bluuebunny/crossref_metadata_2025 huggingface dataset:
Silencing of Essential Genes within a Highly Coordinated Operon in Escherichia coli
Authors: Goh Shan , Hohmeier Angela , Stone Timothy C. , Offord Victoria , Sarabia Francisco , Garcia-Ruiz Cristina , Good Liam
Published: June 2015

Essential bacterial genes located within operons are particularly challenging to study independently because of coordinated gene expression and the nonviability of knockout mutants. Essentiality scores for many operon genes remain uncertain. Antisense RNA (asRNA) silencing or in-frame gene disruption of genes may help establish essentiality but can lead to polar effects on genes downstream or upstream of the target gene. Here, the
Escherichia coli
ribF-ileS-lspA-fkpB-ispH
operon was used to evaluate the possibility of independently studying an essential gene using expressed asRNA and target gene overexpression to deregulate coupled expression. The gene requirement for growth in conditional silencing strains was determined by the relationship of target mRNA reduction with growth inhibition as the minimum transcript level required for 50% growth (MTL
50
). Mupirocin and globomycin, the protein inhibitors of IleS and LspA, respectively, were used in sensitization assays of strains containing both asRNA-expressing and open reading frame-expressing plasmids to examine deregulation of the overlapping
ileS-lspA
genes. We found upstream and downstream polar silencing effects when either
ileS
or
lspA
was silenced, indicating coupled expression. Weighted MTL
50
values (means and standard deviations) of
ribF
,
ileS
, and
lspA
were 0.65 ± 0.18, 0.64 ± 0.06, and 0.76 ± 0.10, respectively. However, they were not significantly different (
P
= 0.71 by weighted one-way analysis of variance). The gene requirement for
ispH
could not be determined due to insufficient growth reduction. Mupirocin and globomycin sensitization experiments indicated that
ileS-lspA
expression could not be decoupled. The results highlight the inherent challenges associated with genetic analyses of operons; however, coupling of essential genes may provide opportunities to improve RNA-silencing antimicrobials.
Feed Fermentation with Reuteran- and Levan-Producing Lactobacillus reuteri Reduces Colonization of Weanling Pigs by Enterotoxigenic Escherichia coli
Authors: Yang Yan , Galle Sandra , Le Minh Hong Anh , Zijlstra Ruurd T. , Gänzle Michael G.
Published: June 2015

This study determined the effect of feed fermentation with
Lactobacillus reuteri
on growth performance and the abundance of enterotoxigenic
Escherichia coli
(ETEC) in weanling piglets.
L. reuteri
strains produce reuteran or levan, exopolysaccharides that inhibit ETEC adhesion to the mucosa, and feed fermentation was conducted under conditions supporting exopolysaccharide formation and under conditions not supporting exopolysaccharide formation. Diets were chosen to assess the impact of organic acids and the impact of viable
L. reuteri
bacteria. Fecal samples were taken throughout 3 weeks of feeding; at the end of the 21-day feeding period, animals were euthanized to sample the gut digesta. The feed intake was reduced in pigs fed diets containing exopolysaccharides; however, feed efficiencies did not differ among the diets. Quantification of
L. reuteri
by quantitative PCR (qPCR) detected the two strains used for feed fermentation throughout the intestinal tract. Quantification of
E. coli
and ETEC virulence factors by qPCR demonstrated that fermented diets containing reuteran significantly (
P
< 0.05) reduced the copy numbers of genes for
E. coli
and the heat-stable enterotoxin in feces compared to those achieved with the control diet. Any fermented feed significantly (
P
< 0.05) reduced the abundance of
E. coli
and the heat-stable enterotoxin in colonic digesta at 21 days; reuteran-containing diets reduced the copy numbers of the genes for
E. coli
and the heat-stable enterotoxin below the detection limit in samples from the ileum, the cecum, and the colon. In conclusion, feed fermentation with
L. reuteri
reduced the level of colonization of weaning piglets with ETEC, and feed fermentation supplied concentrations of reuteran that may specifically contribute to the effect on ETEC.
A Minimal Set of Glycolytic Genes Reveals Strong Redundancies in Saccharomyces cerevisiae Central Metabolism
Authors: Solis-Escalante Daniel , Kuijpers Niels G. A. , Barrajon-Simancas Nuria , van den Broek Marcel , Pronk Jack T. , Daran Jean-Marc , Daran-Lapujade Pascale
Published: June 2015

As a result of ancestral whole-genome and small-scale duplication events, the genomes of
Saccharomyces cerevisiae
and many eukaryotes still contain a substantial fraction of duplicated genes. In all investigated organisms, metabolic pathways, and more particularly glycolysis, are specifically enriched for functionally redundant paralogs. In ancestors of the
Saccharomyces
lineage, the duplication of glycolytic genes is purported to have played an important role leading to
S. cerevisiae
's current lifestyle favoring fermentative metabolism even in the presence of oxygen and characterized by a high glycolytic capacity. In modern
S. cerevisiae
strains, the 12 glycolytic reactions leading to the biochemical conversion from glucose to ethanol are encoded by 27 paralogs. In order to experimentally explore the physiological role of this genetic redundancy, a yeast strain with a minimal set of 14 paralogs was constructed (the “minimal glycolysis” [MG] strain). Remarkably, a combination of a quantitative systems approach and semiquantitative analysis in a wide array of growth environments revealed the absence of a phenotypic response to the cumulative deletion of 13 glycolytic paralogs. This observation indicates that duplication of glycolytic genes is not a prerequisite for achieving the high glycolytic fluxes and fermentative capacities that are characteristic of
S. cerevisiae
and essential for many of its industrial applications and argues against gene dosage effects as a means of fixing minor glycolytic paralogs in the yeast genome. The MG strain was carefully designed and constructed to provide a robust prototrophic platform for quantitative studies and has been made available to the scientific community.
Prevalence and clinical significance of cardiac murmurs in schoolchildren
Authors: Kang Guanyang , Xiao Jianmin , Wang Yitong , Wang Jieying , Chen Yuqiang , Liu Qingchun , Chen Qiaozhu , Yang Fan , Li Wei , Chen Jiuhao
Published: June 2015

Objective

To determine the prevalence and clinical significance of heart murmurs detected during heart disease screening among apparently healthy schoolchildren.

Design

Cross-sectional study.

Setting

32 elementary schools in Dongguan City of China.

Patients

81 213 schoolchildren aged 5–13 years from different elementary schools.

Main outcome measures

The prevalence and clinical significance of heart murmurs among schoolchildren.

Results

Murmurs were detected in 2193 schoolchildren (2.7%), of whom 215 had a structural heart disease (SHD). Of patients who had SHD, 198 children had congenital heart disease (CHD), 12 had mitral valve prolapse and 5 had rheumatic heart disease. In patients who had CHD, the most common diagnosis was a ventricular septal defect. With respect to sex, SHDs were equally distributed between males and females. Of the schoolchildren who had a murmur, 1797 (81.9%) had a murmur with the loudness of grade 1 or 2 and 396 (18.1%) had a murmur with the loudness of grades 3–6. The prevalence of SHD fell significantly with increasing age.

Conclusions

The study suggested that apparently healthy schoolchildren with grade ≤2 cardiac murmurs are least likely to have underlying SHD, especially in those aged ≥10 years. However, echocardiography should be performed in younger schoolchildren with cardiac murmur grade ≥3.
A systematic review protocol examining the effect of vitamin D supplementation on endothelial function
Authors: Alyami A , Soares MJ , Sherriff JL , Zhao Y , Hallett J , Coombes F
Published: June 2015

Introduction

Vitamin D has potential benefits for extraskeletal health. These could include an anti-inflammatory effect as well as a reduction in endothelial dysfunction. We aim to provide quality evidence for the hypothesis that supplementation with vitamin D will improve endothelial function (EF), possibly through the abrogation of systemic inflammation.

Methods and analysis

We will conduct a systematic review of all randomised controlled trials on vitamin D supplementation and EF lasting 12 weeks or more. The search will cover the period 2000–2015 and include studies that describe direct measures of EF, markers of endothelial cell (EC) activation and if concurrently reported, indicators of systemic inflammation. Study selection will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and study quality will be assessed by the Jadad score in addition to an evaluation of allocation concealment and data analysis. If sufficient data are available, a meta-analysis will be conducted. The effect sizes will be generated using Hedges’ g score, for both fixed and random effect models. I2statistics and Galbraith plots will be used to assess heterogeneity and identify their potential sources. Potential publication and small sample size bias will be assessed by visual inspections of funnel plots and also Egger's test. Meta-regression analysis (if feasible) will be conducted with restricted maximum likelihood (REML) estimation method, controlling for potential confounders (demographics, study methods, location, etc). A backward elimination process will be applied in the regression modelling procedure. Subgroup analysis, conditional on number of studies retrieved and their sample size, will be stratified on participant disease category, total dose administered, degree of 25(OH)D change and type of supplement used.

Ethics and dissemination

Formal ethical approval is not required as primary data will not be collected. The results will be disseminated through a peer-reviewed publication, conference presentation and the popular press.

Trial registration number

International Prospective Register for Systematic Reviews (PROSPERO) number CRD42014013523.
Development and evaluation of an online tool for management of overweight children in primary care: a pilot study
Authors: Park Min Hae , Skow Áine , Puradiredja Dewi Ismajani , Lucas Anna , Syrad Hayley , Sovio Ulla , White Billy , Kessel Anthony S , Taylor Barry , Saxena Sonia , Viner Russell M , Kinra Sanjay
Published: June 2015

Objective

To explore the acceptability of implementing an online tool for the assessment and management of childhood obesity (Computer-Assisted Treatment of CHildren, CATCH) in primary care.

Design and setting

An uncontrolled pilot study with integral process evaluation conducted at three general practices in northwest London, UK (November 2012–April 2013).

Participants

Families with concerns about excess weight in a child aged 5–18 years (n=14 children).

Intervention

Families had a consultation with a doctor or nurse using CATCH, which assessed child weight status, cardiometabolic risk and risk of emotional and behavioural difficulties and provided personalised lifestyle advice. Families and practitioners completed questionnaires to assess the acceptability and usefulness of the consultation, and participated in semistructured interviews which explored user experiences.

Outcome measures

The primary outcome was family satisfaction with the tool-assisted consultation. Secondary outcomes were practitioners’ satisfaction, and acceptability and usefulness of the intervention to families and practitioners.

Results

The majority of families (86%, n=12) and all practitioners (n=4) were satisfied with the consultation. Participants reported that the tool was easy to use, the personalised lifestyle advice useful and the use of visual aids beneficial. Families and practitioners identified a need for practical, structured support for weight management following the consultation.

Conclusions

The results of this pilot study indicate that an online tool for assessment and management of childhood obesity can be implemented in primary care, and is acceptable to patients, families and practitioners. Further development and evaluation of the tool is warranted.
Presentation of respiratory symptoms prior to diagnosis in general practice: a case–control study examining free text and morbidity codes
Authors: Hayward Richard A , Chen Ying , Croft Peter , Jordan Kelvin P
Published: June 2015

Objective

General practitioners can record patients’ presenting symptoms by using a code or free text. We compared breathlessness and wheeze symptom codes and free text recorded prior to diagnosis of ischaemic heart disease (IHD), chronic obstructive pulmonary disease (COPD) and asthma.

Design

A case–control study.

Setting

11 general practices in North Staffordshire, UK, contributing to the Consultations in Primary Care Archive consultation database.

Participants

Cases with an incident diagnosis of IHD, COPD or asthma in 2010 were matched to controls (four per case) with no such diagnosis. All prior consultations with codes for breathlessness or wheeze symptoms between 2004 and 2010 were identified. Free text of cases and controls were also searched for mention of these symptoms.

Results

592 cases were identified, 194 (33%) with IHD, 182 (31%) with COPD and 216 (37%) with asthma. 148 (25%) cases and 125 (5%) controls had a prior coded consultation for breathlessness. Prevalence of a prior coded symptom of breathlessness or wheeze was 30% in cases, 6% in controls. Median time from first coded symptom to diagnosis among cases was 57 weeks. After adding symptoms recorded in text, prevalence rose to 62% in cases and 25% in controls. Median time from first recorded symptom increased to 144 weeks. The associations between diagnosis of cases and prior symptom codes was strong IHD relative risk ratio (RRR) 3.21 (2.15 to 4.79); COPD RRR 9.56 (6.74 to 13.60); asthma RRR 10.30 (7.17 to 14.90).

Conclusions

There is an association between IHD, COPD and asthma diagnosis and earlier consultation for respiratory symptoms. Symptoms are often noted in free text by GPs long before they are coded. Free text searching may aid investigation of early presentation of long-term conditions using GP databases, and may be an important direction for future research.
Safety of lamotrigine in paediatrics: a systematic review
Authors: Egunsola Oluwaseun , Choonara Imti , Sammons Helen M
Published: June 2015

Objectives

To identify adverse drug reactions associated with lamotrigine in children and compare the safety profile with other antiepileptic drugs.

Setting

Databases EMBASE (1974–April 2015), MEDLINE (1946–April 2015), PubMed and the Cochrane library for randomised controlled trials were searched for studies on safety of lamotrigine.

Participants

All studies involving paediatric patients aged ≤18 years who have received at least a single dose of lamotrigine with safety as an outcome measure were included.

Primary and secondary outcome measures

The primary outcome measure was safety of lamotrigine. Drug interaction of lamotrigine was the secondary outcome.

Results

A total of 78 articles involving 3783 paediatric patients were identified. There were 2222 adverse events (AEs) reported. Rash was the most commonly reported AE, occurring in 7.3% of the patients. Stevens-Johnson syndrome was rarely reported, with a risk of 0.09 per 100 patients. Discontinuation due to an adverse drug reaction (ADR) was recorded in 72 children (1.9% of all treated patients). Fifty-eight per cent of treatment discontinuation was attributed to different forms of rash and 21% due to increased seizures. Children on lamotrigine monotherapy had lower incidences of AEs. Headache (p=0.02), somnolence (<0.001), nausea (p=0.01), vomiting (p<0.001), dizziness (p<0.001) and abdominal pain (p=0.01) were significantly lower among children on monotherapy.

Conclusions

Rash was the most common ADR of lamotrigine and the most common reason for treatment discontinuation. Children receiving polytherapy have a higher risk of AEs than monotherapy users.

Trial registration number

CRD42013006910.
Predictive model for patients with poor-grade subarachnoid haemorrhage in 30-day observation: a 9-year cohort study
Authors: Szklener Sebastian , Melges Anna , Korchut Agnieszka , Zaluska Wojciech , Trojanowski Tomasz , Rejdak Robert , Rejdak Konrad
Published: June 2015

Objective

The purpose of this study was to identify prognostic factors and build the predictive model based on poor-grade subarachnoid haemorrhage (SAH) population received only supportive symptomatic treatment.

Design

Prospective observational cohort study.

Setting

Intensive care unit at the Clinical Department of Neurology.

Participants

A total of 101 patients with spontaneous SAH disqualified from neurosurgical operative treatment due to poor clinical condition. Data were collected over a 9-year period.

Outcome measures

Unfavourable outcome was defined as a modified Rankin Score ≥5 at 30 days of observation.

Results

Multivariable logistic regression analysis indicated the World Federation of Neurosurgical Societies Scale score, increasing age, Fisher grade and admission leucocytosis as independent predictive factors. The proposed scale subdivides the study population into four prognostic groups with significantly different outcomes: grade I: probability of favourable outcome 89.9%; grade II: 47.5%; grade III: 4.2%; grade IV: 0%. The receiver operating characteristic (ROC) curve for the prediction of outcome performed by the new scale had an area under the curve (AUC)=0.910 (excellent accuracy).

Conclusions

Unfavourable outcome in non-operated patients with poor-grade SAH is strongly predicted by traditional unmodifiable factors such as age, amount of bleeding in CT, level of consciousness as well as leucocytosis. A new predictive scale based on the above parameters seems to reliably predict the outcome and may contribute to more effective planning of therapeutic management in patients with poor-grade SAH.
Access and barriers to healthcare in the Kingdom of Saudi Arabia, 2013: findings from a national multistage survey
Authors: El Bcheraoui Charbel , Tuffaha Marwa , Daoud Farah , Kravitz Hannah , AlMazroa Mohammad A , Al Saeedi Mohammad , Memish Ziad A , Basulaiman Mohammed , Al Rabeeah Abdullah A , Mokdad Ali H
Published: June 2015

Objectives

We analysed data from a large household survey to identify barriers to healthcare in the Kingdom of Saudi Arabia.

Methods

The Saudi Health Interview Survey (SHIS) is a national multistage survey of individuals aged 15 years or older. The survey combined a household questionnaire and a laboratory blood analysis. We used a backward elimination multivariate logistic regression model to measure association between (1) diagnosis, (2) treatment, and (3) control of hypertension or diabetes and sociodemographic factors, history of diagnosis with chronic conditions, and type of, and distance travelled to, the clinic last visited.

Results

Between April and June 2013, a total of 10 735 participants completed SHIS and were invited to the local health clinics. Among hypertensive individuals, women, older individuals, and those previously diagnosed with diabetes and hypercholesterolaemia were more likely to have been diagnosed with hypertension than their counterparts. Among participants diagnosed with hypertension, the likelihood of being treated increased with age and education. The likelihood of having uncontrolled blood pressure despite treatment increased with education and a history of diagnosis with hypercholesterolaemia. Type of clinic visited and distance travelled to last clinic visit were not associated with diagnosis or treatment of hypertension or control of blood pressure. Similar factors were associated with the likelihood of diagnosis and treatment among individuals with diabetes. Having uncontrolled glycated haemoglobin levels, despite treatment, was less common among those who visited governmental clinics other than those of the Ministry of Health, compared with those who visited Ministry clinics.

Conclusions

Our findings highlight the importance of individual characteristics in healthcare-seeking practices rather than system-based potential barriers. Saudis seem to mostly seek healthcare when sick. Hence, the Saudi Ministry of Health needs to implement a comprehensive plan including health education and investigations, to understand the barriers and bottlenecks to healthcare-seeking behaviour.
Changes in body mass index and the prevalence of obesity during 1994–2008: repeated cross-sectional surveys and longitudinal analyses. The Tromsø Study
Authors: Jacobsen Bjarne K , Aars Nils Abel
Published: June 2015

Objectives

To determine the mean body mass index (BMI, kg/m2) and prevalence of low weight (BMI<20) and obesity (BMI≥30) in 3 population-based surveys, and to describe the longitudinal changes during 1994–2008 in mean BMI, and the prevalence of low weight and obesity.

Setting

A population study in Tromsø, Norway.

Participants

A total of 29 688 different participants in 1 or more of 3 surveys (1994–1995, 2001–2002 and 2007–2008). Longitudinal analyses comprised 9845 participants aged 25–69 in 1994 who participated in the 1994–1995 and 2007–2008 surveys and 4202 men and women who participated in all 3 surveys.

Outcome measures

Mean age-specific and sex-specific BMI, prevalence of low weight and obesity, and changes in BMI and prevalence of low weight and obesity during 1994–2008, according to sex and birth cohort.

Results

The age-adjusted (ages 30–84) prevalence of obesity increased from 9.8% and 11.8% in men and women, respectively, in 1994–1995 to 20.9% and 18.5%, respectively, in 2007–2008. The increase in mean age-adjusted BMI was stronger from 1994–1995 to 2001–2002 than from 2001–2002 to 2007–2008. Longitudinal results confirmed that the change in BMI from 1994–1995 to 2001–2002 was larger (0.9 kg/m2(95% CI 0.8 to 1.0) in men and 1.3 kg/m2(95% CI 1.2 to 1.4) in women) than from 2001–2002 to 2007–2008 (0.2 kg/m2(95% CI 0.1 to 0.3) in men and women). The most recently born had the largest increase (p<0.001).

Conclusions

The mean BMI and the prevalence of obesity are still increasing in Tromsø, and the increase is strongest in the youngest age groups. However, the increase in BMI was less marked in the last period (from 2001–2002 to 2007–2008) than in the first period (1994–1995 to 2001–2002).
Improving management of gout in primary care using a customised electronic records template
Authors: Moffat Keith , McNab Duncan
Published: June 2015

It is known that the management of chronic gout in relation to serum uric acid (SUA) monitoring, allopurinol dosing, and lifestyle advice is often sub-optimal in primary care.[1] A quality improvement project in the form of a criterion based audit was carried out in an urban general practice to improve the care of patients being treated for gout.

Baseline searching of EMIS confirmed that management of patients with gout who were taking allopurinol was not in line with current guidance. 51(40%) had a SUA checked in the past 12 months, 88(25%) had a SUA below target level, and gout lifestyle advice was not being recorded.

An audit was performed to measure and improve the following criteria:

• Monitoring of SUA levels in the past 12 months

• Titration of urate lowering therapy to bring the SUA below target level

• Lifestyle advice in the past 12 months

An audit standard of 60% achievement at 2 months and 80% achievement at 4 months was set.

The intervention consisted of a custom electronic template within EMIS which allowed guidance of gout management to be displayed and for data to be entered. All members of the team including GPs and administrative staff were educated regarding the intervention. This resulted in a sustained improvement over a 6 month period in all 3 components of the audit with 112(84%) having a SUA level checked, 79(51%) having a SUA below target level and 76(57%) receiving lifestyle advice. Although the improvement did not reach the audit standard in 2 of the criteria it would be expected that outcomes would continue given the systems changes which have been made.
Combined mineralocorticoid and glucocorticoid deficiency is caused by a novel founder nicotinamide nucleotide transhydrogenase mutation that alters mitochondrial morphology and increases oxidative stress
Authors: Weinberg-Shukron Ariella , Abu-Libdeh Abdulsalam , Zhadeh Fouad , Carmel Liran , Kogot-Levin Aviram , Kamal Lara , Kanaan Moien , Zeligson Sharon , Renbaum Paul , Levy-Lahad Ephrat , Zangen David
Published: June 2015

Background

Familial glucocorticoid deficiency (FGD) reflects specific failure of adrenocortical glucocorticoid production in response to adrenocorticotropic hormone (ACTH). Most cases are caused by mutations encoding ACTH-receptor components (MC2R, MRAP) or the general steroidogenesis protein (StAR). Recently, nicotinamide nucleotide transhydrogenase (NNT) mutations were found to cause FGD through a postulated mechanism resulting from decreased detoxification of reactive oxygen species (ROS) in adrenocortical cells.

Methods and results

In a consanguineous Palestinian family with combined mineralocorticoid and glucocorticoid deficiency, whole-exome sequencing revealed a novel homozygous NNT_c.598 G>A, p.G200S, mutation. Another affected, unrelated Palestinian child was also homozygous for NNT_p.G200S. Haplotype analysis showed this mutation is ancestral; carrier frequency in ethnically matched controls is 1/200. Assessment of patient fibroblasts for ROS production, ATP content and mitochondrial morphology showed that biallelic NNT mutations result in increased levels of ROS, lower ATP content and morphological mitochondrial defects.

Conclusions

This report of a novel NNT mutation, p.G200S, expands the phenotype of NNT mutations to include mineralocorticoid deficiency. We provide the first patient-based evidence that NNT mutations can cause oxidative stress and both phenotypic and functional mitochondrial defects. These results directly demonstrate the importance of NNT to mitochondrial function in the setting of adrenocortical insufficiency.
Distal access using hyperflexible atraumatic distal tip with optimized proximal stability of the Benchmark intracranial guide catheter for the treatment of cerebral vascular diseases: a technical note
Authors: Chandran Arun , Puthuran Mani , Eldridge Paul R , Nahser Hans C
Published: June 2015

Background

A stable guide catheter position within the intracranial vasculature is critical for safe, successful endovascular treatment.

Objective

To present ourinitial experience with the 0.071 inch inner diameter Benchmark guide catheter used in the treatment of intracranial cerebrovascular pathologies, demonstrating its safety and efficacy.

Methods

We retrospectively reviewed use of the Benchmark guide catheter from September through December 2014 in the management of various neuroendovascular intracranial pathologies. Clinical performance and complication rates were evaluated, with particular consideration of vessel tortuosity. A total of 62 Benchmarks were used, 47 in the anterior circulation, 10 in the posterior circulation, 4 in the external carotid, and 1 in the venous sinus. The five cases with access to the external carotid and venous sinus were excluded.

Results

The Benchmark was able to cross at least one 90° turn in 49 (86%) of the 57 patients. Reversal of the catheter was seen in 15% of 47 anterior circulation cases (4 at one 90° turn; 3 at two 90° turns). We report no complications of dissection or thromboembolic events. All guide catheter positions were safely achieved over a 0.035 Terumo stiff glidewire without need for an inner smaller lumen guide catheter for navigation.

Conclusions

Benchmark is a new guide catheter, with an ideal combination of both hyperflexible, atraumatic distal tip and optimized proximal shaft support to provide stable 6F primary access for a successful neurointerventional procedure. Benchmark can be easily, safely, and consistently positioned in a desired location within intracranial arteries providing a stable position for intervention and adequate angiography.
Role of the paraventricular nucleus in the reflex diuresis to pulmonary lymphatic obstruction in rabbits
Authors: Choudhary Rishabh Charan , Sharma Ravindra Kumar , Gulati Kavita , Ravi Krishnan
Published: June 2015

The changes in urine flow and renal sympathetic nerve activity (RSNA) due to pulmonary lymphatic obstruction (PLO) were examined in anesthetized, artificially ventilated New Zealand white rabbits. PLO was produced by pressurizing an isolated pouch created in the right external jugular vein at the points of entry of the right lymphatic ducts. During this maneuver, urine flow increased from 8.5 ± 0.3 mL/10 min to 12 ± 0.5 mL/10 min (P < 0.0001) and RSNA increased from 24.0 ± 4 to 40.0 ± 5 μV·s (P < 0.0001). Bilateral lesioning of the paraventricular nucleus (PVN) of the hypothalamus or cervical vagotomy abolished these responses. PLO increased c-fos gene expression in the PVN. The increase in urine flow due to PLO was attenuated by muscimol and abolished by kynurenic acid microinjections into the PVN. The results show that (i) neurons in the PVN are an important relay site in the reflex arc, which is activated by PLO; and (ii) this activation is regulated by glutamatergic and partly by GABAergic input to the PVN.
The nature of stress state: numerical and laboratory experiments and some field observations
Authors: Harper T. R. , Hagan J. T.
Published: June 2015

Simulations of the stress state in a region of discontinuously fractured rock revealed a strongly heterogeneous, self-organized stress distribution displaying internally balanced strains and corresponding energy storage. The explicit simulations follow a sequence which may be inferred to be irreversible and strongly dependent on interaction between fractures, implying a time-dependency. The state of the simulated reservoir displays a sensitivity characteristic of marginal stability. These numerical observations are compared with new and previous laboratory and field experiments spanning a wide range of size, stress magnitude and stress difference. The characteristics of the state of the simulated reservoir, laboratory samples and field behaviour are found to be consistent with the numerical predictions. A stress memory is evident. This supports previous conclusions that the concept of stress state as uniform, constant and resulting from averaged values of stresses or displacements, presently applied at remote and artificial boundaries, is grossly oversimplified and flawed.
Advances in Mass Spectrometric Tools for Probing Neuropeptides
Authors: Buchberger Amanda , Yu Qing , Li Lingjun
Published: June 2015

Neuropeptides are important mediators in the functionality of the brain and other neurological organs. Because neuropeptides exist in a wide range of concentrations, appropriate characterization methods are needed to provide dynamic, chemical, and spatial information. Mass spectrometry and compatible tools have been a popular choice in analyzing neuropeptides. There have been several advances and challenges, both of which are the focus of this review. Discussions range from sample collection to bioinformatic tools, although avenues such as quantitation and imaging are included. Further development of the presented methods for neuropeptidomic mass spectrometric analysis is inevitable, which will lead to a further understanding of the complex interplay of neuropeptides and other signaling molecules in the nervous system.
Forensic Mass Spectrometry
Authors: Hoffmann William D. , Jackson Glen P.
Published: June 2015

Developments in forensic mass spectrometry tend to follow, rather than lead, the developments in other disciplines. Examples of techniques having forensic potential born independently of forensic applications include ambient ionization, imaging mass spectrometry, isotope ratio mass spectrometry, portable mass spectrometers, and hyphenated chromatography–mass spectrometry instruments, to name a few. Forensic science has the potential to benefit enormously from developments that are funded by other means, if only the infrastructure and personnel existed to adopt, validate, and implement the new technologies into casework. Perhaps one unique area in which forensic science is at the cutting edge is in the area of chemometrics and the determination of likelihood ratios for the evaluation of the weight of evidence. Such statistical techniques have been developed most extensively for ignitable-liquid residue analyses and isotope ratio analysis. This review attempts to capture the trends, motivating forces, and likely impact of developing areas of forensic mass spectrometry, with the caveat that none of this research is likely to have any real impact in the forensic community unless: (a) The instruments developed are turned into robust black boxes with red and green lights for positives and negatives, respectively, or (b) there are PhD graduates in the workforce who can help adopt these sophisticated techniques.
Cell-Based Microarrays for In Vitro Toxicology
Authors: Wegener Joachim
Published: June 2015

DNA/RNA and protein microarrays have proven their outstanding bioanalytical performance throughout the past decades, given the unprecedented level of parallelization by which molecular recognition assays can be performed and analyzed. Cell microarrays (CMAs) make use of similar construction principles. They are applied to profile a given cell population with respect to the expression of specific molecular markers and also to measure functional cell responses to drugs and chemicals. This review focuses on the use of cell-based microarrays for assessing the cytotoxicity of drugs, toxins, or chemicals in general. It also summarizes CMA construction principles with respect to the cell types that are used for such microarrays, the readout parameters to assess toxicity, and the various formats that have been established and applied. The review ends with a critical comparison of CMAs and well-established microtiter plate (MTP) approaches.
On the Cool Side: Modeling the Atmospheres of Brown Dwarfs and Giant Planets
Authors: Marley M.S. , Robinson T.D.
Published: June 2015

The atmosphere of a brown dwarf or extrasolar giant planet controls the spectrum of radiation emitted by the object and regulates its cooling over time. Although the study of these atmospheres has been informed by decades of experience modeling stellar and planetary atmospheres, the distinctive characteristics of these objects present unique challenges to forward modeling. In particular, complex chemistry arising from molecule-rich atmospheres, molecular opacity line lists (sometimes running to 10 billion absorption lines or more), multiple cloud-forming condensates, and disequilibrium chemical processes all combine to create a challenging task for any modeling effort. This review describes the process of incorporating these complexities into one-dimensional radiative-convective equilibrium models of substellar objects. We discuss the underlying mathematics as well as the techniques used to model the physics, chemistry, radiative transfer, and other processes relevant to understanding these atmospheres. The review focuses on methods for creating atmosphere models and briefly presents some comparisons of model predictions to data. Current challenges in the field and some comments on the future conclude the review.
Transcription Factors That Defend Bacteria Against Reactive Oxygen Species
Authors: Imlay James A.
Published: June 2015

Bacteria live in a toxic world in which their competitors excrete hydrogen peroxide or superoxide-generating redox-cycling compounds. They protect themselves by activating regulons controlled by the OxyR, PerR, and SoxR transcription factors. OxyR and PerR sense peroxide when it oxidizes key thiolate or iron moieties, respectively; they then induce overlapping sets of proteins that defend their vulnerable metalloenzymes. An additional role for OxyR in detecting electrophilic compounds is possible. In some nonenteric bacteria, SoxR appears to control the synthesis and export of redox-cycling compounds, whereas in the enteric bacteria it defends the cell against the same agents. When these compounds oxidize its iron-sulfur cluster, SoxR induces proteins that exclude, excrete, or modify them. It also induces enzymes that defend the cell against the superoxide that such compounds make. Recent work has brought new insight into the biochemistry and physiology of these responses, and comparative studies have clarified their evolutionary histories.
Priming for Enhanced Defense
Authors: Conrath Uwe , Beckers Gerold J.M. , Langenbach Caspar J.G. , Jaskiewicz Michal R.
Published: June 2015

When plants recognize potential opponents, invading pathogens, wound signals, or abiotic stress, they often switch to a primed state of enhanced defense. However, defense priming can also be induced by some natural or synthetic chemicals. In the primed state, plants respond to biotic and abiotic stress with faster and stronger activation of defense, and this is often linked to immunity and abiotic stress tolerance. This review covers recent advances in disclosing molecular mechanisms of priming. These include elevated levels of pattern-recognition receptors and dormant signaling enzymes, transcription factor HsfB1 activity, and alterations in chromatin state. They also comprise the identification of aspartyl-tRNA synthetase as a receptor of the priming activator β-aminobutyric acid. The article also illustrates the inheritance of priming, exemplifies the role of recently identified priming activators azelaic and pipecolic acid, elaborates on the similarity to defense priming in mammals, and discusses the potential of defense priming in agriculture.
The Dynamics of Pollution Permits
Authors: Hasegawa Makoto , Salant Stephen
Published: June 2015

We review the literature on bankable emissions permits that has developed over the last two decades. Most articles analyze either theoretical or simulation models. The theoretical literature considers the problem of minimizing the discounted sum of social costs and the possibility of decentralizing the solution through competitive permit markets. In some cases, authors do not explicitly consider pollution damages but instead assume that the planner’s goal is to minimize the discounted social cost of reducing cumulative emissions by a given amount. In other cases, authors do not explicitly consider an emissions reduction target but assume that the goal is to minimize the discounted sum of pollution damages and abatement costs. Simulations permit evaluation of alternative government policies under uncertainty. We conclude by pointing out directions for future work.
Analysis of cardiovascular responses to the H2S donors Na2S and NaHS in the rat
Authors: Yoo Daniel , Jupiter Ryan C. , Pankey Edward A. , Reddy Vishwaradh G. , Edward Justin A. , Swan Kevin W. , Peak Taylor C. , Mostany Ricardo , Kadowitz Philip J.
Published: June 2015

Hydrogen sulfide (H2S) is an endogenous gaseous molecule formed from L-cysteine in vascular tissue. In the present study, cardiovascular responses to the H2S donors Na2S and NaHS were investigated in the anesthetized rat. The intravenous injections of Na2S and NaHS 0.03–0.5 mg/kg produced dose-related decreases in systemic arterial pressure and heart rate, and at higher doses decreases in cardiac output, pulmonary arterial pressure, and systemic vascular resistance. H2S infusion studies show that decreases in systemic arterial pressure, heart rate, cardiac output, and systemic vascular resistance are well-maintained, and responses to Na2S are reversible. Decreases in heart rate were not blocked by atropine, suggesting that the bradycardia was independent of parasympathetic activation and was mediated by an effect on the sinus node. The decreases in systemic arterial pressure were not attenuated by hexamethonium, glybenclamide, Nw-nitro-l-arginine methyl ester hydrochloride, sodium meclofenamate, ODQ, miconazole, 5-hydroxydecanoate, or tetraethylammonium, suggesting that ATP-sensitive potassium channels, nitric oxide, arachidonic acid metabolites, cyclic GMP, p450 epoxygenase metabolites, or large conductance calcium-activated potassium channels are not involved in mediating hypotensive responses to the H2S donors in the rat and that responses are not centrally mediated. The present data indicate that decreases in systemic arterial pressure in response to the H2S donors can be mediated by decreases in vascular resistance and cardiac output and that the donors have an effect on the sinus node independent of the parasympathetic system. The present data indicate that the mechanism of the peripherally mediated hypotensive response to the H2S donors is uncertain in the intact rat.
Substance P induces cardioprotection in ischemia-reperfusion via activation of AKT
Authors: Jubair Shaiban , Li Jianping , Dehlin Heather M. , Manteufel Edward J. , Goldspink Paul H. , Levick Scott P. , Janicki Joseph S.
Published: June 2015

Accumulating evidence indicates that substance P is cardioprotective following ischemia-reperfusion primarily due to its potent coronary vasodilator actions. However, an anti-apoptotic effect of substance P has been observed in tenocytes following ischemia, which involved activation of the AKT pathway. This suggests the possibility that substance P also provides cardioprotection via direct actions to activate AKT in myocardial cells. The purpose of this study was to test the hypothesis that substance P attenuates ischemia-related cell death via direct effects on myocardial cells by activating cell survival pathways. Seven-week-old male Sprague-Dawley rats, anesthetized with intraperitoneal pentobarbital sodium (100 mg/kg), were used. The ability of substance P to prevent cellular damage was assessed following ischemia-reperfusion in an isolated heart preparation and in short-term hypoxia without reperfusion using a left ventricular tissue slice culture preparation. In addition, the NK-1 receptor and AKT involvement was assessed using the NK-1 receptor antagonist L732138 and the AKT inhibitor LY294002. The results indicate that substance P reduced the ischemia-related release of lactate dehydrogenase in both preparations and the degree of apoptosis and necrosis in the hypoxic left ventricular slices, indicating its ability to attenuate cell damage; and induced AKT phosphorylation, with both the AKT inhibitor and NK-1 receptor antagonist preventing the increased phosphorylation of AKT and the ability of substance P to attenuate hypoxic cellular damage. It is concluded that substance P reduces ischemia/hypoxia-induced myocardial cell death by acting directly on cardiac cells to initiate cell survival pathways via the NK-1 receptor and AKT.
Mechanical support of the pressure overloaded right ventricle: an acute feasibility study comparing low and high flow support
Authors: Verbelen Tom , Verhoeven Jelle , Goda Motohiko , Burkhoff Daniel , Delcroix Marion , Rega Filip , Meyns Bart
Published: June 2015

The objectives of this study were to assess the feasibility of low flow right ventricular support and to describe the hemodynamic effects of low versus high flow support in an animal model of acute right ventricular pressure overload. A Synergy Pocket Micro-pump (HeartWare International, Framingham, MA) was implanted in seven sheep. Blood was withdrawn from the right atrium to the pulmonary artery. Hemodynamics and pressure-volume loops were recorded in baseline conditions, after banding the pulmonary artery, and after ligating the right coronary artery in these banded sheep. End-organ perfusion (reflected by total cardiac output and arterial blood pressure) improved in all conditions. Intrinsic right ventricular contractility was not significantly impacted by support. Diastolic unloading of the pressure overloaded right ventricle (reflected by decreases in central venous pressure, end-diastolic pressure and volume, and ventricular capacitance) was successful, but with a concomitant and flow-dependent increase of the systolic afterload. This unloading diminished with right ventricular ischemia. Right ventricular mechanical support improves arterial blood pressure and cardiac output. It provides diastolic unloading of the right ventricle, but with a concomitant and right ventricular assist device flow-dependent increase of systolic afterload. These effects are most distinct in the pressure overloaded right ventricle without profound ischemic damage. We advocate the low flow strategy, which is potentially beneficial for the afterload sensitive right ventricle and has the advantage of avoiding excessive increases in pulmonary artery pressure when pulmonary hypertension exists. This might protect against the development of pulmonary edema and hemorrhage.
Cardioprotective HIF-1α-frataxin signaling against ischemia-reperfusion injury
Authors: Nanayakkara Gayani , Alasmari Abdullah , Mouli Shravanthi , Eldoumani Haitham , Quindry John , McGinnis Graham , Fu Xiaoyu , Berlin Avery , Peters Bridget , Zhong Juming , Amin Rajesh
Published: June 2015

Previous studies have demonstrated the protective signaling of hypoxia-inducible factor (HIF)-1 α against ischemia-reperfusion (I/R) injury in the heart. In the present study, we provide further evidence for a cardioprotective mechanism by HIF-1α against I/R injury exerted via the mitochondrial protein frataxin, which regulates mitochondrial Fe-S cluster formation. Disruption of frataxin has been found to induce mitochondrial iron overload and subsequent ROS production. We observed that frataxin expression was elevated in mice hearts subjected to I/R injury, and this response was blunted in cardiomyocyte-specific HIF-1α knockout (KO) mice. Furthermore, these HIF-1α KO mice sustained extensive cardiac damage from I/R injury compared with control mice. Similarly, reduction of HIF-1α by RNA inhibition resulted in an attenuation of frataxin expression in response to hypoxia in H9C2 cardiomyocytes. Therefore, we postulated that HIF-1α transcriptionally regulates frataxin expression in response to hypoxia and offers a cardioprotective mechanism against ischemic injury. Our promoter activity and chromatin immunoprecipitation assays confirmed the presence of a functional hypoxia response element in the frataxin promoter. Our data also suggest that increased frataxin mitigated mitochondrial iron overload and subsequent ROS production, thus preserving mitochondrial membrane integrity and viability of cardiomyocytes. We postulate that frataxin may exert its beneficial effects by acting as an iron storage protein under hypoxia and subsequently facilitates the maintenance of mitochondrial membrane potential and promotes cell survival. The findings from our study revealed that HIF-1α-frataxin signaling promotes a protective mechanism against hypoxic/ischemic stress.