bluuebunny/crossref_metadata_2025 huggingface dataset:
Extracellular vesicle protein levels are related to brain atrophy and cerebral white matter lesions in patients with manifest vascular disease: the SMART-MR study
Authors: Kanhai Danny A , de Kleijn Dominique P V , Kappelle L Jaap , Uiterwaal Cuno S P M , van der Graaf Yolanda , Pasterkamp Gerard , Geerlings Mirjam I , Visseren Frank L J ,   on behalf of the SMART Study Group
Published: January 2014

Objectives

Extracellular vesicles (EVs) and their protein levels have been identified as a potential risk marker for the development of vascular disease. In the present study, we assessed whether levels of four previously identified EV proteins (cystatin C, serpin G1, serpin F2 and CD14) are associated with cerebral white matter lesions (WMLs) and brain atrophy.

Design

Cohort study; cross-sectional and prospective.

Setting

Single centre, secondary and tertiary setting.

Participants

1309 patients with manifest vascular disease from the Second Manifestations of ARTerial disease-MR (SMART-MR) study, of which 994 had successful brain MRI and EV protein level measurements.

Outcomes

WML and brain parenchymal fraction (BPF), as parameter for brain atrophy, at baseline and follow-up.

Statistical methods

The relationship between EV protein levels and WML volume (expressed as log transformed percentage of intracranial volume) and BPF (expressed percentage of intracranial volume) on 1.5 T brain MRI was assessed with multivariable linear regression modelling. Subsequently, the relationship between baseline EV protein levels and progression of atrophy and WML was analysed in 534 patients, in whom a follow-up MRI was obtained after 4 years.

Results

Higher EV-cystatin C and EV-CD14 were significantly associated with larger WML volume (linear regression coefficient (95% CI) 0.10 log %/SD (0.04 to 0.17) and 0.14 log %/SD (0.07 to 0.20), respectively. Higher EV-CD14 was associated with more brain atrophy (–0.14%/SD; –0.27 to –0.01). Baseline EV-CD14 was significantly associated with increase of WMLs (0.11 log %/SD (0.04 to 0.18)). No relationship with EV-serpins was observed at baseline or at follow-up.

Conclusions

EV proteins cystatin C and CD14 are related to cerebral WMLs and the progression of brain atrophy in patients with manifest vascular disease, potentially identifying EVs in the aetiology of structural brain changes.
Information needs of parents for acute childhood illness: determining ‘what, how, where and when’ of safety netting using a qualitative exploration with parents and clinicians
Authors: Jones Caroline H D , Neill Sarah , Lakhanpaul Monica , Roland Damian , Singlehurst-Mooney Hayley , Thompson Matthew
Published: January 2014

Objective

To explore the views of parents and clinicians regarding the optimal content, format and delivery of safety netting information for acute childhood illness.

Design

Qualitative study including semistructured focus groups and interviews.

Setting

First contact care settings, community centres, children's centres and nurseries in the Midlands, UK.

Participants

27 parents from a travelling community, Asian British community and white British community. Sixteen clinicians including 10 doctors and 6 nurses from a general practice surgery, an out-of-hours service and two emergency departments (paediatric and combined adult and paediatric).

Results

Participants described a need for safety netting to contain information on signs and symptoms of serious and common illnesses, illness management and where and when to seek help. Resources should be basic, simple to use and contain simple symbols. A key criterion was professional endorsement of resources. Internet-based information was desired which is reliable, consistent and up-to-date. Participants described a need for different types of information: that which could be delivered during consultations, as well as more general information for parents to access before consulting a healthcare professional. Face-to-face education, written materials and digital media were suggested delivery mechanisms. Audiovisual material was preferred by families with low literacy. Participants commonly suggested internet-based and phone-based resources, but the travelling community was less comfortable with these approaches.

Conclusions

A multifaceted and tailored approach to safety netting is needed so that effective resources are available for parents with varying information needs, literacy levels and ability to use information technology. We have identified key aspects of content, quality criteria, format and delivery mechanisms for safety netting information from the perspectives of clinicians and parents. Resources should be coproduced with parents and clinicians to ensure that they are valued and utilised by both groups.
Mobility decline in old age: the combined effect of mobility-related fatigue and socioeconomic position
Authors: Nilsson Charlotte Juul , Siersma Volkert , Mänty Minna , Avlund Kirsten , Vass Mikkel , Lund Rikke
Published: January 2014

Background

Mobility-related fatigue and low socioeconomic position predicts mobility limitations and disability in old age, but the interplay between these two factors is unknown. To evaluate whether mobility-related fatigue is a stronger risk factor for mobility limitations in certain socioeconomic groups, the aim of this study was to examine the combined effect of mobility-related fatigue and socioeconomic position on mobility limitations in a prospective study among older Danish men and women.

Methods

Multivariate linear regression models with combined exposure variables using generalised estimating equations were performed using four waves of data on 2874 individuals without mobility limitations at baseline from The Danish Intervention Study on Preventive Home Visits.

Results

Low socioeconomic position and mobility-related fatigue are risk factors for mobility limitations in old age. The combined exposure to both factors additionally increased the risk, but there was no synergy effect between the two. Notably, fatigue predicted mobility decline at 3-year follow-up among those aged 80 years at baseline with a mean difference in number of mobility limitations from the joint reference category (high socioeconomic position and no fatigue) of −0.52, p<0.0001 among those in high socioeconomic position and −0.96, p<0.0001 among those in low socioeconomic position.

Conclusions

Mobility-related fatigue is not a significantly stronger risk factor for subsequent mobility limitations among those with concomitant exposure to low socioeconomic position, compared with those with high socioeconomic position. Preventive strategies must focus on vulnerable groups of older people with low socioeconomic position as well as on individuals with fatigue.
Fight like a ferret: a novel approach of using art therapy to reduce anxiety in stroke patients undergoing hospital rehabilitation
Authors: Ali Khalid , Gammidge Tony , Waller Diane
Published: January 2014

Rationale

The holistic aspect of stroke rehabilitation to include psychological well-being is currently neglected, with more emphasis placed on physical recovery despite anxiety and depression being common poststroke. From the limited amount of current literature, it seems that creative strategies such as art therapy (AT) can be beneficial in reducing isolation and anxiety among stroke patients.

Methods

Stroke patients (able to consent) in a hospital rehabilitation unit were invited to participate in two weekly AT sessions for 6 weeks, facilitated by an art psychotherapist using paints, crayons, clay, a camera and an iPad. Hospital anxiety and depression scales (HAD) and therapy outcome measures (TOM) were measured at the beginning and end of the study.

Results

Six male patients were recruited, average age 69 years (38–85). Group discussions allowed patients to express openly feelings of frustration as well as hope for physical and emotional recovery: ‘fight like a ferret’, an expression used by a group member. The group produced several art objects and photographic images that were collated using stop-frame animation to produce a 10 min film. Median HAD score for the group was eight points upon entering the study and six points on finishing the study.

Key conclusions

There is little attention to the emotional needs of stroke patients in rehabilitation. Properly designed research studies exploring the role of AT in addressing anxiety and depression poststroke are needed. Our study showed that AT was a feasible intervention that helped patients explore the sequel of stroke in an open supportive environment.
Last resort: case of clot translocation in intra-arterial stroke therapy
Authors: John Seby , Burgess Richard , Cheng-Ching Esteban , Wisco Dolora , Taqui Ather , Bain Mark , Toth Gabor , Uchino Ken , Hui Ferdinand , Hussain Muhammad Shazam
Published: January 2014

A patient was taken for emergent intra-arterial stroke therapy for an acute left middle cerebral artery stroke syndrome, with CT angiography showing a left internal carotid artery (ICA) occlusion. Through a 6 F Neuron MAX sheath, a 5 Max ACE Penumbra aspiration catheter was advanced to the thrombus and direct suction was performed through the ACE catheter and Neuron MAX sheath. Upon pull back, the thrombus became wedged in the Neuron MAX sheath and despite several attempts to aspirate the thrombus, no clot could be obtained. The Neuron MAX sheath was withdrawn to the left common carotid artery, and gently advanced to the origin of the external carotid artery (ECA). A glide wire was advanced and the thrombus dislodged into the ECA. Another pass with the 5 Max ACE was used to remove a remaining thrombus in the left ICA terminus, resulting in Thrombolysis in Cerebral Infarction (TICI) 3 flow. With improved devices for embolectomy, large and rigid emboli that exceed the inner diameter of large guide sheaths and balloon guide catheters can become lodged, and cannot be withdrawn through a catheter. While uncommon, strategies to overcome this are important to keep in mind during acute stroke intervention.
Prolonged hypotension following elective stenting of an internal carotid artery stenosis
Authors: Winters Hugh Stephen , Anderson Craig , Parker Geoff
Published: January 2014

We report a case of a 72-year-old man who had undergone elective stenting of an asymptomatic high grade stenosis of the proximal left internal carotid artery. The indication was progression of the stenosis over a 3 year period despite receiving maximal medical therapy, and patient preference for stenting over endarterectomy. He became profoundly hypotensive in the immediate post-stent period and required immediate and prolonged vasopressor support over the next week. The etiological hypothesis is baroreceptor hyperactivity related to procedure induced unilateral stretching of the carotid body.
Flaxseed enhances the beneficial effect of low-dose estrogen therapy at reducing bone turnover and preserving bone microarchitecture in ovariectomized rats
Authors: Sacco Sandra M. , Chen Jianmin , Ganss Bernhard , Thompson Lilian U. , Ward Wendy E.
Published: January 2014

Our previous research showed greatest protection to vertebral bone mineral density and strength in ovariectomized (OVX) rats when lignan- and α-linolenic acid-rich flaxseed (FS) is combined with low-dose estrogen therapy (LD) compared with either treatment alone. This study determined the effects of combined FS+LD on serum and tissue markers of bone turnover and microarchitecture to explain our previous findings. Three-month-old OVX rats were randomized to negative control (NEG), FS, LD or FS+LD for 2 or 12 weeks, meaningful time points for determining effects on markers of bone metabolism and bone structure, respectively. Ground FS was added to the AIN-93M diet (100 g/kg diet) and LD (0.42 μg 17β-estradiol/(kg body weight·day)) was delivered by subcutaneous implant. Sham rats were included as positive control. Bone formation (e.g., osteocalcin), bone resorption (e.g., tartrate-resistant acid phosphatase-5β (TRAP-5β)), as well as osteoprotegerin (OPG) and receptor activator of nuclear factor κ-B ligand (RANKL) were analyzed from the 2-week study by commercial assays (serum) and (or) histology (vertebra). Vertebral bone microarchitecture was measured from the 12-week study using microcomputed tomography. In serum, FS+LD and LD induced lower TRAP-5β and osteocalcin, and higher OPG and OPG/RANKL ratio versus NEG and FS (p < 0.05). In vertebrae, FS+LD induced higher OPG and lower osteocalcin versus NEG (p < 0.01) and did not differ from LD and FS. FS+LD improved bone microarchitecture versus NEG, FS, and LD (p < 0.05). In conclusion, FS+LD protects bone tissue because of a reduction in bone turnover. However, elucidating the distinctive action of FS+LD on bone turnover compared with LD requires further investigation.
Termites and ungulates affect arbuscular mycorrhizal richness and infectivity in a semiarid savanna
Authors: Petipas Renee H. , Brody Alison K.
Published: January 2014

In savanna ecosystems, mound-building termites and ungulate herbivores profoundly affect the abundance and diversity of aboveground organisms. Yet, surprisingly little is known about how these two groups interact to impact belowground communities. Using the Kenya Long-term Exclosure Experiment (KLEE), where ungulate herbivores have been excluded for over 15 years, we examined how the presence of termites and ungulate herbivore exclusion affected species richness, community composition, and infectivity of arbuscular mycorrhizal fungi (AMF). We also measured plant richness and soil nutrients to examine how the effects of termites and ungulate exclusion may indirectly impact AMF communities. AMF richness and infectivity and plant richness were significantly lower on termite mounds than in off-mound areas. AMF infectivity and plant richness were significantly higher in off-mound areas, especially where herbivores had access. Our results revealed a strong suppressive effect of termites on AMF communities that was not enhanced or ameliorated by the presence of ungulate herbivores. Herbivores, by contrast, enhanced the relationship between plants and their fungal symbionts but only in the absence of the suppressive effects of termites. Our results underscore the importance of multiple drivers affecting the patterns of both above- and below-ground communities.
Conodonts recovered from the carbonate xenoliths in the kimberlites confirm the Paleozoic cover on the Hall Peninsula, Nunavut
Authors: Zhang Shunxin , Pell Jennifer
Published: January 2014

Hall Peninsula, located on southeastern Baffin Island, Nunavut, hosts the newly discovered Chidliak kimberlite province. Presently, this area lacks Phanerozoic sedimentary cover, except for the unconsolidated glacial deposits; however, Late Ordovician and Early Silurian microfossil conodonts have been recovered from carbonate xenoliths preserved in the Late Jurassic – Early Cretaceous kimberlites. Over 1300 conodont specimens were recovered, among which 32 species representing 23 genera are recognized, with four elements indeterminate. The well-preserved conodont faunas provide reliable evidence on the Hall Peninsula for (i) reconstructing the Lower Paleozoic stratigraphic units, including the Upper Ordovician Frobisher Bay, Amadjuak, Akpatok, and Foster Bay formations, and the Lower Silurian Severn River Formation, (ii) estimating a total of 270–305 m in thickness of Lower Paleozoic sedimentary cover prior to the emplacement of the kimberlites, (iii) tracing the erosion history after the emplacement of the kimberlites, and (iv) calculating a minimum erosion rate of 2 m/Ma. The conodonts have a wide range of conodont Color Alteration Index (CAI) values between 1.5 and 8, which is the largest range recorded in any known suite of xenoliths entrained in kimberlites.
The near threshold π- p →ηn reaction in an effective Lagrangian approach
Authors: Lü Qi-Fang , Liu Xiao-Hao , Xie Ju-Jun , Li De-Min
Published: January 2014

The near threshold π- p →ηn reaction is studied within an effective Lagrangian approach and the isobar model. By considering the contributions from s- and u-channel nucleon pole and N*(1535) resonance, the total and differential cross-sections of the π- p →ηn reaction near threshold are calculated. Our theoretical results can fairly reproduce the current experimental data. It is also shown that while the center-of-mass energy lies in the range from the reaction threshold up to 1.65 GeV, s-channel N*(1535) resonance plays the dominant role. The effect from nucleon pole is found to be small but the interference terms between the N*(1535) resonance and the nucleon pole are significant. The contributions from t-channel processes are negligible in the present calculation.
NEW SOLVABLE SIGMA MODELS IN PLANE-PARALLEL WAVE BACKGROUND
Authors: HLAVATÝ LADISLAV , PETR IVO
Published: January 2014

We explicitly solve the classical equations of motion for strings in backgrounds obtained as non-Abelian T-duals of a homogeneous isotropic plane-parallel wave. To construct the dual backgrounds, semi-Abelian Drinfeld doubles are used which contain the isometry group of the homogeneous plane wave metric. The dual solutions are then found by the Poisson–Lie transformation of the explicit solution of the original homogeneous plane wave background. Investigating their Killing vectors, we have found that the dual backgrounds can be transformed to the form of more general plane-parallel waves.
MOMENTUM RESOLVED RADIO FREQUENCY SPECTROSCOPY OF A UNITARY FERMI GAS WITH EXTENDED GMB APPROXIMATION
Authors: RUAN XIAO-XIA , GONG HAO , DU LONG , JIANG YU , SUN WEI-MIN , ZONG HONG-SHI
Published: January 2014

In this paper, the momentum-resolved radio-frequency spectra of a unitary Fermi gas in the normal phase are presented and analyzed on the basis of the framework of the non-self-consistent T-matrix approximation with the extended Gorkov and Melik-Barkhudarov (GMB) approximation. We report the calculated occupied spectral intensity and energy distribution curves for different temperatures above T c . Our results indicate the existence of pseudogap phenomenon which would be helpful for further understanding of the pseudogap in high-temperature superconductivity.
Multimodal nonlinear imaging of atherosclerotic plaques differentiation of triglyceride and cholesterol deposits
Authors: Matthäus Christian , Cicchi Riccardo , Meyer Tobias , Lattermann Annika , Schmitt Michael , Romeike Bernd F. M. , Krafft Christoph , Dietzek Benjamin , Brehm Bernhard R. , Pavone Francesco S. , Popp Jürgen
Published: January 2014

Cardiovascular diseases in general and atherothrombosis as the most common of its individual disease entities is the leading cause of death in the developed countries. Therefore, visualization and characterization of inner arterial plaque composition is of vital diagnostic interest, especially for the early recognition of vulnerable plaques. Established clinical techniques provide valuable morphological information but cannot deliver information about the chemical composition of individual plaques. Therefore, spectroscopic imaging techniques have recently drawn considerable attention. Based on the spectroscopic properties of the individual plaque components, as for instance different types of lipids, the composition of atherosclerotic plaques can be analyzed qualitatively as well as quantitatively. Here, we compare the feasibility of multimodal nonlinear imaging combining two-photon fluorescence (TPF), coherent anti-Stokes Raman scattering (CARS) and second-harmonic generation (SHG) microscopy to contrast composition and morphology of lipid deposits against the surrounding matrix of connective tissue with diffraction limited spatial resolution. In this contribution, the spatial distribution of major constituents of the arterial wall and atherosclerotic plaques like elastin, collagen, triglycerides and cholesterol can be simultaneously visualized by a combination of nonlinear imaging methods, providing a powerful label-free complement to standard histopathological methods with great potential for in vivo application.
Research of service selection algorithm for net-centric simulation task community
Authors: Sun Liyang , Lin Jianning , Ju Zhenqi , Mao Shaojie , Liu Zhong , Lu Di
Published: January 2014

Being a new-generation C4ISR system simulation method, the construction approach of net-centric simulation (NCS) is developing toward net-centric from the traditional approach of platform-centric. NCS is mainly completed by the construction of the simulation task community (STC), the key to which being the dynamic integration of the various services spread in the network in order to form a new STC that meets the requirements of different users. In this study, a simulation task community service selection algorithm (STCSSA) is proposed. The main idea of this algorithm is to transform the construction of STC to the searching of optimal multi-objectives services with QoS global constraints. This paper first introduces the QoS model of STC and evaluates the service composition process, then presents the detailed operating process of STCSSA and design of the dynamic inertia weight strategy of the algorithm, and also proposes an optional variation method. Comparative tests were performed on STCSSA with other particle swarm optimization algorithms. It was validated from the perspective of performance that the proposed algorithm has advantages in improving the rate of convergence and avoiding local optimum, and from the perspective of practical application STCSSA also demonstrated feasibility in the construction of large-scale NCS task community.
Fully discrete two-step mixed element method for the symmetric regularized long wave equation
Authors: Zhao Meng , Liu Yang , Li Hong
Published: January 2014

A numerical method based on the explicit two-step method in time direction and the mixed finite element method in spatial direction is presented for the symmetric regularized long wave (SRLW) equation. The optimal a priori error estimates (O((Δt)2 + hm+1 + hk+1)) for fully discrete explicit two-step mixed scheme are derived. Moreover, a numerical example is provided to confirm our theoretical results.
Effect of nanoparticle diameter on the forced convective heat transfer of nanofluid (water + Al2O3) in the fully developed laminar region
Authors: Azimi Seyyed Shahabeddin , Kalbasi Mansour , Namazi Mohammad Hosain
Published: January 2014

Nanofluid is a suspension of nanoparticles (solid particles with diameters below 100 nm) in a conventional base fluid with significantly improved heat transfer characteristics compared to the original fluid. The heat transfer coefficient is a quantitative characteristic of the convective heat transfer. The purpose of this paper is to study the effect of the nanoparticle size (diameter) on the heat transfer coefficient of forced convective heat transfer of nanofluid in the fully developed laminar region of a horizontal tube. Using thermal conductivity model which is a function of the nanoparticle size, flow of a nanofluid (water + Al 2 O 3) in a circular tube submitted to a constant wall temperature is numerically investigated with two particle sizes of 11 nm and 47 nm. The calculated results show that the nanoparticle size does not significantly affect the heat transfer coefficient, however, the heat transfer coefficient decreases as the particle size increases.
Palaeohurricane reconstructions from sedimentary archives along the Gulf of Mexico, Caribbean Sea and western North Atlantic Ocean margins
Authors: Wallace Davin J. , Woodruff Jonathan D. , Anderson John B. , Donnelly Jeffrey P.
Published: January 2014

Hurricanes annually threaten the Atlantic Ocean margins. Historical hurricane records are relatively short and palaeohurricane sedimentary archives provide a geological and climatic context that sheds light on future hurricane activity. Here we review palaeo-trends in hurricane activity elucidated from sedimentary archives. We discuss dating methods, site selection and statistics associated with previously published records. These archives have been useful for understanding the long-term evolution of coastal systems and the response of intense hurricane activity to climatic changes. Regional shifts in hurricane overwash on centennial to millennial timescales have been linked to various climatic modes of variability, including El Niño/Southern Oscillation and the North Atlantic Oscillation, but could also reflect regional-scale controls on hurricane activity.
HuR and other turnover- and translation-regulatory RNA-binding proteins: implications for the kidney
Authors: Pullmann Rudolf , Rabb Hamid
Published: January 2014

The posttranscriptional regulation of gene expression occurs through cis RNA regulatory elements by the action of trans factors, which are represented by noncoding RNAs (especially microRNAs) and turnover- and translation-regulatory (TTR) RNA-binding proteins (RBPs). These multifactorial proteins are a group of heterogeneous RBPs primarily implicated in controlling the decay and translation rates of target mRNAs. TTR-RBPs usually shuttle between cellular compartments (the nucleus and cytoplasm) in response to various stimuli and undergo posttranslational modifications such as phosphorylation or methylation to ensure their proper subcellular localization and function. TTR-RBPs are emerging as key regulators of a wide variety of genes influencing kidney physiology and pathology. This review summarizes the current knowledge of TTR-RBPs that influence renal metabolism. We will discuss the role of TTR-RBPs as regulators of kidney ischemia, fibrosis and matrix remodeling, angiogenesis, membrane transport, immunity, vascular tone, hypertension, and acid-base balance as well as anemia, bone mineral disease, and vascular calcification.
Iodinated contrast media cause direct tubular cell damage, leading to oxidative stress, low nitric oxide, and impairment of tubuloglomerular feedback
Authors: Liu Zhi Zhao , Schmerbach Kristin , Lu Yuan , Perlewitz Andrea , Nikitina Tatiana , Cantow Kathleen , Seeliger Erdmann , Persson Pontus B. , Patzak Andreas , Liu Ruisheng , Sendeski Mauricio M.
Published: January 2014

Iodinated contrast media (CM) have adverse effects that may result in contrast-induced acute kidney injury. Oxidative stress is believed to play a role in CM-induced kidney injury. We test the hypothesis that oxidative stress and reduced nitric oxide in tubules are consequences of CM-induced direct cell damage and that increased local oxidative stress may increase tubuloglomerular feedback. Rat thick ascending limbs (TAL) were isolated and perfused. Superoxide and nitric oxide were quantified using fluorescence techniques. Cell death rate was estimated using propidium iodide and trypan blue. The function of macula densa and tubuloglomerular feedback responsiveness were measured in isolated, perfused juxtaglomerular apparatuses (JGA) of rabbits. The expression of genes related to oxidative stress and the activity of superoxide dismutase (SOD) were investigated in the renal medulla of rats that received CM. CM increased superoxide concentration and reduced nitric oxide bioavailability in TAL. Propidium iodide fluorescence and trypan blue uptake increased more in CM-perfused TAL than in controls, indicating increased rate of cell death. There were no marked acute changes in the expression of genes related to oxidative stress in medullary segments of Henle's loop. SOD activity did not differ between CM and control groups. The tubuloglomerular feedback in isolated JGA was increased by CM. Tubular cell damage and accompanying oxidative stress in our model are consequences of CM-induced direct cell damage, which also modifies the tubulovascular interaction at the macula densa, and may therefore contribute to disturbances of renal perfusion and filtration.
Renoprotective effect of renal liver-type fatty acid binding protein and angiotensin II type 1a receptor loss in renal injury caused by RAS activation
Authors: Ichikawa Daisuke , Kamijo-Ikemori Atsuko , Sugaya Takeshi , Shibagaki Yugo , Yasuda Takashi , Katayama Kimie , Hoshino Seiko , Igarashi-Migitaka Junko , Hirata Kazuaki , Kimura Kenjiro
Published: January 2014

The aim of this study was to assess the renoprotective effect of renal human liver-type fatty acid binding protein (hL-FABP) and angiotensin II (ANG II) type 1A receptor (AT1a) loss in renal injury caused by renin-angiotensin system (RAS) activation. We established hL-FABP chromosomal transgenic mice (L-FABP+/−AT1a+/+), crossed the L-FABP+/−AT1a+/+ with AT1a knockdown homo mice (L-FABP−/−AT1a−/−), and generated L-FABP+/−AT1a hetero mice (L-FABP+/−AT1a+/−). After the back-cross of these cubs, L-FABP+/−AT1a−/− were obtained. To activate the renal RAS, wild-type mice (L-FABP−/−AT1a+/+), L-FABP+/−AT1a+/+, L-FABP−/−AT1a+/−, L-FABP+/−AT1a+/−, L-FABP−/−AT1a−/−, and L-FABP+/−AT1a−/− were administered high-dose systemic ANG II infusion plus a high-salt diet for 28 days. In the L-FABP−/−AT1a+/+, RAS activation (L-FABP−/−AT1a+/+RAS) caused hypertension and tubulointerstitial damage. In the L-FABP+/−AT1a+/+RAS, tubulointerstitial damage was significantly attenuated compared with L-FABP−/−AT1a+/+RAS. In the AT1a partial knockout (AT1a+/−) or complete knockout (AT1a−/−) mice, reduction of AT1a expression led to a significantly lower degree of renal injury compared with L-FABP−/−AT1a+/+RAS or L-FABP+/−AT1a+/+RAS mice. Renal injury in L-FABP+/−AT1a+/−RAS mice was significantly attenuated compared with L-FABP−/−AT1a+/−RAS mice. In both L-FABP−/−AT1a−/−RAS and L-FABP+/−AT1a−/−RAS mice, renal damage was rarely found. The degrees of renal hL-FABP expression and urinary hL-FABP levels increased by RAS activation and gradually decreased along with reduction of AT1a expression levels. In conclusion, in this mouse model, renal hL-FABP expression and a decrease in AT1a expression attenuated tubulointerstitial damage due to RAS activation.
Microbubbles are detected prior to larger bubbles following decompression
Authors: Swan J. G. , Wilbur J. C. , Moodie K. L. , Kane S. A. , Knaus D. A. , Phillips S. D. , Beach T. L. , Fellows A. M. , Magari P. J. , Buckey J. C.
Published: January 2014

Using dual-frequency ultrasound (DFU), microbubbles (<10 μm diameter) have been detected in tissue following decompression. It is not known if these microbubbles are the precursors for B-mode ultrasound-detectable venous gas emboli (bmdVGE). The purpose of this study was to determine if microbubbles could be detected intravascularly postdecompression and to investigate the temporal relationship between microbubbles and larger bmdVGE. Anesthetized swine ( n = 15) were exposed to 4.0–4.5 ATA for 2 h, followed by decompression to 0.98 ATA. Microbubble presence and VGE grade were measured using DFU and B-mode ultrasound, respectively, before and for 1 h postdecompression, approximately every 4–5 min. Microbubbles appeared in the bloodstream postdecompression, both in the presence and absence of bmdVGE. In swine without bmdVGE, microbubbles remained elevated for the entire 60-min postdecompression period. In swine with bmdVGE, microbubble signals were detected initially but then returned to baseline. Microbubbles were not detected with the sham dive. Mean bmdVGE grade increased over the length of the postdecompression data collection period. Comparison of the two response curves revealed significant differences at 5 and 10 min postdecompression, indicating that microbubbles preceded bmdVGE. These findings indicate that decompression-induced microbubbles can 1) be detected intravascularly at multiple sites, 2) appear in the presence and absence of bmdVGE, and 3) occur before bmdVGE. This supports the hypothesis that microbubbles precede larger VGE bubbles. Microbubble presence may be an early marker of decompression stress. Since DFU is a low-power ultrasonic method, it may be useful for operational diving applications.
Immunoglobulin Fc Domain Fusion to TRAIL Significantly Prolongs Its Plasma Half-Life and Enhances Its Antitumor Activity
Authors: Wang Haizhen , Davis Jennifer S. , Wu Xiangwei
Published: January 2014

TRAIL (Apo2L) is a potent inducer of cell death. Interest in TRAIL has increased, following the observation that TRAIL can selectively kill a wide variety of human cancer cells without killing normal cells both in vitro and when grown as xenografts. Therefore, TRAIL has been proposed as a promising anticancer agent and currently is being tested in clinical trials. However, recombinant TRAIL has a very short plasma half-life, which limits its therapeutic potential. To overcome this limitation, we investigated the ability of the human IgG1 fragment crystallizable region (Fc) to enhance TRAIL stability. In this report, we show that Fc-TRAIL chimeric protein displays higher specific activity in vitro and a significantly longer half-life in mice than recombinant human TRAIL (rh-TRAIL). No short-term toxicity, especially liver toxicity, was observed. More importantly, Fc-TRAIL was much more effective in inhibiting tumor growth in a xenograft tumor model compared with rh-TRAIL. Our data suggest that fusion of Fc to TRAIL is able to improve the bioavailability and activity of TRAIL both in vitro and in vivo, and Fc-TRAIL may be explored for future clinical applications in cancer treatment and prevention. Mol Cancer Ther; 13(3); 643–50. ©2014 AACR.
Synuclein γ Compromises Spindle Assembly Checkpoint and Renders Resistance to Antimicrotubule Drugs
Authors: Miao Suyu , Wu Kejin , Zhang Bo , Weng Ziyi , Zhu Mingjie , Lu Yunshu , Krishna Ramadas , Shi Yuenian Eric
Published: January 2014

Defects in the spindle assembly checkpoint (SAC) have been proposed to contribute to the chromosomal instability in human cancers. One of the major mechanisms underlying antimicrotubule drug (AMD) resistance involves acquired inactivation of SAC. Synuclein γ (SNCG), previously identified as a breast cancer–specific gene, is highly expressed in malignant cancer cells but not in normal epithelium. Here, we show that SNCG is sufficient to induce resistance to AMD-caused apoptosis in breast cancer cells and cancer xenografts. SNCG binds to spindle checkpoint kinase BubR1 and inhibits its kinase activity. Specifically, the C-terminal (Gln106-Asp127) of SNCG binds to the N-terminal TPR (tetratricopeptidelike folds) motif of BubR1. SNCG–BubR1 interaction induces a structure change of BubR1, attenuates its interaction with other key checkpoint proteins of Cdc20, and thus compromises SAC function. SNCG expression in breast cancers from patients with a neoadjuvant clinical trial showed that SNCG-positive tumors are resistant to chemotherapy-induced apoptosis. These data show that SNCG renders AMD resistance by inhibiting BubR1 activity and attenuating SAC function. Mol Cancer Ther; 13(3); 699–713. ©2014 AACR.
JAK2 Expression Is Associated with Tumor-Infiltrating Lymphocytes and Improved Breast Cancer Outcomes: Implications for Evaluating JAK2 Inhibitors
Authors: Miller Chris P. , Thorpe Jason D. , Kortum Amanda N. , Coy Catherine M. , Cheng Wei-Yi , Yang Tai-Hsien Ou , Anastassiou Dimitris , Beatty J. David , Urban Nicole D. , Blau C. Anthony
Published: January 2014

Janus kinase-2 (JAK2) supports breast cancer growth, and clinical trials testing JAK2 inhibitors are under way. In addition to the tumor epithelium, JAK2 is also expressed in other tissues including immune cells; whether the JAK2 mRNA levels in breast tumors correlate with outcomes has not been evaluated. Using a case–control design, JAK2 mRNA was measured in 223 archived breast tumors and associations with distant recurrence were evaluated by logistic regression. The frequency of correct pairwise comparisons of patient rankings based on JAK2 levels versus survival outcomes, the concordance index (CI), was evaluated using data from 2,460 patients in three cohorts. In the case–control study, increased JAK2 was associated with a decreasing risk of recurrence (multivariate P = 0.003, n = 223). Similarly, JAK2 was associated with a protective CI (<0.5) in the public cohorts: NETHERLANDS CI = 0.376, n = 295; METABRIC CI = 0.462, n = 1,981; OSLOVAL CI = 0.452, n = 184. Furthermore, JAK2 was strongly correlated with the favorable prognosis LYM metagene signature for infiltrating T cells (r = 0.5; P < 2 × 10−16; n = 1,981) and with severe lymphocyte infiltration (P = 0.00003, n = 156). Moreover, the JAK1/2 inhibitor ruxolitinib potently inhibited the anti-CD3–dependent production of IFN-γ, a marker of the differentiation of Th cells along the tumor-inhibitory Th1 pathway. The potential for JAK2 inhibitors to interfere with the antitumor capacities of T cells should be evaluated. Cancer Immunol Res; 2(4); 301–6. ©2014 AACR.
NR5A1 Gene Mutations: Clinical, Endocrine and Genetic Features in Two Girls with 46,XY Disorder of Sex Development
Authors: Bertelloni Silvano , Dati Eleonora , Baldinotti Fulvia , Toschi Benedetta , Marrocco Giacinto , Sessa Maria R. , Michelucci Angela , Simi Paolo , Baroncelli Giampiero I.
Published: January 2014

Background: Steroidogenic factor 1, encoded by the NR5A1 gene, is a key regulator of endocrine function within the hypothalamic-pituitary-steroidogenic axis. Both homozygous, compound heterozygous and heterozygous mutations in the NR5A1 gene may determine 46,XY disorders of sex development (DSD). Patients and Methods:NR5A1 gene sequencing was performed in a cohort of 6 patients with 46,XY DSD without specific diagnosis. Results: Heterozygous NR5A1 gene mutations were found in 2 girls, aged 0.5 years and 14 years. The older girl harbored the c.250C>T transition in exon 4 (p.Arg84Cys), previously reported in a Japanese girl. The younger girl presented a de novo novel exon 6 heterozygous frameshift mutation (c.1074dupG) in codon 359 associated with the p.Gly146Ala polymorphism the latter inherited from her father. This baby showed severe impairment of androgen secretion from the first months of life. Overt adrenal insufficiency did not occur, but the older girl showed subnormal cortisol peak after ACTH stimulation. Conclusions:NR5A1 gene mutations are a relatively frequent cause of 46,XY DSD in humans. Clear indications for management of these individuals remain elusive, mainly when diagnosis is made in infancy. Long-term monitoring of adrenal function should be recommended.
Longitudinal Polysomnographic Assessment from Acute to Subacute Phase in Infratentorial versus Supratentorial Stroke
Authors: Manconi Mauro , Zavalko Irina , Cereda Carlo , Pisarenco Iraida , Ott Sebastian , Fulda Stephany , Bassetti Claudio L.
Published: January 2014

Background: Regulation of sleep and sleep-related breathing resides in different brain structures. Vascular lesions can be expected to differ in their consequences on sleep depending on stroke topography. However, studies addressing the differences in sleep and sleep-related breathing depending on stroke topography are scarce. The aim of the present investigation was to compare the sleep and sleep-related breathing of patients with supratentorial versus infratentorial stroke. Methods: This study was part of the prospective multicenter study SAS-CARE-1 (Sleep-Disordered Breathing in Transient Ischemic Attack (TIA)/Ischemic Stroke and Continuous Positive Airway Pressure (CPAP) Treatment Efficacy (SAS-CARE); NCT01097967). We prospectively included 14 patients (13 male, age 66 ± 6 years) with infratentorial lesions and 14 patients (14 male, age 64 ± 7 years) with supratentorial lesions, matched for age and stroke severity. Polysomnography was recorded in all during the acute phase within 9 days after stroke onset and 3 months later. Results: During the acute phase after stroke, patients with infratentorial lesions had significantly more sleep-related breathing disorders than patients with supratentorial lesions with an apnea-hypopnea index >20 observed in 8 (57%) patients with infratentorial stroke and in only 2 (14%) patients with supratentorial stroke. Sleep-related breathing improved from the acute to the subacute phase (3 months), albeit remaining elevated in a significant proportion of subjects. Sleep parameters did not differ between the two patient groups but there was a general improvement of sleep from the acute to the subacute phase which was comparable for both patient groups. Although stroke severity was mild, recovery after 3 months was worse in patients with infratentorial stroke with 12 of 14 patients with supratentorial stroke being symptom free (NIHSS = 0), while this was the case for only 6 of 14 patients with infratentorial stroke. Conclusions: Patients with infratentorial lesions are at an increased risk for sleep-related breathing disorders, which are frequent in this group. Monitoring of sleep-related breathing is therefore especially recommended in patients with infratentorial stroke. Because of the absence of reliable differences in sleep parameters between the two patient groups, polygraphy, with reduced diagnostic costs, rather than polysomnography could be considered. The higher prevalence of sleep-related breathing disorders and the poorer recovery of patients with infratentorial lesions suggest that early treatment interventions should be considered.
Predictive Value of Thrombus Attenuation on Thin-Slice Non-Contrast CT for Persistent Occlusion after Intravenous Thrombolysis
Authors: Niesten J.M. , van der Schaaf I.C. , van der Graaf Y. , Kappelle L.J. , Biessels G.J. , Horsch A.D. , Dankbaar J.W. , Luitse M.J.A. , van Seeters T. , Smit E.J. , Mali W.P.Th.M. , Velthuis B.K. ,   on behalf of the DUtch acute Stroke Trial (DUST)
Published: January 2014

Background: In stroke erythrocyte-rich thrombi are more sensitive to intravenous thrombolysis with recombinant tissue plasminogen activator (IV-rtPA) and have higher density on non-contrast CT (NCCT). We investigated the relationship between thrombus density and recanalization and whether persistent occlusions can be predicted by Hounsfield unit (HU) measurements. Methods: In 88 IV-rtPA-treated patients with intracranial ICA or MCA occluding thrombus and follow-up imaging, thrombus and contralateral vessel attenuation measurements were performed on thin-slice NCCT. Mean absolute and relative HU were compared between patients with persistent occlusion (modified Thrombolysis in Cerebral Infarction system, grade 0/1/2a) and recanalization (grade 2b/3). Univariate and multivariate (adjusted for stroke subtype, clot burden score, occlusion site and time to thrombolysis) odds ratios for persistent occlusion were calculated. Additional prognostic value for persistent occlusion was estimated by adding HU measurements to the area under the curve (AUC) of known determinants and calculating optimal cut-off values. Results: Patients with persistent occlusion (n = 19) had significant lower mean HU (absolute 52.2 ± 9.5, relative 1.29 ± 0.20) compared to recanalization (absolute 63.1 ± 10.7, relative 1.54 ± 0.23, both p < 0.0001). Odds ratios for persistent occlusion were 3.1 (95% confidence interval, CI 1.6-6.0) univariate and 3.1 (95% CI 1.7-5.7) multivariate per 10 absolute HU decrease and 3.2 (95% CI 1.6-6.5) univariate and 4.1 (95% CI 1.8-9.1) multivariate per 0.20 relative HU decrease. Attenuation measurements significantly increased the AUC (0.67) of the known determinants to 0.84 (absolute HU) and 0.86 (relative HU). Cut-off values of <56.5 absolute HU and <1.38 relative HU showed optimal predictive values for persistent occlusion. Conclusions: Thrombus density is related to recanalization rate. Lower absolute and relative HU are independently related to persistent occlusion and HU measurements significantly increase discriminative performances of known recanalization determinants.
Metastatic Cancer of Cowper's Gland: A Rare Cancer Managed Successfully by Molecular Profiling
Authors: Myers Charles E. , Gatalica Zoran , Spinelli Anthony , Castro Michael , Linden Erica , Sartor Oliver , Sargent Mathew
Published: January 2014

Cancer of Cowper's gland is a very rare cancer. This case represents the 9th case in the medical literature. As such, there are no phase II or phase III trials to guide treatment. In this article, we report the successful treatment of a patient over a 7-year period guided solely by molecular profiling. Through multiple cycles to treatment, the cancer was controlled using drugs targeting c-kit, as the cancer steadily increased the expression of c-kit. This report also documents the use of a novel drug combination based on sunitinib that was well tolerated and may warrant testing in other c-kit-dependent cancers.
Regulation of Akt Signaling by Sirtuins
Authors: Pillai Vinodkumar B. , Sundaresan Nagalingam R. , Gupta Mahesh P.
Published: January 2014

Cardiac hypertrophy is a multifactorial disease characterized by multiple molecular alterations. One of these alterations is change in the activity of Akt, which plays a central role in regulating a variety of cellular processes ranging from cell survival to aging. Akt activation is mainly achieved by its binding to phosphatidylinositol (3,4,5)-triphosphate. This results in a conformational change that exposes the kinase domain of Akt for phosphorylation and activation by its upstream kinase, 3-phosphoinositide–dependent protein kinase 1, in the cell membrane. Recent studies have shown that sirtuin isoforms, silent information regulator (SIRT) 1, SIRT3, and SIRT6, play an essential role in the regulation of Akt activation. Although SIRT1 deacetylates Akt to promote phosphatidylinositol (3,4,5)-triphosphate binding and activation, SIRT3 controls reactive oxygen species–mediated Akt activation, and SIRT6 transcriptionally represses Akt at the level of chromatin. In the first part of this review, we discuss the mechanisms by which sirtuins regulate Akt activation and how they influence other post-translational modifications of Akt. In the latter part of the review, we summarize the implications of sirtuin-dependent regulation of Akt signaling in the control of major cellular processes such as cellular growth, angiogenesis, apoptosis, autophagy, and aging, which are involved in the initiation and progression of several diseases.
Vitamin D and Cardiovascular Disease
Authors: Norman P.E. , Powell J.T.
Published: January 2014

Vitamin D plays a classical hormonal role in skeletal health by regulating calcium and phosphorus metabolism. Vitamin D metabolites also have physiological functions in nonskeletal tissues, where local synthesis influences regulatory pathways via paracrine and autocrine mechanisms. The active metabolite of vitamin D, 1α,25-dihydroxyvitamin D, binds to the vitamin D receptor that regulates numerous genes involved in fundamental processes of potential relevance to cardiovascular disease, including cell proliferation and differentiation, apoptosis, oxidative stress, membrane transport, matrix homeostasis, and cell adhesion. Vitamin D receptors have been found in all the major cardiovascular cell types including cardiomyocytes, arterial wall cells, and immune cells. Experimental studies have established a role for vitamin D metabolites in pathways that are integral to cardiovascular function and disease, including inflammation, thrombosis, and the renin–angiotensin system. Clinical studies have generally demonstrated an independent association between vitamin D deficiency and various manifestations of degenerative cardiovascular disease including vascular calcification. However, the role of vitamin D supplementation in the management of cardiovascular disease remains to be established. This review summarizes the clinical studies showing associations between vitamin D status and cardiovascular disease and the experimental studies that explore the mechanistic basis for these associations.