bluuebunny/crossref_metadata_2025 huggingface dataset:
Immediate and Ongoing Detection of Prions in the Blood of Hamsters and Deer following Oral, Nasal, or Blood Inoculations
Authors: Elder Alan M. , Henderson Davin M. , Nalls Amy V. , Hoover Edward A. , Kincaid Anthony E. , Bartz Jason C. , Mathiason Candace K.
Published: April 2015

Infectious prions traverse epithelial barriers to gain access to the circulatory system, yet the temporal parameters of transepithelial transport and persistence in the blood over time remain unknown. We used whole-blood real-time quaking-induced conversion (wbRT-QuIC) to analyze whole blood collected from transmissible spongiform encephalopathy (TSE)-inoculated deer and hamsters throughout the incubation period for the presence of common prion protein-conversion competent amyloid (PrP
C
-CCA). We observed PrP
C
-CCA in the blood of TSE-inoculated hosts throughout the disease course from minutes postexposure to terminal disease.
Human Coronavirus HKU1 Spike Protein Uses
O
-Acetylated Sialic Acid as an Attachment Receptor Determinant and Employs Hemagglutinin-Esterase Protein as a Receptor-Destroying Enzyme
Authors: Huang Xingchuan , Dong Wenjuan , Milewska Aleksandra , Golda Anna , Qi Yonghe , Zhu Quan K. , Marasco Wayne A. , Baric Ralph S. , Sims Amy C. , Pyrc Krzysztof , Li Wenhui , Sui Jianhua
Published: April 2015

Human coronavirus (hCoV) HKU1 is one of six hCoVs identified to date and the only one with an unidentified cellular receptor. hCoV-HKU1 encodes a hemagglutinin-esterase (HE) protein that is unique to the group a betacoronaviruses (group 2a). The function of HKU1-HE remains largely undetermined. In this study, we examined binding of the S1 domain of hCoV-HKU1 spike to a panel of cells and found that the S1 could specifically bind on the cell surface of a human rhabdomyosarcoma cell line, RD. Pretreatment of RD cells with neuraminidase (NA) and trypsin greatly reduced the binding, suggesting that the binding was mediated by sialic acids on glycoproteins. However, unlike other group 2a CoVs, e.g., hCoV-OC43, for which 9-
O
-acetylated sialic acid (9-
O
-Ac-Sia) serves as a receptor determinant, HKU1-S1 bound with neither 9-
O
-Ac-Sia-containing glycoprotein(s) nor rat and mouse erythrocytes. Nonetheless, the HKU1-HE was similar to OC43-HE, also possessed sialate-
O
-acetylesterase activity, and acted as a receptor-destroying enzyme (RDE) capable of eliminating the binding of HKU1-S1 to RD cells, whereas the
O
-acetylesterase-inactive HKU1-HE mutant lost this capacity. Using primary human ciliated airway epithelial (HAE) cell cultures, the only
in vitro
replication model for hCoV-HKU1 infection, we confirmed that pretreatment of HAE cells with HE but not the enzymatically inactive mutant blocked hCoV-HKU1 infection. These results demonstrate that hCoV-HKU1 exploits
O
-Ac-Sia as a cellular attachment receptor determinant to initiate the infection of host cells and that its HE protein possesses the corresponding sialate-
O
-acetylesterase RDE activity.

IMPORTANCE
Human coronaviruses (hCoV) are important human respiratory pathogens. Among the six hCoVs identified to date, only hCoV-HKU1 has no defined cellular receptor. It is also unclear whether hemagglutinin-esterase (HE) protein plays a role in viral entry. In this study, we found that, similarly to other members of the group 2a CoVs, sialic acid moieties on glycoproteins are critical receptor determinants for the hCoV-HKU1 infection. Interestingly, the virus seems to employ a type of sialic acid different from those employed by other group 2a CoVs. In addition, we determined that the HKU1-HE protein is an
O
-acetylesterase and acts as a receptor-destroying enzyme (RDE) for hCoV-HKU1. This is the first study to demonstrate that hCoV-HKU1 uses certain types of
O
-acetylated sialic acid residues on glycoproteins to initiate the infection of host cells and that the HKU1-HE protein possesses sialate-
O
-acetylesterase RDE activity.
Recombination Analysis of Herpes Simplex Virus 1 Reveals a Bias toward GC Content and the Inverted Repeat Regions
Authors: Lee Kyubin , Kolb Aaron W. , Sverchkov Yuriy , Cuellar Jacqueline A. , Craven Mark , Brandt Curtis R.
Published: April 2015

Herpes simplex virus 1 (HSV-1) causes recurrent mucocutaneous ulcers and is the leading cause of infectious blindness and sporadic encephalitis in the United States. HSV-1 has been shown to be highly recombinogenic; however, to date, there has been no genome-wide analysis of recombination. To address this, we generated 40 HSV-1 recombinants derived from two parental strains, OD4 and CJ994. The 40 OD4-CJ994 HSV-1 recombinants were sequenced using the Illumina sequencing system, and recombination breakpoints were determined for each of the recombinants using the Bootscan program. Breakpoints occurring in the terminal inverted repeats were excluded from analysis to prevent double counting, resulting in a total of 272 breakpoints in the data set. By placing windows around the 272 breakpoints followed by Monte Carlo analysis comparing actual data to simulated data, we identified a recombination bias toward both high GC content and intergenic regions. A Monte Carlo analysis also suggested that recombination did not appear to be responsible for the generation of the spontaneous nucleotide mutations detected following sequencing. Additionally, kernel density estimation analysis across the genome found that the large, inverted repeats comprise a recombination hot spot.

IMPORTANCE
Herpes simplex virus 1 (HSV-1) virus is the leading cause of sporadic encephalitis and blinding keratitis in developed countries. HSV-1 has been shown to be highly recombinogenic, and recombination itself appears to be a significant component of genome replication. To date, there has been no genome-wide analysis of recombination. Here we present the findings of the first genome-wide study of recombination performed by generating and sequencing 40 HSV-1 recombinants derived from the OD4 and CJ994 parental strains, followed by bioinformatics analysis. Recombination breakpoints were determined, yielding 272 breakpoints in the full data set. Kernel density analysis determined that the large inverted repeats constitute a recombination hot spot. Additionally, Monte Carlo analyses found biases toward high GC content and intergenic and repetitive regions.
A novel measure of socioeconomic status using individual housing data to assess the association of SES with rheumatoid arthritis and its mortality: a population-based case–control study
Authors: Ghawi Husam , Crowson Cynthia S , Rand-Weaver Jennifer , Krusemark Elizabeth , Gabriel Sherine E , Juhn Young J
Published: April 2015

Objectives

To assess whether HOUSES (HOUsing-based index of socioeconomic status (SES)) is associated with risk of and mortality after rheumatoid arthritis (RA).

Design

We conducted a population-based case–control study which enrolled population-based RA cases and their controls without RA.

Setting

The study was performed in Olmsted County, Minnesota.

Participants

Study participants were all residents of Olmsted County, Minnesota, with RA identified using the 1987 American College of Rheumatology criteria for RA from 1 January 1988, to 31 December 2007, using the auspices of the Rochester Epidemiology Project. For each patient with RA, one control was randomly selected from Olmsted County residents of similar age and gender without RA.

Primary and secondary outcome measure

The disease status was RA cases and their matched controls in relation to HOUSES as an exposure. As a secondary aim, post-RA mortality among only RA cases was an outcome event. The associations of SES measured by HOUSES with the study outcomes were assessed using logistic regression and Cox models. HOUSES, as a composite index, was formulated based on a summed z-score for housing value, square footage and number of bedrooms and bathrooms.

Results

Of the eligible 604 participants, 418 (69%) were female; the mean age was 56±15.6 years. Lower SES, as measured by HOUSES, was associated with the risk of developing RA (0.5±3.8 for controls vs −0.2±3.1 for RA cases, p=0.003), adjusting for age, gender, calendar year of RA index date, smoking status and BMI. The lowest quartile of HOUSES was significantly associated with increased post-RA mortality compared to higher quartiles of HOUSES (HR 1.74; 95% CI 1.10 to 2.74; p=0.017) in multivariate analysis.

Conclusions

Lower SES, as measured by HOUSES, is associated with increased risk of RA and mortality after RA. HOUSES may be a useful tool for health disparities research concerning rheumatological outcomes when conventional SES measures are unavailable.
Use of corticosteroids in patients with rheumatoid arthritis treated with infliximab: treatment implications based on a real-world Canadian population
Authors: Haraoui Boulos , Jovaisas Algis , Bensen William G , Faraawi Rafat , Kelsall John , Dixit Sanjay , Rodrigues Jude , Sheriff Maqbool , Rampakakis Emmanouil , Sampalis John S , Lehman Allen J , Otawa Susan , Nantel Francois , Shawi May
Published: April 2015

Objective

To describe the rate of concomitant oral corticosteroid use at antitumour necrosis factor (TNF) initiation and at disease remission, and to assess its effect on incidence of infection and sustainability of remission among patients with rheumatoid arthritis (RA) treated with infliximab in Canadian routine care.

Methods

Biological naïve patients with RA followed in theBiologicTreatmentRegistryAcrossCanada (BioTRAC) were included. The time-dependent association between corticosteroid dose (no use, ≤5 mg/day, >5 mg/day) and the incidence of first infection, while considering possible confounders, remission sustainability and the incidence of subsequent infections were assessed with Cox regression.

Results

838 patients were included; mean (SD) baseline age and disease duration were 55.6 (13.5) and 10.5 (9.8) years, respectively. After a mean (SD) of 51.3 (43.6) months, the total incidence of adverse events (AEs) and infections were 110.2 and 19.6 per 100 person-years (PY), respectively. In multivariate analysis, the HR (95% CI) for acquiring an infection was 2.48 (1.24 to 4.98) with >5 mg/day of corticosteroids versus no corticosteroids. Similarly, ≤5 mg/day of corticosteroids was associated with increased hazard for infection (2.12 (0.97 to 4.66)). Despite DAS28 (disease activity score 28) or Clinical Disease Activity Index (CDAI) remission, corticosteroids were continued in 16.4% and 16.7% of cases, respectively. Continued corticosteroid treatment was not associated with sustainability of remission (HRDAS28(95% CI) 1.40 (0.95 to 2.06); HRCDAI1.19 (0.75 to 1.88)), however, it had a significant impact on development of infection (HRDAS28(95% CI) 1.78 (1.00 to 3.19); HRCDAI2.38 (1.14 to 4.99)).

Conclusions

Oral corticosteroid treatment was associated with increased risk of development of infection without impacting sustainability of remission. These results support the notion that corticosteroids should be used concomitantly with anti-TNF for the shortest period possible to achieve remission, and then tapered.

Trial registration number

NCT00741793.
Prescribed burning of canopy gaps facilitates tree seedling establishment in restoration of pine-dominated boreal forests
Authors: Pasanen Hannes , Rehu Virve , Junninen Kaisa , Kouki Jari
Published: April 2015

Because many currently protected forests are former timber production areas, restoration activities are often used to re-establish their natural structures. In this experimental study, we monitored the establishment of tree seedlings in previously managed but currently protected Scots pine (Pinus sylvestris L.) dominated stands in boreal forests 5 years after restoration measures. The study included eight study areas (115 sample plots) in southern Finland. We compared seedling abundance between five study groups: untreated control forest, unburned canopy gap, burned full-canopy forest, burned canopy gap, and thinned and burned forest. Density of tree seedlings was highest in burned canopy gaps (mean 25.4 seedlings/100 m2 compared with 6.0 seedlings/100 m2 in control sites). In particular, birch (Betula spp.) and Scots pine were significantly more abundant within burned canopy gaps than in unburned gaps. We conclude that opening within-stand canopy gaps, especially in combination with prescribed burning, can be useful in forest restoration as the gaps diversify age-class structure and tree species composition of single-cohort pine stands.
Feces of feedlot cattle contain a diversity of bacteriophages that lyse non-O157 Shiga toxin-producing Escherichia coli
Authors: Wang Jiaying , Niu Yan D. , Chen Jinding , Anany Hany , Ackermann Hans-W. , Johnson Roger P. , Ateba Collins N. , Stanford Kim , McAllister Tim A.
Published: April 2015

This study aimed to isolate and characterize bacteriophages that lyse non-O157 Shiga toxin-producing Escherichia coli (STEC) from cattle feces. Of 37 non-O157 STEC-infecting phages isolated, those targeting O26 (AXO26A, AYO26A, AYO26B), O103 (AXO103A, AYO103A), O111 (AXO111A, AYO111A), O121 (AXO121A, AXO121B), and O145 (AYO145A, AYO145B) were further characterized. Transmission electron microscopy showed that the 11 isolates belonged to 3 families and 6 genera: the families Myoviridae (types rV5, T4, ViI, O1), Siphoviridae (type T5), and Podoviridae (type T7). Genome size of the phages as determined by pulsed-field gel electrophoresis ranged from 38 to 177 kb. Excluding phages AXO26A, AYO103A, AYO145A, and AYO145B, all other phages were capable of lysing more than 1 clinically important strain from serogroups of O26, O91, O103, O111, O113, O121, and O128, but none exhibited infectivity across all serogroups. Moreover, phages AYO26A, AXO121A, and AXO121B were also able to lyse 4 common phage types of STEC O157:H7. Our findings show that a diversity of non-O157 STEC-infecting phages are harbored in bovine feces. Phages AYO26A, AYO26B, AXO103A, AXO111A, AYO111A, AXO121A, and AXO121B exhibited a broad host range against a number of serogroups of STEC and have potential for the biocontrol of STEC in the environment.
Delay in post-ovariectomy estrogen replacement negates estrogen-induced augmentation of post-exercise muscle satellite cell proliferation
Authors: Mangan Gary , Iqbal Sobia , Hubbard Andrew , Hamilton Victoria , Bombardier Eric , Tiidus Peter M.
Published: April 2015

This study examined the effects of a delay in post-ovariectomy replacement of 17β-estradiol (estrogen) on the post-exercise proliferation of muscle satellite cells. Nine-week-old, ovariectomized, female Sprague–Dawley rats (n = 64) were distributed among 8 groups based on estrogen status (0.25 mg estrogen pellet or sham), exercise status (90 min run at 17 m·min–1 and a grade of –13.5° or unexercised), and estrogen replacement (“proximal”, estrogen replacement within 2 weeks; or “delayed”, estrogen replacement at 11 weeks following ovariectomy). Significant increases in satellite cells were found in the soleus and white gastrocnemius muscle (immunofluorescent colocalization of nuclei with Pax7) 72 h following eccentric exercise (p < 0.05) in all exercised groups. Proximal E2 replacement resulted in a further augmentation of muscle satellite cells in exercised rats (p < 0.05) relative to the delayed estrogen replacement group. Expression of PI3K was unaltered and phosphorylation of Akt relative to total Akt increased following estrogen supplementation and exercise. Exercise alone did not alter the expression levels of Akt. An 11 week delay in post-ovariectomy estrogen replacement negated the augmenting influence seen with proximal (2 week delay) post-ovariectomy estrogen replacement on post-exercise muscle satellite cell proliferation. This effect appears to be independent of the PI3K–Akt signaling pathway.
Radiation biophysical aspects of charged particles: From the nanoscale to therapy
Authors: Scifoni Emanuele
Published: April 2015

Charged particle applications for radiotherapy are motivated by their specific advantages in terms of dose delivery and biological effect. These advantages have to a large extent originated from the peculiarities of ion beam energy deposition patterns in the medium on a microscopic, down to a nanoscopic scale. A large amount of research was conducted in this direction, especially in the last two decades, profiting also from the parallel investigations going on in radiation protection for space exploration.

The main biophysical aspects of charged particles, which are relevant to hadrontherapy are shortly reviewed in the present contribution, namely focusing on relative biological effectiveness (RBE), oxygen enhancement ratio (OER) and combination with radiosensitizers. A summary of present major research direction on both microscopic and macroscopic assessment of the specific mechanism of radiation damage will be given, as well as several open challenges for a better understanding of the whole process, which still limit the full exploitation of ion beams for radiotherapy.
Gantries and dose delivery systems
Authors: Meer David , Psoroulas Serena
Published: April 2015

Particle therapy is a field in remarkable development, with the goal of increasing the number of indications which could benefit from such treatments and the access to the therapy. The therapeutic usage of a particle beam defines the technical requirements of all the elements of the therapy chain: we summarize the main characteristics of accelerators, the beam line, the treatment room, the integrated therapy and imaging systems used in particle therapy. Aiming at a higher flexibility in the choice of treatments, an increasing number of centers around the world have chosen to equip their treatment rooms with gantries, rotating beam line structures that allow a complete flexibility in the choice of the treatment angle. We review the current designs. A particle therapy gantry though is a quite expensive structure, and future development will increasingly consider reducing the cost and the footprint.

Increasing the number of indications also means development in the delivery techniques and solving some of the issues which traditionally affected particle therapy, for example the precision of the delivery in presence of motion and the large penumbras for low depths. We show the current strategies in these fields, focusing on pencil beam scanning (PBS), and give some hints about future developments.
Effective fluid FLRW cosmologies of minimal massive gravity
Authors: Yılmaz Nejat Tevfik
Published: April 2015

By using a solution ansatz we partially decouple the metric and the Stückelberg sectors of the minimal massive gravity (MMGR). In this scheme for a diagonal physical metric we find the general solutions for the scalars of the theory and the particular fiducial (background) metric which leads to these solutions. Then we adopt this general formalism to construct the derivation of new Friedmann–Lemaitre–Robertson–Walker (FLRW) cosmologies of the theory in the presence of a so-called effective ideal fluid which arises from our solution ansatz as a modifying, non-physical source for the Einstein and the corresponding Friedmann equations.
Electropolymerization of cobalto(5,10,15-tris(4-aminophenyl)-20-phenylporphyrin) for electrochemical detection of antioxidant-antipyrine
Authors: Anandan Sambandam , Manivel Arumugam , Asiri Abdullah M. , Wu Jerry J.
Published: April 2015

Porphyrins are a kind of aromatic molecules possessing unique physic-chemical properties. In this manuscript, it was thus utilized to synthesize 5,10,15-tris(4-aminophenyl)-20-phenylporphyrin and cobalto(5,10,15-tris(4-aminophenyl)-20-phenylporphyrin). In addition, conducting cobalto(5,10,15-tris(4-aminophenyl)-20-phenylporphyrin) polymeric films were successfully prepared by electropolymerization approach on glassy carbon electrode in the presence of dimethyl formamide solution and 0.1 M tetra-n-butyl ammonium perchlorate at 100 mV/s scan rate. The synthesized polymeric films were evaluated as the active electrode materials to detect an antioxidant (Antipyrine) present in pharmaceuticals and the limit of detection is ~ 74 μM.
On Finsler manifolds of negative flag curvature
Authors: Fang Yong , Foulon Patrick
Published: April 2015

One of the key differences between Finsler metrics and Riemannian metrics is the non-reversibility, i.e. given two points p and q, the Finsler distance d(p, q) is not necessarily equal to d(q, p). In this paper, we build the main tools to investigate the non-reversibility in the context of large-scale geometry of uniform Finsler Cartan–Hadamard manifolds.

In the second part of this paper, we use the large-scale geometry to prove the following dynamical theorem: Let φ be the geodesic flow of a closed negatively curved Finsler manifold. If its Anosov splitting is C2, then its cohomological pressure is equal to its Liouville metric entropy. This result generalizes a previous Riemannian result of U. Hamenstädt.
Forearm cutaneous vascular and sudomotor responses to whole body passive heat stress in young smokers
Authors: Moyen Nicole E. , Anderson Hannah M. , Burchfield Jenna M. , Tucker Matthew A. , Gonzalez Melina A. , Robinson Forrest B. , Ganio Matthew S.
Published: April 2015

The purpose of this study was to compare smokers and nonsmokers' sudomotor and cutaneous vascular responses to whole body passive heat stress. Nine regularly smoking (SMK: 29 ± 9 yr; 10 ± 6 cigarettes/day) and 13 nonsmoking (N-SMK: 27 ± 8 yr) males were passively heated until core temperature (TC) increased 1.5°C from baseline. Forearm local sweat rate (LSR) via ventilated capsule, sweat gland activation (SGA), sweat gland output (SGO), and cutaneous vasomotor activity via laser-Doppler flowmetry (CVC) were measured as mean body temperature increased (ΔTb) during passive heating using a water-perfused suit. Compared with N-SMK, SMK had a smaller ΔTb at the onset of sweating (0.52 ± 0.19 vs. 0.35 ± 0.14°C, respectively; P = 0.03) and cutaneous vasodilation (0.61 ± 0.21 vs. 0.31 ± 0.12°C, respectively; P < 0.01). Increases in LSR and CVC per °C ΔTb (i.e., sensitivity) were similar in N-SMK and SMK (LSR: 0.63 ± 0.21 vs. 0.60 ± 0.40 Δmg/cm2/min/°C ΔTb, respectively, P = 0.81; CVC: 82.5 ± 46.2 vs. 58.9 ± 23.3 Δ%max/°C ΔTb, respectively; P = 0.19). However, the plateau in LSR during whole body heating was higher in N-SMK vs. SMK (1.00 ± 0.13 vs. 0.79 ± 0.26 mg·cm−2·min−1; P = 0.03), which was likely a result of higher SGO (8.94 ± 3.99 vs. 5.94 ± 3.49 μg·gland−1·min−1, respectively; P = 0.08) and not number of SGA (104 ± 7 vs. 121 ± 9 glands/cm2, respectively; P = 0.58). During whole body passive heat stress, smokers had an earlier onset for forearm sweating and cutaneous vasodilation, but a lower local sweat rate that was likely due to lower sweat output per gland. These data provide insight into local (i.e., forearm) thermoregulatory responses of young smokers during uncompensatory whole body passive heat stress.
Muc1 is protective during kidney ischemia-reperfusion injury
Authors: Pastor-Soler Núria M. , Sutton Timothy A. , Mang Henry E. , Kinlough Carol L. , Gendler Sandra J. , Madsen Cathy S. , Bastacky Sheldon I. , Ho Jacqueline , Al-bataineh Mohammad M. , Hallows Kenneth R. , Singh Sucha , Monga Satdarshan P. , Kobayashi Hanako , Haase Volker H. , Hughey Rebecca P.
Published: April 2015

Ischemia-reperfusion injury (IRI) due to hypotension is a common cause of human acute kidney injury (AKI). Hypoxia-inducible transcription factors (HIFs) orchestrate a protective response in renal endothelial and epithelial cells in AKI models. As human mucin 1 (MUC1) is induced by hypoxia and enhances HIF-1 activity in cultured epithelial cells, we asked whether mouse mucin 1 (Muc1) regulates HIF-1 activity in kidney tissue during IRI. Whereas Muc1 was localized on the apical surface of the thick ascending limb, distal convoluted tubule, and collecting duct in the kidneys of sham-treated mice, Muc1 appeared in the cytoplasm and nucleus of all tubular epithelia during IRI. Muc1 was induced during IRI, and Muc1 transcripts and protein were also present in recovering proximal tubule cells. Kidney damage was worse and recovery was blocked during IRI in Muc1 knockout mice compared with congenic control mice. Muc1 knockout mice had reduced levels of HIF-1α, reduced or aberrant induction of HIF-1 target genes involved in the shift of glucose metabolism to glycolysis, and prolonged activation of AMP-activated protein kinase, indicating metabolic stress. Muc1 clearly plays a significant role in enhancing the HIF protective pathway during ischemic insult and recovery in kidney epithelia, providing a new target for developing therapies to treat AKI. Moreover, our data support a role specifically for HIF-1 in epithelial protection of the kidney during IRI as Muc1 is present only in tubule epithelial cells.
Protein- and diabetes-induced glomerular hyperfiltration: role of glucagon, vasopressin, and urea
Authors: Bankir Lise , Roussel Ronan , Bouby Nadine
Published: April 2015

A single protein-rich meal (or an infusion of amino acids) is known to increase the glomerular filtration rate (GFR) for a few hours, a phenomenon known as “hyperfiltration.” It is important to understand the factors that initiate this upregulation because it becomes maladaptive in the long term. Several mediators and paracrine factors have been shown to participate in this upregulation, but they are not directly triggered by protein intake. Here, we explain how a rise in glucagon and in vasopressin secretion, directly induced by protein ingestion, might be the initial factors triggering the hepatic and renal events leading to an increase in the GFR. Their effects include metabolic actions in the liver and stimulation of sodium chloride reabsorption in the thick ascending limb. Glucagon is not only a glucoregulatory hormone. It is also important for the excretion of nitrogen end products by stimulating both urea synthesis in the liver (along with gluconeogenesis from amino acids) and urea excretion by the kidney. Vasopressin allows the concentration of nitrogenous end products (urea, ammonia, etc.) and other protein-associated wastes in a hyperosmotic urine, thus allowing a very significant water economy characteristic of all terrestrial mammals. No hyperfiltration occurs in the absence of one or the other hormone. Experimental results suggest that the combined actions of these two hormones, along with the complex intrarenal handling of urea, lead to alter the composition of the tubular fluid at the macula densa and to reduce the intensity of the signal activating the tubuloglomerular feedback control of GFR, thus allowing GFR to raise. Altogether, glucagon, vasopressin, and urea contribute to set up the best compromise between efficient urea excretion and water economy.
A Molecular Dynamic Simulation of Hydrated Proton Transfer in Perfluorosulfonate Ionomer Membranes (Nafion 117)
Authors: Sun Hong , Yu Mingfu , Li Zhijie , Almheiri Saif
Published: April 2015

A molecular dynamic model based on Lennard-Jones Potential, the interaction force between two particles, molecular diffusion, and radial distribution function (RDF) is presented. The diffusion of the hydrated ion, triggered by both Grotthuss and vehicle mechanisms, is used to study the proton transfer in Nafion 117. The hydrated ion transfer mechanisms and the effects of the temperature, the water content in the membrane, and the electric field on the diffusion of the hydrated ion are analyzed. The molecular dynamic simulation results are in good agreement with those reported in the literature. The modeling results show that when the water content in Nafion 117 is low, H3O+is the main transfer ion among the different hydrated ions. However, at higher water content, the hydrated ion in the form of H+(H2O)2is the main transfer ion. It is also found that the negatively charged sulfonic acid group as the fortified point facilitates the proton transfer in Nafion 117 better than the free water molecule. The diffusion of the hydrated ion can be improved by increasing the cell temperature, the water content in Nafion, and the electric field intensity.
An Animal Model Using Metallic Ions to Produce Autoimmune Nephritis
Authors: Ramírez-Sandoval Roxana , Luévano-Rodríguez Nayeli , Rodríguez-Rodríguez Mayra , Pérez-Pérez María Elena , Saldívar-Elias Sergio , Gurrola-Carlos Reinaldo , Avalos-Díaz Esperanza , Bollain-y-Goytia Juan José , Herrera-Esparza Rafael
Published: April 2015

Autoimmune nephritis triggered by metallic ions was assessed in a Long-Evans rat model. The parameters evaluated included antinuclear autoantibody production, kidney damage mediated by immune complexes detected by immunofluorescence, and renal function tested by retention of nitrogen waste products and proteinuria. To accomplish our goal, the animals were treated with the following ionic metals: HgCl2, CuSO4, AgNO3, and Pb(NO3)2. A group without ionic metals was used as the control. The results of the present investigation demonstrated that metallic ions triggered antinuclear antibody production in 60% of animals, some of them with anti-DNA specificity. Furthermore, all animals treated with heavy metals developed toxic glomerulonephritis with immune complex deposition along the mesangium and membranes. These phenomena were accompanied by proteinuria and increased concentrations of urea. Based on these results, we conclude that metallic ions may induce experimental autoimmune nephritis.
Relevance of Sympathetic Nervous System Activation in Obesity and Metabolic Syndrome
Authors: Thorp Alicia A. , Schlaich Markus P.
Published: April 2015

Sympathetic tone is well recognised as being implicit in cardiovascular control. It is less readily acknowledged that activation of the sympathetic nervous system is integral in energy homeostasis and can exert profound metabolic effects. Accumulating data from animal and human studies suggest that central sympathetic overactivity plays a pivotal role in the aetiology and complications of several metabolic conditions that can cluster to form the Metabolic Syndrome (MetS). Given the known augmented risk for type 2 diabetes, cardiovascular disease, and premature mortality associated with the MetS understanding the complex pathways underlying the metabolic derangements involved has become a priority. Many factors have been proposed to contribute to increased sympathetic nerve activity in metabolic abnormalities including obesity, impaired baroreflex sensitivity, hyperinsulinemia, and elevated adipokine levels. Furthermore there is mounting evidence to suggest that chronic sympathetic overactivity can potentiate two of the key metabolic alterations of the MetS, central obesity and insulin resistance. This review will discuss the regulatory role of the sympathetic nervous system in metabolic control and the proposed pathophysiology linking sympathetic overactivity to metabolic abnormalities. Pharmacological and device-based approaches that target central sympathetic drive will also be discussed as possible therapeutic options to improve metabolic control in at-risk patient cohorts.
Skewed Epigenetics: An Alternative Therapeutic Option for Diabetes Complications
Authors: Togliatto Gabriele , Dentelli Patrizia , Brizzi Maria Felice
Published: April 2015

Vascular complications are major causes of morbidity and mortality in type 2 diabetes patients. Mitochondrial reactive oxygen species (ROS) generation and a lack of efficient antioxidant machinery, a result of hyperglycaemia, mainly contribute to this problem. Although advances in therapy have significantly reduced both morbidity and mortality in diabetic individuals, diabetes-associated vascular complications are still one of the most challenging health problems worldwide. New healing options are urgently needed as current therapeutics are failing to improve long-term outcomes. Particular effort has recently been devoted to understanding the functional relationship between chromatin structure regulation and the persistent change in gene expression which is driven by hyperglycaemia and which accounts for long-lasting diabetic complications. A detailed investigation into epigenetic chromatin modifications in type 2 diabetes is underway. This will be particularly useful in the design of mechanism-based therapeutics which interfere with long-lasting activating epigenetics and improve patient outcomes. We herein provide an overview of the most relevant mechanisms that account for hyperglycaemia-induced changes in chromatin structure; the most relevant mechanism is called “metabolic memory.”
Ellis-van Creveld Syndrome: Mutations Uncovered in Lebanese Families
Authors: Valencia Maria , Tabet Lara , Yazbeck Nadine , Araj Alia , Ruiz-Perez Victor L. , Charaffedine Khalil , Fares Farah , Badra Rebecca , Farra Chantal
Published: April 2015

Background. Ellis-van Creveld (EvC) syndrome is a rare, autosomal recessive disorder characterized by short stature, short limbs, growth retardation, polydactyly, and ectodermal defects with cardiac anomalies occurring in around 60% of cases. EVC syndrome has been linked to mutations inEVCandEVC2genes.Case Presentation. We report EvC syndrome in two unrelated Lebanese families both having homozygous mutations in theEVC2gene, c.2653C>T (p.(Arg885*)) and c.2012_2015del (p.(Leu671*)) in exons 15 and 13, respectively, with the latter being reported for the first time.Conclusion. Although EvC has been largely described in the medical literature, clinical features of this syndrome vary. While more research is required to explore other genes involved in EvC, early diagnosis and therapeutic care are important to achieve a better quality of life.
An Efficient Primitive-Based Method to Recognize Online Sketched Symbols with Autocompletion
Authors: Deng Wei , Wu Lingda , Zhang Yougen , Yang Chao
Published: April 2015

We present a new structural method of sketched symbol recognition, which aims to recognize a hand-drawn symbol before it is fully completed. It is invariant to scale, stroke number, and order. We also present two novel descriptors to represent the spatial distribution between two primitives. One is invariant to rotation and the other is not. Then a symbol is represented as a set of descriptors. The distance between the input symbol and the template one is calculated based on the assignment problem. Moreover, a fast nearest neighbor (NN) search algorithm is proposed for recognition. The method achieves a satisfactory recognition rate in real time.
Notch Signaling Pathway Was Involved in Regulating Programmed Cell Death 1 Expression during Sepsis‐Induced Immunosuppression
Authors: Pan Tingting , Liu Zhaojun , Yin Jianyong , Zhou Tianyun , Liu Jialin , Qu Hongping
Published: April 2015

Programmed cell death 1 (PD‐1) plays an important pathologic role in sepsis‐induced immunosuppression. However, whether PD‐1 overexpression occurs early during septic shock is unknown and its regulation mechanism is also unknown. Our study investigated the expressions of PD‐1/programmed death‐ligand 1 (PD‐L1) on immune cells in peripheral blood from the early‐stage septic shock patients. We found that both PD‐1 and PD‐L1 showed increased expressions on the CD4+ T cells and monocytes. It indicated that PD‐1 expression might be an early biomarker to assess illness severity and predict the prognosis of septic shock. Then, we further investigated the mechanism underlying the regulation of PD‐1 expression. Our data showed that Notch signaling pathway was activated in both septic shock patients and lipopolysaccharide‐ (LPS‐) tolerant THP1 cells and both interleukin‐10 (IL‐10) and PD‐1 were increased in the THP1 cells. Inhibition of Notch signaling by N‐[N‐(3,5‐difluorophenacetyl)‐L‐alanyl]‐S‐phenyl glycinet‐butyl ester (DAPT) induced significantly decreased expressions of PD‐1 and IL‐10 in the LPS‐tolerant cell model. Our work suggested that Notch signaling pathway was involved in the regulation of PD‐1 expression.
Carmellose Mucoadhesive Oral Films Containing Vermiculite/Chlorhexidine Nanocomposites as Innovative Biomaterials for Treatment of Oral Infections
Authors: Gajdziok Jan , Holešová Sylva , Štembírek Jan , Pazdziora Erich , Landová Hana , Doležel Petr , Vetchý David
Published: April 2015

Infectious stomatitis represents the most common oral cavity ailments. Current therapy is insufficiently effective because of the short residence time of topical liquid or semisolid medical formulations. An innovative application form based on bioadhesive polymers featuring prolonged residence time on the oral mucosa may be a solution to this challenge. This formulation consists of a mucoadhesive oral film with incorporated nanocomposite biomaterial that is able to release the drug directly at the target area. This study describes the unique approach of preparing mucoadhesive oral films from carmellose with incorporating a nanotechnologically modified clay mineral intercalated with chlorhexidine. The multivariate data analysis was employed to evaluate the influence of the formulation and process variables on the properties of the medical preparation. This evaluation was complemented by testing the antimicrobial and antimycotic activity of prepared films with the aim of finding the most suitable composition for clinical application. Generally, the best results were obtained with sample containing 20 mg of chlorhexidine diacetate carried by vermiculite, with carmellose in the form of nonwoven textile in its structure. In addition to its promising physicomechanical, chemical, and mucoadhesive properties, the formulation inhibited the growth ofStaphylococcusandCandida; the effect was prolonged for tens of hours.
Prognostic Value of18F-FDG PET-CT in Nasopharyngeal Carcinoma: Is Dynamic Scanning Helpful?
Authors: Huang Bingsheng , Wong Ching-Yee Oliver , Lai Vincent , Kwong Dora Lai-Wan , Khong Pek-Lan
Published: April 2015

Objectives. To evaluate the differences in prognostic values of static and dynamic PET-CT in nasopharyngeal carcinoma (NPC).Material and Methods. Forty-five patients who had static scan were recruited. Sixteen had dynamic scan. The primary lesions were delineated from standardized uptake value (SUV) maps from static scan andKimaps from dynamic scan. The average follow-up lasted for 34 months. The patients who died or those with recurrence/residual disease were considered “poor outcome”; otherwise they were considered “good outcome.” Fisher’s exact test and ROC analysis were used to evaluate the prognostic value of various factors.Results. Tumor volume thresholded by 40% of maximal SUV (VOLSUV40) significantly predicted treatment outcome (p=0.024) in the whole cohort. In 16 patients with dynamic scan, all parameters by dynamic scan were insignificant in predicting the outcome. The combination of maximal SUV, maximalKi,VOLSUV40, andVOLKi37(the tumor volume thresholded by 37% maximalKi) achieved the highest predicting accuracy for treatment outcome with sensitivity, specificity, and accuracy of 100% in these 16 patients; however this improvement compared toVOLSUV40was insignificant.Conclusion. Tumor volume from static scan is useful in NPC prognosis. However, the role of dynamic scanning was not justified in this small cohort.
Bromoenol Lactone, an Inhibitor of Calcium‐Independent Phospholipase A2, Suppresses Carrageenan‐Induced Prostaglandin Production and Hyperalgesia in Rat Hind Paw
Authors: Tsuchida Keiichiro , Ibuki Takae , Matsumura Kiyoshi
Published: April 2015

Prostaglandin (PG) E2 and PGI2 are essential to hyperalgesia in inflammatory tissues. These prostaglandins are produced from arachidonic acid, which is cleaved from membrane phospholipids by the action of phospholipase A2 (PLA2). Which isozyme of PLA2 is responsible for the cleavage of arachidonic acid and the production of prostaglandins essential to inflammation‐induced hyperalgesia is not clear. In this study, we examined the effects of two PLA2 isozyme‐specific inhibitors on carrageenan‐induced production of PGE2 and PGI2 in rat hind paw and behavioral nociceptive response to radiant heat. Local administration of bromoenol lactone (BEL), an inhibitor of calcium‐independent PLA2 (iPLA2), significantly reduced carrageenan‐induced elevation of prostaglandins in the inflamed foot pad 3 h after injection. It also ameliorated the hyperalgesic response between 1 h and 3 h after carrageenan injection. On the other hand, AACOCF3, an inhibitor of cytosolic PLA2, suppressed neither prostaglandin production nor the hyperalgesic response. BEL did not suppress the mRNA levels of iPLA2β, iPLA2γ, cyclooxygenase‐2, microsomal prostaglandin E synthase, prostaglandin I synthase, or proinflammatory cytokines in the inflamed foot pad, indicating that BEL did not suppress inflammation itself. These results suggest that iPLA2 is involved in the production of prostaglandins and hyperalgesia at the inflammatory loci.
A New Method for Proving Existence Theorems for Abstract Hammerstein Equations
Authors: Chidume C. E. , Chidume C. O. , Minjibir Ma’aruf Shehu
Published: April 2015

An abstract Hammerstein equation is an equation of the formu+KFu=0. Anew methodis introduced to prove the existence of a solution of this equation whereKandFare nonlinear accretive (monotone) operators. The method does not involve the complicated technique of factorizing a linear map via a Hilbert space and does not involve the use of deep variational techniques.
Stress Assignment Errors in Surface Dyslexia: Evidence from Two Italian Patients with a Selective Deficit of the Orthographic Input Lexicon
Authors: Folegatti Alessia , Pia Lorenzo , Berti Anna , Cubelli Roberto
Published: April 2015

Surface dyslexia designates a selective impairment in reading irregular words, with spared ability to read regular and novel words, following a cerebral damage usually located in the left dominant hemisphere. In Italian language, which is regular at the segmental level, surface dyslexia is characterized by stress assignment errors. Here we report on two cases of Italian surface dyslexic patients who produced stress assignment errors, mainly in reading irregular words. In reading nonwords they usually applied the regular stress pattern. Both patients were also impaired in lexical decision and in semantic discrimination tasks when the processing of homophones was required. Our patients’ performance relied almost exclusively on the phonological coding of the stimulus, revealing a deficit in accessing the orthographical input lexicon. In addition, one patient showed a cerebral lesion limited to the right thalamus, providing evidence of a possible role of the right hemisphere in the reading process.
Use of Virtual Reality Tools for Vestibular Disorders Rehabilitation: A Comprehensive Analysis
Authors: Bergeron Mathieu , Lortie Catherine L. , Guitton Matthieu J.
Published: April 2015

Classical peripheral vestibular disorders rehabilitation is a long and costly process. While virtual reality settings have been repeatedly suggested to represent possible tools to help the rehabilitation process, no systematic study had been conducted so far. We systematically reviewed the current literature to analyze the published protocols documenting the use of virtual reality settings for peripheral vestibular disorders rehabilitation. There is an important diversity of settings and protocols involving virtual reality settings for the treatment of this pathology. Evaluation of the symptoms is often not standardized. However, our results unveil a clear effect of virtual reality settings-based rehabilitation of the patients’ symptoms, assessed by objectives tools such as the DHI (mean decrease of 27 points), changing symptoms handicap perception from moderate to mild impact on life. Furthermore, we detected a relationship between the duration of the exposure to virtual reality environments and the magnitude of the therapeutic effects, suggesting that virtual reality treatments should last at least 150 minutes of cumulated exposure to ensure positive outcomes. Virtual reality offers a pleasant and safe environment for the patient. Future studies should standardize evaluation tools, document putative side effects further, compare virtual reality to conventional physical therapy, and evaluate economical costs/benefits of such strategies.
A Randomized Phase II Trial of Sipuleucel-T with Concurrent versus Sequential Abiraterone Acetate plus Prednisone in Metastatic Castration-Resistant Prostate Cancer
Authors: Small Eric J. , Lance Raymond S. , Gardner Thomas A. , Karsh Lawrence I. , Fong Lawrence , McCoy Candice , DeVries Todd , Sheikh Nadeem A. , GuhaThakurta Debraj , Chang Nancy , Redfern Charles H. , Shore Neal D.
Published: April 2015

Purpose: This phase II open-label study evaluated the effect of concurrent or sequential administration of abiraterone acetate plus prednisone (AA + P) on sipuleucel-T manufacture and immune responses in metastatic castration-resistant prostate cancer (mCRPC) patients.

Experimental Design: mCRPC patients received sipuleucel-T followed by AA + P 1 day (concurrent) or 10 weeks (sequential) after the first sipuleucel-T infusion. AA + P treatment continued for 26 weeks. The primary endpoint was cumulative antigen presenting cell (APC) activation, and secondary endpoints included cumulative APC number and total nucleated cell counts. Additional endpoints included in vivo peripheral immune responses to sipuleucel-T (T-cell responses, T-cell proliferation, humoral responses, and antigen spread) as well as safety.

Results: Sixty-nine mCRPC patients were enrolled, with 35 and 34 patients randomized to the concurrent and sequential arms, respectively. Ex vivo APC activation was significantly greater at the second and third infusions compared with baseline in both arms (P < 0.05), indicative of an immunologic prime-boost effect. In both arms, sipuleucel-T product parameter profiles and peripheral immune responses were consistent with previously conducted sipuleucel-T phase III trials. Antigen spread was similarly observed in both arms and consistent with the other immunologic endpoints.

Conclusions: These data suggest that sipuleucel-T can be successfully manufactured during concurrent administration of AA + P without blunting immunologic effects or altering immune parameters that correlate with sipuleucel-T's clinical benefit. Combination of these agents was well tolerated, with no new safety signals emerging. Clin Cancer Res; 21(17); 3862–9. ©2015 AACR.
Is Immediate Radical Cystectomy Necessary for All Patients with Non-Muscle-Invasive Micropapillary Bladder Cancer?
Authors: Jackson Benjamin L. , Mohammed Aza , Mayer Nick , Dormer John , Griffiths T.R. Leyshon
Published: April 2015

Introduction: We aim to review the outcomes of micropapillary urothelial carcinoma (MPUC) of the bladder from a single institution. The hypothesis is that non-muscle-invasive (NMI) MPUC may have a heterogeneous prognosis, and detailed pathological analysis may identify patients that could be managed without immediate cystectomy. Patients and Methods: This is a retrospective analysis of patients presenting with MPUC in a primary transurethral resection specimen (n = 40). The pattern of micropapillary (MP) differentiation [surface/non-invasive (sMP) or invasive (iMP)], extent of MP differentiation and lymphovascular invasion (LVI) were correlated with overall survival (OS), recurrence-free survival and upstaging at re-resection. Results: Sixteen of 40 patients died after a median follow-up of 37 months. Tumour stage was strongly predictive of OS (p < 0.0001). LVI was associated with increased mortality (hazard ratio 12.4, 95% CI: 3.5-44.5, p = 0.0001), higher pathological stage (p = 0.001), lymph node involvement (p = 0.001) and iMP differentiation (p = 0.006). In NMI patients not undergoing cystectomy (n = 17), NMI-sMP compared with NMI-iMP differentiation was associated with an improved OS when compared with iMP (63 vs. 47 months, p = 0.05). Conclusions: MPUC is an aggressive variant of urothelial carcinoma (UC). Similar to conventional UC, LVI associated with MPUC is an adverse prognostic indicator. iMP is a morphological marker for LVI. Histopathological reports should distinguish between sMP and iMP differentiation.