bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional Dissection of Intersubunit Interactions in the EspR Virulence Regulator of Mycobacterium tuberculosis
Authors: Blasco Benjamin , Japaridze Aleksandre , Stenta Marco , Wicky Basile I. M. , Dietler Giovanni , Dal Peraro Matteo , Pojer Florence , Cole Stewart T.
Published: March 2014

The nucleoid-associated protein EspR, a chromosome organizer, has pleiotropic effects on expression of genes associated with cell wall function and pathogenesis in
Mycobacterium tuberculosis
. In particular, EspR binds to several sites upstream of the
espACD
locus to promote its expression, thereby ensuring full function of the ESX-1 secretion system, a major virulence determinant. The N terminus of EspR contains the helix-turn-helix DNA-binding domain, whereas the C-terminal dimerization domain harbors residues involved in intersubunit interactions. While direct binding to DNA appears to be mediated by an EspR dimer-of-dimers, where two helix-turn-helix motifs remain free for long-range interactions, the mechanism of EspR higher-order organization and its impact on chromosome structure and gene expression are not understood. To investigate these processes, we identified seven amino acid residues using molecular dynamics and replaced them with Ala in order to probe interactions at either the dimer or the dimer-of-dimers interfaces. Arg70, Lys72, and Arg101 were important for protein stability and optimal DNA-binding activity. Moreover, the Arg70 mutant showed decreased dimerization in a mycobacterial two-hybrid system. To correlate these defects with higher-order organization and transcriptional activity, we used atomic force microscopy to observe different EspR mutant proteins in complex with the
espACD
promoter region. In addition, complementation of an
M. tuberculosis
espR
knockout mutant was performed to measure their impact on EspA expression. Our results pinpoint key residues required for EspR function at the dimer (Arg70) and the dimer-of-dimers (Lys72) interface and demonstrate that EspR dimerization and higher-order oligomerization modulate
espACD
transcriptional activity and hence pathogenesis.
Outer Membrane Protein OmpW Participates with Small Multidrug Resistance Protein Member EmrE in Quaternary Cationic Compound Efflux
Authors: Beketskaia Maria S. , Bay Denice C. , Turner Raymond J.
Published: March 2014

In
Escherichia coli
, the small multidrug resistance (SMR) transporter protein EmrE confers host resistance to a broad range of toxic quaternary cation compounds (QCC) via proton motive force in the plasma membrane. Biologically produced QCC also act as EmrE osmoprotectant substrates within the cell and participate in host pH regulation and osmotic tolerance. Although
E. coli
EmrE is one of the most well-characterized SMR members, it is unclear how the substrates it transports into the periplasm escape across the outer membrane (OM) in Gram-negative bacteria. We tested the hypothesis that
E. coli
EmrE relies on an unidentified OM protein (OMP) to complete the extracellular release of its QCC. Eleven OMP candidates were screened using an alkaline phenotypic growth assay to identify OMP involvement in EmrE-mediated QCC efflux.
E. coli
single-gene deletion strains were transformed with plasmid-carried copies of
emrE
to detect reduced-growth and rescued-growth phenotypes under alkaline conditions. Among the 11 candidates, only the Δ
ompW
strain showed rescued alkaline growth tolerance when transformed with pEmrE, supporting the corresponding protein's involvement in EmrE osmoprotectant efflux. Coexpression of plasmids carrying the
ompW
and
emrE
genes transformed into the
E. coli
Δ
ompW
and Δ
emrE
strains demonstrated a functional complementation restoring the original alkaline loss-of-growth phenotype. Methyl viologen drug resistance assays of pEmrE and pOmpW plasmid-complemented
E. coli
Δ
ompW
and wild-type strains found higher host drug resistance than with other plasmid combinations. This study confirms our hypothesis that the porin OmpW participates in the efflux of EmrE-specific substrates across the OM.
Biochemical Characterization of a Nitrogen-Type Phosphotransferase System Reveals that Enzyme EI
Ntr
Integrates Carbon and Nitrogen Signaling in Sinorhizobium meliloti
Authors: Goodwin Reed A. , Gage Daniel J.
Published: March 2014

In
Sinorhizobium meliloti
, catabolite repression is influenced by a noncanonical nitrogen-type phosphotransferase system (PTS
Ntr
). In this PTS
Ntr
, the protein HPr is phosphorylated on histidine-22 by the enzyme EI
Ntr
and the flux of phosphate through this residue onto downstream proteins leads to an increase in succinate-mediated catabolite repression (SMCR). In order to explore the molecular determinants of HPr phosphorylation by EI
Ntr
, both proteins were purified and the activity of EI
Ntr
was measured. Experimentally determined kinetic parameters of EI
Ntr
activity were significantly slower than those determined for the carbohydrate-type EI in
Escherichia coli
. Enzymatic assays showed that glutamine, a signal of nitrogen availability in many Gram-negative bacteria, strongly inhibits EI
Ntr
. Binding experiments using the isolated GAF domain of EI
Ntr
(EI
GAF
) showed that it is the domain responsible for detection of glutamine. EI
Ntr
activity was not affected by α-ketoglutarate, and no binding between the EI
GAF
and α-ketoglutarate could be detected. These data suggest that in
S. melilloti
, EI
Ntr
phosphorylation of HPr is regulated by signals from both carbon metabolism (phosphoenolpyruvate) and nitrogen metabolism (glutamine).
In Vivo
Disassembly and Reassembly of Protein Aggregates in Escherichia coli
Authors: Govers Sander K. , Dutré Philip , Aertsen Abram
Published: March 2014

Protein misfolding and aggregation are inevitable but detrimental cellular processes. Cells therefore possess protein quality control mechanisms based on chaperones and proteases that (re)fold or hydrolyze unfolded, misfolded, and aggregated proteins. Besides these conserved quality control mechanisms, the spatial organization of protein aggregates (PAs) inside the cell has been proposed as an important additional strategy to deal with their cytotoxicity. In the bacterium
Escherichia coli
, however, it remained unclear how this spatial organization is established and how this process of assembling PAs in the cell poles affects cellular physiology. In this report, high hydrostatic pressure was used to transiently reverse protein aggregation in living
E. coli
cells, allowing the subsequent (re)assembly of PAs to be studied in detail. This approach revealed PA assembly to be dependent on intracellular energy and metabolic activity, with the resulting PA structure being confined to the cell pole by nucleoid occlusion. Moreover, a correlation could be observed between the time needed for PA reassembly and the individual lag time of the cells, which might prevent symmetric segregation of cytotoxic PAs among siblings to occur and ensure rapid spatial clearance of molecular damage throughout the emerging population.
Anabolic agents: recent strategies for their detection and protection from inadvertent doping
Authors: Geyer Hans , Schänzer Wilhelm , Thevis Mario
Published: March 2014

According to the World Anti-Doping Agency (WADA) Prohibited List, anabolic agents consist of exogenous anabolic androgenic steroids (AAS), endogenous AAS and other anabolic agents such as clenbuterol and selective androgen receptor modulators (SARMs). Currently employed strategies for their improved detection include the prolongation of the detection windows for exogenous AAS, non-targeted and indirect analytical approaches for the detection of modified steroids (designer steroids), the athlete’s biological passport and isotope ratio mass spectrometry for the detection of the misuse of endogenous AAS, as well as preventive doping research for the detection of SARMs. The recent use of these strategies led to 4–80-fold increases of adverse analytical findings for exogenous AAS, to the detection of the misuse of new designer steroids, to adverse analytical findings of different endogenous AAS and to the first adverse analytical findings of SARMs. The strategies of the antidoping research are not only focused on the development of methods to catch the cheating athlete but also to protect the clean athlete from inadvertent doping. Within the past few years several sources of inadvertent doping with anabolic agents have been identified. Among these are nutritional supplements adulterated with AAS, meat products contaminated with clenbuterol, mycotoxin (zearalenone) contamination leading to zeranol findings, and natural products containing endogenous AAS. The protection strategy consists of further investigations in case of reasonable suspicion of inadvertent doping, publication of the results, education of athletes and development of methods to differentiate between intentional and unintentional doping.
Systematic review and meta-analysis of opioid antagonists for smoking cessation
Authors: David Sean P , Chu Isabella M , Lancaster Tim , Stead Lindsay F , Evins A Eden , Prochaska Judith J
Published: March 2014

Objectives

This meta-analysis sought to evaluate the efficacy of opioid antagonists in promoting long-term smoking cessation. Post-treatment abstinence was examined as a secondary outcome and effects on withdrawal symptoms, craving and reduced consumption were also explored.

Design

The search strategy for this meta-analysis included clinical trials (published and unpublished data) in the Cochrane Tobacco Addiction Group Specialized Register and MEDLINE.

Participants

Adult smokers.

Interventions

We included randomised trials comparing opioid antagonists to placebo or an alternative therapy for smoking cessation and reported data on abstinence for a minimum of 6 months.

Primary and secondary outcome measures

Outcomes included smoking abstinence at long-term follow-up (primary); abstinence at end of treatment (secondary); and effects on withdrawal, craving and smoking consumption (exploratory).

Results

8 trials with a total of 1213 participants were included. Half the trials examined the benefit of adding naltrexone versus placebo to nicotine replacement therapy (NRT). There was no significant difference between naltrexone and placebo alone (relative risk (RR) 1.00; 95% CI 0.66 to 1.51) or as an adjunct to NRT (RR 0.95; 95% CI 0.70 to 1.30), with an overall pooled estimate of RR 0.97; 95% CI 0.76 to 1.24. Findings for naltrexone effects on withdrawal, craving and reduced smoking were equivocal.

Conclusions

The findings indicate no beneficial effect of naltrexone alone or as an adjunct to NRT on short-term or long-term smoking abstinence. While further trials may narrow the confidence limits, they are unlikely to appreciably alter the conclusion.
Lung protective ventilation in patients undergoing major surgery: a systematic review protocol
Authors: Zhang Zhongheng , Hu Xiaoyun , Zhang Xia , Zhu Xiuqi , Zhu Li , Chen Liqian , Huai Jiaping , Du Bin ,   for the China Critical Care Clinical Trials Group (CCCCTG)
Published: March 2014

Introduction

There is growing interest in the use of low tidal volume ventilation in patients undergoing general anaesthesia. However, its potential benefit has long been debated and conflicting results have been reported. We describe here the protocol of a systematic review and meta-analysis for investigating the beneficial effects of low tidal volume ventilation in patients undergoing general anaesthesia.

Methods and analysis

Data sources include PubMed, Scopus, Embase and EBSCO. Patients undergoing general anaesthesia will be included irrespective of type of surgery. The intervention is low tidal volume ventilation or protective ventilation, and the control is conventional ventilation. The quality of included trials will be assessed by using Delphi consensus. Outcomes include new onset lung injury, atelectasis, arrhythmia, levels of inflammatory biomarkers, arterial oxygenation, partial pressure of carbon dioxide and alveolar–arterial oxygen gradient. Conventional approaches for meta-analysis will be used, and heterogeneity will be investigated by using subgroup analysis and meta-regression if appropriate. The Bayesian method will be used for the synthesis of binary outcome data.

Ethics and dissemination

The systematic review was approved by the ethics committee of Jinhua hospital of Zhejiang university and will be published in a peer-reviewed journal and will be disseminated electronically and in print.

Registration details

The study protocol has been registered in PROSPERO (http://www.crd.york.ac.uk/PROSPERO/) under registration number CRD42013006416.
Comparison of patients diagnosed with gonorrhoea through community screening with those self-presenting to the genitourinary medicine clinic
Authors: Cook Penny A , Evans-Jones John , Mallinson Harry , Wood Martyn , Alloba Fath , Jones Kathy , Strodtbeck Sara , Hanna-Bashara Layla
Published: March 2014

Objectives

To compare the clinical, socioeconomic and demographic characteristics of individuals diagnosed withNeisseria gonorrhoeae(NG) in the community using a concomitant nucleic acid amplification test (NAAT, AptimaCombo2) as part of the (community-based) UKChlamydiaScreening Programme (CSP), with those diagnosed in hospital-based genitourinary medicine (GUM) services.

Design

A retrospective case note review of all 643 patients treated for NG at a GUM in north west England (January 2007–April 2009).

Participants

All 643 treated for NG (including CSP cases, since all cases were referred to GUM for treatment). Limited data were available for 13 CSP cases who failed to attend GUM.

Primary outcome measure

Whether the case was detected in the community or GUM services. Predictors were demographics (age, gender, postcode for deprivation analysis), sexual history (eg, number of partners) and clinical factors (eg, culture positivity).

Results

131 cases were diagnosed by CSP (13 of whom did not attend GUM). A further four cases were contacts of these. The GUM caseload was thus inflated by 23% (from 521 to 643). Community cases were overwhelmingly female (85% vs 27% in GUM, p<0.001) and younger (87% females were <25 years vs 70% GUM females, p=0.001). Logistic regression analysis restricted to the target age of the CSP (<25 years) revealed that CSP cases, compared with GUM cases, were more likely to reside in deprived areas (adjusted OR=5.6, 95% CI 1.4 to 21.8 and 5.3, CI 1.7 to 16.6 for the most and second most deprived group respectively, compared with the averagely deprived group, p=0.037) and be asymptomatic (adjusted OR=1.9, CI 1.1 to 3.4, p=0.02).

Conclusions

Community screening for NG led to a 79% increase in the number of infections detected in women aged <25 years. Screening is targeted at young people, and tends to disproportionately attract young women, a group under-represented at GUM. Screening also contributed further to case detection in deprived areas.
Dissemination of a simulation-based mastery learning intervention reduces central line-associated bloodstream infections
Authors: Barsuk Jeffrey H , Cohen Elaine R , Potts Steven , Demo Hany , Gupta Shanu , Feinglass Joe , McGaghie William C , Wayne Diane B
Published: March 2014

Background

Approximately 41 000 central line-associated bloodstream infections (CLABSI) occur annually in US hospitals. We previously developed a simulation-based mastery learning (SBML) curriculum in central venous catheter (CVC) insertion that significantly reduced CLABSI rates. In this study, we evaluated the effect of dissemination of the SBML curriculum on trainee skills and CLABSI rates at a community hospital.

Methods

The authors performed a cohort study of residents who rotated in the intensive care unit (ICU) at Mercy Hospital and Medical Center from September 2010 to May 2012. Residents underwent an SBML CVC insertion curriculum and were required to meet or exceed a minimum passing score on a simulated internal jugular (IJ) and subclavian (SC) CVC insertion before ICU patient care. Infection control personnel measured CLABSI rates in the ICU before and after the educational intervention.

Results

Residents scored a mean IJ pretest of 35.5% (10.29/29, SD=8.30) compared with a post-test mean of 93.0% (26.96/29, SD=1.50; p<0.001). Their mean SC pretest score was 23.0% (6.68/29; SD=9.58) and increased to 96.1% (27.88/29, SD=1.41) at post-test (p<0.001). Patients experienced 3.82 infections per 1000 catheter-days (20 infections in 5235 catheter-days) in the ICU in the 23 months before the educational intervention. During the 21 months after the intervention, there were 1.29 infections per 1000 catheter-days (six infections in 4670 catheter-days (p=0.019)). The incidence rate ratio derived from the Poisson regression was 0.26 (95% CI 0.09 to 0.74) after controlling for Acute Physiology and Chronic Health Evaluation III score indicating that there was a 74% reduction in the incidence of CLABSI in the medical ICU after the intervention.

Conclusions

This study demonstrates successful dissemination and implementation of a CVC SBML curriculum and shows that rigorous medical education is a powerful quality improvement tool.
ANALYSIS OF PATIENTS' COMMENTS ABOUT HOSPITALS IN THE ENGLISH NHS VIA TWITTER, AND COMPARISON WITH PATIENT SURVEYS
Authors: Greaves Felix , Laverty Anthony , Ramirez-Cano Daniel , Pulman Stephen , Moilanen Karo , Darzi Ara , Millett Christopher
Published: March 2014

Introduction

Twitter and other social media are increasingly used by patients to discuss their experiences of healthcare. Social media might provide a new way for health services to listen to the voices of patients and improve their services. Little is known about how patients are communicating with hospitals via this route, and whether there is any association with traditional measures of patient experience such as surveys.

Methods

We recorded tweets aimed at all acute hospital trusts with Twitter accounts in England for one year from April 2012. We performed a qualitative content analysis of a random sample of 1000 tweets, to see what information they contained about care quality. Using natural language processing techniques, we calculated the sentiment of all the tweets towards hospital. We compared twitter sentiment to patient experience measured by traditional survey at the hospital level, using Spearman's rank correlation coefficient.

Results

We collected 187,000 tweets over one year. The mean number of tweets per trust was 2499. 9.8% of tweets were related to quality of care care – and most of these related to patients' experience of interactions with staff. We found no correlation between the sentiment of tweets about hospitals and patient experience measure by traditional survey methodology (Rho=0.08, p=0.56).

Discussion

Although social media are increasingly used by both the public and healthcare professionals to communicate, caution should be taken in using social media data to measure care quality. The information contained within tweets was able to provide valuable individual insights about some patients' experiences of care, however the views expressed appeared less likely to be representative of the experiences of the wider population receiving care.

Declaration of competing interests

This work has been funded by the Commonwealth Fund.
Implementing human factors in clinical practice
Authors: Timmons Stephen , Baxendale Bryn , Buttery Andrew , Miles Giulia , Roe Bridget , Browes Simon
Published: March 2014

Objectives

To understand whether aviation-derived human factors training is acceptable and useful to healthcare professionals. To understand whether and how healthcare professionals have been able to implement human factors approaches to patient safety in their own area of clinical practice.

Methods

Qualitative, longitudinal study using semi-structured interviews and focus groups, of a multiprofessional group of UK NHS staff (from the emergency department and operating theatres) who have received aviation-derived human factors training.

Results

The human factors training was evaluated positively, and thought to be both acceptable and relevant to practice. However, the staff found it harder to implement what they had learned in their own clinical areas, and this was principally attributed to features of the informal organisational cultures.

Conclusions

In order to successfully apply human factors approaches in hospital, careful consideration needs to be given to the local context and informal culture of clinical practice.
Diagnostic accuracy of frozen-section analysis of cancer-containing bladder transurethral resection specimens for the presence of muscularis propria invasion
Authors: Goyal Rajen , Zhu Bing , Parimi Vamsi , Lin Xiaoqi , Rohan Stephen M
Published: March 2014

Aims

Frozen section (FS) consultation is generally an accurate diagnostic modality. At our institution, we are frequently asked to assess transurethral resection specimens (TURBT) at FS for muscularis propria (MP) invasion by carcinoma. This study documents our experience in evaluating cancer-containing TURBT specimens at FS for MP invasion.

Methods

32 TURBT sent for FS from 2008–2010 were identified. The FS and permanent section (PS) diagnoses were reviewed. Cases excluded from the calculation of test performance included: (1) cases without cancer on FS or PS slides, (2) FS diagnosis deferred, (3) cases without MP on FS and subsequent PS slides. Sensitivity (SEN), specificity (SPEC), positive predictive value (PPV), and negative predictive value (NPV) for identifying MP invasion at FS were calculated.

Results

In 6 cases, no cancer was present in FS or PS slides (18%). The FS diagnosis was deferred on 3 cases (9%). In one case (3%) MP was not present in the FS or the subsequent PS slides. Of the remaining 22 cases, 2 false positive and 6 false negative diagnoses of MP invasion were identified. The test performance for FS assessment of MP invasion in TURB were SEN=33%, SPEC=84%, PPV=60%, and NPV=64%.

Conclusions

Identifying MP invasion on PS can be difficult, and our results suggest that this is more difficult at FS. Though this study is based on small numbers, our results point to the conclusion that examination of TURBT specimens for MP invasion is best done on PS.
Emergency carotid artery stenting in patients with acute ischemic stroke due to occlusion or stenosis of the proximal internal carotid artery: a single-center experience
Authors: Son Seungnam , Choi Dae Seob , Oh Min Kyun , Kim Soo-Kyoung , Kang Heeyoung , Park Ki-Jong , Choi Nack-Cheon , Kwon Oh-Young , Lim Byeong Hoon
Published: March 2014

Background

The feasibility, safety and effectiveness of emergency carotid artery stenting (eCAS) in patients with acute ischemic stroke (AIS) due to proximal internal carotid artery (ICA) stenosis or occlusion are still controversial. In this study we analyzed our experience with eCAS in patients with AIS.

Methods

Twenty-two eCAS procedures for proximal ICA stenosis or occlusion were performed in 22 patients at our institution between January 2011 and November 2013. The mean time from stroke symptom onset to presentation was 204 min (range 50–630 min) and the mean initial score on the National Institutes of Health Stroke Scale (NIHSS) was 12.55 (range 5–23). Ten patients had total occlusion of the proximal ICA and the remaining 12 patients had near total occlusion or severe stenosis (mean degree 90.7%, range 80–100%). Eleven patients also had tandem occlusion on the more distal intracranial arteries.

Results

Successful stent insertion was achieved in all patients and additional thrombectomy using a Solitaire stent or Penumbra aspiration catheter achieved a Thrombolysis In Cerebral Infarction grade of more than 2a in all patients with distal tandem occlusion. Procedure-related complications occurred in one patient (cerebral hyperperfusion syndrome) who recovered successfully. The mean NIHSS score at discharge was 3.55 (range 0–18). The mean modified Rankin Scale score at 3 months was 1±1.67 (range 0–6).

Conclusions

eCAS in patients with AIS due to proximal ICA stenosis or occlusion appears to be a technically feasible and effective method for achieving good clinical outcomes.
Local scour at piled bridge piers including an examination of the superposition method
Authors: Amini Ata , Melville Bruce W. , Ali Thamer M.
Published: March 2014

An experimental investigation of clear water scour at complex piers is presented. Five complex piers, comprising different configurations of piles, pile cap, and column, were tested in a laboratory flume using uniform bed material. The piers were tested for a range of possible elevations relative to the streambed elevation. Experiments were undertaken using the complex piers and also using the individual components of each complex pier. A comparison of the results for the intact piers and for their components enabled an evaluation of the prediction methods involving superposition of scour depths at piles, pile cap, and pier column. The superposition method is found to give inadequate estimates of total scour depth in many cases.
Age-associated abnormalities of intrinsic automaticity of sinoatrial nodal cells are linked to deficient cAMP-PKA-Ca2+signaling
Authors: Liu Jie , Sirenko Syevda , Juhaszova Magdalena , Sollott Steven J. , Shukla Shweta , Yaniv Yael , Lakatta Edward G.
Published: March 2014

A reduced sinoatrial node (SAN) functional reserve underlies the age-associated decline in heart rate acceleration in response to stress. SAN cell function involves an oscillatory coupled-clock system: the sarcoplasmic reticulum (SR), a Ca2+clock, and the electrogenic-sarcolemmal membrane clock. Ca2+-activated-calmodulin-adenylyl cyclase/CaMKII-cAMP/PKA-Ca2+signaling regulated by phosphodiesterase activity drives SAN cells automaticity. SR-generated local calcium releases (LCRs) activate Na+/Ca2+exchanger in the membrane clock, which initiates the action potential (AP). We hypothesize that SAN cell dysfunctions accumulate with age. We found a reduction in single SAN cell AP firing in aged (20–24 mo) vs. adult (3–4 mo) mice. The sensitivity of the SAN beating rate responses to both muscarinic and adrenergic receptor activation becomes decreased in advanced age. Additionally, age-associated coincident dysfunctions occur stemming from compromised clock functions, including a reduced SR Ca2+load and a reduced size, number, and duration of spontaneous LCRs. Moreover, the sensitivity of SAN beating rate to a cAMP stress induced by phosphodiesterase inhibitor is reduced, as are the LCR size, amplitude, and number in SAN cells from aged vs. adult mice. These functional changes coincide with decreased expression of crucial SR Ca2+-cycling proteins, including SR Ca2+-ATPase pump, ryanodine receptors, and Na+/Ca2+exchanger. Thus a deterioration in intrinsic Ca2+clock kinetics in aged SAN cells, due to deficits in intrinsic SR Ca2+cycling and its response to a cAMP-dependent pathway activation, is involved in the age-associated reduction in intrinsic resting AP firing rate, and in the reduction in the acceleration of heart rate during exercise.
ZIPK is critical for the motility and contractility of VSMCs through the regulation of nonmuscle myosin II isoforms
Authors: Komatsu Satoshi , Ikebe Mitsuo
Published: March 2014

Migration of medial vascular smooth muscle cells (VSMCs) into the intimal layer contributes to pathological remodeling of the blood vessel in arterial hypertension and atherosclerosis. It is well established that reorganization of cytoskeletal networks is an essential component of cellular motile events. However, there is currently a lack of insight into the cellular characteristics of VSMC migration under three-dimensional environments. Here, we investigated the mechanisms of VSMC migration and remodeling using two different collagen matrix assays as in vitro models: migration of VSMCs within a collagen matrix for VSMC invasion and contraction of a collagen gel by VSMCs for VSMC remodeling and contraction. We found that nonmuscle myosin IIA (NMIIA) and nonmuscle myosin IIB (NMIIB) differentially contribute to the migratory capacity of VSMCs via NMII isoform-dependent cytoskeletal reorganization. Depletion of NMIIA by short hairpin RNA revealed a unique interplay between actomyosin and microtubules during VSMC migration. On the other hand, NMIIB was required for the structural maintenance of migrating VSMC. Interestingly, there was a significant difference between NMIIA and NMIIB knockdown in the VSMC migration but not in the VSMC-mediated collagen gel contraction. Furthermore, depletion of zipper-interacting protein kinase by short hairpin RNA resulted in an impairment of VSMC migration and a substantial decrease of VSMC-mediated collagen gel contraction. These results suggest that NMIIA and NMIIB uniquely control VSMC migration and may contribute to vascular remodeling, which are both regulated by zipper-interacting protein kinase.
Nox2 and p47phox modulate compensatory growth of primary collateral arteries
Authors: DiStasi Matthew R. , Unthank Joseph L. , Miller Steven J.
Published: March 2014

The role of NADPH oxidase (Nox) in both the promotion and impairment of compensatory collateral growth remains controversial because the specific Nox and reactive oxygen species involved are unclear. The aim of this study was to identify the primary Nox and reactive oxygen species associated with early stage compensatory collateral growth in young, healthy animals. Ligation of the feed arteries that form primary collateral pathways in rat mesentery and mouse hindlimb was used to assess the role of Nox during collateral growth. Changes in mesenteric collateral artery Nox mRNA expression determined by real-time PCR at 1, 3, and 7 days relative to same-animal control arteries suggested a role for Nox subunits Nox2 and p47phox. Administration of apocynin or Nox2ds-tat suppressed collateral growth in both rat and mouse models, suggesting the Nox2/p47phox interaction was involved. Functional significance of p47phox expression was assessed by evaluation of collateral growth in rats administered p47phox small interfering RNA and in p47phox−/− mice. Diameter measurements of collateral mesenteric and gracilis arteries at 7 and 14 days, respectively, indicated no significant collateral growth compared with control rats or C57BL/6 mice. Chronic polyethylene glycol-conjugated catalase administration significantly suppressed collateral development in rats and mice, implying a requirement for H2O2. Taken together, these results suggest that Nox2, modulated at least in part by p47phox, mediates early stage compensatory collateral development via a process dependent upon peroxide generation. These results have important implications for the use of antioxidants and the development of therapies for peripheral arterial disease.
IL-6 regulates adipose deposition and homeostasis in lymphedema
Authors: Cuzzone Daniel A. , Weitman Evan S. , Albano Nicholas J. , Ghanta Swapna , Savetsky Ira L. , Gardenier Jason C. , Joseph Walter J. , Torrisi Jeremy S. , Bromberg Jacqueline F. , Olszewski Waldemar L. , Rockson Stanley G. , Mehrara Babak J.
Published: March 2014

Lymphedema (LE) is a morbid disease characterized by chronic limb swelling and adipose deposition. Although it is clear that lymphatic injury is necessary for this pathology, the mechanisms that underlie lymphedema remain unknown. IL-6 is a known regulator of adipose homeostasis in obesity and has been shown to be increased in primary and secondary models of lymphedema. Therefore, the purpose of this study was to determine the role of IL-6 in adipose deposition in lymphedema. The expression of IL-6 was analyzed in clinical tissue specimens and serum from patients with or without LE, as well as in two mouse models of lymphatic injury. In addition, we analyzed IL-6 expression/adipose deposition in mice deficient in CD4+ cells (CD4KO) or IL-6 expression (IL-6KO) or mice treated with a small molecule inhibitor of IL-6 or CD4 depleting antibodies to determine how IL-6 expression is regulated and the effect of changes in IL-6 expression on adipose deposition after lymphatic injury. Patients with LE and mice treated with lymphatic excision of the tail had significantly elevated tissue and serum expression of IL-6 and its downstream mediator. The expression of IL-6 was associated with adipose deposition and CD4+ inflammation and was markedly decreased in CD4KO mice. Loss of IL-6 function resulted in significantly increased adipose deposition after tail lymphatic injury. Our findings suggest that IL-6 is increased as a result of adipose deposition and CD4+ cell inflammation in lymphedema. In addition, our study suggests that IL-6 expression in lymphedema acts to limit adipose accumulation.
SIRT1 protects against cigarette smoke-induced lung oxidative stress via a FOXO3-dependent mechanism
Authors: Yao Hongwei , Sundar Isaac K. , Ahmad Tanveer , Lerner Chad , Gerloff Janice , Friedman Alan E. , Phipps Richard P. , Sime Patricia J. , McBurney Michael W. , Guarente Leonard , Rahman Irfan
Published: March 2014

Oxidative and carbonyl stress is increased in lungs of smokers and patients with chronic obstructive pulmonary disease (COPD), as well as in cigarette smoke (CS)-exposed rodent lungs. We previously showed that sirtuin1 (SIRT1), an antiaging protein, is reduced in lungs of CS-exposed mice and patients with COPD and that SIRT1 attenuates CS-induced lung inflammation and injury. It is not clear whether SIRT1 protects against CS-induced lung oxidative stress. Therefore, we determined the effect of SIRT1 on lung oxidative stress and antioxidants in response to CS exposure using loss- and gain-of-function approaches, as well as a pharmacological SIRT1 activation by SRT1720. We found that CS exposure increased protein oxidation and lipid peroxidation in lungs of wild-type (WT) mice, which was further augmented in SIRT1-deficient mice. Furthermore, both SIRT1 genetic overexpression and SRT1720 treatment significantly decreased oxidative stress induced by CS exposure. FOXO3 deletion augmented lipid peroxidation products but reduced antioxidants in response to CS exposure, which was not affected by SRT1720. Interestingly, SRT1720 treatment exhibited a similar effect on lipid peroxidation and antioxidants (i.e., manganese superoxide dismutase, heme oxygenase-1, and NADPH quinone oxidoreductase-1) in WT and nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-deficient mice in response to CS exposure. This indicates that SIRT1 protects against CS-induced oxidative stress, which is mediated by FOXO3, but is independent of Nrf2. Overall, these findings reveal a novel function of SIRT1, which is to reduce CS-induced oxidative stress, and this may contribute to its protective effects against lung inflammation and subsequent development of COPD.
Psychopathology of Time in Brain Disease and Schizophrenia
Authors: Cutting John , Silzer Herta
Published: March 2014

The literature on disturbance of time-sense in brain disease and schizophrenia is reviewed and the subjective experience of altered time-sense reported by 45 out of 350 personally interviewed schizophrenics is analyzed. A review of the literature on the effect of brain damage revealed that some phenomena (déjà vu, reduplication of time, altered tempo to events) were linked with right hemisphere dysfunction, one phenomenon (incorrect sequencing of events) was linked with left anterior brain damage, and others (disrupted “biological clock”, disturbed serise of rate of flow of current or past events) could arise from subcortical as well as focal cortical damage. The sparse literature on disturbed time-sense in schizophrenia suggested that there was a shared psychopathology in this respect with right hemisphere dysfunction. The phenomena encountered in the 45 schizophrenics are described and classified.
Tics
Authors: Lees A. J.
Published: March 2014

Tics are an incontinent form of non-verbal communication associated with obsessional and aggressive urges and anxiety. The motor phenomena seen in socially acceptable forms of emotional release are compared and contrasted with tics. It is proposed that brain dysfunction in Gilles de la Tourette syndrome involves frontal limbic and basal ganglia loops.
Body Concept, Disability, and Depression in Patients with Spasmodic Torticollis
Authors: Jahanshahi M. , Marsden C. D.
Published: March 2014

Eighty-five patients with idiopathic spasmodic torticollis were compared with an equally chronic group of 49 cervical spondylosis sufferers in terms of body concept, depression, and disability. The torticollis patients were significantly more depressed and disabled and had a more negative body concept. Depression had different determinants in the two groups. Extent of disfigurement was a major predictor of depression in torticollis. Neuroticism accounted for the greatest proportion of the variance of depression in cervical spondylosis.
Sleep Disturbances and Epileptiform Activity in a Subpopulation of Children with Attention Deficit Hyperactivity Disorder (ADHD): A Literature Review Generating an Hypothesis with Implications for Drug Therapy
Authors: Miller L. G. , Kraft I. A.
Published: March 2014

The use of electroencephalography and sleep studies in attention deficit hyperactivity disorder (ADHD), and the associated behavioral disorders is reviewed. Based on the available literature, we propose a hypothesis indicating four subtypes of ADHD. The usefulness of EEGs and sleep laboratory indices in detecting a subgroup of patients with submaximal responses to methylphenidate is also discussed.
Transformation of Broca’s Aphasia into Conduction Aphasia: A Case Report
Authors: Kazui S. , Sawada T. , Tanabe H. , Inoue N.
Published: March 2014

We describe a patient with a cerebral infarction localized mainly in the left posterior frontal and anterior parietal subcortices who experienced a Broca's aphasia which evolved into a conduction aphasia. Such a rare recovery pattern of aphasia appeared to result from amelioration of the damage to the left precentral gyrus.
Do Some Cases of Anorexia Nervosa Reflect Underlying Autistic-Like Conditions?
Authors: Gillberg C. , Råstam M.
Published: March 2014

In a sample of 51 teenagers with anorexia nervosa (AN)—which included 24 cases constituting the total population of AN cases born in 1970—several had shown social, communicative and behaviour patterns suggestive of autistic-like conditions as children, long before the onset of AN. One of the three boys in the AN group had Asperger syndrome. Three of the 48 girls had histories suggesting high functioning autism and continued to show many features typical of autism. Two further girls had Tourette syndrome and obsessive–compulsive traits in combination with social interaction problems. Eighteen other girls met criteria for obsessive–compulsive personality disorder (OCPD) and most of these also had had moderate–severe childhood social interaction problems. In a sex- and age-matched comparison group from the same schools, two girls had OCPD, but none had autistic-like conditions or Tourette syndrome. The results are discussed in the context of a recently suggested link between Asperger syndrome, Tourette syndrome and obsessive–compulsive problems, and it is suggested that AN in a subgroup of cases might represent a disorder belonging in the same class as autism and autistic-like conditions.
Imitation in Autism. A Preliminary Research Note
Authors: Heimann M. , Ullstadius E. , Dahlgren S.-O. , Gillberg C.
Published: March 2014

Previous studies have claimed that children with autism are poor imitators and a lack of imitative capacity has been included by some investigators as one early sign of autism. Presented here are results from a pilot study focusing on observed imitation after presenting 15 tasks to five children with autism (mental age 25–51 months). Imitation tasks involving simple object manipulation, vocal responses, facial and manual gestures, and object substitution were presented to each child. The performance of the children with autism is compared with (1) three normal 4-year-old children (for all 15 tasks), and (2) observations from 28 healthy 1-year-olds (for 10 of the tasks used). The findings indicate that the autistic group displayed the highest level of imitation on object manipulation and vocal tasks while object substitution, facial, and motor imitation acts seemed to be difficult for children with autism. However, the small number of children included as well as the individual variation observed among the autistic subjects precludes any definite conclusions from these pilot observations. It is hypothesized that imitation in children with autism has to be studied separately for different domains and probably also for different subgroups within the autistic population.
Factors Affecting the Clinical Measurement of Visuo-Spatial Neglect
Authors: Pizzamiglio L. , Bergego C. , Halligan P. , Homberg V. , Robertson I. , Weber E. , Wilson B. , Zoccolotti P. , Deloche G.
Published: March 2014

The present study examined a battery of tests to evaluate unilateral spatial neglect; the tests included different tasks involving several modalities of spatial exploration mapping perceptual, motor, attentional and personal or extrapersonal space dimensions. The subjects, 121 right-brain-damaged patients with unilateral neglect, were studied in seven laboratories in four European countries. Relationships among the various tests were examined by correlations, a cluster analysis and by an analysis of individual cases. Different sensitivity was found among various tests for detecting neglect performances. Both the cluster analysis and the single case analysis clearly showed a segregation between personal and extrapersonal neglect. Analysis of the large cluster, including a variety of tests of extra personal neglect, together with the study of single cases, suggests the possibility of differentiating the various manifestations of spatial neglect which can be interpreted on the basis of the descriptions of other individual cases previously reported in the literature. Finally, the present study indicated the relative stability of neglect following the acute phase and its independence from age.
Obsessive–Compulsive Symptoms in Neurologic Disease: A Review
Authors: George M. S. , Melvin J. A. , Kellner C. H.
Published: March 2014

Obsessive–compulsive disorder (OCD) is an increasingly recognized disorder with a prevalence of 2–3% (Robins et al., 1984). Once thought to be psychodynamic in origin, OCD is now generally recognized as having a neurobiological cause. Although the exact pathophysiology of OCD in its pure form remains unknown, there are numerous reports of obsessive–compulsive symptoms arising in the setting of known neurological disease. In this paper, we review the reported cases of obsessive–compulsive symptoms associated with neurologic diseases and outline the known facts about the underlying neurobiology of OCD. Finally, we synthesize these findings into a proposed theory of the pathophysiology of OCD, in both its pure form and when it accompanies other neurological illness.
A Prospective Psychological Study of Patients with Undiagnosed Episodes of Disturbed Consciousness
Authors: Blumhardt L. D. , Barnes D. , Howell S. J. , Ghadiali E.
Published: March 2014

We have carried out a prospective psychological and clinical study of neurological out-patients with episodes of disturbed consciousness that were mostly unexplained after clinical assessments and prolonged follow up. When compared with matched healthy subjects, both the undiagnosed patients and a control group with chronic epilepsy, had evidence of abnormal personality and psychological disturbance. However, in the undiagnosed patients there were significant differences between two subgroups defined by the results of clinical follow up. Patients whose symptoms resolved spontaneously were psychologically indistinguishable from healthy control subjects, whereas patients whose unexplained symptoms continued, with or without empirical treatment trials, had highly abnormal personality profiles. Although the basic psychological tests we used cannot reliably separate individual patients with epilepsy from those with non-epilepsy, they do have some predictive value with respect to the prognosis of unexplained symptoms. Further detailed prospective studies may help to establish the relationship between psychological disorder and unexplained symptoms and perhaps reduce the need for repeated, expensive investigations.
A Case with Probable Herpes Simplex Encephalitis Characterized by Specific Emotional and Behavioral Disorders and Gogi (Word-Meaning) Aphasia-Like Syndrome with Neologism and Neologistic Kanji Processing
Authors: Jibiki I. , Yamaguchi N.
Published: March 2014

A right-handed male patient with probable herpes simplex encephalitis is presented because of the rarity of the clinicial picture. Brain X-ray CT scans showed lesions located in the bilateral fronto-temporal regions primarily involving the left lower temporal lobe. The clinical picture following the acute phase of the disease was characterized by specific emotional and behavioral disorders, i.e. oral tendency, hyperactivity, thoughtless talkativeness, random speech and exhilaration, which were partly compatible with the Klüver-Bucy syndrome. Furthermore, this case was characterized by Gogi (word-meaning) aphasia-like transcortical sensory aphasia and neologism produced saliently when naming objects and peculiar neologistic kanji processing in writing to dictation and oral reading. Both the neologism and neologistic kanji processing varied in quantity in parallel with the specific emotional and behavioral disorders. The relationships of these clinical features to lesional sites demonstrated by X-ray CT are discussed.
Hemifacial Display of Emotion in the Resting State
Authors: Mandal M. K. , Asthana H. S. , Madan S. K. , Pandey R.
Published: March 2014

The human face at rest displays distinguishable asymmetries with some lateralization of emotion or expression. The asymmetrical nature of the resting face was examined by preparing hemifacial composites, left–left, right–right, along with normal facial orientation. The left side and right side composites were constructed by using the lateral half of one side of the face and its mirror-reversal. The left side facial composites were found to be more emotional than the right side or normal facial orientations of neutral expressions.
A 54-Point Verbal-Performance IQ Discrepancy on the WISC-R: Cognitive Functioning of a Child from an Alternative School
Authors: Lapierre D. , Braun C. M. J. , Le Pailleur L.
Published: March 2014

Marked WISC-R verbal-performance discrepancy commonly leads to the assumption that such children have brain pathology or cognitive disorders. Children without brain dysfunction may also exhibit wide discrepancy, but a discrepancy score of 30 is assumed to occur in only 2% of the population. The actual investigation presents an 11-year-old child showing a 54-point discrepancy between the two scales of the WISC-R. Results of wide ranging testing and other considerations strongly suggested that this child didn't manifest any kind of brain dysfunction. It was concluded that the particular academic environment of the child, an alternative school, exerted a very strong influence on her results on the WISC-R. This conclusion is furthermore supported by the results of a follow-up evaluation, done 1 year after the child has been transferred to a traditional school, which revealed a WISC-R verbal-performance discrepancy of only 12 points.