bluuebunny/crossref_metadata_2025 huggingface dataset:
Perforin expression in eyelid sebaceous carcinomas: a useful and specific immunomarker for the differential diagnosis of eyelid carcinomas
Authors: Mittal Ruchi , Araujo Iguaracyra , Czanner Gabriela , Coupland Sarah E.
Published: February 2016

Purpose

Eyelid sebaceous carcinoma (SC) remains a common diagnostic pitfall for both the clinician and histopathologist. The aim of this study was to describe perforin as a new marker in the immunohistochemistry panel for SC.

Methods

A total of 29 cases were retrieved from the Pathology archives, including 11 sebaceous neoplasms (nine SC; two sebaceomas), 10 squamous cell carcinomas (SCC) and eight basal cell carcinomas (BCC). These were stained using the monoclonal antibody for perforin, epithelial membrane antigen (EMA), Ber‐EP4 and adipophilin (ADP). Sensitivity and specificity of perforin as an immunohistologic marker for sebaceous tumours were compared to EMA, ADP and Ber‐EP4.

Results

Perforin stained strongly 9/11 (81%) of the sebaceous neoplasms (SN), 7/9 SC and 2/2 of sebaceomas (2/2), similar to ADP. Epithelial membrane antigen (EMA) stained 8/9 SC and was negative (1/2) or only very weakly expressed (1/2) in sebaceomas. The specificity of perforin in identifying SN versus SCC and BCC was 100% (95% CI 69–100), while EMA specificity in identifying SN varied according the comparison group (SCC: 50%, 95% CI 18–81, 100% (95% CI 63–100). Perforin better highlighted the intraepithelial spread of SC than EMA. Ber‐EP4 was strongly expressed in six of nine SC, but was consistently negative in sebaceomas.

Conclusions

The expression pattern of perforin in sebaceous neoplasms enables us to recommend the use of perforin as a new immunohistochemical marker for sebaceous neoplasms.
Unbiased Estimation of Biomarker Panel Performance When Combining Training and Testing Data in a Group Sequential Design
Authors: Tayob Nabihah , Do Kim-Anh , Feng Ziding
Published: February 2016

Motivated by an ongoing study to develop a screening test able to identify patients with undiagnosed Sjögren's Syndrome in a symptomatic population, we propose methodology to combine multiple biomarkers and evaluate their performance in a two-stage group sequential design that proceeds as follows: biomarker data is collected from first stage samples; the biomarker panel is built and evaluated; if the panel meets pre-specified performance criteria the study continues to the second stage and the remaining samples are assayed. The design allows us to conserve valuable specimens in the case of inadequate biomarker panel performance. We propose a nonparametric conditional resampling algorithm that uses all the study data to provide unbiased estimates of the biomarker combination rule and the sensitivity of the panel corresponding to specificity of 1-t on the receiver operating characteristic curve (ROC). The Copas and Corbett (2002) correction, for bias resulting from using the same data to derive the combination rule and estimate the ROC, was also evaluated and an improved version was incorporated. An extensive simulation study was conducted to evaluate finite sample performance and propose guidelines for designing studies of this type. The methods were implemented in the National Cancer Institutes Early Detection Network Urinary PCA3 Evaluation Trial.
Pancreatic polypeptide and its central Y4 receptors are essential for cued fear extinction and permanent suppression of fear
Authors: Verma D , Hörmer B , Bellmann‐Sickert K , Thieme V , Beck‐Sickinger A G , Herzog H , Sperk G , Tasan R O
Published: February 2016

Background and purpose

Avoiding danger and finding food are closely related behaviours that are essential for surviving in a natural environment. Growing evidence supports an important role of gut‐brain peptides in modulating energy homeostasis and emotional‐affective behaviour. For instance, postprandial release of pancreatic polypeptide (PP) reduced food intake and altered stress‐induced motor activity and anxiety by activating central Y4 receptors.

Experimental approach

We characterized [K30(PEG2)]hPP2‐36 as long‐acting Y4 receptor agonist and injected it peripherally into wildtype and Y4 receptor knockout (Y4KO) C57Bl/6NCrl mice to investigate the role of Y4 receptors in fear conditioning. Extinction and relapse after extinction was measured by spontaneous recovery and renewal.

Key results

The Y4KO mice showed impaired cued and context fear extinction without affecting acquisition, consolidation or recall of fear. Correspondingly, peripheral injection of [K30(PEG2)]hPP2‐36 facilitated extinction learning upon fasting, an effect that was long‐lasting and generalized. Furthermore, peripherally applied [K30(PEG2)]hPP2‐36 before extinction inhibited the activation of orexin‐expressing neurons in the lateral hypothalamus in WT, but not in Y4KO mice.

Conclusions and implications

Our findings suggests suppression of excessive arousal as a possible mechanism for the extinction‐promoting effect of central Y4 receptors and provide strong evidence that fear extinction requires integration of vegetative stimuli with cortical and subcortical information, a process crucially depending on Y4 receptors. Importantly, in the lateral hypothalamus two peptide systems, PP and orexin, interact to generate an emotional response adapted to the current homeostatic state. Detailed investigations of feeding‐relevant genes may thus deliver multiple intervention points for treating anxiety‐related disorders.
‘I want to be better than you:’ lived experiences of intergenerational child maltreatment prevention among teenage mothers in and beyond foster care
Authors: Aparicio Elizabeth M.
Published: February 2016

The growing body of research on teenage motherhood in foster care has largely focused on the risks involved for both mother and child, yet these mothers depict a much more complex picture of their own experience of becoming and being mothers. The current study employed interpretative phenomenological analysis to explore 18 in‐depth, qualitative interviews from six participants on the meaning and experience of motherhood among teenage mothers in foster care and in the years immediately after ageing out. This study focused on a particular dimension of motherhood: participants' efforts to break the cycle of child abuse and neglect with their own children. Two themes emerged as characteristic of these experiences: (i) treating children well/parenting differently and avoiding the system; and (ii) reducing isolation and enhancing support. Given the increased likelihood of the children of teen mothers – particularly those who have been maltreated – becoming involved with the child welfare system, study findings suggest possible strategies for disrupting cycles of intergenerational child welfare involvement generated by young mothers themselves. Practice implications for addressing possible substance abuse, mental health and relational and parenting needs are discussed.
Increased Expression of Transient Receptor Potential Vanilloid 4 in Cortical Lesions of Patients with Focal Cortical Dysplasia
Authors: Chen Xin , Sun Fei‐Ji , Wei Yu‐Jia , Wang Lu‐Kang , Zang Zhen‐Le , Chen Bing , Li Song , Liu Shi‐Yong , Yang Hui
Published: February 2016

Aim

Focal cortical dysplasia (FCD) represents a well‐known cause of medically intractable epilepsy. Studies found that transient receptor potential vanilloid receptor 4 (TRPV4) may participate in the occurrence of seizures. This study investigated the expression patterns of TRPV4 in FCD and the cascade that regulate functional state of TRPV4 in cortical neurons.

Methods

Thirty‐nine surgical specimens from FCD patients and 10 age‐matched control samples from autopsies were included in this study. Protein expression and distribution were detected by Western blot, immunohistochemistry, and immunofluorescence staining. Calcium imaging was used to detect the TRPV4‐mediated Ca2+ influx in cortical neurons.

Results

(1) The protein levels of TRPV4 and of an upstream factor, protein kinase C (PKC), were markedly elevated in FCD. (2) TRPV4 staining was stronger in the dysplastic cortices of FCD and mainly observed in neuronal microcolumns and malformed cells. (3) The activation of TRPV4 was central for [Ca2+]i elevation in cortical neurons, and this activity of TRPV4 in cortical neurons was regulated by the PKC, but not the PKA, pathway.

Conclusion

The overexpression and altered cellular distribution of TRPV4 in FCD suggest that TRPV4 may potentially contribute to the epileptogenesis of FCD.
Is an Investing Institution One Shareholder or a Collection of Separate Funds?
Authors: Armitage Seth , Haig Alistair , Hodgkinson Lynn
Published: February 2016

Manuscript Type

Empirical

Research Question/Issue

The paper examines whether the fund managers in a given investing institution behave in a coordinated manner, in terms of their trading around the announcement of a major takeover by a company in which the institution has two or more separate holdings.

Research Findings/Insights

Our data show that many institutional holdings consist of subholdings managed by separate fund managers. We find that trading around takeover announcements is coordinated in a majority of cases, but there is material disagreement within institutions in a substantial minority of cases, depending on how disagreement is measured. This suggests that blocks, at the level of the institution, do not always exist in the sense of being controlled by a single agent. Institutional ownership is less concentrated than it might appear to be from lists of shareholders in annual reports and databases.

Theoretical/Academic Implications

Research in corporate governance tends to assume implicitly that an institutional holding is a single block. Our findings indicate that it is not safe to make this assumption, especially in the case of larger blocks which are more likely to consist of several subholdings. Some types of research would benefit from using data at the level of the managed fund.

Practitioner/Policy Implications

There is much discussion about the merits of coordinated shareholder action between investing institutions, for example in the Kay Review. The findings imply that there is scope for greater coordination within institutions as well as across institutions.
β‐adrenergic receptor signalling and its functional consequences in the diseased heart
Authors: Najafi Aref , Sequeira Vasco , Kuster Diederik W.D. , van der Velden Jolanda
Published: February 2016

Background

To maintain the balance between the demand of the body and supply (cardiac output), cardiac performance is tightly regulated via the parasympathetic and sympathetic nervous systems. In heart failure, cardiac output (supply) is decreased due to pathologic remodelling of the heart. To meet the demands of the body, the sympathetic system is activated and catecholamines stimulate β‐adrenergic receptors (β‐ARs) to increase contractile performance and cardiac output. Although this is beneficial in the acute phase, chronic β‐ARs stimulation initiates a cascade of alterations at the cellular level, resulting in a diminished contractile performance of the heart.

Materials and methods

This narrative review includes results from previously published systematic reviews and clinical and basic research publications obtained via PubMed up to May 2015.

Results

We discuss the alterations that occur during sustained β‐AR stimulation in diseased myocardium and emphasize the consequences of β‐AR overstimulation for cardiac function. In addition, current treatment options as well as future therapeutic strategies to treat patients with heart failure to normalize consequences of β‐AR overstimulation are discussed.

Conclusions

The heart is able to protect itself from chronic stimulation of the β‐ARs via desensitization and reduced membrane availability of the β‐ARs. However, ultimately this leads to an impaired downstream signalling and decreased protein kinase A (PKA)‐mediated protein phosphorylation. β‐blockers are widely used to prevent β‐AR overstimulation and restore β‐ARs in the failing hearts. However, novel and more specific therapeutic treatments are needed to improve treatment of HF in the future.
Inter‐hemispheric connectivity in the fusiform gyrus supports memory consolidation for faces
Authors: Geiger Maximilian J. , O'Gorman Tuura Ruth , Klaver Peter
Published: February 2016

This study investigated how changes of functional connectivity over time accompany consolidation of face memories. Based on previous research, it was hypothesized that connectivity changes in networks initially active during face perception and face encoding would be associated with individual recognition memory performance. Resting‐state functional connectivity was examined shortly before, shortly after and about 40 min after incidental learning of faces. Memory performance was assessed in a surprise recognition test shortly after the last resting‐state session. Results reveal that memory performance‐related connectivity between the left fusiform face area and other brain areas gradually changed over the course of the experiment. Specifically, the increase in connectivity with the contralateral fusiform gyrus, the hippocampus, the amygdala and the inferior frontal gyrus correlated with recognition memory performance. As the increase in connectivity in the two final resting‐state sessions was associated with memory performance, the present results demonstrate that memory formation is not restricted to the incidental learning phase but continues and increases in the following 40 min. It is discussed that the delayed increase in inter‐hemisphere connectivity between the left and right fusiform gyrus is an indicator for memory formation and consolidation processes.
Endovascular stroke therapy in Austria: a nationwide 1‐year experience
Authors: Serles W. , Gattringer T. , Mutzenbach S. , Seyfang L. , Trenkler J. , Killer‐Oberpfalzer M. , Deutschmann H. , Niederkorn K. , Wolf F. , Gruber A. , Hausegger K. , Weber J. , Thurnher S. , Gizewski E. , Willeit J. , Karaic R. , Fertl E. , Našel C. , Brainin M. , Erian J. , Oberndorfer S. , Karnel F. , Grisold W. , Auff E. , Fazekas F. , Haring H.‐P. , Lang W. ,   the Austrian Stroke Unit Registry Collaborators
Published: February 2016

Background and purpose

Based on a tight network of stroke units (SUs) and interventional centres, endovascular treatment of acute major intracranial vessel occlusion has been widely implemented in Austria. Documentation of all patients in the nationwide SU registry has thereby become mandatory.

Methods

Demographic, clinical and interventional characteristics of patients who underwent endovascular treatment for acute ischaemic stroke in 11 Austrian interventional centres between 1 October 2013 and 30 September 2014 were analysed.

Results

In total, 301 patients (50.5% women; median age 70.5 years; median National Institutes of Health Stroke Scale score 17) were identified.193 patients (64.1%) additionally received intravenous thrombolysis. The most frequent vessel occlusion sites were the M1 segment of the middle cerebral artery (n = 161, 53.5%), the intracranial internal carotid artery (n = 60, 19.9%) and the basilar artery (n = 40, 13.3%). Stent retrievers were used in 235 patients (78.1%) and adequate reperfusion (modified Thrombolysis in Cerebral Infarction scores 2b and 3, median onset to reperfusion time 254 min) was achieved in 242 patients (81.4%). Symptomatic intracranial haemorrhage occurred in 7%. 43.8% of patients (n = 132) had good functional outcome (modified Rankin Scale score 0–2) and the mortality rate was 20.9% (n = 63) after 3 months. Compared to the anterior circulation, vertebrobasilar stroke patients had higher mortality. Patients with secondary hospital transportation had better outcomes after 3 months than in‐house treated patients.

Conclusion

Our results document nationwide favourable outcome and safety rates of endovascular stroke treatment comparable to recent randomized trials. The ability to provide such data and the need to further optimize such an approach also underscore the contribution of respective registries.
Ambient insect pressure and recipient genotypes determine fecundity of transgenic crop‐weed rice hybrid progeny: Implications for environmental biosafety assessment
Authors: Xia Hui , Zhang Hongbin , Wang Wei , Yang Xiao , Wang Feng , Su Jun , Xia Hanbing , Xu Kai , Cai Xingxing , Lu Bao‐Rong
Published: February 2016

Transgene introgression into crop weedy/wild relatives can provide natural selective advantages, probably causing undesirable environmental impact. The advantages are likely associated with factors such as transgenes, selective pressure, and genetic background of transgene recipients. To explore the role of the environment and background of transgene recipients in affecting the advantages, we estimated the fitness of crop‐weed hybrid lineages derived from crosses between marker‐free insect‐resistant transgenic (Bt/CpTI) rice with five weedy rice populations under varied insect pressure. Multiway anova indicated the significant effect of both transgenes and weedy rice genotypes on the performance of crop‐weed hybrid lineages in the high‐insect environment. Increased fecundity was detected in most transgene‐present F1 and F2 hybrid lineages under high‐insect pressure, but varied among crop‐weed hybrid lineages with different weedy rice parents. Increased fecundity of transgenic crop‐weed hybrid lineages was associated with the environmental insect pressure and genotypes of their weedy rice parents. The findings suggest that the fitness effects of an insect‐resistant transgene introgressed into weedy populations are not uniform across different environments and genotypes of the recipient plants that have acquired the transgene. Therefore, these factors should be considered when assessing the environmental impact of transgene flow to weedy or wild rice relatives.
Infrared A radiation promotes survival of human melanocytes carrying ultraviolet radiation‐induced DNA damage
Authors: Kimeswenger Susanne , Schwarz Agatha , Födinger Dagmar , Müller Susanne , Pehamberger Hubert , Schwarz Thomas , Jantschitsch Christian
Published: February 2016

The link between solar radiation and melanoma is still elusive. Although infrared radiation (IR) accounts for over 50% of terrestrial solar energy, its influence on human skin is not well explored. There is increasing evidence that IR influences the expression patterns of several molecules independently of heat. A previous in vivo study revealed that pretreatment with IR might promote the development of UVR‐induced non‐epithelial skin cancer and possibly of melanoma in mice. To expand on this, the aim of the present study was to evaluate the impact of IR on UVR‐induced apoptosis and DNA repair in normal human epidermal melanocytes. The balance between these two effects is a key factor of malignant transformation. Human melanocytes were exposed to physiologic doses of IR and UVR. Compared to cells irradiated with UVR only, simultaneous exposure to IR significantly reduced the apoptotic rate. However, IR did not influence the repair of UVR‐induced DNA damage. IR partly reversed the pro‐apoptotic effects of UVR via modification of the expression and activity of proteins mainly of the extrinsic apoptotic pathway. In conclusion, IR enhances the survival of melanocytes carrying UVR‐induced DNA damage and thereby might contribute to melanomagenesis.
Low‐cycle fatigue of 316L stainless steel under proportional and nonproportional loadings
Authors: Jin D. , Tian D.J. , Li J.H. , Sakane M.
Published: February 2016

This paper discusses low‐cycle fatigue characteristics of 316L stainless steel under proportional and nonproportional loadings. Tension–torsion multiaxial low‐cycle fatigue tests were performed using five strain paths. Additional hardening was observed under nonproportional loadings and was more significant in tests with larger nonproportionality. Mises equivalent strain, Smith–Watson–Topper, Fatemi–Socie, Kandil–Brown–Miller and nonproportional strain parameters were applied to the experimental data to evaluate the multiaxial low‐cycle fatigue damage. The applicability of the damage laws to practical design was discussed.
Early signs of range disjunction of submountainous plant species: an unexplored consequence of future and contemporary climate changes
Authors: Kuhn Emilien , Lenoir Jonathan , Piedallu Christian , Gégout Jean‐Claude
Published: February 2016

Poleward and upward species range shifts are the most commonly anticipated and studied consequences of climate warming. However, these global responses to climate change obscure more complex distribution change patterns. We hypothesize that the spatial arrangement of mountain ranges and, consequently, climatic gradients in Europe, will result in range disjunctions. This hypothesis was investigated for submountainous forest plant species at two temporal and spatial scales: (i) under future climate change (between 1950–2000 and 2061–2080 periods) at the European scale and (ii) under contemporary climate change (between 1914–1987 and 1997–2013 periods) at the French scale. We selected 97 submountainous forest plant species occurring in France, among which distribution data across Europe are available for 25 species. By projecting future distribution changes for the 25 submountainous plant species across Europe, we demonstrated that range disjunction is a likely consequence of future climate change. To assess whether it is already taking place, we used a large forest vegetation‐plot database covering the entire French territory over 100 years (1914–2013) and found an average decrease in frequency (−0.01 ± 0.004) in lowland areas for the 97 submountainous species – corresponding to a loss of 6% of their historical frequency – along with southward and upward range shifts, suggesting early signs of range disjunctions. Climate‐induced range disjunctions should be considered more carefully since they could have dramatic consequences on population genetics and the ability of species to face future climate changes.
Time vs. Money: A Quantitative Evaluation of Monitoring Frequency vs. Monitoring Duration
Authors: McHugh Thomas E. , Kulkarni Poonam R. , Newell Charles J.
Published: February 2016

The National Research Council has estimated that over 126,000 contaminated groundwater sites are unlikely to achieve low ug/L clean‐up goals in the foreseeable future. At these sites, cost‐effective, long‐term monitoring schemes are needed in order to understand the long‐term changes in contaminant concentrations. Current monitoring optimization schemes rely on site‐specific evaluations to optimize groundwater monitoring frequency. However, when using linear regression to estimate the long‐term zero‐order or first‐order contaminant attenuation rate, the effect of monitoring frequency and monitoring duration on the accuracy and confidence for the estimated attenuation rate is not site‐specific. For a fixed number of monitoring events, doubling the time between monitoring events (e.g., changing from quarterly monitoring to semi‐annual monitoring) will double the accuracy of estimated attenuation rate. For a fixed monitoring frequency (e.g., semi‐annual monitoring), increasing the number of monitoring events by 60% will double the accuracy of the estimated attenuation rate. Combining these two factors, doubling the time between monitoring events (e.g., quarterly monitoring to semi‐annual monitoring) while decreasing the total number of monitoring events by 38% will result in no change in the accuracy of the estimated attenuation rate. However, the time required to collect this dataset will increase by 25%. Understanding that the trade‐off between monitoring frequency and monitoring duration is not site‐specific should simplify the process of optimizing groundwater monitoring frequency at contaminated groundwater sites.
Inhibitors in haemophilia A: a perspective on clotting factor products as a potential contributing factor
Authors: Mathew P. , Dinter H. , Church N. , Humphries T. J. , Kulkarni R.
Published: February 2016

Introduction

The occurrence of a neutralizing antibody in previously untreated patients (PUPs) with haemophilia A appears to be the result of an intricate interplay of both genetic and environmental factors. Recently, the type of factorVIII(FVIII) product used in thePUPs population has been implicated as a risk factor for inhibitor development.

Aim

The aim of this review was to explore in a systematic manner potential hypotheses for the product‐related findings in these studies (i.e. differences in the expression system of the cell lines used to produce recombinantFVIII[rFVIII], differences in the administered antigen load or changes in clinical practice over time).

Results

Review of the available clinical studies illustrates the high degree of variability for the risk of inhibitor development for the same products across different studies. Differences in cell lines or antigen load were not found to provide a reasonable explanation.

Conclusion

The possibility of changes in clinical practice over time and patient selection bias (i.e. the preferential use of one product over another in patients at higher risk for inhibitors) offers a potential explanation and should be carefully considered when evaluating the studies.
Baseline factor VIII plasma levels and age at first bleeding in patients with severe forms of von Willebrand disease
Authors: Siboni S. M. , Biguzzi E. , Caiani V. , Mistretta C. , Bucciarelli P. , Peyvandi F.
Published: February 2016

Introduction

von Willebrand disease (VWD) is the most common inherited bleeding disorder. The age of bleeding onset is highly variable, also in patients with similar degree of severity.

Aim

The primary aim of this study was to evaluate whether baseline factor VIII (FVIII) plasma levels correlate with age at first bleeding in patients with extremely low levels of VWF:RCo (<6 IU dL−1).

Methods

One hundred and three patients with VWF:RCo <6 IU dL−1 (6 VWD1, 73 VWD2 and 24 VWD3) undergoing a medical examination between September 2010 and September 2013 were included. The relationship between baseline FVIII levels and age at first bleeding was tested in a multivariable linear regression model, adjusting for sex.

Results

The median age at first bleeding was lower in patients with VWD3 than in those with severe forms of VWD1 or VWD2 (1 year vs. 7 and 8 years, respectively, P < 0.0001). A positive non‐linear relationship between FVIII levels and age at first bleeding was found, the latter increasing by 5 years for every 10 IU dL−1 increase of FVIII (β = 4.95 [95% CI: 2.02–7.87]) until levels of 30 IU dL−1, after which the age increased slowly. This relationship was not found in VWD 2A and 2B. In 65 patients (63%) there was a more than 6‐month delay between bleeding onset and VWD diagnosis, with no difference over decades.

Conclusions

Baseline FVIII plasma levels influence the age at bleeding onset in VWD patients with extremely low levels of VWF:RCo, except in those with types 2A and 2B.
Virological responses to lamivudine or emtricitabine when combined with tenofovir and a protease inhibitor in treatment‐naïve HIV‐1‐infected patients in the Dutch AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort
Authors: Rokx C , Gras L , van de Vijver DAMC , Verbon A , Rijnders BJA ,   the ATHENA National Observational Cohort Study
Published: February 2016

Objectives

Lamivudine (3TC) and emtricitabine (FTC) are considered interchangeable in recommended tenofovir disoproxil‐fumarate (TDF)‐containing combination antiretroviral therapies (cARTs). This statement of equivalence has not been systematically studied. We compared the treatment responses to 3TC and FTC combined with TDF in boosted protease inhibitor (PI)‐based cART for HIV‐1‐infected patients.

Methods

An observational study in the AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort was carried out between 2002 and 2013. Virological failure rates, time to HIV RNA suppression < 400 copies/mL, and time to treatment failure were analysed using multivariable logistic regression and Cox proportional hazard models. Sensitivity analyses included propensity score‐adjusted models.

Results

A total of 1582 ART‐naïve HIV‐1‐infected patients initiated 3TC or FTC with TDF and ritonavir‐boosted darunavir (29.6%), atazanavir (41.5%), lopinavir (27.1%) or another PI (1.8%). Week 48 virological failure rates on 3TC and FTC were comparable (8.9% and 5.6%, respectively; P = 0.208). The multivariable adjusted odds ratio of virological failure when using 3TC instead of FTC with TDF in PI‐based cART was 0.75 [95% confidence interval (CI) 0.32–1.79; P = 0.51]. Propensity score‐adjusted models showed comparable results. The adjusted hazard ratio (HR) for treatment failure of 3TC compared with FTC was 1.15 (95% CI 0.58–2.27) within 240 weeks after cART initiation. The time to two consecutive HIV RNA measurements < 400 copies/mL within 48 weeks (HR 0.94; 95% CI 0.78–1.16) and the time to treatment failure after suppression < 400 copies/mL (HR 0.94; 95% CI 0.36–2.50) were not significantly influenced by the use of 3TC in TDF/PI‐containing cART.

Conclusions

The virological responses were not significantly different in treatment‐naïve HIV‐1‐infected patients starting either 3TC/TDF or FTC/TDF and a ritonavir‐boosted PI.
The macrophage activation product sCD163 is associated with a less favourable metabolic profile in prepubertal children
Authors: Carreras‐Badosa G. , Prats‐Puig A. , Diaz‐Roldan F. , Platero‐Gutierrez E. , Osiniri I. , Riera‐Perez E. , de Zegher F. , Ibañez L. , Bassols J. , López‐Bermejo A.
Published: February 2016

Objective

Macrophages are known to be involved in low‐grade inflammatory processes such as obesity. soluble cluster of differentiation 163 (sCD163) is shed from the cell surface as specific macrophage activation marker. In prepubertal children, we studied if circulating sCD163 is associated with metabolic and cardiovascular risk markers.

Methods

A population of 236 school‐aged Caucasian children (111 girls and 125 boys) aged 8 ± 1 year [81 normal weight (body mass index [BMI]‐SDS < 1); 74 overweight (1 ≤ BMI‐standard deviation score [SDS] < 2) and 81 with obesity (BMI‐SDS ≥ 2)] were studied. BMI, waist circumference, fat mass and visceral fat were measured. Fasting serum sCD163, homeostatic model assessment of insulin resistance, high sensitivity C‐reactive protein, gamma‐glutamyl transpeptidase and lipids were quantified.

Results

Circulating sCD163 concentrations were higher in children with obesity (p < 0.0001). Associations were observed between circulating sCD163 and a less favourable metabolic profile as judged by higher waist circumference, fat mass, visceral fat, epicardial fat, homeostatic model assessment of insulin resistance, high sensitivity C‐reactive protein, gamma‐glutamyl transpeptidase and triglycerides (all between r = 0.173 and r = 0.363; p < 0.05 to p < 0.0001) and lower high‐density lipoprotein‐cholesterol (r = −0.285, p < 0.0001). In multiple regression analyses, circulating sCD163 was independently associated with HOMA‐IR (β = 0.162, p = 0.016; model R2 = 0.179) and high density lipoprotein‐cholesterol/triglycerides ratio (β = −0.167, p = 0.012; model R2 = 0.209).

Conclusions

Childhood obesity may increase the risk of developing metabolic diseases later in life through chronic macrophage activation having deleterious effects on metabolism.
Paired box 5 is a frequently methylated lung cancer tumour suppressor gene interfering β‐catenin signalling and GADD45G expression
Authors: Zhao Lijuan , Li Shuman , Gan Lin , Li Chunhong , Qiu Zhu , Feng Yixiao , Li Jisheng , Li Lili , Li Chen , Peng Weiyan , Xu Can , Wang Zhenyu , Hui Tianli , Ren Guosheng , Tao Qian , Xiang Tingxiu
Published: February 2016

Recent studies suggest that paired box 5 (PAX5) is down‐regulated in multiple tumours through its promoter methylation. However, the role of PAX5 in non‐small cell lung cancer (NSCLC) pathogenesis remains unclear. The aim of this study is to examine PAX5 expression, its methylation status, biological functions and related molecular mechanism in NSCLC. We found that PAX5 was widely expressed in normal adult tissues but silenced or down‐regulated in 88% (7/8) of NSCLC cell lines. PAX5 expression level was significantly lower in NSCLC than that in adjacent non‐cancerous tissues (P = 0.0201). PAX5 down‐regulation was closely associated with its promoter hypermethylation status and PAX5 expression could be restored by demethylation treatment. Frequent PAX5 promoter methylation in primary tumours (70%) was correlated with lung tumour histological types (P = 0.006). Ectopic expression of PAX5 in silenced lung cancer cell lines (A549 and H1975) inhibited their colony formation and cell viability, arrested cell cycle at G2 phase and suppressed cell migration/invasion as well as tumorigenicity in nude mice. Restoration of PAX5 expression resulted in the down‐regulation of β‐catenin and up‐regulation of tissue inhibitors of metalloproteinase 2, GADD45G in lung tumour cells. In summary, PAX5 was found to be an epigenetically inactivated tumour suppressor that inhibits NSCLC cell proliferation and metastasis, through down‐regulating the β‐catenin pathway and up‐regulating GADD45G expression.
Unproductive exocytosis
Authors: Kreft Marko , Jorgačevski Jernej , Vardjan Nina , Zorec Robert
Published: February 2016

Regulated exocytosis is a multistage process involving a merger between the vesicle and the plasma membrane, leading to the formation of a fusion pore, a channel, through which secretions are released from the vesicle to the cell exterior. A stimulus may influence the pore by either dilating it completely (full‐fusion exocytosis) or mediating a reversible closure (transient exocytosis). In neurons, these transitions are short‐lived and not accessible for experimentation. However, in some neuroendocrine cells and astrocytes, initial fusion pores may reopen several hundred times, indicating their stability. Frequently, these pores are too narrow to pass luminal molecules to the extracellular space (unproductive exocytosis), but their diameter can dilate upon stimulation. To explain the stability of the initial narrow fusion pores, anisotropic membrane constituents with a non‐axisymmetric shape were proposed to accumulate in the fusion pore membrane. Although the nature of these is unclear, they may consist of lipids and proteins, including SNAREs, which may facilitate and regulate the pre‐ and post‐fusional stages of exocytosis. This review highlights models and experimental studies revealing mechanisms of fusion pore stabilization in a narrow, release unproductive state.

image

The fusion pore is a channel that forms when the vesicle and the plasma membranes merge, and mediates the release of secretions from the vesicle lumen to the cell exterior. Frequently, these pores are too narrow to pass molecules to the extracellular space. Anisotropic membrane constituents with a non‐axisymmetric shape were proposed to accumulate in the fusion pore membrane.

This article is part of a mini review series on Chromaffin cells (ISCCB Meeting, 2015).
Knowledge, Beliefs, Behaviors, and Social Norms Related to Use of Alternative Tobacco Products Among Undergraduate and Graduate Nursing Students in an Urban U.S. University Setting
Authors: VanDevanter Nancy , Zhou Sherry , Katigbak Carina , Naegle Madeline , Sherman Scott , Weitzman Michael
Published: February 2016

Purpose

The purpose of the study was to assess nursing students’ knowledge, beliefs, behaviors, and social norms regarding use of alternative tobacco products (ATPs).

Design and Methods

This anonymous online survey was conducted with all students enrolled in a college of nursing. The survey utilized measures from several national tobacco studies to assess knowledge and beliefs about ATPs (hookahs, cigars or cigarillos, bidis, kreteks, smokeless tobacco, electronic cigarettes) compared to cigarettes, health effects of ATPs, personal use of ATPs, and social norms. Data were analyzed in SPSS 22.0 (SPSS Inc., Chicago, IL, USA). Descriptive statistics and frequencies were performed for basic sociodemographic data. Paired samples t tests were performed to determine differences for scaled measures.

Findings

Nursing students demonstrated very low levels of knowledge about ATPs and their health consequences, despite high rates of ATP personal use. About 76% of participants reported use of one or more ATPs once or more in their lifetimes. A greater proportion of students had used hookahs or waterpipes (39.6%) compared to cigarettes (32.7%).

Conclusions

Nurses’ lack of knowledge about the emerging use and health threats associated with ATPs may undermine their ability to provide appropriate tobacco cessation counseling. Research is needed to identify gaps in nurses’ education regarding tobacco cessation counseling and to develop new counseling approaches specific to use of ATPs.

Clinical Relevance

Nurses play critical roles in counseling their patients for tobacco cessation. Further research and education about the risks presented by ATPs are critical to reducing excess tobacco‐related mortality.
Marginal Gap of Milled versus Cast Gold Restorations
Authors: Johnson Russell , Verrett Ronald , Haney Stephan , Mansueto Michael , Challa Suman
Published: February 2016

Purpose

This in vitro study evaluated and compared the vertical marginal gap of cast and milled full coverage gold copings using two margin designs (chamfer and chamfer bevel) before and after fitting adjustments.

Materials and Methods

Ten impressions were made of two metal master dies (one chamfer margin, one chamfer‐bevel margin) and poured twice in Type IV stone. The 20 subsequent casts with 40 dies were split into four groups (n = 10); cast gold bevel, cast gold chamfer, milled gold bevel, and milled gold chamfer groups. The cast specimens received approximately 40 μm die relief no closer than 1 mm from the finish line. Cast copings were hand waxed, cast in a high noble gold alloy, chemically divested, and the sprues were removed. For milled gold copings, casts were scanned and copings designed using 3shape D900 scanner and software. Parameters were set to approximate analog fabrication (cement gap = 0.01 mm; extra cement gap = 0.04 mm, drill radius = 0.65 mm). Copings were milled from the same high noble alloy. All copings were seated on their respective master die in a custom scanning jig and measured using a measuring microscope at 90× (60 measurements per specimen, 15 per surface). Following initial measurements, all copings were adjusted on stone dies. The number of adjustment cycles was recorded and post‐adjustment measurements were made using the same method. Data were analyzed using independent and paired t‐tests.

Results

Milled gold copings with a beveled margin (11.7 ± 20.4 μm) had a significantly (p < 0.05) smaller marginal gap than cast gold copings with a beveled margin (43.6 ± 46.8 μm) after adjustment. Cast gold copings with a chamfer margin (22.7 ± 24.7 μm) had a significantly (p < 0.05) smaller marginal gap than milled gold copings with a chamfer margin (27.9 ± 31.6 μm) following adjustments. Adjustments significantly decreased marginal gap for both cast groups (p < 0.05) and the milled chamfer bevel group (p < 0.05) but had no significant effect on the milled chamfer group.

Conclusions

Within the limitations of this study, results indicate that gold restorations milled with the tested parameters provide a vertical marginal gap that is an acceptable alternative to traditional gold crown casting techniques.
Effects of Hot Chemical Etching and 10‐Metacryloxydecyl Dihydrogen Phosphate (MDP) Monomer on the Bond Strength of Zirconia Ceramics to Resin‐Based Cements
Authors: Akay Canan , Çakırbay Tanış Merve , Şen Murat
Published: February 2016

Purpose

The purpose of this in vitro study was to evaluate the hot chemical etching method on the shear bond strength between zirconia and two resin cements.

Materials and Methods

Sixty zirconia specimens (13 × 7.5 × 2.5 mm3) were prepared and treated as follows: (1) airborne‐particle abrasion with 50 μm Al2O3 particles; (2) hot chemical etching for 10 minutes; (3) hot chemical etching for 30 minutes. Sixty composite cylinders of 3 mm diameter and height were prepared and bonded to zirconia specimens, which were divided into subgroups A and B. Group A: cemented with conventional resin cement (Variolink II); group B: cemented with 10‐metacryloxydecyl dihydrogen phosphate (MDP) monomer containing resin cement (Panavia SA) after the application of surface treatments. Next, the specimens were stored in 37ºC distilled water for 24 hours. Following water storage, shear bond strength test was performed at a 1 mm/min crosshead speed in a universal testing machine. The statistical analyses were performed with one‐way ANOVA and post hoc Tukey tests. p < 0.05 was considered statistically significant.

Results

The results from all of the tested groups exhibited lower shear bond strength values than group II‐B and higher shear bond strength values than group I‐A (p < 0.05).

Conclusion

The use of the hot chemical etching method for 10 minutes increased the shear bond strength of zirconia ceramics to both conventional and resin cements and seems to be an effective method. The MDP monomer‐containing resin cement, Panavia SA, improved the resin bonding of zirconia ceramics when combined with airborne‐particle abrasion.
Relationships between nutritional knowledge, obesity, and sleep disorder severity
Authors: Rose Shiho , Pretto Jeffrey , Paul Christine , Emmett Brooke , Hensley Michael , Henskens Frans
Published: February 2016

Obstructive sleep apnea affects 20% of the adult population. Weight control is considered the best non‐medical means of managing the condition, therefore improving nutritional knowledge in individuals may be an appropriate strategy. This study aimed to describe the relationship between nutritional knowledge and: (i) sleep disorder severity; (ii) body mass index; and (iii) demographic characteristics in persons suspected of obstructive sleep apnea. Nutrition knowledge scores were also compared with the general population. Consecutive newly‐referred patients attending the sleep laboratory for diagnostic polysomnography were invited to participate. Those who consented (n = 97) were asked to complete a touchscreen survey. Apnea–hypopnea index to measure sleep disorder severity and anthropometric measurements were obtained from the clinic. A quarter of participants were diagnosed with severe obstructive sleep apnea; and a majority (88%) were classed as being overweight or obese. The overall mean nutrition knowledge score was 58.4 ± 11.6 (out of 93). Nutrition knowledge was not associated with sleep disorder severity, body mass index or gender. The only significant difference detected was in relation to age, with older (≥35 years) participants demonstrating greater knowledge in the ‘food choices’ domain compared with their younger counterparts (18–34 years; P < 0.030). Knowledge scores were similar to the general population. The findings suggest that nutrition knowledge alone is not an important target for weight control interventions for people with obstructive sleep apnea. However, given the complexities of sleep disorders, it may complement other strategies.
Novobiocin binding to NalD induces the expression of the MexAB‐OprM pump in Pseudomonas aeruginosa
Authors: Chen Weizhong , Wang Dan , Zhou Wenquan , Sang Hong , Liu Xichun , Ge Zhiyun , Zhang Jin , Lan Lefu , Yang Cai‐Guang , Chen Hao
Published: February 2016

NalD was reported to be the secondary repressor of the MexAB‐OprM multidrug efflux pump, the major system contributing to intrinsic multidrug resistance in Pseudomonas aeruginosa. Here, we show that novobiocin binds directly to NalD, which leads NalD to dissociate from the DNA promoter, and thus de‐represses the expression of the MexAB‐OprM pump. In addition, we have solved the crystal structure of NalD at a resolution of 2.90 Å. The structural alignment of NalD to its homologue TtgR reveals that the residues N129 and H167 in NalD are involved in its novobiocin‐binding ability. We have confirmed the function of these two amino acids by EMSA and plate assay. The results presented here highlight the importance and diversity of regulatory mechanism in bacterial antibiotic resistance, and provide further insight for novel antimicrobial development.
Transcript level coordination of carbon pathways during silicon starvation‐induced lipid accumulation in the diatom Thalassiosira pseudonana
Authors: Smith Sarah R. , Glé Corine , Abbriano Raffaela M. , Traller Jesse C. , Davis Aubrey , Trentacoste Emily , Vernet Maria , Allen Andrew E. , Hildebrand Mark
Published: February 2016

Diatoms are one of the most productive and successful photosynthetic taxa on Earth and possess attributes such as rapid growth rates and production of lipids, making them candidate sources of renewable fuels. Despite their significance, few details of the mechanisms used to regulate growth and carbon metabolism are currently known, hindering metabolic engineering approaches to enhance productivity.

To characterize the transcript level component of metabolic regulation, genome‐wide changes in transcript abundance were documented in the model diatom Thalassiosira pseudonana on a time‐course of silicon starvation. Growth, cell cycle progression, chloroplast replication, fatty acid composition, pigmentation, and photosynthetic parameters were characterized alongside lipid accumulation.

Extensive coordination of large suites of genes was observed, highlighting the existence of clusters of coregulated genes as a key feature of global gene regulation in T. pseudonana. The identity of key enzymes for carbon metabolic pathway inputs (photosynthesis) and outputs (growth and storage) reveals these clusters are organized to synchronize these processes.

Coordinated transcript level responses to silicon starvation are probably driven by signals linked to cell cycle progression and shifts in photophysiology. A mechanistic understanding of how this is accomplished will aid efforts to engineer metabolism for development of algal‐derived biofuels.
DEVELOPMENT AND EVALUATION OF A SYSTEM DYNAMICS MODEL FOR INVESTIGATING AGRICULTURALLY DRIVEN LAND TRANSFORMATION IN THE NORTH CENTRAL UNITED STATES
Authors: TURNER BENJAMIN L. , WUELLNER MELISSA , NICHOLS TIMOTHY , GATES ROGER , TEDESCHI LUIS O. , DUNN BARRY H.
Published: February 2016

Land transformation from grassland to cropland in the Northern Great Plains (NGP) has become a growing concern among many stakeholders. A growing body of work has sought to determine the amount and rate of land use change with less emphasis on the systemic structures or feedback processes of land use decisions. This paper presents the development of a system dynamics simulation model to integrate ecological, economic, and social components influencing land use decisions, including cattle ranching, cropland production, rural communities, land quality, and public policies. Evaluation indicated that the model satisfactorily predicted historical land, agricultural commodity, and rural community data from the model structure. Reference modes for key variables, including the farmland area, were characterized by a bias correction of 0.999, root mean squared error of prediction of 0.053, R2 of 0.921, and concordance correlation coefficient of 0.0959. The model was robust under extreme and varying sensitivity tests, as well as adequately predicting land use under changing system context. The model's major contributions were the inclusion of decision‐making feedbacks from economic and social signals with connectivity to land quality and elasticity values that drive land transformation. Limitations include lack of spatial input and output capabilities useful for visual interfacing.