in fitness on bean leaves. Activation of betaine catabolism at high osmotic stress resulted, in part, from induction ofgbdR, which encodes the transcriptional activator GbdR. Betaine catabolism was subject to partial repression by succinate under hyperosmotic stress conditions, in contrast to strong repression in the absence of stress, suggesting that betaine functions both in nutrition and as an intracellular signal modulating solute synthesis under hyperosmotic stress conditions. Collectively, these results begin to provide a detailed mechanistic understanding of howP. syringaetransitions from reliance on exogenously derived betaine to the use of endogenous solutes during adaptation to hyperosmotic conditions.
EscE and EscG Are Cochaperones for the Type III Needle Protein EscF of Enteropathogenic Escherichia coli
Authors: Sal-Man Neta , Setiaputra Dheva , Scholz Roland , Deng Wanyin , Yu Angel C. Y. , Strynadka Natalie C. J. , Finlay B. Brett
Published: March 2013

Type III secretion systems (T3SSs) are central virulence mechanisms used by a variety of Gram-negative bacteria to inject effector proteins into host cells. The needle polymer is an essential part of the T3SS that provides the effector proteins a continuous channel into the host cytoplasm. It has been shown for a few T3SSs that two chaperones stabilize the needle protein within the bacterial cytosol to prevent its premature polymerization. In this study, we characterized the chaperones of the enteropathogenic
Escherichia coli
(EPEC) needle protein EscF. We found that Orf2 and Orf29, two poorly characterized proteins encoded within the EPEC locus of enterocyte effacement (LEE), function as the needle protein cochaperones. Our finding demonstrated that both Orf2 and Orf29 are essential for type III secretion (T3S). In addition, we found that Orf2 and Orf29 associate with the bacterial membrane and form a complex with EscF. Orf2 and Orf29 were also shown to disrupt the polymerization of EscF
in vitro
. Prediction of the tertiary structures of Orf2 and Orf29 showed high structural homology to chaperones of other T3SS needle proteins. Overall, our data suggest that Orf2 and Orf29 function as the chaperones of the needle protein, and therefore, they have been renamed EscE and EscG.
The General Stress Response Factor EcfG Regulates Expression of the C-2 Hopanoid Methylase HpnP in Rhodopseudomonas palustris TIE-1
Authors: Kulkarni Gargi , Wu Chia-Hung , Newman Dianne K.
Published: March 2013

Lipid molecules preserved in sedimentary rocks facilitate the reconstruction of events that have shaped the evolution of the Earth's biosphere. A key limitation for the interpretation of many of these molecular fossils is that their biological roles are still poorly understood. Here, we use
Rhodopseudomonas palustris
TIE-1 to identify factors that induce biosynthesis of 2-methyl hopanoids (2-MeBHPs), progenitors of 2-methyl hopanes, one of the most abundant biomarkers in the rock record. This is the first dissection of the regulation of
hpnP
, the gene encoding the C-2 hopanoid methylase, at the molecular level. We demonstrate that EcfG, the general stress response factor of alphaproteobacteria, regulates expression of
hpnP
under a variety of challenges, including high temperature, pH stress, and presence of nonionic osmolytes. Although higher
hpnP
transcription levels did not always result in higher amounts of total methylated hopanoids, the fraction of a particular kind of hopanoid, 2-methyl bacteriohopanetetrol, was consistently higher in the presence of most stressors in the wild type, but not in the Δ
ecfG
mutant, supporting a beneficial role for 2-MeBHPs in stress tolerance. The Δ
hpnP
mutant, however, did not exhibit a growth defect under the stress conditions tested except in acidic medium. This indicates that the inability to make 2-MeBHPs under most of these conditions can readily be compensated. Although stress is necessary to regulate 2-MeBHP production, the specific conditions under which 2-MeBHP biosynthesis is essential remain to be determined.
A Plasmid-Encoded Phosphatase Regulates Bacillus subtilis Biofilm Architecture, Sporulation, and Genetic Competence
Authors: Parashar Vijay , Konkol Melissa A. , Kearns Daniel B. , Neiditch Matthew B.
Published: March 2013

Bacillus subtilis
biofilm formation is tightly regulated by elaborate signaling pathways. In contrast to domesticated lab strains of
B. subtilis
which form smooth, essentially featureless colonies, undomesticated strains such as NCIB 3610 form architecturally complex biofilms. NCIB 3610 also contains an 80-kb plasmid absent from laboratory strains, and mutations in a plasmid-encoded homolog of a Rap protein, RapP, caused a hyperrugose biofilm phenotype. Here we explored the role of
rapP phrP
in biofilm formation. We found that RapP is a phosphatase that dephosphorylates the intermediate response regulator Spo0F. RapP appears to employ a catalytic glutamate to dephosphorylate the Spo0F aspartyl phosphate, and the implications of the RapP catalytic glutamate are discussed. In addition to regulating
B. subtilis
biofilm formation, we found that RapP regulates sporulation and genetic competence as a result of its ability to dephosphorylate Spo0F. Interestingly, while
rap phr
gene cassettes routinely form regulatory pairs; i.e., the mature
phr
gene product inhibits the activity of the
rap
gene product, the
phrP
gene product did not inhibit RapP activity in our assays. RapP activity was, however, inhibited by PhrH
in vivo
but not
in vitro
. Additional genetic analysis suggests that RapP is directly inhibited by peptide binding. We speculate that PhrH could be subject to posttranslational modification
in vivo
and directly inhibit RapP activity or, more likely, PhrH upregulates the expression of a peptide that, in turn, directly binds to RapP and inhibits its Spo0F phosphatase activity.
Vibrio cholerae VttR
A
and VttR
B
Regulatory Influences Extend beyond the Type 3 Secretion System Genomic Island
Authors: Chaand Mudit , Dziejman Michelle
Published: March 2013

A subset of non-O1/non-O139 serogroup strains of
Vibrio cholerae
cause disease using type 3 secretion system (T3SS)-mediated mechanisms. An ∼50-kb genomic island carries genes encoding the T3SS structural apparatus, effector proteins, and two transmembrane transcriptional regulators, VttR
A
and VttR
B
, which are ToxR homologues. Previous experiments demonstrated that VttR
A
and VttR
B
are necessary for colonization
in vivo
and promote bile-dependent T3SS gene expression
in vitro
. To better understand the scope of genes that are potential targets of VttR
A
and VttR
B
regulation, we performed deep RNA sequencing using O39 serogroup strain AM-19226 and derivatives carrying deletions in
vttR
A
and
vttR
B
grown in bile. Comparison of the transcript profiles from Δ
vttR
A
and Δ
vttR
B
mutant strains to the isogenic parent strain confirmed that VttR
A
and VttR
B
regulate expression of some T3SS island genes and provided additional information about relative expression levels and operon organization. Interestingly, the data also suggested that additional genes, located outside the T3SS island and encoding functions involved in motility, chemotaxis, type 6 secretion, transcriptional regulation, and stress responses, may also by regulated by VttR
A
and VttR
B
. We verified transcript levels for selected genes by quantitative reverse transcription (RT)-PCR and then focused additional studies on motility and biofilm formation. The results suggest that VttR
A
and VttR
B
act as part of a complex transcriptional network that coordinates virulence gene expression with multiple cellular phenotypes. VttR
A
and VttR
B
therefore represent horizontally acquired transcriptional regulators with the ability to influence global gene expression in addition to modulating gene expression within the T3SS genomic island.
The Interacting Cra and KdpE Regulators Are Involved in the Expression of Multiple Virulence Factors in Enterohemorrhagic Escherichia coli
Authors: Njoroge Jacqueline W. , Gruber Charley , Sperandio Vanessa
Published: March 2013

The human pathogen enterohemorrhagic
Escherichia coli
(EHEC) O157:H7 codes for two interacting DNA binding proteins, Cra and KdpE, that coregulate expression of the locus of enterocyte effacement (LEE) genes in a metabolite-dependent manner. Cra is a transcription factor that uses fluctuations in the concentration of carbon metabolism intermediates to positively regulate virulence of EHEC. KdpE is a response regulator that activates the transcription of homeostasis genes in response to salt-induced osmolarity and virulence genes in response to changes in metabolite concentrations. Here, we probed the transcriptional profiles of the Δ
cra
, Δ
kdpE
, and Δ
cra
Δ
kdpE
mutant strains and show that Cra and KdpE share several targets besides the LEE, but both Cra and KdpE also have independent targets. Several genes within O-islands (genomic islands present in EHEC but absent from
E. coli
K-12), such as
Z0639
,
Z0640
,
Z3388
,
Z4267
, and
espFu
(encoding an effector necessary for formation of attaching and effacing lesions on epithelial cells), were directly regulated by both Cra and KdpE, while
Z2077
was only regulated by Cra. These studies identified and confirmed new direct targets for Cra and KdpE that included putative virulence factors as well as characterized virulence factors, such as EspFu and EspG. These results map out the role of the two interacting regulators, Cra and KdpE, in EHEC pathogenesis and global gene regulation.
A novel approach in management of lateral luxation of primary tooth
Authors: Wankhade Abhijit D , Pandey Ramesh Kumar , Singh Rajeev Kumar , Gondhalekar Rajashree
Published: March 2013

Lateral luxation is defined as the displacement of the tooth in a direction other than axially. The present case report narrates management of laterally luxated primary maxillary central incisor with occlusal interference using an inclined plane fabricated with composite resin. The composite resin inclined plane was successfully used for correction of cross-bite caused due to lateral luxation particularly in delayed presentation of the case to the Pedodontics clinic after traumatic injury with occlusal interference.
Transient cauda equina syndrome: a subtle but sinister sign
Authors: Corns Robert , Hasegawa Harutomo , Jeffcote Toby , Ashkan Keyoumars
Published: March 2013

A 54-year-old man presented with symptoms of cauda equina syndrome, which spontaneously resolved. Initial MRI did not show any compression of the cauda equine; however, an unusual pattern of epidural fat lead to further investigation and ultimately the diagnosis.
Pigmented epithelioid melanocytoma: a new concept encompassing animal-type melanoma and epithelioid blue nevus
Authors: Gavriilidis Paschalis , Michalopoulou Ilektra , Chatzikakidou Kleopatra , Nikolaidou Anastasia
Published: March 2013

Pigmented epithelioid melanocytoma (PEM) is a recently proposed term which encompasses those melanocytic tumours previously designated as ‘animal-type melanoma’ or ‘pigment-synthesising melanoma’ and ‘epithelioid blue nevus’, the latter known to be associated with Carney's complex. We report a case of PEM in a previously well 26-year-old Caucasian woman who presented with a dark pigmented nodule on the anterior chest wall.
Factors associated with illness in athletes participating in the London 2012 Paralympic Games: a prospective cohort study involving 49 910 athlete-days
Authors: Schwellnus Martin , Derman Wayne , Jordaan Esme , Blauwet Cheri A , Emery Carolyn , Pit-Grosheide Pia , Patino Marques Norma-Angelica , Martinez-Ferrer Oriol , Stomphorst Jaap , Van de Vliet Peter , Webborn Nick , Willick Stuart E
Published: March 2013

Background

The incidence and factors associated with illness in Paralympic athletes have not been documented.

Aim

To determine the factors associated with illness in athletes participating in the London 2012 Paralympic Games.

Methods

A cohort of 3565 athletes from 160 of the 164 participating countries in the London 2012 Paralympic Games were followed over a 14-day period (precompetition period=3 days, competition period=11 days; 49 910 athlete-days). Daily illness data were obtained from (1) teams with their own medical support who completed a daily illness log (78 teams, 3329 athletes) on a novel web-based system and (2) teams without their own medical support through the local organising committee database (82 teams, 236 athletes). Illness information from all athletes included age, gender, type of sport and the main system affected.

Main outcome measurement

Incidence rate (IR) of illness (illness per 1000 athlete-days) and factors associated with IR (time period, gender, age and sport).

Results

The IR of illness was 13.2 (95% CI 12.2 to 14.2). The highest IR of illness was in the respiratory system, followed by the skin, digestive, nervous and genitourinary systems. The IR in the precompetition period was similar to that in the competition period, but the IR was significantly higher in athletics compared with other sports. Age and gender were not independent predictors of illness.

Conclusions

Illness is common in Paralympic athletes and the main factor associated with higher IR of illness was the type of sport (athletics).
Psychiatric disorders among women and men in assisted reproductive technology (ART) treatment. The Danish National ART-Couple (DANAC) cohort: protocol for a longitudinal, national register-based cohort study
Authors: Schmidt Lone , Hageman Ida , Hougaard Charlotte Ørsted , Sejbaek Camilla Sandal , Assens Maria , Ebdrup Ninna Hinchely , Pinborg Anja
Published: March 2013

Introduction

There are complex causal associations between mental disorders, fertility treatment, fertility treatment outcome and infertility per se. Eating disorders cause endocrine disturbances, anovulation and thereby infertility, and research has shown that infertility as well as unsuccessful assisted reproductive technology (ART) treatment are potential risk factors for developing a depression on a long-term basis. Despite the fact that worldwide more than 400 000 ART treatment cycles are performed every year, the causal associations between mental disorders, use of medication for mental disorders and ART treatment in both sexes have only been sparsely explored.

Method and analysis

The main objective of this national register-based cohort study is to assess women's and men's mental health before, during, and after ART treatment in comparison with the mental health in an age-matched population-based cohort of couples with no history of ART treatment. Furthermore, the objective is to study the reproductive outcome of ART treatment among women who have a registered diagnosis of a mental disorder or have used medication for mental disorders prior to ART treatment compared with women in ART treatment without a mental disorder. We will establish the Danish National ART-Couple (DANAC) cohort including all women registered with ART treatment in the Danish in vitro fertilisation Register during 1994–2009 (N=42 915) and their partners. An age-matched population-based comparison cohort of women without ART treatment (n=215 290) and their partners will be established. Data will be cross-linked with data from national registers on psychiatric disorders, medical prescriptions for mental disorders, births, causes of deaths and sociodemographic data. Survival analyses and other statistical analyses will be conducted on the development of mental disorders and use of medication for mental disorders for women and men both prior to and after ART treatment.
Reduction in arterial stiffness and vascular age by naltrexone-induced interruption of opiate agonism: a cohort study
Authors: Reece Albert Stuart , Hulse Gary Kenneth
Published: March 2013

Objective

To prospectively assess if opiate antagonist treatment or the opiate-free status could reverse opiate-related vasculopathy.

Design

Longitudinal Open Observational, Serial ‘N of One’, over 6.5 years under various treatment conditions: opiate dependence, naltrexone and opiate-free.

Setting

Primary care, Australia.

Participants

20 opiate-dependent patients (16 males: 16 cases of buprenorphine 4.11±1.17 mg, two of methadone 57.5±12.5 mg and two of heroin 0.75±0.25 g).

Intervention

Studies of central arterial stiffness and vascular reference age (RA) were performed longitudinally by SphygmoCor Pulse Wave Analysis (AtCor, Sydney).

Primary outcomes

Primary outcome was vascular age and arterial stiffness accrual under different treatment conditions.

Results

The mean chronological age (CA) was 33.62±2.03 years. The opiate-free condition was associated with a lower apparent vascular age both in itself (males: p=0.0402 and females: p=0.0360) and in interaction with time (males: p=0.0001 and females: p=0.0004), and confirmed with other measures of arterial stiffness. The mean modelled RA was 38.82, 37.73 and 35.05 years in the opiate, naltrexone and opiate-free conditions, respectively. The opiate-free condition was superior to opiate agonism after full multivariate adjustment (p=0.0131), with modelled RA/CA of 1.0173, 0.9563 and 0.8985 (reductions of 6.1% and 11.9%, respectively).

Conclusions

Data demonstrate that opiate-free status improves vascular age and arterial stiffness in previous chronic opiate users. The role of opiate antagonist treatment in achieving these outcomes requires future clarification and offers hope of novel therapeutic remediation.
TeamGAINS: a tool for structured debriefings for simulation-based team trainings
Authors: Kolbe Michaela , Weiss Mona , Grote Gudela , Knauth Axel , Dambach Micha , Spahn Donat R , Grande Bastian
Published: March 2013

Background

Improving patient safety by training teams to successfully manage emergencies is a major concern in healthcare. Most current trainings use simulation of emergency situations to practice and reflect on relevant clinical and behavioural skills. We developed TeamGAINS, a hybrid, structured debriefing tool for simulation-based team trainings in healthcare that integrates three different debriefing approaches: guided team self-correction, advocacy-inquiry and systemic-constructivist techniques.

Methods

TeamGAINS was administered during simulation-based trainings for clinical and behavioural skills for anaesthesia staff. One of the four daily scenarios involved all trainees, whereas the remaining three scenarios each involved only two trainees with the others observing them. Training instructors were senior anaesthesiologists and psychologists. To determine debriefing quality, we used a post-test-only (debriefing quality) and a pre-post-test (psychological safety, leader inclusiveness), no-control-group design. After each debriefing all trainees completed a self-report debriefing quality scale which we developed based on the Debriefing Assessment for Simulation in Healthcare and the Observational Structured Assessment of Debriefing. Perceived psychological safety and leader inclusiveness were measured before trainees’ first (premeasure) and after their last debriefing (postmeasure) at which time trainees’ reactions to the overall training were measured as well.

Results

Four senior anaesthetists, 29 residents and 28 nurses participated in a total of 40 debriefings resulting in 235 evaluations. Utility of debriefings was evaluated as highly positive. Pre-post comparisons revealed that psychological safety and leader inclusiveness significantly increased after the debriefings.

Conclusions

The results indicate that TeamGAINS could provide a useful debriefing tool for training anaesthesia staff on all levels of work experience. By combining state-of-the-art debriefing methods and integrating systemic-constructivist techniques, TeamGAINS has the potential to allow for a surfacing, reflecting on and changing of the dynamics of team interactions. Further research is necessary to systematically compare the effects of TeamGAINS’ components on the debriefing itself and on trainees’ changes in attitudes and behaviours.
Trans-jugular intrahepatic porto-systemic shunt placement for refractory ascites: a ‘real-world’ UK health economic evaluation
Authors: Parker Matthew J , Guha Neil , Stedman Brian , Hacking Nigel , Wright Mark
Published: March 2013

Objective

To assess the benefit of trans-jugular intrahepatic porto-systemic shunt (TIPS) placement for refractory ascites.

Design

A retrospective observational study of all patients undergoing TIPS for refractory ascites in our hospital between 2003 and 2012.

Setting

Secondary care.

Patients

Cirrhotic patients with refractory ascites.

Main outcome measures

We examined direct real-world (National Health Service) health related costs in the year before and after the TIPS procedure took place. Data were collected relating to the need for reintervention and hepatic encephalopathy.

Results

Data were available for 24 patients who underwent TIPS for refractory ascites (86% of eligible patients). TIPS was technically successful in all cases. Mean number of bed days in the year prior to TIPS was 30.3 and 14.3 in the year following (p=0.005). No patient had ascites at the end of the year after the TIPS with less requirement for paracentesis over the course of the year (p<0.001). Mean reduction in cost was £2759 per patient. TIPS was especially cost-effective in patients requiring between 6 and 12 drains per year with a mean saving of £9204 per patient.

Conclusions

TIPS is both a clinically effective and economically advantageous therapeutic option for selected patients with refractory ascites.
Hormone receptor expression in breast cancer: postanalytical issues
Authors: Lee Ming , Lee Cheok Soon , Tan Puay Hoon
Published: March 2013

Hormone receptor expression is a critical part of the pathological evaluation of breast cancer. Underpinning not only therapeutic decisions and prognosis, oestrogen receptor (ER) and progesterone receptor (PR) have been a consistent thread in the expanding knowledge of breast cancer. Accurate laboratory testing requires care and precision in preanalytical, analytical and postanalytical processes. In this report, postanalytical issues of pathologist interpretation of ER and PR status in breast cancer are discussed. Apart from key elements of the actual pathological assessment, it is important to realise that there are additional factors that can impact on sensitivity, specificity and dynamic range of hormone receptor expression as rendered on pathology. These include tumour characteristics and heterogeneity, biological changes of tumour progression and interacting molecules, all of which can influence the degree of hormone responsiveness in a particular individual with hormone receptor-positive breast cancer. There is a need to ensure participation in quality assurance programmes and slide exchanges, as well as to constantly keep abreast of emerging data on clinical trials and outcomes of hormone receptor-positive breast cancer.
Failure to improve door-to-needle time by switching to emergency physician-initiated thrombolysis for ST elevation myocardial infarction
Authors: Loch Alexander , Lwin Tint , Zakaria Idzwan Mohd , Abidin Imran Zainal , Wan Ahmad Wan Azman , Hautmann Oliver
Published: March 2013

Introduction

Achieving target door–needle times for ST elevation myocardial infarction remains challenging. Data on emergency department (ED) doctor-led thrombolysis in developing countries and factors causing delay are limited.

Objectives

To assess the effect on door–needle times by transferring responsibility for thrombolysis to the ED doctors and to identify predictors of prolonged door–needle times.

Methodology

Data on medical on-call team-led thrombolysis at a tertiary Asian hospital were prospectively collected from May 2007 to Aug 2008 (1st study period). In September 2008, ED doctors were empowered to perform thrombolysis. The practice change was accompanied by new guidelines, tick chart implementation, and training sessions. Data were then consecutively collected from September 2008 to May 2009 (2nd study period). Door-to-needle times for the 1st and 2nd study periods were compared. All cases were analysed for factors of delay by multiple logistic regression.

Results

297 patients were thrombolysed, 169 by the medical on-call team during the 1st study period and 128 by the ED doctors during the 2nd study period. Median door–needle times were 54 and 48 min, respectively (p=0.76). Significant delays were predicted by ‘incorrect initial ECG interpretation’ (adjusted OR (aOR) 14.3), ‘inappropriate triage’ (aOR 10.4) and ‘multiple referrals’ (aOR 5.9). No cases of inappropriate thrombolysis were recorded.

Conclusions

Transfer of responsibility for thrombolysis to the ED doctors did not improve door–needle times despite measures introduced to facilitate this change. Key causative factors for this failure were identified.
Restless legs syndrome: pathophysiology and modern management
Authors: Nagandla Kavitha , De Somsubhra
Published: March 2013

Restless legs syndrome (RLS) is a common sensory motor neurological disorder that is characterised by an irresistible urge to move the legs that significantly affects the quality of life of the patient. Prevalence in the general population is 5–25% and it is twice as prevalent in women as in men. RLS is the most common movement disorder in pregnancy with a fourfold increased risk of developing this disorder later in life. The pathophysiology of RLS is centred on dopaminergic dysfunction, reduced central nervous system iron, genetic linkages, or alteration in neurotransmitters such as hypocretins, endorphins levels and immune dysfunction and inflammatory mechanisms. With the emergence of new evidence, there are changes to the previous treatment recommendations for RLS. There is sufficient evidence to conclude that dopamine agonists such as rotigotine transdermal patch, pramipexole, ropinirole, gabapentin enacarbil, pregabalin and gabapentin are effective in the short-term treatment of RLS and rotigotine, followed by gabapentin enacarbil, ropinirole, pramipexole and gabapentin for long-term treatment. Based on expert consensus, the recommendation for daily RLS is dopamine agonists or gabapentin or low-potency opioids. Levodopa is less preferred for treating daily RLS due to its high risk of augmentation. For intermittent RLS, it is levodopa or dopamine agonists or low-potency opioids or benzodiazepines. For refractory RLS, the choice is to change to gabapentin or a different dopamine agonist, addition of a second agent like gabapentin or benzodiazepine to the existing drug or changing to a high-potency opioid or tramadol. Medications with safety record in pregnancy include opioids and antiepileptics such as carbamazepine and gabapentin. There are concerns that patients with RLS are at risk for metabolic deregulation, autonomic dysfunction and cardiovascular morbidity. However, a recent study concluded that RLS is not associated with increased risk of cardiovascular complications.
Interactions between A2A adenosine receptors, hydrogen peroxide, and KATP channels in coronary reactive hyperemia
Authors: Sharifi-Sanjani Maryam , Zhou Xueping , Asano Shinichi , Tilley Stephen , Ledent Catherine , Teng Bunyen , Dick Gregory M. , Mustafa S. Jamal
Published: March 2013

Myocardial metabolites such as adenosine mediate reactive hyperemia, in part, by activating ATP-dependent K+ (KATP) channels in coronary smooth muscle. In this study, we investigated the role of adenosine A2A and A2B receptors and their signaling mechanisms in reactive hyperemia. We hypothesized that coronary reactive hyperemia involves A2A receptors, hydrogen peroxide (H2O2), and KATP channels. We used A2A and A2B knockout (KO) and A2A/2B double KO (DKO) mouse hearts for Langendorff experiments. Flow debt for a 15-s occlusion was repaid 128 ± 8% in hearts from wild-type (WT) mice; this was reduced in hearts from A2A KO and A2A/2B DKO mice (98 ± 9 and 105 ± 6%; P < 0.05), but not A2B KO mice (123 ± 13%). Patch-clamp experiments demonstrated that adenosine activated glibenclamide-sensitive KATP current in smooth muscle cells from WT and A2B KO mice (90 ± 23% of WT) but not A2A KO or A2A/A2B DKO mice (30 ± 4 and 35 ± 8% of WT; P < 0.05). Additionally, H2O2 activated KATP current in smooth muscle cells (358 ± 99%; P < 0.05). Catalase, an enzyme that breaks down H2O2, attenuated adenosine-induced coronary vasodilation, reducing the percent increase in flow from 284 ± 53 to 89 ± 13% ( P < 0.05). Catalase reduced the repayment of flow debt in hearts from WT mice (84 ± 9%; P < 0.05) but had no effect on the already diminished repayment in hearts from A2A KO mice (98 ± 7%). Our findings suggest that adenosine A2A receptors are coupled to smooth muscle KATP channels in reactive hyperemia via the production of H2O2 as a signaling intermediate.
Mechanical induction of group V phospholipase A2causes lung inflammation and acute lung injury
Authors: Meliton Angelo Y. , Muñoz Nilda M. , Meliton Lucille N. , Birukova Anna A. , Leff Alan R. , Birukov Konstantin G.
Published: March 2013

Ventilation at high tidal volume may cause lung inflammation and barrier dysfunction that culminates in ventilator-induced lung injury (VILI). However, the mechanisms by which mechanical stimulation triggers the inflammatory response have not been fully elucidated. This study tested the hypothesis that onset of VILI is triggered by activation of secretory group V phospholipase A2(gVPLA2) in pulmonary vascular endothelium exposed to excessive mechanical stretch. High-magnitude cyclic stretch (18% CS) increased expression and surface exposure of gVPLA2 in human pulmonary endothelial cells (EC). CS-induced gVPLA2 activation was required for activation of ICAM-1 expression and polymorphonuclear neutrophil (PMN) adhesion to CS-preconditioned EC. By contrast, physiological CS (5% CS) had no effect on gVPLA2 activation or EC-PMN adhesion. CS-induced ICAM-1 expression and EC-PMN adhesion were attenuated by the gVPLA2-blocking antibody (MCL-3G1), general inhibitor of soluble PLA2, LY311727, or siRNA-induced EC gVPLA2 knockdown. In vivo, ventilator-induced lung leukocyte recruitment, cell and protein accumulation in the alveolar space, and total lung myeloperoxidase activity were strongly suppressed in gVPLA2 mouse knockout model or upon administration of MCL-3G1. These results demonstrate a novel role for gVPLA2 as the downstream effector of pathological mechanical stretch leading to an inflammatory response associated with VILI.
Exon B of human surfactant protein A2 mRNA, alone or within its surrounding sequences, interacts with 14-3-3; role ofcis-elements and secondary structure
Authors: Noutsios Georgios T. , Silveyra Patricia , Bhatti Faizah , Floros Joanna
Published: March 2013

Human surfactant protein A, an innate immunity molecule, is encoded by two genes: SFTPA1 (SP-A1) and SFTPA2 (SP-A2). The 5′ untranslated (5′UTR) splice variant of SP-A2 (ABD), but not of SP-A1 (AD), contains exon B (eB), which is an enhancer for transcription and translation. We investigated whether eB contains cis-regulatory elements that bind trans-acting factors in a sequence-specific manner as well as the role of the eB mRNA secondary structure. Binding of cytoplasmic NCI-H441 proteins to wild-type eB, eB mutant, AD, and ABD 5′UTR mRNAs were studied by RNA electromobility shift assays (REMSAs). The bound proteins were identified by mass spectroscopy and specific antibodies (Abs). We found that 1) proteins bind eB mRNA in a sequence-specific manner, with two cis-elements identified within eB to be important; 2) eB secondary structure is necessary for binding; 3) mass spectroscopy and specific Abs in REMSAs identified 14-3-3 proteins to bind (directly or indirectly) eB and the natural SP-A2 (ABD) splice variant but not the SP-A1 (AD) splice variant; 4) other ribosomal and cytoskeletal proteins, and translation factors, are also present in the eB mRNA-protein complex; 5) knockdown of 14-3-3 β/α isoform resulted in a downregulation of SP-A2 expression. In conclusion, proteins including the 14-3-3 family bind two cis-elements within eB of hSP-A2 mRNA in a sequence- and secondary structure-specific manner. Differential regulation of SP-A1 and SP-A2 is mediated by the 14-3-3 protein family as well as by a number of other proteins that bind UTRs with or without eB mRNA.
Survey and Challenges of QoE Management Issues in Wireless Networks
Authors: Baraković Sabina , Skorin-Kapov Lea
Published: March 2013

With the move towards converged all-IP wireless network environments, managing end-user Quality of Experience (QoE) poses a challenging task, aimed at meeting high user expectations and requirements regarding reliable and cost-effective communication, access to any service, anytime and anywhere, and across multiple operator domains. In this paper, we give a survey of state-of-the-art research activities addressing the field of QoE management, focusing in particular on the domain of wireless networks and addressing three management aspects: QoE modeling, monitoring and measurement, and adaptation and optimization. Furthermore, we identify and discuss the key aspects and challenges that need to be considered when conducting research in this area.
LHC Signatures of Vector-Like Quarks
Authors: Okada Yasuhiro , Panizzi Luca
Published: March 2013

This work provides an overview on the current status of phenomenology and searches for heavy vector-like quarks, which are predicted in many models of new physics beyond the Standard Model. Searches at Tevatron and at the LHC, here listed and shortly described, have not found any evidence for new heavy fermionic states (either chiral or vector-like) and have therefore posed strong bounds on their masses: depending on specific assumptions on the interactions and on the observed final state, vector-like quarks with masses up to roughly 400–600 GeV have been excluded by all experiments. In order to be as simple and model independent as possible, the chosen framework for the phenomenological analysis is an effective model with the addition of a vector-like quark representation (singlet, doublet, or triplet underSU(2)L) which couples through Yukawa interactions with all SM families. The relevance of different observables for the determination of bounds on mixing parameters is then discussed and a complete overview of possible two body final states for every vector-like quark is provided, including their subsequent decay into SM particles. A list and short description of phenomenological analyses present in the literature are also provided for reference purposes.
Approximate Controllability of Fractional Sobolev-Type Evolution Equations in Banach Spaces
Authors: Mahmudov N. I.
Published: March 2013

We discuss the approximate controllability of semilinear fractional Sobolev-type differential system under the assumption that the corresponding linear system is approximately controllable. Using Schauder fixed point theorem, fractional calculus and methods of controllability theory, a new set of sufficient conditions for approximate controllability of fractional Sobolev-type differential equations, are formulated and proved. We show that our result has no analogue for the concept of complete controllability. The results of the paper are generalization and continuation of the recent results on this issue.
Laparoscopic Repair of a Large Duodenal Perforation Secondary to an Indwelling Nasogastric Tube in a Tracheotomized Adult
Authors: Zachariah Sanoop Koshy
Published: March 2013

Laparoscopic repair of perforated duodenal ulcers is safe and effective in centers with experience and increasingly performed by laparoscopic surgeons. However, the role of laparoscopy for the management of large duodenal perforations (>1 cm) is unclear. To date, no experience has been reported with emergency laparoscopic repair of large perforations for gastroduodenal ulcers. The commonest reason for conversion to open surgery is a perforation size of more than 1 cm. This paper reports a case of a large duodenal perforation due to a nasogastric tube in a 26-year-old male who had undergone a tracheostomy, following a cut-throat injury. This large perforation was successfully diagnosed and repaired laparoscopically. This is probably the first paper in the English literature to report duodenal perforation due to a nasogastric tube in an adult and also the first report of a successful laparoscopic repair of a large duodenal perforation.
Towards Human Capture Movement: Estimation of Anatomical Movements of the Shoulder
Authors: Salmerón-Quiroz B. B. , Mendez-Barrios C. F. , Guerrero-Castellanos J. F. , Rodriguez-Paredes S. A. , Villegas-Medina G.
Published: March 2013

In this paper we focus on the human arm motion capture, which is motivated by the requirements in physical rehabilitation and training of stroke patients in the same way as monitoring of elderly person activities. The proposed methodology uses a data fusion of low-cost and low-weight MEMS sensors jointly to an a priori knowledge of the arm anatomy. The main goal is to estimate the arm position, the anatomical movements of the shoulder and its accelerations. We propose a discrete optimization based-approach which aims to search the optimal attitude ambiguity directly without decorrelation of ambiguity, and to computing the baseline vector consequently. The originality of this paper is to apply the discrete optimization to track the desired trajectory of a nonlinear system such as the Human Movement in the presence of uncertainties. The global asymptotic convergence of the nonlinear observer is guaranteed. Extensive tests of the presented methodology with real world data illustrate the effectiveness of the proposed procedure.
CpG ODN and ISCOMATRIX Adjuvant: A Synergistic Adjuvant Combination Inducing Strong T-Cell IFN-γResponses
Authors: McCluskie Michael J. , Weeratna Risini D. , Evans Dana M. , Makinen Shawn , Drane Debbie , Davis Heather L.
Published: March 2013

For the induction of robust humoral and cellular immune responses, a strong rationale exists to use vaccine-adjuvant combinations possessing both immune modulatory and enhanced delivery capabilities. Herein, we evaluated the combination of 2 different adjuvants, a TLR9 agonist, composed of synthetic oligodeoxynucleotides (ODN) containing immunostimulatory CpG motifs (CpG), and ISCOMATRIX adjuvant (ISCOMATRIX), composed of saponin, phospholipid, and cholesterol, which possesses both immunostimulatory and delivery properties. While both individual adjuvants have been shown effective in numerous preclinical and clinical studies, it is likely that for optimal adjuvant activity a combined adjuvant approach will be necessary. Herein, using three different antigens, namely, hepatitis B surface antigen (HBsAg), ovalbumin (OVA), and influenza A haemagglutinin antigen (HA), we show in mice that some adjuvant effects of CpG and ISCOMATRIX are further enhanced if they are used in combination. In particular, with all three antigens, IFN-γlevels were greatly increased with the CpG/ISCOMATRIX combination. The ability of the CpG/ISCOMATRIX combination to induce antitumor responses when administered with OVA following administration to mice of a highly metastatic OVA-secreting tumor cell line (B16-OVA melanoma) was also demonstrated. Thus the CpG/ISCOMATRIX combination may prove to be a valuable tool in the development of novel or improved vaccines.
Formation and Propagation of Local Traffic Jam
Authors: Qi Hong-sheng , Wang Dian-hai , Chen Peng
Published: March 2013

Large scale traffic congestion often stems from local traffic jam in single road or intersection. In this paper, macroscopic method was used to explore the formation and propagation of local traffic jam. It is found that (1) the propagation of traffic jam can be seen as the propagation of traffic signal parameters, that is, virtual split and virtual green time; (2) for a road with endogenous flow, entrance location influences the jam propagation. With the same demand (upstream links flow and entrance flow), the upstream got more influence; (3) when a one-lane road is thoroughly congested, virtual signal parameters everywhere are the same as that at stop line; for a basic road, the virtual signals work in a cooperative manner; (4) phase sequence is one important parameter that influences traffic performances during peak hour where spill back of channelization takes place. The same phase plan for left-turn flow and through flow would be preferred; (5) signal coordination plays an important role in traffic jam propagation and hence effective network signal parameters should be designed to prevent jam from propagation to the whole network. These findings would serve as a basis for future network traffic congestion control.
Overview and Discussion of the OECD/NRC Benchmark Based on NUPEC PWR Subchannel and Bundle Tests
Authors: Avramova M. , Rubin A. , Utsuno H.
Published: March 2013

The Pennsylvania State University (PSU) under the sponsorship of the US Nuclear Regulatory Commission (NRC) has prepared, organized, conducted, and summarized the Organisation for Economic Co-operation and Development/US Nuclear Regulatory Commission (OECD/NRC) benchmark based on the Nuclear Power Engineering Corporation (NUPEC) pressurized water reactor (PWR) subchannel and bundle tests (PSBTs). The international benchmark activities have been conducted in cooperation with the Nuclear Energy Agency (NEA) of OECD and the Japan Nuclear Energy Safety Organization (JNES), Japan. The OECD/NRC PSBT benchmark was organized to provide a test bed for assessing the capabilities of various thermal-hydraulic subchannel, system, and computational fluid dynamics (CFDs) codes. The benchmark was designed to systematically assess and compare the participants’ numerical models for prediction of detailed subchannel void distribution and department from nucleate boiling (DNB), under steady-state and transient conditions, to full-scale experimental data. This paper provides an overview of the objectives of the benchmark along with a definition of the benchmark phases and exercises. The NUPEC PWR PSBT facility and the specific methods used in the void distribution measurements are discussed followed by a summary of comparative analyses of submitted final results for the exercises of the two benchmark phases.
Noncanonical Regulation of the Hedgehog Mediator GLI1 by c-MYC in Burkitt Lymphoma
Authors: Yoon Joon Won , Gallant Marisa , Lamm Marilyn LG , Iannaccone Stephen , Vieux Karl-Frederic , Proytcheva Maria , Hyjek Elizabeth , Iannaccone Philip , Walterhouse David
Published: March 2013

Although Hedgehog signaling plays a major role in GLI1 transcription, there is now evidence suggesting that other pathways/genes, such as c-MYC, may also regulate GLI1 expression. We initiated studies in Burkitt lymphoma cells, which constitutively express c-MYC due to a chromosomal translocation, to determine whether Hedgehog or c-MYC regulates GLI1 expression. We show that all Burkitt lymphoma cell lines tested express GLI1, PTCH1, and SMO and that five of six Burkitt lymphomas express GLI1. Exposure to Sonic or Indian Hedgehog or cyclopamine (SMO inhibitor) does not modulate GLI1 expression, cell proliferation, or apoptosis in most Burkitt lymphoma cell lines. Sequence analysis of PTCH1, SMO, and SuFu failed to show mutations that might explain the lack of Hedgehog responsiveness, and we did not detect primary cilia, which may contribute to it. We show that c-MYC interacts with the 5′-regulatory region of GLI1, using chromatin immunoprecipitation (ChIP) assay, and E-box–dependent transcriptional activation of GLI1 by c-MYC in NIH3T3 and HeLa cells. The c-MYC small-molecule inhibitor 10058-F4 downregulates GLI1 mRNA and protein and reduces the viability of Burkitt lymphoma cells. Inhibition of GLI1 by GANT61 increases apoptosis and reduces viability of some Burkitt lymphoma cells. Collectively, our data provide evidence that c-MYC directly regulates GLI1 and support an antiapoptotic role for GLI1 in Burkitt lymphoma. Burkitt lymphoma cells do not seem to be Hedgehog responsive. These findings suggest a mechanism for resistance to SMO inhibitors and have implications for using SMO inhibitors to treat human cancers. Mol Cancer Res; 11(6); 604–15. ©2013 AACR.
Right Ventricular Function, Pulmonary Pressure Estimation, and Clinical Outcomes in Cardiac Resynchronization Therapy
Authors: Campbell Patricia , Takeuchi Madoka , Bourgoun Mikhail , Shah Amil , Foster Elyse , Brown Mary W. , Goldenberg Ilan , Huang David T. , McNitt Scott , Hall W. Jackson , Moss Arthur , Pfeffer Marc A. , Solomon Scott D. ,   for the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT) Investigators
Published: March 2013

Background—

Right ventricular function (RVF) is an important determinant of outcome in patients with heart failure, and those with severe RV dysfunction have worse outcome after cardiac resynchronization therapy (CRT). We used data from the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) Trial to determine whether therapy with CRT is influenced by or affects RV function and to define the relationship between RV function and outcomes.

Methods and Results—

A total of 1820 patients were randomly assigned to CRT plus implantable cardioverter defibrillator or implantable cardioverter defibrillator-only in a 3:2 ratio. We assessed RVF as RV fractional area change by echocardiography at baseline and after 1 year of therapy (n=1511 and 1273, respectively). The median RV fractional area change was 41%, with 10.9% of patients <35% at baseline. Baseline RVF did not modify the treatment effect of CRT on the primary outcome (interaction
P
=0.19). Randomization to CRT-implantable cardioverter defibrillator was associated with a greater improvement in RVF (ΔRV fractional area change 8.1% versus 5.4%;
P
<0.001), and improvement in RVF was related to subsequent outcomes. Every 5-point increase in RV fractional area change was associated with a 22% reduction in event rates (hazard ratio, 0.78; 95% confidence interval, 0.66–0.92;
P
=0.003), although this was not independent of the concurrent improvement in left ventricular function. Baseline tricuspid regurgitant velocity, a measure of pulmonary systolic pressure, was predictive of events in a multivariate analysis (hazard ratio, 1.86; 95% confidence interval, 1.24–2.8;
P
=0.003).

Conclusions—

In this population with mild heart failure symptoms, CRT was associated with improvement in RVF, which improved in parallel with improvement in left ventricular function. Patients with the best RVF at 1 year demonstrated the lowest subsequent event rates.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01294449.