4 (90%) than 8.0 or less (25%) mg/L (Hazard ratio: 95% confidence interval, 1.92: 1.01-3.64) in the model adjusted for age, sex, and metabolic risk factors. Adjustment for N-terminal pro-B-type natriuretic peptide and nutritional status did not substantially alter this risk estimate, although the association ceased to be statistically significant. Adjustment for physical function did attenuate the relationship, however, which ceased see more to be apparent upon exclusion of disability or death occurring within 3 years of follow-up.

The relationship between adiponectin and the composite

outcome of incident disability and death was at least partly explained by reduced physical function and wasting in participants with higher adiponectin levels.”
“The effects of hypnotic drugs on driving performance are most often evaluated on young healthy subjects by using a monotonous

motorway driving test. The effects of drugs in urban driving situations have not yet been evaluated in any age group. Our objectives were to assess residual effects of the most prescribed hypnotics, zolpidem and zopiclone, on older middle-age drivers’ capacities Selleckchem GSK2118436 in an urban situation.

Sixteen healthy subjects aged 55 to 65 years underwent this double-blind, balanced, cross-over study. Zopiclone (7.5 mg), zolpidem (10 mg), and flunitrazepam (1 mg; used as positive control) or a placebo were administered at each subject’s home at 11:00 pm under the supervision of an investigator. The next morning, the subjects had to drive in a simulated urban environment where accident scenarios were introduced. Accident scenarios were implemented using data from real accident cases.

Hypnotics did not significantly increase the number of collisions. However, significantly

higher speeds were found with zopiclone and Florfenicol flunitrazepam; moreover, zolpidem and zopiclone induced modifications of the lateral position of the car on the road.

This study did not reveal any major residual effects of the hypnotics studied on driving performance in aging drivers. However, the urban driving situations used here for the first time in the evaluation of drugs revealed some modifications in driving habits which could lead to risky behavior. It thus appears that urban driving simulations are useful for gaining knowledge about the effects of drugs on driving behavior.”
“Sickness refers to a set of coordinated physiological and behavioral changes in response to systemic inflammation. It is characterized by fever, malaise, social withdrawal, fatigue, and anorexia. While these responses collectively represent a protective mechanism against infection and injury, increasing lines of evidence indicate that over-exaggerated or persistent sickness can damage the brain, and could possibly raise the risk to developing delirium. Therefore, a clear understanding in sickness will be beneficial.

To date it has not been possible to consistently differentiate brain responses to emotion-specific affective states or stimuli, and some evidence to suggests the theta ERS more likely measures general arousal processes Inflammation inhibitor rather than yielding veridical indices of specific emotional states. Perhaps cortical EEG patterns will never be able to be used to distinguish discrete

emotional states from the surface of the brain. The implications and limitations of such approaches for understanding human emotions are discussed. (C) 2011 Elsevier Ltd. All rights reserved.”
“Aims:

Bacillus halodurans C-125 is a Gram-positive bacterium that was the first alkaliphilic species to have its genome completely sequenced. Despite its many years as a model for alkaliphily and source of industrially important enzymes, genetic manipulation of B. halodurans C-125 remains difficult, and therefore, we sought to develop a robust method to allow routine transformation of this organism.

Methods and Results:

A plasmid artificial modification system (PAM system, <link rid=”"b7″”>Yasui et al. 2008) for B. halodurans C-125 was created that increases transformation ASP2215 ic50 efficiency

by 10- to 1000-fold. Also, recovering transformed protoplasts on succinate nutrient agar (SNA) yields faster, more robust colony recovery than on the traditional recovery medium. Combining these Lck two techniques often allows recovery of transformants in as little as 48 h.

Conclusions:

Use of the B. halodurans

C-125 PAM system and SNA greatly improves the efficiency and speed of protoplast transformation of B. halodurans C-125.

Significance and Impact of the Study:

These techniques allow routine genetic manipulation of B. halodurans C-125, a model alkaliphilic bacterium with important industrial properties.”
“Major depression (MD) might be conceptualized as pathological under-arousal of positive affective systems as parts of a network of brain regions assessing, reconciling and storing emotional stimuli versus an over-arousal of parts of the same network promoting separation-distress/GRIEF. In this context depression can be explained as an emotional pain state that is the result of a disregulation of several sub-systems that under physiological conditions are concerned with bodily or emotional homeostasis of the human organism in a social context. Physiologically, homeostasis is maintained by influences of the SEEKING system represented – amongst others – by the medial forebrain bundle (MFB). Neuroimaging studies show that the MFB has a proven access to the GRIEF/Sadness system. A functional decoupling of these systems with a dysfunctional GRIEF pathway might result in MD. Therewith GRIEF and SEEKING/PLEASURE systems play important roles as opponents in maintenance of emotional homeostasis.

We also observed that only CC1 reduces axonal and dendritic run lengths. These results suggest different functions for p50 and p150 in the dynactin complex in DCV transport. These findings are significant because they demonstrate that dynactin functions as a motor coordinator for the transport of DCVs in primary cultured rat hippocampal neurons. Crown Copyright (C) 2009 Published by Elsevier Ltd on behalf of IBRO. All rights reserved.”
“Diminished

levels of docosahexaenoic acid (DHA, 22:6n-3), the major polyunsaturated fatty acid (FA) synthesized from alpha linolenic acid (ALA, 18:3n-3), have been implicated in changes in neurotransmitter production, ion channel disruption and impairments of a variety of cognitive, behavioral selleck chemicals and motor functions in the perinatal eFT508 in vitro and adult mammal. Neuronal migration in the cortex and hippocampus of newborn and postnatal rats after ALA-deficiency, beginning on the 2nd day after conception and continuing for three weeks, was investigated. A marked decrease in the migration of bromodeoxyuridine((+))/neuronal nuclei((+))/neurofilament((+)) and glia fibrillary acidic protein((-)) neuronal cells to the dense cortical plate was accompanied by a corresponding abundance of non-migrating cells in several regions such as cortical layers IV-VI, corpus callosum and the sub-ventricular zone of ALA-deficient

newborns. Similarly, a delayed migration of cells to CA1 and dentate gyrus areas was noticed while most cells were retained in the subicular area adjacent to the hippocampus. The reversibility of delay in migration in the hippocampus

and cortex, after one and two weeks respectively, may be attributed to a temporary reelin disorganization or partial deficiency. Transient obstruction of neuronal cell migration Cediranib (AZD2171) may have long-lasting consequences on the organization of neuronal assemblies, on the connection between neurons (lateral connections) and acquisition of function in the adult brain. (C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved.”
“Ca2+ influx through voltage-gated Ca2+ channels is a fundamental signaling event in neurons; however, non-traditional routes, such as non-selective cation channels, also permit Ca2+ entry. The present study examines the Ca2+ permeability of a cation channel that drives an afterdischarge in Aplysia bag cell neurons. The firing of these neurons induces peptide release and reproduction. Single channel-containing inside-out patches excised from cultured bag cell neurons, with the cytoplasmic face bathed in K+-aspartate and the extracellular face bathed in artificial seawater (11 mM Ca2+), had a reversal potential near + 50 mV. In keeping with Ca2+ permeability, this was right-shifted to approximately +60 mV in high Ca2+ (substituted for Mg2+) and left-shifted to around +40 mV in zero Ca2+ (replaced with Mg2+).

Prior evaluations

suggest Pevonedistat Medicaid’s PACE capitation exceeds its spending for comparable admissions in alternative care, although the latter may be underestimated. We test whether Medicaid payments to PACE are lower than predicted fee-for-service outlays in a long-term care admission cohort.

Methods. Using grade-of-membership methods, we model health deficits for dual eligibles aged 55 or more entering waiver, PACE, and NH in South Carolina (n = 3,988). Clinical types, membership vectors, and program type prevalences are estimated. We calculate a blend, fitting PACE between fee-for-service cohorts, whose postadmission 1-year utilization was converted to attrition-adjusted outlays. PACE’s capitation is compared with blend-based expenditure predictions.

Results. Four

clinical types describe population health deficits/service needs. The waiver cohort is most represented in the least impaired type (1: 47.1%), NH entrants in the most disabled (4: 38.5%). check details Most prevalent in PACE was a dementia type, 3 (32.7%). PACE’s blend was waiver: 0.5602 (95% CI: 0.5472, 0.5732) and NH: 0.4398 (0.4268.0.4528). Average Medicaid attrition adjusted 1-year payments for waiver and NH were $4,177 and $77,945. The mean predicted cost for PACE patients in alternative long-term care was $36,620 ($35,662 and $37,580). PACE’s Medicaid capitation was $27,648-28% below the lower limit of predicted fee-for-service payments.

Conclusions. PACE’s capitation was well under outlays for equivalent patients in alternative care-a substantial savings for Medicaid.

Our methods provide a rate-setting element for PACE and other managed long-term care.”
“The hypothalamus is the central regulatory region of the brain that links the nervous system to the endocrine system via the pituitary gland. It synthesizes and secretes neuropeptide hormones, which in turn act to stimulate or inhibit the secretion of pituitary hormones. We have undertaken a detailed MS investigation of the peptides present in the bovine Cell press hypothalamus by adapting a novel heat stabilization methodology, which improved peptide discovery to direct our studies into the molecular mechanisms involved in bovine reproduction. The untreated samples contained large numbers of protein degradation products that interfered with the analysis of the neuropeptides. In the thermally stabilized samples, we were able to identify many more neuropeptides that are known to be expressed in the bovine hypothalamus. Furthermore, we have characterized a range of post-translational modifications that indicate the presence of processed intact mature neuropeptides in the stabilized tissue samples, whereas we detected many trimmed or truncated peptides resulting from post-mortem degradation in the untreated tissue samples.

. Six patients (all with HCV genotype 1a) had viral breakthrough while receiving therapy, and resistance mutations to both antiviral agents were found in all cases; 1 patient had a viral response at the end of treatment but had a relapse after the treatment period. All 10 patients in group B had a sustained virologic response at 12 weeks after treatment, and 9 had a sustained virologic response at 24 weeks after treatment. Diarrhea was the most common adverse VX-765 order event in both groups. Six patients had transient elevations of alanine aminotransferase levels to more than 3 times the upper limit of

the normal range.

CONCLUSIONS This preliminary study involving patients with HCV genotype 1 infection who had not had a response to prior therapy showed that a sustained virologic response can be achieved with two direct-acting antiviral agents only. In addition, a high rate of sustained virologic response was achieved when the two direct-acting antiviral agents were combined with selleckchem peginterferon alfa-2a and ribavirin. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT01012895.)”
“Aims: Kava beverages are highly perishable even under refrigerated conditions. This study aimed

to investigate the bacterial community dynamics in kava beverages during refrigeration.

Methods and Results: Four freshly made kava beverages were obtained from kava bars and stored at 4 degrees C. On days 0, 3 and 6, the aerobic plate count (APC), lactic acid bacteria (LAB) count and yeast and mould SSR128129E count (YMC) of the samples were determined. Meanwhile, bacterial DNA was extracted from

each sample and subjected to the polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE). Moreover, species-specific PCR assays were employed to identify predominant Pseudomonas spp. involved in kava spoilage. Over the storage period, the APC, LAB count and YMC of the four kava beverages all increased, whereas their pH values decreased. The DGGE profile revealed diverse bacterial populations in the samples. LAB, such as Weissella soli, Lactobacillus spp. and Lactococcus lactis, were found in the kava beverages. Species-specific PCR assays detected Pseudomonas putida and Pseudomonas fluorescens in the samples; Ps. fluorescens became dominant during refrigeration.

Conclusions: LAB and Pseudomonas may play a significant role in the spoilage of kava beverages.

Significance and Impact of the Study: This study provides important information that may be used to extend the shelf life of kava beverages.”
“Swarming is the fastest known bacterial mode of surface translocation and enables the rapid colonization of a nutrient-rich environment and host tissues. This complex multicellular behavior requires the integration of chemical and physical signals, which leads to the physiological and morphological differentiation of the bacteria into swarmer cells.

Picrotoxin reduced the acute stress anticonvulsive effect, proving that this effect operates through the GABA(A) receptor. Contrary to progesterone (up to 30 mg/kg), etifoxine (50 mg/kg), allopregnanolone selleck screening library (10 mg/kg), and clonazepam (10 mu g/kg) inhibited the finasteride effect in stressed animals. The effect of etifoxine was blocked in the presence of finasteride and picrotoxin combined in stressed animals.

Conclusions These findings support the hypothesis suggesting an involvement of neuroactive steroids in the anticonvulsive effect of restraint stress. The dual and complementary mechanisms of action of etifoxine (directly on the GABA(A) receptor and

indirectly via the neuroactive steroids) may represent a therapeutic benefit in the treatment of various anxiety disorders with abnormal production of neuroactive steroids.”
“The high dose requirements of biopharmaceutical products led to the development of mammalian cell culture technologies that increase biomanufacturing capacity. The disposable Wave bioreactor is one of the most promising technologies, providing ease ROCK inhibitor of operation and no cross-contamination, and using an innovative undulation movement that ensures good mixing and oxygen transfer without cell damage. However, its recentness demands further characterization. This study evaluated the residence time distribution (RTD)

in Wave, allowing the characterization of mixing and flow and the comparison with ideal models and a Stirred tank

reactor (STR) used for mammalian cell culture. RTD was determined using methylene blue with pulse input methodology, at three flow rates common in mammalian cell culture (3.3 x 10(-5) m(3)/h, 7.9 x 10(-5) m(3)/h, and 1.25 x 10(-4) m(3)/h) and one typical of microbial culture (5 x 10(-3) m(3)/h). Samples were taken periodically and the absorbance read at 660 nm. It was observed that Wave behavior diverted from ideal models, but was similar to STR. Therefore, the deviations are not related to the particular oxyclozanide Wave rocking mechanism, but could be associated with the inadequacy of these reactors to operate in continuous mode or to a possible inability of the theoretical models to properly describe the behavior of reactors designed for mammalian cell culture. Thus, the development of new theoretical models could better characterize the performance of these reactors.”
“Iron is essential for life, yet excessive iron can damage tissues and organs. To prevent iron deficiency and overload, iron balance is regulated by the hormone hepcidin. Hepcidin levels increase in response to iron sufficiency, decreasing intestinal iron absorption and inhibiting release of iron from stores and macrophages. Iron deficiency lowers hepcidin, leading to enhanced iron absorption and mobilization of iron from stores. Hepcidin is also increased by inflammation, and has a major role in the anemia of chronic disease.

Diagnoses included neurogenic bladder (21), cloacal exstrophy (5), solitary kidney/ectopic ureter (1), posterior urethral valves (1) and rhabdomyosarcoma of prostate (1). Gastric Selleckchem Ruxolitinib segment was used as gastrocystoplasty (21), composite gastroenteric cystoplasty (6), demucosalized gastrocystoplasty (1) and continent gastric reservoir (1).

Results: Mean followup was 13.9 years (range 9 to 16.5). Complications were seen in 15 (51.7%) patients. Seven patients had the hematuria-dysuria

syndrome, which was intractable in 1 and necessitated excision of the gastric patch. Due to severe complications necessitating major reoperations 3 patients underwent re-augmentation with enteric segments without excision of the gastric tissue (composite). One patient who underwent demucosalized gastrocystoplasty had excision of the gastric tissue and re-augmentation with enteric segment due to contraction of the gastric patch. A stone developed in 1 patient with a composite gastroenteric reservoir.

Malignancy developed in the reservoir in 3 patients 11, 12 and 14 years after gastrocystoplasty, and all 3 died of metastasis.

Conclusions: We do not recommend the use of gastric segments for reconstruction JNK-IN-8 nmr of the lower urinary tract due to the high incidence of reoperations and complications. In patients in whom gastric segments were used in the past for lower urinary tract reconstruction, regular surveillance and close followup are strongly advocated.”
“Consumption of coffee is associated with reduced risk of Parkinson’s disease (PD), an effect that has largely been attributed to caffeine. However, coffee contains numerous components that may also be neuroprotective. One of these compounds is eicosanoyl-5-hydroxytryptamide (EHT), which ameliorates the phenotype of alpha-synuclein

transgenic mice associated with decreased protein aggregation and phosphorylation, improved neuronal integrity and reduced neuroinflammation. Here, we sought to investigate if EHT has an effect in the MPTP model of PD. Mice fed a diet containing EHT for four weeks exhibited dose-dependent preservation of nigral dopaminergic neurons following MPTP challenge compared to animals given control feed. Reductions in striatal dopamine and tyrosine hydroxylase content were also less pronounced with EHT treatment. The neuroinflammatory response to MPTP was markedly attenuated, and indices these of oxidative stress and JNK activation were significantly prevented with EHT. In cultured primary microglia and astrocytes, EHT had a direct anti-inflammatory effect demonstrated by repression of lipopolysaccharide-induced NF kappa B activation, iNOS induction, and nitric oxide production. EHT also exhibited a robust anti-oxidant activity in vitro. Additionally, in SH-SY5Y cells, MPP+-induced demethylation of phosphoprotein phosphatase 2A (PP2A), the master regulator of the cellular phosphoregulatory network, and cytotoxicity were ameliorated by EHT.

Enzyme-linked immunosorbent assay was used to quantify two novel and potentially useful analytes, soluble intercellular adhesion molecule-1 (sICAM-1) and Axl receptor tyrosine kinase (Axl).

Results: The mean concentration of sICAM-1 and Axl was 85 and 482 times higher separately in 30 healthy AF samples than in 110 CVF samples of normal pregnancies. Comparing 110 CVF samples of PROM/Preterm PROM with 110 CVF samples of normal pregnancies, the diagnostic value for PROM was demonstrated by their high sensitivity and specificity (96.4 and Selleck CB-839 92.7%, respectively, for sICAM-1, and 92.4 and 90.4%, respectively, for Axl).

Conclusions and clinical relevance: The results indicate that sICAM-1 and Axl

in AF leaked to vagina are sensitive and specific biomarkers for the diagnosis

of PROM. Furthermore, sICAM-1 or Axl can be developed into a rapid strip test for bedside use.”
“Until fairly recently, experience with advanced endovascular technologies, including fenestrated endovascular repair (FEVAR), has been limited to a relatively small number of practitioners worldwide. Excellent outcomes have been achieved by these accomplished surgeons who, at least initially, have primarily used custom-made devices constructed by a single endograft manufacturer. Access to this technology has been limited by the skills necessary for such procedures and by the customization process with industry partners. However, several issues are changing rapidly with FEVAR. Increasing numbers of surgeons now have the necessary endovascular skills, and off-the-shelf endografts from several manufacturers Stattic solubility dmso have become, or are becoming, available. Also, the regulatory landscape Erastin supplier is changing with device approval in the United States. Surgeons and patients alike are anticipating the widespread adoption of this advanced technology that

will surely benefit increasing numbers of patients. Or will it? Will widespread adoption in a larger number of smaller-volume hospitals, by less experienced surgeons, result in poor patient outcomes, or will excellent results continue with more patients benefitting from these technologic advances? These are important questions to ask before such adoption and are the subject of this debate. (J Vasc Surg 2013;57:875-83.)”
“Purpose: Chronic allograft nephropathy (CAN) remains the leading cause of renal graft loss after the first year following renal transplantation. This study aimed to identify novel urinary proteomic profiles, which could distinguish and predict CAN in susceptible individuals.

Experimental design: The study included 34 renal transplant patients with histologically proven CAN and 36 patients with normal renal transplant function. High-throughput proteomic profiles were generated from urine samples with three different ProteinChip arrays by surface-enhanced laser-desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS).

No study has yet investigated the predictive value of early changes of sBDNF for final treatment outcome of the individual patient The aim of this study was to investigate in patients with MDD, whether i) the non-increase of sBDNF in the early course of treatment is a specific and sensitive marker for final treatment failure, ii) whether the sensitivity and specificity of early non-improvement for treatment

failure can be increased by combining it with the marker “”early non-increase of sBDNF”". For this purpose, we performed a pilot study with 41 inpatients with MDD according to DSM-IV, who were treated in a naturalistic setting. Depression severity and sBDNF were measured in weekly intervals from baseline to week six with the 21-item Hamilton Depression Rating Scale Trametinib order (HAMD-21) and PSI-7977 cost ELISA, respectively. The individual markers sBDNF non-increase and HAMD-21 non-improvement from baseline to day 7 or 14 predicted later non-response and non-remission with moderate to high specificity. The combined marker sBDNF non-increase plus HAMD-21 non-improvement at day 14 increased

the specificity for non-response and non-remission to 100%. Our data provide the first evidence that the absence of an early increase of sBDNF in conjunction with early non-improvement might be a highly specific peripheral marker predictive for treatment failure in patients with MDD. If replicated, this combined marker could be considered useful for prospective confirmatory trials in patients with MDD. (C) 2010 Elsevier Inc. All rights reserved.”
“Administration of N-methyl-d-aspartate receptor antagonist phencyclidine (PCP) to rat pups at postnatal day (PND) 7, 9, and 11 [neonatal PCP (neoPCP) model] induces cognitive deficits similar to those observed in schizophrenia. Expression of presynaptic SNARE protein, synaptosomal-associated protein Montelukast Sodium of 25 kDa (Snap25), has been shown to be downregulated in postmortem brains from patients with schizophrenia. The present study

was designed to investigate the long-term effects of neoPCP administration on expression of presynaptic markers altered in schizophrenia. Using radioactive in-situ hybridization, the expression of Snap25 was measured in the prefrontal cortex and the hippocampal formation (CA1, CA3, CA4, and dentate gyrus) at PND 29 and 80 in neoPCP and control rats. As a secondary presynaptic marker, the expressional level of synaptophysin was also measured in the same areas. Stereological estimation of the number of neurons and volume was used to exclude potential bias in cell numbers. A significant reduction in the expression of Snap25 in the hippocampal CA4 region was observed in adult neoPCP rats (PND 80, P<0.01), but not in preadolescent rats (PND 29), indicating a late developmental manifestation of a presynaptic pathology. The number of neurons and volume of the CA4 region showed no change in PCP rats compared with the controls.

Materials and Methods: A total of 16 patients with carcinoma in situ refractory to bacillus Calmette-Guerin were enrolled in a phase I, open

label, single institution study. A minimum of 3 eligible patients were included per dose level. Paclitaxel-hyaluronic acid solution (ONCOFID-P-B (TM)) was administered for 6 consecutive weeks. The primary objective was to identify the maximum tolerated dose and the recommended dose. As secondary objectives the safety profile of ONCOFID-P-B, SBI-0206965 the pharmacokinetic profile after each instillation and the tumor response were also evaluated.

Results: No dose limiting toxicity occurred at any drug level evaluated. The plasma levels of the study drug were always below the lower limit of quantification at all tested doses after each instillation. A total of 11 adverse events were reported by 7 patients and BTSA1 ic50 9 (60%) showed complete treatment response.

Conclusions: Intravesical instillation of ONCOFID-P-B for carcinoma in situ refractory to bacillus Calmette-Guerin showed minimal toxicity and no systemic absorption in the first human intravesical clinical trial to our knowledge. Finally, satisfactory response rates were observed.”
“Cultures of neonatal and adult dorsal root ganglion (DRG) neurons are commonly used in in vitro models to study the ion channels and signaling events associated with peripheral sensation under various

conditions. Differential responsiveness between neonatal and adult DRG neurons to physiological or pathological stimuli suggests potential differences in their

gene expression profiles. We performed a microarray analysis of cultured adult and neonatal rat DRG neurons, which revealed distinct gene expression profiles especially of ion channels and signaling molecules at the genomic level. For example, Ca(2+)-stimulated adenylyl cyclase (AC) isoforms AC3 and AC8, PKC delta and CaMKIl alpha, the voltage-gated sodium channel beta buy Palbociclib 1 and beta 4, and potassium channels K(v)1.1, K(v)3.2, K(v)4.1, K(v)9.1, K(v)9.3, K(ir)3.4, K(ir)7.1, K(2p)1.1/TWIK-1 had significantly higher mRNA expression in adult rat DRG neurons, while Ca(2+)-inhibited AC5 and AC6, sodium channel Na(v)1.3 alpha subunit, potassium channels K(ir)6.1, K(2p)10.1/TREK-2, calcium channel Ca(v)2.2 alpha 1 subunit, and its auxiliary subunits beta 1 and beta 3 were conversely down regulated in adult neurons. Importantly, higher adult neuron expression of ERK1/2, PI3K/P110 alpha, but not of TRPV1 and TrkA, was found and confirmed by PCR and western blot. These latter findings are consistent with the key role of ERK and PI3K signaling in sensitization of TRPV1 by NGF and may explain our previously published observation that adult, but not neonatal, rat DRG neurons are sensitized by NGF. (C) 2011 Elsevier Ireland Ltd. All rights reserved.