bluuebunny/crossref_metadata_2025 huggingface dataset:
Reducing postnatal depression, anxiety and stress using an infant sleep intervention
Authors: Symon Brian , Bammann Michael , Crichton Georgina , Lowings Chris , Tucsok James
Published: September 2012

Objective

To examine the psychological well-being of mothers following participation in a behavioural modification programme previously shown to improve infant sleep.

Design, setting and participants

A 45 min consultation with either a general practitioner (GP) or trained nurse providing verbal and written information describing sleep physiology in infants and strategies to improve infant sleep. Eighty mothers of infants 6−12 months of age with established infant sleep problems at a single general practice, Adelaide, South Australia.

Main outcome measures

The Depression Anxiety Stress Scale 21 (DASS21) immediately prior to the first consultation and again at follow-up approximately 3 weeks later. The number of infant nocturnal awakenings requiring parental support was also reported by mothers on both occasions.

Results

All measures of maternal well-being and infant nocturnal awakenings improved significantly. The mean number of maximum nocturnal awakenings decreased from 5.0 to 0.5 (mean difference 4.4, 95% CI 3.4 to 5.5). All measures of DASS21 improved significantly. The mean total DASS21 decreased from 29.1 to 14.9 (mean decrease 14.2, 95% CI 10.2 to 18.2); mean depression decreased from 7.9 to 2.8 (mean difference 5.2, 95% CI 3.7 to 6.7); mean anxiety decreased from 4.6 to 2.6 (mean difference 2.0, 95% CI 0.7 to 3.2); mean stress decreased from 16.6 to 9.5 (mean difference 7.0, 95% CI 5.1 to 9.0). The proportion of mothers assessed as having any degree of depression decreased by 85% from 26/80 (32.5%) to 4/80 (5%).

Conclusions

The number of nocturnal awakenings requiring parental support among infants aged 6−12 months significantly decreased following a single consultation on infant sleep physiology and teaching behavioural strategies to improve sleep. Significant improvements in maternal stress, anxiety and depression were also observed.
Early rehabilitation in critical care (eRiCC): functional electrical stimulation with cycling protocol for a randomised controlled trial
Authors: Parry Selina M , Berney Sue , Koopman René , Bryant Adam , El-Ansary Doa , Puthucheary Zudin , Hart Nicholas , Warrillow Stephen , Denehy Linda
Published: September 2012

Introduction

Intensive care-acquired weakness is a common problem, leads to significant impairment in physical functioning and muscle strength, and is prevalent in individuals with sepsis. Early rehabilitation has been shown to be safe and feasible; however, commencement is often delayed due to a patient's inability to co-operate. An intervention that begins early in an intensive care unit (ICU) admission without the need for patient volition may be beneficial in attenuating muscle wasting. The eRiCC (early rehabilitation in critical care) trial will investigate the effectiveness of functional electrical stimulation-assisted cycling and cycling alone, compared to standard care, in individuals with sepsis.

Methods and analysis

This is a single centre randomised controlled trial. Participants (n=80) aged ≥18 years, with a diagnosis of sepsis or severe sepsis, who are expected to be mechanically ventilated for ≥48 h and remain in the intensive care ≥4 days will be randomised within 72 h of admission to (1) standard care or (2) intervention where participants will receive functional electrical muscle stimulation-assisted supine cycling on one leg while the other leg undergoes cycling alone. Primary outcome measures include: muscle mass (quadriceps ultrasonography; bioelectrical impedance spectroscopy); muscle strength (Medical Research Council Scale; hand-held dynamometry) and physical function (Physical Function in Intensive Care Test; Functional Status Score in intensive care; 6 min walk test). Blinded outcome assessors will assess measures at baseline, weekly, at ICU discharge and acute hospital discharge. Secondary measures will be evaluated in a nested subgroup (n=20) and will consist of biochemical/histological analyses of collected muscle, urine and blood samples at baseline and at ICU discharge.

Ethics and dissemination

Ethics approval has been obtained from the relevant institution, and results will be published to inform clinical practice in the care of patients with sepsis to optimise rehabilitation and physical function outcomes.

Trial registration

Australian and New Zealand Clinical Trials Registry ACTRN12612000528853.
Using Healthcare Failure Mode and Effect Analysis to reduce medication errors in the process of drug prescription, validation and dispensing in hospitalised patients
Authors: Vélez-Díaz-Pallarés Manuel , Delgado-Silveira Eva , Carretero-Accame María Emilia , Bermejo-Vicedo Teresa
Published: September 2012

Objectives

To identify actions to reduce medication errors in the process of drug prescription, validation and dispensing, and to evaluate the impact of their implementation.

Methods

A Health Care Failure Mode and Effect Analysis (HFMEA) was supported by a before-and-after medication error study to measure the actual impact on error rate after the implementation of corrective actions in the process of drug prescription, validation and dispensing in wards equipped with computerised physician order entry (CPOE) and unit-dose distribution system (788 beds out of 1080) in a Spanish university hospital. The error study was carried out by two observers who reviewed medication orders on a daily basis to register prescription errors by physicians and validation errors by pharmacists. Drugs dispensed in the unit-dose trolleys were reviewed for dispensing errors. Error rates were expressed as the number of errors for each process divided by the total opportunities for error in that process times 100.

Results

A reduction in prescription errors was achieved by providing training for prescribers on CPOE, updating prescription procedures, improving clinical decision support and automating the software connection to the hospital census (relative risk reduction (RRR), 22.0%; 95% CI 12.1% to 31.8%). Validation errors were reduced after optimising time spent in educating pharmacy residents on patient safety, developing standardised validation procedures and improving aspects of the software's database (RRR, 19.4%; 95% CI 2.3% to 36.5%). Two actions reduced dispensing errors: reorganising the process of filling trolleys and drawing up a protocol for drug pharmacy checking before delivery (RRR, 38.5%; 95% CI 14.1% to 62.9%).

Conclusions

HFMEA facilitated the identification of actions aimed at reducing medication errors in a healthcare setting, as the implementation of several of these led to a reduction in errors in the process of drug prescription, validation and dispensing.
Role of routine pelvic radiography in initial evaluation of stable, high-energy, blunt trauma patients
Authors: Paydar Shahram , Ghaffarpasand Fariborz , Foroughi Mehdi , Saberi Ali , Dehghankhalili Maryam , Abbasi Hamidreza , Malekpoor Babak , Bananzadeh Ali Mohammad , Vahid Hosseini Mohammad , Bolandparvaz Shahram
Published: September 2012

Background

Pelvic fractures are among the most devastating traumatic injuries accompanied by high morbidity and mortality rate leading to catastrophic outcomes and haemodynamic consequences. Although Advanced Trauma Life Support (ATLS) recommends performing pelvic radiography in all major blunt trauma patients, several lines of evidence recommend that it can be limited to those blunt trauma patients who are haemodynamically unstable or have positive pelvic physical examination. Thus, we performed this study in order to evaluate the efficacy of routine pelvic radiography in haemodynamically stable, high-energy, blunt trauma patients.

Methods

This was a prospective cross-sectional study including all the haemodynamically stable, high-energy, blunt trauma patients with negative pelvic physical examination referring to our trauma centre during a 5-month period (May–September 2010). Pelvic radiographies were performed and reviewed for abnormalities. In those who had negative pelvic physical examination and the radiography was not revealing enough, CT imaging was requested and reviewed.

Results

During the study period, 1679 high-energy blunt trauma patients referred to our centre out of which 389 were haemodynamically stable and had negative pelvic physical examination. Pelvic radiography was found to be normal in all the patients except one (0.25%) who had pelvic fracture. Only three patients required CT imaging out of which two (0.5%) were found to be normal.

Conclusions

Pelvic radiography could be eliminated from the primary survey protocol of the patients with high-energy blunt trauma who are haemodynamically stable and have negative pelvic physical examination.
Avoidable emergency admissions?
Authors: Lillebo Borge , Dyrstad Bodil , Grimsmo Anders
Published: September 2012

Background

Use of specialist healthcare services is increasing.

Aim

To evaluate whether alternative healthcare services could reduce the need for admissions to specialist care hospitals.

Design

Prospective observational study of emergency referrals for admission to specialist care.

Setting

A single out-of-hours primary care centre (OPCC) in Norway.

Method

Out-of-hours physicians registered their referrals for hospital admission and stated whether the admission could have been avoided given the availability of six other healthcare services.

Results

Of 1083 registered encounters at the OPCC, 152 (14%) were referred for specialist care hospital admission. According to the referring physician, 32 (21%) of these referrals could have been avoided. The most eligible alternatives to such referrals were next-day appointments at a specialist outpatient clinic (11 of 32 referrals), or admission to a community hospital (21 of 32 referrals), or a nursing home (nine of 32 referrals). Respiratory (eight of 32 referrals) and gastrointestinal problems (12 of 32 referrals) were the most common among avoidable admissions.

Conclusions

The use of specialist care hospital admission can be reduced if appropriate alternatives are available.
A TWO-SPECIES HYDRODYNAMIC MODEL OF PARTICLES INTERACTING THROUGH SELF-ALIGNMENT
Authors: NAVORET LAURENT
Published: September 2012

In this paper, we present a two-species Vicsek model, that describes alignment interactions of self-propelled particles which can either move or not. The model consists in two populations with distinct Vicsek dynamics that interact only via the passage of the particles from one population to the other. The derivation of a macroscopic description of this model is performed using the methodology used for the Vicsek model: we find out a regime where alignment in the whole population occurs. We obtain a new macroscopic model for the densities of each population and the common mean direction of the particles. The treatment of the non-conservativity of the interactions requires a detail study of the linearized interaction operator.
PROPAGATION OF CHAOS IN A COAGULATION MODEL
Authors: ESCOBEDO M. , PEZZOTTI F.
Published: September 2012

The dynamics of a finite system of coalescing particles in a finite volume is considered. It is shown that, in the thermodynamic limit, a coagulation equation is recovered and propagation of chaos holds for all time.
SIMULATIONS OF THE LIFSHITZ–SLYOZOV EQUATIONS: THE ROLE OF COAGULATION TERMS IN THE ASYMPTOTIC BEHAVIOR
Authors: GOUDON THIERRY , LAGOUTIÈRE FRÉDÉRIC , TINE LÉON MATAR
Published: September 2012

We consider the Lifshitz–Slyozov system that describes the kinetics of precipitation from supersaturated solid solutions. We design specific Finite Volume schemes and we investigate numerically the behavior of the solutions, in particular the large time asymptotics. Our purpose is two-fold: first, we introduce an adapted scheme based on downwinding techniques in order to reduce the numerical diffusion; second, we discuss the influence of coagulation effects on the selection of the asymptotic profile.
DETERMINATION OF THE EQUIVALENT ANISOTROPY PROPERTIES OF POLYCRYSTALLINE MAGNETIC MATERIALS: THEORETICAL ASPECTS AND NUMERICAL ANALYSIS
Authors: BOTTAUSCIO ORIANO , PIAT VALERIA CHIADÒ , ELEUTERI MICHELA , LUSSARDI LUCA , MANZIN ALESSANDRA
Published: September 2012

The aim of this paper is the determination of the equivalent anisotropy properties of polycrystalline magnetic materials, modeled as an assembly of monocrystalline grains with a stochastic spatial distribution of easy axes. The theory of Γ-convergence is here adopted to homogenize the anisotropic contribution in the energy functional and derive the equivalent anisotropy properties. The reliability of this approach is investigated focusing on the computation of the static hysteresis loops of polycrystalline magnetic thin films, starting from the numerical integration of the Landau–Lifshitz–Gilbert equation.
QUASI-STATIC EVOLUTIONS IN LINEAR PERFECT PLASTICITY AS A VARIATIONAL LIMIT OF FINITE PLASTICITY: A ONE-DIMENSIONAL CASE
Authors: GIACOMINI ALESSANDRO , MUSESTI ALESSANDRO
Published: September 2012

In the framework of the energetic approach to rate-independent evolutions, we show that one-dimensional linear perfect plasticity can be obtained by linearization as a variational limit of a finite plasticity model with hardening proposed by A. Mielke (SIAM J. Math. Anal., 2004).
SELECTION AND ASSESSMENT OF PHENOMENOLOGICAL MODELS OF TUMOR GROWTH
Authors: ODEN J. TINSLEY , PRUDENCIO ERNESTO E. , HAWKINS-DAARUD ANDREA
Published: September 2012

We address general approaches to the rational selection and validation of mathematical and computational models of tumor growth using methods of Bayesian inference. The model classes are derived from a general diffuse-interface, continuum mixture theory and focus on mass conservation of mixtures with up to four species. Synthetic data are generated using higher-order base models. We discuss general approaches to model calibration, validation, plausibility, and selection based on Bayesian-based methods, information theory, and maximum information entropy. We also address computational issues and provide numerical experiments based on Markov chain Monte Carlo algorithms and high performance computing implementations.
SOME RESULTS ON THE INTERSECTION GRAPHS OF IDEALS OF RINGS
Authors: AKBARI S. , NIKANDISH R. , NIKMEHR M. J.
Published: September 2012

Let R be a ring with unity and I(R)* be the set of all nontrivial left ideals of R. The intersection graph of ideals of R, denoted by G(R), is a graph with the vertex set I(R)* and two distinct vertices I and J are adjacent if and only if I ∩ J ≠ 0. In this paper, we study some connections between the graph-theoretic properties of this graph and some algebraic properties of rings. We characterize all rings whose intersection graphs of ideals are not connected. Also we determine all rings whose clique number of the intersection graphs of ideals is finite. Among other results, it is shown that for a ring R, if the clique number of G(R) is finite, then the chromatic number is finite and if R is a reduced ring, then both are equal.
Inflammasomes and Their Roles in Health and Disease
Authors: Lamkanfi Mohamed , Dixit Vishva M.
Published: September 2012

Inflammasomes are a set of intracellular protein complexes that enable autocatalytic activation of inflammatory caspases, which drive host and immune responses by releasing cytokines and alarmins into circulation and by inducing pyroptosis, a proinflammatory cell death mode. The inflammasome type mediating these responses varies with the microbial pathogen or stress factor that poses a threat to the organism. Since the discovery that polymorphisms in inflammasome genes are linked to common autoimmune diseases and less frequent periodic fever syndromes, inflammasome signaling has been dissected at the molecular level. In this review, we present recently gained insight on the distinct inflammasome types, their activation and effector mechanisms, and their modulation by microbial virulence factors. In addition, we discuss recently gained knowledge on the role of deregulated inflammasome activity in human autoinflammatory, autoimmune, and infectious diseases.
5-Methylcytosine DNA Demethylation: More Than Losing a Methyl Group
Authors: Franchini Don-Marc , Schmitz Kerstin-Maike , Petersen-Mahrt Svend K.
Published: September 2012

Demethylation of 5-methylcytosine in DNA is integral to the maintenance of an intact epigenome. The balance between the presence or absence of 5-methylcytosine determines many physiological aspects of cell metabolism, with a turnover that can be measured in minutes to years. Biochemically, addition of the methyl group is shared among all living kingdoms and has been well characterized, whereas the removal or reversion of this mark seems diverse and much less understood. Here, we present a summary of how DNA demethylation can be initiated directly, utilizing the ten-eleven translocation (TET) family of proteins, activation-induced deaminase (AID), or other DNA modifying enzymes, or indirectly, via transcription, RNA metabolism, or DNA repair; how intermediates in those pathways are substrates of the DNA repair machinery; and how demethylation pathways are linked and possibly balanced, avoiding mutations.
Neural Regeneration in Caenorhabditis elegans
Authors: Bejjani Rachid El , Hammarlund Marc
Published: September 2012

Axon regeneration is a medically relevant process that can repair damaged neurons. This review describes current progress in understanding axon regeneration in the model organism Caenorhabditis elegans. Factors that regulate axon regeneration in C. elegans have broadly similar roles in vertebrate neurons. This means that using C. elegans as a tool to leverage discovery is a legitimate strategy for identifying conserved mechanisms of axon regeneration.
Uncovering the Molecular and Cellular Mechanisms of Heart Development Using the Zebrafish
Authors: Staudt David , Stainier Didier
Published: September 2012

Over the past 20 years, the zebrafish has emerged as a powerful model organism for studying cardiac development. Its ability to survive without an active circulation and amenability to forward genetics has led to the identification of numerous mutants whose study has helped elucidate new mechanisms in cardiac development. Furthermore, its transparent, externally developing embryos have allowed detailed cellular analyses of heart development. In this review, we discuss the molecular and cellular processes involved in zebrafish heart development from progenitor specification to development of the valve and the conduction system. We focus on imaging studies that have uncovered the cellular bases of heart development and on zebrafish mutants with cardiac abnormalities whose study has revealed novel molecular pathways in cardiac cell specification and tissue morphogenesis.
What Is the Metabolic State of the Oligotrophic Ocean? A Debate
Authors: Ducklow Hugh W. , Doney Scott C.
Published: September 2012

For more than a decade there has been controversy in oceanography regarding the metabolic state of the oligotrophic subtropical gyres of the open ocean. Here we review the background of this controversy, commenting on several issues to set the context for a moderated debate between two groups of scientists. In one of the two companion articles, Williams et al. (2013) take the view that these gyres exhibit a state of net autotrophy—that is, their gross primary production (GPP) exceeds community respiration (R) when averaged over some suitably extensive region and over a long duration. In the other companion article, Duarte et al. (2013) take the opposite view, that these gyres are net heterotrophic, with R exceeding the GPP. This idea—that large, remote areas of the upper ocean could be net heterotrophic—raises a host of fundamental scientific questions about the metabolic processes of photosynthesis and respiration that underlie ocean ecology and global biogeochemistry. The question remains unresolved in part because the net state is finely balanced between large opposing fluxes and most current measurements have large uncertainties. This challenging question must be studied against the background of large, anthropogenically driven changes in ocean ecology and biogeochemistry. Current trends of anthropogenic change make it an urgent problem to solve and also greatly complicate finding that solution.
The Hydrogen Games and Other Adventures in Chemistry
Authors: Zare Richard N.
Published: September 2012

I seem to have started off on the wrong foot in life, but I am extremely fortunate that I soon found my footing in the company of physical chemists. I consider myself to be very lucky to be doing something that constantly brings me in contact with bright minds, stimulating conversations, and exciting experiments. My work has allowed me to learn astounding facts about the molecules and atoms that make up our surroundings and ourselves. For this article, I focus on one aspect of my research, understanding the fundamental principles of the simple reaction between a hydrogen atom and a hydrogen molecule. Although my group and others have been studying this seemingly simple reaction for well over 30 years, it continues to provoke questions about the properties of matter.
Functional Insights from Glutamate Receptor Ion Channel Structures
Authors: Kumar Janesh , Mayer Mark L.
Published: September 2012

X-ray crystal structures for the soluble amino-terminal and ligand-binding domains of glutamate receptor ion channels, combined with a 3.6-Å-resolution structure of the full-length AMPA receptor GluA2 homotetramer, provide unique insights into the mechanisms of the assembly and function of glutamate receptor ion channels. Increasingly sophisticated biochemical, computational, and electrophysiological experiments are beginning to reveal the mechanism of action of partial agonists and suggest new models for the mechanism of action of allosteric modulators. Newly identified NMDA receptor ligands acting at novel sites offer hope for the development of subtype-selective modulators. The many unresolved issues include the role of the amino-terminal domain in AMPA receptor signaling and the mechanisms by which auxiliary proteins regulate receptor activity. The structural basis for ion permeation and ion channel block also remain areas of uncertainty, and despite substantial progress, molecular dynamics simulations have yet to reveal how glutamate binding opens the ion channel pore.
A novel nutrient sensing mechanism underlies substrate-induced regulation of monocarboxylate transporter-1
Authors: Borthakur Alip , Priyamvada Shubha , Kumar Anoop , Natarajan Arivarasu A. , Gill Ravinder K. , Alrefai Waddah A. , Dudeja Pradeep K.
Published: September 2012

Monocarboxylate transporter isoform-1 (MCT1) plays an important role in the absorption of short-chain fatty acids (SCFAs) in the colon. Butyrate, a major SCFA, serves as the primary energy source for the colonic mucosa, maintains epithelial integrity, and ameliorates intestinal inflammation. Previous studies have shown substrate (butyrate)-induced upregulation of MCT1 expression and function via transcriptional mechanisms. The present studies provide evidence that short-term MCT1 regulation by substrates could be mediated via a novel nutrient sensing mechanism. Short-term regulation of MCT1 by butyrate was examined in vitro in human intestinal C2BBe1 and rat intestinal IEC-6 cells and ex vivo in rat intestinal mucosa. Effects of pectin feeding on MCT1, in vivo, were determined in rat model. Butyrate treatment (30–120 min) of C2BBe1 cells increased MCT1 function {p-(chloromercuri) benzene sulfonate (PCMBS)-sensitive [14C]butyrate uptake} in a pertussis toxin-sensitive manner. The effects were associated with decreased intracellular cAMP levels, increased Vmax of butyrate uptake, and GPR109A-dependent increase in apical membrane MCT1 level. Nicotinic acid, an agonist for the SCFA receptor GPR109A, also increased MCT1 function and decreased intracellular cAMP. Pectin feeding increased apical membrane MCT1 levels and nicotinate-induced transepithelial butyrate flux in rat colon. Our data provide strong evidence for substrate-induced enhancement of MCT1 surface expression and function via a novel nutrient sensing mechanism involving GPR109A as a SCFA sensor.
TLR4 deficiency promotes autophagy during cigarette smoke-induced pulmonary emphysema
Authors: An Chang Hyeok , Wang Xiao Mei , Lam Hilaire C. , Ifedigbo Emeka , Washko George R. , Ryter Stefan W. , Choi Augustine M. K.
Published: September 2012

Toll-like receptors (TLRs) exert important nonimmune functions in lung homeostasis. TLR4 deficiency promotes pulmonary emphysema. We examined the role of TLR4 in regulating cigarette smoke (CS)-induced autophagy, apoptosis, and emphysema. Lung tissue was obtained from chronic obstructive lung disease (COPD) patients. C3H/HeJ ( Tlr4-mutated) mice and C57BL/10ScNJ ( Tlr4-deficient) mice and their respective control strains were exposed to chronic CS or air. Human or mouse epithelial cells (wild-type, Tlr4-knockdown, and Tlr4-deficient) were exposed to CS-extract (CSE). Samples were analyzed for TLR4 expression, and for autophagic or apoptotic proteins by Western blot analysis or confocal imaging. Chronic obstructive lung disease lung tissues and human pulmonary epithelial cells exposed to CSE displayed increased TLR4 expression, and increased autophagic [microtubule-associated protein-1 light-chain-3B (LC3B)] and apoptotic (cleaved caspase-3) markers. Beas-2B cells transfected with TLR4 siRNA displayed increased expression of LC3B relative to control cells, basally and after exposure to CSE. The basal and CSE-inducible expression of LC3B and cleaved caspase-3 were elevated in pulmonary alveolar type II cells from Tlr4-deficient mice. Wild-type mice subjected to chronic CS-exposure displayed airspace enlargement;, however, the Tlr4-mutated or Tlr4-deficient mice exhibited a marked increase in airspace relative to wild-type mice after CS-exposure. The Tlr4-mutated or Tlr4-deficient mice showed higher levels of LC3B under basal conditions and after CS exposure. The expression of cleaved caspase-3 was markedly increased in Tlr4-deficient mice exposed to CS. We describe a protective regulatory function of TLR4 against emphysematous changes of the lung in response to CS.
δ ENaC: a novel divergent amiloride-inhibitable sodium channel
Authors: Ji Hong-Long , Zhao Run-Zhen , Chen Zai-Xing , Shetty Sreerama , Idell Steven , Matalon Sadis
Published: September 2012

The fourth subunit of the epithelial sodium channel, termed delta subunit (δ ENaC), was cloned in human and monkey. Increasing evidence shows that this unique subunit and its splice variants exhibit biophysical and pharmacological properties that are divergent from those of α ENaC channels. The widespread distribution of epithelial sodium channels in both epithelial and nonepithelial tissues implies a range of physiological functions. The altered expression of SCNN1D is associated with numerous pathological conditions. Genetic studies link SCNN1D deficiency with rare genetic diseases with developmental and functional disorders in the brain, heart, and respiratory systems. Here, we review the progress of research on δ ENaC in genomics, biophysics, proteomics, physiology, pharmacology, and clinical medicine.
Positive end-expiratory pressure oscillation facilitates brain vascular reactivity monitoring
Authors: Brady Ken M. , Easley R. Blaine , Kibler Kathleen , Kaczka David W. , Andropoulos Dean , Fraser Charles D. , Smielewski Peter , Czosnyka Marek , Adams Gerald J. , Rhee Christopher J. , Rusin Craig G.
Published: September 2012

The pressure reactivity index (PRx) identifies optimal cerebral perfusion pressure after traumatic brain injury. We describe a method to improve PRx precision by induced variations in arterial blood pressure (ABP) using positive end-expiratory pressure (PEEP) modulation ( iPRx). Neonatal swine ( n = 10) were ventilated with static PEEP and then with PEEP oscillated between 5 and 10 cmH2O at a frequency of 1/min. PRx was recorded as a moving correlation coefficient between ABP and intracranial pressure (ICP) from spontaneous ABP activity (0.05-0.003 Hz) during static PEEP. iPRx was similarly recorded with PEEP oscillation-induced ABP waves. The lower limit of autoregulation (LLA) was delineated with continuous cortical laser Doppler flux monitoring. PEEP oscillation increased autoregulation-monitoring precision. The ratios of median absolute deviations to range of possible values for the PRx and iPRx were 9.5% (8.3–13.7%) and 6.2% (4.2–8.7%), respectively ( P = 0.006; median, interquartile range). The phase-angle difference between ABP and ICP above LLA was 161° (150°–166°) and below LLA, −31° (−42° to 12°, P < 0.0001). iPRx above LLA was −0.42 (−0.67 to −0.29) and below LLA, 0.32 (0.22–0.43, P = 0.0004). A positive iPRx was 97% specific and 91% sensitive for perfusion pressure below LLA. PEEP oscillation caused stable, low-frequency ABP oscillations that reduced noise in the PRx. Safe translation of these findings to clinical settings is expected to yield more accurate and rapid delineation of individualized optimal perfusion-pressure goals for patients.
p21-Activated Kinase 1 Is Required for Efficient Tumor Formation and Progression in a Ras-Mediated Skin Cancer Model
Authors: Chow Hoi Yee , Jubb Adrian M. , Koch Jennifer N. , Jaffer Zahara M. , Stepanova Dina , Campbell David A. , Duron Sergio G. , O'Farrell Marie , Cai Kathy Q. , Klein-Szanto Andres J.P. , Gutkind J. Silvio , Hoeflich Klaus P. , Chernoff Jonathan
Published: September 2012

The RAS genes are the most commonly mutated oncogenes in human cancer and present a particular therapeutic dilemma, as direct targeting of Ras proteins by small molecules has proved difficult. Signaling pathways downstream of Ras, in particular Raf/Mek/Erk and PI3K/Akt/mTOR, are dominated by lipid and protein kinases that provide attractive alternate targets in Ras-driven tumors. As p21-activated kinase 1 (Pak1) has been shown to regulate both these signaling pathways and is itself upregulated in many human cancers, we assessed the role of Pak1 in Ras-driven skin cancer. In human squamous cell carcinoma (SCC), we found a strong positive correlation between advanced stage and grade and PAK1 expression. Using a mouse model of Kras-driven SCC, we showed that deletion of the mouse Pak1 gene led to markedly decreased tumorigenesis and progression, accompanied by near total loss of Erk and Akt activity. Treatment of KrasG12D mice with either of two distinct small molecule Pak inhibitors (PF3758309 and FRAX597) caused tumor regression and loss of Erk and Akt activity. Tumor regression was also seen in mice treated with a specific Mek inhibitor, but not with an Akt inhibitor. These findings establish Pak1 as a new target in KRAS-driven tumors and suggest a mechanism of action through the Erk, but not the Akt, signaling pathway. Cancer Res; 72(22); 5966–75. ©2012 AACR.
Regulation of Pattern Recognition Receptors by the Apolipoprotein A-I Mimetic Peptide 4F
Authors: White C. Roger , Smythies Lesley E. , Crossman David K. , Palgunachari Mayakonda N. , Anantharamaiah G.M. , Datta Geeta
Published: September 2012

Objective—

The apolipoprotein A-I (apoA-I) mimetic peptide 4F favors the differentiation of human monocytes to an anti-inflammatory phenotype and attenuates lipopolysaccharide (LPS)-induced inflammatory responses. We investigated the effects of LPS on the Toll-like receptor (TLR) signaling pathway in 4F-differentiated monocyte-derived macrophages.

Methods and Results—

Monocyte-derived macrophages were pretreated with 4F or vehicle for 7 days. 4F downregulated cell-surface TLRs (4, 5, and 6) as determined by flow cytometry. 4F attenuated the LPS-dependent upregulation of genes encoding TLR1, 2, and 6 and genes of the MyD88-dependent (CD14, MyD88, TRAF6, interleukin-1 receptor–associated kinase 4, and inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta) and MyD88-independent (interferon regulatory factor 3, TANK-binding kinase 1, and Toll-interleukin 1 receptor domain–containing adaptor-inducing interferon-β) pathways as determined by microarray analysis and quantitative reverse transcriptase polymerase chain reaction. Functional analyses of monocyte-derived macrophages showed that 4F reduced LPS-dependent TLR4 recycling, phosphorylation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha, activation and translocation of nuclear factor-κB and inhibited the secretion of tumor necrosis factor-α and interleukin-6 induced by LPS or lipoteichoic acid. These changes were associated with depletion of cellular cholesterol and caveolin, components of membrane lipid rafts.

Conclusion—

These data suggest that disruption of rafts by 4F alters the assembly of TLR–ligand complexes in cell membranes and inhibits proinflammatory gene expression in monocyte-derived macrophages, thus attenuating the responsiveness of macrophages to LPS.
Single-Ring Posterior Left Atrial (Box) Isolation Results in a Different Mode of Recurrence Compared With Wide Antral Pulmonary Vein Isolation on Long-Term Follow-Up
Authors: Lim Toon Wei , Koay Choon Hiang , See Valerie A. , McCall Rebecca , Chik William , Zecchin Robert , Byth Karen , Seow Swee-Chong , Thomas Liza , Ross David L. , Thomas Stuart P.
Published: September 2012

Background—

Electric isolation of the pulmonary veins and posterior left atrium with a single ring of radiofrequency lesions (single-ring isolation [SRI]) may result in fewer atrial fibrillation (AF) recurrences than wide antral pulmonary vein isolation (wide antral isolation [WAI]) by abolishing extravenous AF triggers. The effect of mitral isthmus line (MIL) ablation on outcomes after SRI has not previously been assessed.

Methods and Results—

We randomly assigned 220 consecutive patients (58±10 years old; 82% men) with highly symptomatic AF (61% paroxysmal, 39% persistent/longstanding persistent) to undergo either SRI or WAI. Half of each cohort was also randomly allocated to have left lateral MIL ablation (2×2 factorial study design). Patients were followed clinically and with 7-day Holter studies for arrhythmia recurrences. The primary end points were recurrence of AF and organized atrial tachyarrhythmias. AF-free survival at 2 years was better after SRI (74% [95% CI, 65%–82%]) than WAI (61% [51%–70%];
P
=0.031). Organized atrial tachyarrhythmia–free survival was similar after SRI and WAI (67% [57%–75%] ersus 64% [54%–72%], respectively, at 2 years;
P
=0.988). MIL ablation resulted in better 2-year organized atrial tachyarrhythmia–free survival (71% [62%–79%] versus 60% [50%–69%];
P
=0.07), which approached statistical significance. Survival free of any atrial arrhythmia after one procedure was not significantly affected by isolation technique or MIL ablation.

Conclusions—

SRI resulted in fewer AF recurrences compared with WAI on long-term follow-up but did not reduce the recurrence of all atrial arrhythmias. MIL ablation may reduce organized atrial tachyarrhythmia recurrences.

Clinical Trial Registration—

http://www.anzctr.org.au
; ACTRN12606000467538.
Age-Dependent Effect of β-Blockers in Preventing Vasovagal Syncope
Authors: Sheldon Robert S. , Morillo Carlos A. , Klingenheben Thomas , Krahn Andrew D. , Sheldon Aaron , Rose M. Sarah
Published: September 2012

Background—

β-blockers have little effectiveness in preventing vasovagal syncope in unselected populations, but they might be effective in older patients. We determined whether β-blockers prevent vasovagal syncope in an age-related fashion.

Methods and Results—

Two populations were studied. A proportional hazards analysis was performed on an observational cohort study of 153 patients with vasovagal syncope, 52 of whom received β-blockers. A multivariable proportional hazards model stratified by center was performed on 208 participants in the randomized Prevention of Syncope Trial (POST), examining the interaction between age group and treatment with metoprolol. Age-specific hazard ratios were estimated for both studies and combined using the inverse variance meta-analytic method. In the cohort study, the hazard ratio for syncope if treated with β-blockers was 1.54 (95% CI, 0.78–3.05) for patients aged <42 years and 0.48 (95% CI, 0.12–1.92) for patients aged ≥42 years. In POST, the proportional hazards model showed interactions between age and treatment effect (
P
=0.026). The hazard ratio for patients aged ≥42 years who received metoprolol was 0.53 (95% CI, 0.25–1.10); in patients aged <42 years, the hazard ratio was 1.62 (95% CI, 0.85–3.10). A pooled analysis of both studies yielded an estimate of the hazard ratio of 1.58 (CI, 1.00–2.31) for patients aged <42 years, and the hazard ratio was 0.52 (CI, 0.27–1.01) for patients aged ≥42 years. The 2 age groups differed significantly in response to β-blockers (
P
=0.007).

Conclusions—

β-blocker treatment may suppress vasovagal syncope in middle-aged patients aged >42 years.
Connexin45 Provides Optimal Atrioventricular Nodal Conduction in the Adult Mouse Heart
Authors: Frank Marina , Wirth Angela , Andrié René P. , Kreuzberg Maria M. , Dobrowolski Radoslaw , Seifert Gerald , Offermanns Stefan , Nickenig Georg , Willecke Klaus , Schrickel Jan W.
Published: September 2012

Rationale:

The gap junctional protein connexin (Cx) 45 is strongly expressed in the early embryonic myocardium. In the adult hearts of mice and humans, the expression mainly is restricted to the cardiac conduction system. Cx45 plays an essential role for development and function of the embryonic heart because general and cardiomyocyte-directed deficiencies of Cx45 in mice lead to embryonic lethality attributable to morphological and functional cardiovascular defects. The function of Cx45 in the adult mouse has not yet been cleared.

Objective:

To clarify the function of Cx45 in the adult mouse heart.

Methods and Results:

To circumvent the embryonic lethality resulting from Cx45 deficiency, mice were generated in which deletion of Cx45 specifically was induced in cardiomyocytes of adult mice. These Cx45-deficient mice were viable but showed a decrease in atrioventricular nodal conductivity. In addition, the Cx30.2 protein that is coexpressed with Cx45 in the cardiac conduction system was posttranscriptionally reduced by 70% in mutant hearts. Furthermore, deletion of both Cx45 and Cx30.2 resulted in viable mice that, however, showed stronger impairment of atrioventricular nodal conduction than the single Cx45-deficient mice.

Conclusions:

Cx45 is required for optimal impulse propagation in the atrioventricular node and stabilizes the level of the coexpressed Cx30.2 protein in the adult mouse heart. In contrast to the embryo, Cx45 is not essential for the viability of adult mice.
Association of Mild to Moderate Chronic Kidney Disease With Venous Thromboembolism
Authors: Mahmoodi Bakhtawar K. , Gansevoort Ron T. , Næss Inger Anne , Lutsey Pamela L. , Brækkan Sigrid K. , Veeger Nic J.G.M. , Brodin Ellen E. , Meijer Karina , Sang Yingying , Matsushita Kunihiro , Hallan Stein I. , Hammerstrøm Jens , Cannegieter Suzanne C. , Astor Brad C. , Coresh Josef , Folsom Aaron R. , Hansen John-Bjarne , Cushman Mary
Published: September 2012

Background—

Recent findings suggest that chronic kidney disease (CKD) may be associated with an increased risk of venous thromboembolism (VTE). Given the high prevalence of mild-to-moderate CKD in the general population, in depth analysis of this association is warranted.

Methods and Results—

We pooled individual participant data from 5 community-based cohorts from Europe (second Nord-Trøndelag Health Study [HUNT2], Prevention of Renal and Vascular End-stage Disease [PREVEND], and the Tromsø study) and the United States (Atherosclerosis Risks in Communities [ARIC] and Cardiovascular Health Study [CHS]) to assess the association of estimated glomerular filtration rate (eGFR), albuminuria, and CKD with objectively verified VTE. To estimate adjusted hazard ratios for VTE, categorical and continuous spline models were fit by using Cox regression with shared-frailty or random-effect meta-analysis. A total of 1178 VTE events occurred over 599 453 person-years follow-up. Relative to eGFR 100 mL/min per 1.73 m
2
, hazard ratios for VTE were 1.29 (95% confidence interval, 1.04–1.59) for eGFR 75, 1.31 (1.00–1.71) for eGFR 60, 1.82 (1.27–2.60) for eGFR 45, and 1.95 (1.26–3.01) for eGFR 30 mL/min per 1.73 m
2
. In comparison with an albumin-to-creatinine ratio (ACR) of 5.0 mg/g, the hazard ratios for VTE were 1.34 (1.04–1.72) for ACR 30 mg/g, 1.60 (1.08–2.36) for ACR 300 mg/g, and 1.92 (1.19–3.09) for ACR 1000 mg/g. There was no interaction between clinical categories of eGFR and ACR (
P
=0.20). The adjusted hazard ratio for CKD, defined as eGFR <60 mL/min per 1.73 m
2
or albuminuria ≥30 mg/g, (versus no CKD) was 1.54 (95% confidence interval, 1.15–2.06). Associations were consistent in subgroups according to age, sex, and comorbidities, and for unprovoked versus provoked VTE, as well.

Conclusions—

Both eGFR and ACR are independently associated with increased risk of VTE in the general population, even across the normal eGFR and ACR ranges.
Higher Stroke Unit Volume Associated With Improved Quality of Early Stroke Care and Reduced Length of Stay
Authors: Svendsen Marie Louise , Ehlers Lars Holger , Ingeman Annette , Johnsen Søren Paaske
Published: September 2012

Background and Purpose—

Specialized stroke unit care improves outcome among patients with stroke, but it is unclear whether there are any scale advantages in costs and clinical outcome from treating a larger number of patients. We examined whether the case volume in stroke units was associated with quality of early stroke care, mortality, and hospital bed-day use.

Methods—

In a nationwide population-based cohort study, we identified 63 995 patients admitted to stroke units in Denmark between 2003 and 2009. Data on exposure, outcome, and covariates were collected prospectively. Comparisons were clustered within stroke units and adjusted for patient and hospital characteristics.

Results—

Patients in high-volume stroke units overall had a better prognostic profile than patients in low-volume stroke units. Patients in high-volume stroke units also received more processes of care in the early phase of stroke compared with patients in low-volume stroke units (unadjusted difference, 9.84 percentage points; 95% CI, 3.98–15.70). High stroke unit volume was associated with shorter length of the initial hospital stay (adjusted ratio, 0.49; 95% CI, 0.41–0.59) and reduced bed-day use in the first year after stroke (adjusted ratio, 0.79; 95% CI, 0.70–0.87). No association between volume and mortality was found.

Conclusions—

Patients admitted to high-volume stroke units received a higher quality of early stroke care and spent fewer days in the hospital compared with patients in low-volume units. We observed no association between volume and mortality.
Detailed Analysis of Periprocedural Strokes in Patients Undergoing Intracranial Stenting in Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS)
Authors: Fiorella David , Derdeyn Colin P. , Lynn Michael J. , Barnwell Stanley L. , Hoh Brian L. , Levy Elad I. , Harrigan Mark R. , Klucznik Richard P. , McDougall Cameron G. , Pride G. Lee , Zaidat Osama O. , Lutsep Helmi L. , Waters Michael F. , Hourihane J. Maurice , Alexandrov Andrei V. , Chiu David , Clark Joni M. , Johnson Mark D. , Torbey Michel T. , Rumboldt Zoran , Cloft Harry J. , Turan Tanya N. , Lane Bethany F. , Janis L. Scott , Chimowitz Marc I.
Published: September 2012

Background and Purpose—

Enrollment in the Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis (SAMMPRIS) trial was halted due to the high risk of stroke or death within 30 days of enrollment in the percutaneous transluminal angioplasty and stenting arm relative to the medical arm. This analysis focuses on the patient and procedural factors that may have been associated with periprocedural cerebrovascular events in the trial.

Methods—

Bivariate and multivariate analyses were performed to evaluate whether patient and procedural variables were associated with cerebral ischemic or hemorrhagic events occurring within 30 days of enrollment (termed periprocedural) in the percutaneous transluminal angioplasty and stenting arm.

Results—

Of 224 patients randomized to percutaneous transluminal angioplasty and stenting, 213 underwent angioplasty alone (n=5) or with stenting (n=208). Of these, 13 had hemorrhagic strokes (7 parenchymal, 6 subarachnoid), 19 had ischemic stroke, and 2 had cerebral infarcts with temporary signs within the periprocedural period. Ischemic events were categorized as perforator occlusions (13), embolic (4), mixed perforator and embolic (2), and delayed stent occlusion (2). Multivariate analyses showed that higher percent stenosis, lower modified Rankin score, and clopidogrel load associated with an activated clotting time above the target range were associated (
P
≤0.05) with hemorrhagic stroke. Nonsmoking, basilar artery stenosis, diabetes, and older age were associated (
P
≤0.05) with ischemic events.

Conclusions—

Periprocedural strokes in SAMMPRIS had multiple causes with the most common being perforator occlusion. Although risk factors for periprocedural strokes could be identified, excluding patients with these features from undergoing percutaneous transluminal angioplasty and stenting to lower the procedural risk would limit percutaneous transluminal angioplasty and stenting to a small subset of patients. Moreover, given the small number of events, the present data should be used for hypothesis generation rather than to guide patient selection in clinical practice.

Clinical Trial Registration Information—

URL:
http://clinicaltrials.gov
. Unique Identifier: NCT00576693.
Mutant Erythropoietin Without Erythropoietic Activity Is Neuroprotective Against Ischemic Brain Injury
Authors: Gan Yu , Xing Juan , Jing Zheng , Stetler R. Anne , Zhang Feng , Luo Yumin , Ji Xunming , Gao Yanqin , Cao Guodong
Published: September 2012

Background and Purpose—

Erythropoietin (EPO) confers potent neuroprotection against ischemic injury. However, treatment for stroke requires high doses and multiple administrations of EPO, which may cause deleterious side effects due to its erythropoietic activity. This study identifies a novel nonerythropoietic mutant EPO and investigates its potential neuroprotective effects and underlying mechanism in an animal model of cerebral ischemia.

Methods—

We constructed a series of mutant EPOs, each containing a single amino acid mutation within the erythropoietic motif, and tested their erythropoietic activity. Using cortical neuronal cultures exposed to
N
-methyl
-d-
aspartate neurotoxicity and a murine model of transient middle cerebral artery occlusion, neuroprotection and neurofunctional outcomes were assessed as well as activation of intracellular signaling pathways.

Results—

The serine to isoleucine mutation at position 104 (S104I-EPO) completely abolished the erythropoietic and platelet-stimulating activity of EPO. Administration of S104I-EPO significantly inhibited
N
-methyl-
d
-aspartate-induced neuronal death in primary cultures and protected against cerebral infarction and neurological deficits with an efficacy similar to that of wild-type EPO. Both S104-I-EPO and wild-type EPO activated similar prosurvival signaling pathways such as phosphatidylinositol 3-kinase/AKT, mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2, and STAT5. Inhibition of phosphatidylinositol 3-kinase/AKT or mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 signaling pathways significantly attenuated the neuroprotective effects of S104-I-EPO, indicating that activation of these pathways underlies the neuroprotective mechanism of mutant EPO against cerebral ischemia.

Conclusions—

S104-I-EPO confers neuroprotective effects comparable to those of wild-type EPO against ischemic brain injury with the added benefit of lacking erythropoietic and platelet-stimulating side effects. Our novel findings suggest that the nonerythropoietic mutant EPO is a legitimate candidate for ischemic stroke intervention.