Joining aluminum alloy 5052 sheets via novel hybrid resistance spot clinching process

Publication date: 15 March 2017
Source:Materials & Design, Volume 118
Author(s): Yu Zhang, He Shan, Yang Li, Jing Guo, Zhen Luo, Cheng Yong Ma
Aluminum alloy 5052 sheets (thickness: 1mm) were joined using a novel method (resistance spot clinching) that combines mechanical clinching and resistance spot welding processes. A pair of molds combine with processing tapes were exerted in this process. The microstructure of the fusion zone under novel process presents more portion of equiaxed dendritic zone compared with that of the resistance spot welded joint, which is due to the different temperature gradient feature during solidification. The mechanical properties of the joints were evaluated via orthogonal trials of tensile shear tests performed on the joints. The results revealed that, even under lower heat input, the load-bearing capacity of the resistance spot clinching joints is superior to that of the traditional resistance spot welding joints. Digital image correlation was used to evaluate the distortion behavior of the weld joints during testing. Compared with the stiffness of traditional joints, the higher stiffness of the resistance spot clinching joint generated a higher tensile stress component in the periphery of the fusion zone during testing (which resulted in a higher peak load).

Graphical abstract

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A rare complication of middle ear cholesteatoma – Pseudoaneurysm of petrous internal carotid artery

Publication date: Available online 13 January 2017
Source:Egyptian Journal of Ear, Nose, Throat and Allied Sciences
Author(s): L.Y. Lim, I. Mohamad, J.H. Lau, I.P. Tang
ObjectivesTo report a rare complication of middle ear cholesteatoma resulting pseudoaneurysm of petrous internal carotid artery (ICA).Case reportA 39year old lady presented with sudden profuse bleeding from the right ear. Previously, she had been having bilateral intermittent foul smelling ear discharge for a year. Otoscope finding was insignificant as only blood seen. Computed tomography of temporal bone and magnetic resonance imaging of brain suggested locally aggressive cholesteatoma. Right ICA angiography showed pseudoaneurysm of petrous part of ICA. She underwent coil embolisation followed by bilateral modified radical mastoidectomy a month later. She recovered well after surgery and remained symptoms free.ConclusionsPseudoaneurysm of petrous ICA as a complication of middle ear cholesteatoma is extremely rare. Spontaneous profuse bleeding maybe the only clinical presentation. Radiological imaging is important to diagnose and assist in treatment. Endovascular technique may be required, followed by surgical treatment for infection control



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Δ14CO2 from dark respiration in plants and its impact on the estimation of atmospheric fossil fuel CO2

Publication date: April 2017
Source:Journal of Environmental Radioactivity, Volumes 169–170
Author(s): Xiaohu Xiong, Weijian Zhou, Peng Cheng, Shugang Wu, Zhenchuan Niu, Hua Du, Xuefeng Lu, Yunchong Fu, George S. Burr
Radiocarbon (¹⁴C) has been widely used for quantification of fossil fuel CO2 (CO2ff) in the atmosphere and for ecosystem source partitioning studies. The strength of the technique lies in the intrinsic differences between the ¹⁴C signature of fossil fuels and other sources. In past studies, the ¹⁴C content of CO2 derived from plants has been equated with the ¹⁴C content of the atmosphere. Carbon isotopic fractionation mechanisms vary among plants however, and experimental study on fractionation associated with dark respiration is lacking. Here we present accelerator mass spectrometry (AMS) radiocarbon results of CO2 respired from 21 plants using a lab-incubation method and associated bulk organic matter. From the respired CO2 we determine Δ¹⁴Cres values, and from the bulk organic matter we determine Δ¹⁴Cbom values. A significant difference between Δ¹⁴Cres and Δ¹⁴Cbom (P < 0.01) was observed for all investigated plants, ranging from −42.3‰ to 10.1‰. The results show that Δ¹⁴Cres values are in agreement with mean atmospheric Δ¹⁴CO2 for several days leading up to the sampling date, but are significantly different from corresponding bulk organic Δ¹⁴C values. We find that although dark respiration is unlikely to significantly influence the estimation of CO2ff, an additional bias associated with the respiration rate during a plant's growth period should be considered when using Δ¹⁴C in plants to quantify atmospheric CO2ff.



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Nanoporous hydroxyapatite/sodium titanate bilayer on titanium implants for improved osteointegration

Publication date: Available online 13 January 2017
Source:Dental Materials
Author(s): A. Carradò, F. Perrin-Schmitt, Q.V. Le, M. Giraudel, C. Fischer, G. Koenig, L. Jacomine, L. Behr, A. Chalom, L. Fiette, A. Morlet, G. Pourroy
ObjectiveThe aim of this study was to improve the strength and quality of the titanium–hydroxyapatite interface in order to prevent long-term failure of the implanted devices originating from coating delamination and to test it in an in-vivo model.MethodsTi disks and dental commercial implants were etched in Kroll solution. Thermochemical treatments of the acid-etched titanium were combined with sol–gel hydroxyapatite (HA) coating processes to obtain a nanoporous hydroxyapatite/sodium titanate bilayer. The sodium titanate layer was created by incorporating sodium ions onto the Ti surface during a NaOH alkaline treatment and stabilized using a heat treatment. HA layer was added by dip-coating in a sol–gel solution. The bioactivity was assessed in vitro with murine MC3T3-E1 and human SaOs-2 cells. Functional and histopathological evaluations of the coated Ti implants were performed at 22, 34 and 60days of implantation in a dog lower mandible model.ResultsNanoporous hydroxyapatite/sodium titanate bilayer on titanium implants was sensitive neither to crack propagation nor to layer delamination. The in vitro results on murine MC3T3-E1 and human SaOs-2 cells confirm the advantage of this coating regarding the capacity of cell growth and differentiation. Signs of progressive bone incorporation, such as cancellous bone formed in contact with the implant over the existing compact bone, were notable as early as day 22. Overall, osteoconduction and osteointegration mean scores were higher for test implants compared to the controls at 22 and 34 days.SignificanceNanoporous hydroxyapatite/sodium titanate bilayer improves the in-vivo osteoconduction and osteointegration. It prevents the delamination during the screwing and it could increase HA-coated dental implant stability without adhesive failures. The combination of thermochemical treatments with dip coating is a low-cost strategy.



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Mechanical and microbiological properties and drug release modeling of an etch-and-rinse adhesive containing copper nanoparticles

Publication date: Available online 13 January 2017
Source:Dental Materials
Author(s): M.F. Gutiérrez, P. Malaquias, T.P. Matos, A. Szesz, S. Souza, J. Bermudez, A. Reis, A.D. Loguercio, P.V. Farago
ObjectivesTo evaluate the effect of addition of copper nanoparticles (CN) at different concentrations into a two-step etch-and-rinse (2-ER) adhesive on antimicrobial activity (AMA), copper release (CR), ultimate tensile strength (UTS), degree of conversion (DC), water sorption (WS), solubility (SO), as well as the immediate (IM) and 1-year resin–dentin bond strength (μTBS) and nanoleakage (NL).MethodsSeven adhesives were formulated according to the addition of CN (0, 0.0075, 0.015, 0.06, 0.1, 0.5 and 1wt%) in adhesive. The AMA was evaluated against Streptococcus mutans using agar diffusion assay. For CR, WS and SO, specimens were constructed and tested for 28 days. For UTS, specimens were tested after 24h and 28 days. For DC, specimens were constructed and tested after 24h by FTIR. After enamel removal, the ER was applied to dentin. After composite resin build-ups, specimens were sectioned to obtain resin–dentin sticks. For μTBS and NL, specimens were tested after 24h and 1-year periods. All data were submitted to statistical analysis (α=0.05).ResultsThe addition of CN provided AMA to the adhesives at all concentrations. Higher CR was observed in adhesives with higher concentration of CN. UTS, DC, WS and SO were not influenced. For μTBS an increase was observed in 0.1 and 0.5% copper group. For NL, a significant decrease was observed in all groups in comparison with control group. After 1-year, no significant reductions of μTBS and no significant increases of NL were observed for copper containing adhesives compared to the control group.SignificanceThe addition of CN in concentrations up to 1wt% in the 2-ER adhesive may be an alternative to provide AMA and preserve the bonding to dentin, without reducing adhesives' mechanical properties evaluated.



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Application of close-packed structures in dental resin composites

Publication date: Available online 14 January 2017
Source:Dental Materials
Author(s): Ruili Wang, Eric Habib, X.X. Zhu
ObjectiveThe inorganic filler particles in dental resin composites serve to improve their mechanical properties and reduce polymerization shrinkage during their use. Efforts have been made in academia and industry to increase the filler particle content, but, few studies examine the theoretical basis for the maximum particle loading.MethodsThis work evaluates the packing of spherical particles in a close-packed state for highly loaded composites.ResultsCalculations show that for low dispersity particles, the maximum amount of particles is 74.05vol%, regardless of the particle size. This can be further improved by using a mix of large and small particles or by the use of non-spherical particles. For representative spherical particles with a diameter of 1000nm, two types of secondary particles with respective sizes of 414nm (dI) and 225nm (dII) are selected. The results show that after embedding secondary particles I & II into primary spherical particles, the packing factor is increased to 81.19% for the close-packed structures, which shows an improvement of 9.64%, compared to the 74.05% obtained only with primary spherical particles. This packing factor is also higher than either structure with the embedded secondary particles I or II.SignificanceExamples of these mixtures with different spherical particle sizes are shown as a theoretical estimation, serving as a guideline for the design and formulation of new dental resin composites with better properties and improved performance.

Graphical abstract

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Influence of enamel/dentin thickness on the toxic and esthetic effects of experimental in-office bleaching protocols

Abstract

Objectives

This paper aims to assess the whitening effectiveness and toxicity of tooth-bleaching protocols applied to enamel/dentin disks simulating mandibular incisors (ICs) and premolars (PMs).

Materials and methods

A 10% hydrogen peroxide (H₂O₂) gel was applied for 3 × 15, 1 × 15, or 1 × 5 min to enamel/dentin disks simulating mandibular ICs and PMs, and the trans-enamel and trans-dentinal diffusion products were applied to human dental pulp cells (1 h). Professional therapy (35% H₂O₂—3 × 15 min) was used as positive control, and non-bleached samples were used as negative control. Cell viability and morphology, oxidative stress generation, and odontoblastic marker expression were assessed. The H₂O₂ diffusion and enamel color change (ΔE) were also analyzed.

Results

The 10% H₂O₂ gel induced significant cell viability reduction only when applied 3 × 15 min, with the intensity of oxidative stress and down-regulation of odontoblastic markers being higher in the IC group. The other experimental bleaching protocols caused slight alterations regarding the cell parameters evaluated, with intensity being related to enamel/dentin thickness. These effects were also correlated with higher H₂O₂ diffusion in the IC group. ΔE values similar as positive control were found for the 10% 3 × 15 and 1 × 15 protocols on IC group, after 4 and 6 sessions.

Conclusion

Application of a 10% H₂O₂ bleaching gel for 15 or 45 min to thin dental substrate significantly minimizes cell toxicity in comparison with highly concentrated gels associated with similar esthetic outcomes by increasing the number of bleaching sessions.

Clinical relevance

Bleaching gels with 10% H₂O₂ applied in small teeth for short periods may be an interesting alternative to obtain whitening effectiveness without causing toxicity to pulp cells, which may be able to reduce the tooth hypersensitivity claimed by patients.

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Repeated applications of photodynamic therapy on Candida glabrata biofilms formed in acrylic resin polymerized

Abstract

Previous studies have been suggested that photodynamic therapy (PDT) can be used as an adjuvant treatment for denture stomatitis. In this study, we evaluated the effects of multiple sessions of PDT on Candida glabrata biofilms in specimens of polymerized acrylic resin formed after 5 days. Subsequently, four applications of PDT were performed on biofilms in 24-h intervals (days 6–9). Also, we evaluated two types of PDT, including application of laser and methylene blue or light-emitting diode (LED) and erythrosine. The control groups were treated with physiological solution. The effects of PDT on biofilm were evaluated after the first and fourth application of PDT. The biofilm analysis was performed by counting the colony-forming units. The results showed that between the days 6 and 9, the biofilms not treated by PDT had an increase of 5.53 to 6.05 log (p = 0.0271). Regarding the treatments, after one application of PDT, the biofilms decreased from 5.53 to 0.89 log. When it was done four applications, the microbial reduction ranged from 6.05 log to 0.11 log. We observed that one application of PDT with laser or LED caused a reduction of 3.36 and 4.64 compared to the control groups, respectively (p = 0.1708). When it was done four applications of PDT, the reductions achieved were 1.57 for laser and 5.94 for LED (p = 0.0001). It was concluded that repeated applications of PDT on C. glabrata biofilms showed higher antimicrobial activity compared to single application. PDT mediated by LED and erythrosine was more efficient than the PDT mediated by laser and methylene blue.

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Dynamic optical absorption characteristics of blood after slow and fast heating

Abstract

Laser treatment is the most effective therapy in dermatology for vascular skin disorders, such as port-wine stains (PWS). Changes in heat-induced absorbance in blood must be determined for accurate numerical simulation and implementation of multi-pulse laser therapy for treatment of PWS. Thermally induced absorbance changes in hemoglobin in blood were compared in vitro between slow water bath heating and fast heating irradiated by using sub-millisecond Nd:YAG laser. Blood composition at different temperatures was calculated by comparing blood absorption spectra with those of pure HbO₂, Hb, and metHb at room temperature. Blood absorbance to heat energy were categorized into three stages distinguished by metHb and coagulation points, which are the validity and security thresholds of the optimized therapy, respectively. Rapid laser heating can distinctively enhance blood absorbance by photochemically induced strong instability compared with slow heating at a constant temperature. Slow heating facilitates metHb point at 70 °C and coagulation point at 75 °C as the temperature of the water bath increases. However, the temperature at which metHb or coagulation point shifts to higher than 10 °C when pulses and fluence in laser irradiation change. Laser fluence less than 20 J/cm² and more than 50 J/cm² is unsuitable for laser treatment because of its low probability to coagulate vascular hyperplasia and high probability to damage normal tissues adjacent to target lesions, respectively. Few bubbles formed after mediate fluence is beneficial to minimize adverse side-effects. Considering blood absorbance, temperature evolution, and bubble formation, we recommend 30–40 J/cm² and 2–4 Hz frequency as the optimal laser parameters in sub-millisecond Nd:YAG laser.

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Outcome of early surgery in infantile esotropia: Our experience in tertiary care hospital

Publication date: Available online 13 January 2017
Source:Medical Journal Armed Forces India
Author(s): Anirudh Singh, J.K.S. Parihar, S.K. Mishra, R. Maggon, Anurag Badhani
BackgroundInfantile esotropia is a convergent strabismus presenting before 6 months of age and is the most common strabismus disorder presenting in the ophthalmology OPD. The dilemma of whether to go for early surgery and how early has been a matter of research for the last 50 years. We describe our results of surgery in infantile esotropia at variable age groups, as well as with different reoperation rates and compare with the results in western literature.MethodsA prospective study was carried out through a review of 113 cases operated for infantile esotropia between February 2013 and August 2014. The variables studied were: age at surgery, type of fixation, refractive error, associated nystagmus, inferior oblique overaction or dissociated vertical deviation (DVD), type of surgery performed and pre- and postoperative deviation angles.ResultsThere were 67 male and 46 female cases of infantile esotropia. The age group of patients varied from 6 months to 12 years. Latent nystagmus was seen in 22 cases, inferior oblique overaction in 49 cases and DVD (mild) in 14 cases. Bimedial rectus recession was done in 78 cases and recession–resection in non-dominant eye in remaining 35 cases. The postoperative residual deviation was <10 PD in 102 cases, between 10 and 16 PD in 5 cases and more than 16 PD in 6 cases. Only 6 cases (5.3%) required reoperation for correction of residual deviation.ConclusionThe authors recommend surgery before 12 months in all cases of infantile esotropia. The reoperation rates in the current study were considerably low.



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Smoking as a Risk Factor for Breast Reduction: An Analysis of 13,503 Cases

Reduction mammaplasty is one of the most common reconstructive procedures performed by plastic surgeons. Over 100,000 procedures are performed annually. Although important for relieving the painful symptoms associated with macromastia, complication rates of this procedure are not insignificant. They are reported in up to half of cases. Reported risk factors for adverse outcomes include obesity, preoperative wound infection, and advanced ASA status. Smoking has been described as a risk factor for breast reduction.

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Sexual segregation in foraging giraffe

Publication date: February 2017
Source:Acta Oecologica, Volume 79
Author(s): Rosemary Peter Mramba, Obeid Mahenya, Annetjie Siyaya, Karen Marie Mathisen, Harry Peter Andreassen, Christina Skarpe
Sexual segregation in giraffe is known to vary between savannas. In this study, we compared sexual segregation in giraffe in one nutrient-rich savanna, the Serengeti National Park, one nutrient-poor, Mikumi National Park, and one medium rich savanna, Arusha National Park, (from here on referred to just by name) based on effects of sexual size dimorphism and related hypotheses. Data were collected in the wet and dry seasons, by driving road transects and making visual observations of browsing giraffe. Additional data were collected from literature (plant chemistry; mammal communities). There was a noticeable difference in browsing by females and males and in browsing between the three savannas. Females browsed a higher diversity of tree species in Serengeti whereas males browsed a higher diversity in Arusha, while the diversity of species browsed in Mikumi was high and about the same in both sexes. Females selected for high concentrations of nitrogen and low concentrations of tannins and phenolics compared to males in Serengeti but selection in Mikumi was more complex. Males browsed higher in the canopy than females in all sites, but the browsing height was generally higher in Serengeti than Mikumi and Arusha. Season had an effect on the browsing height independent of sex in Mikumi, where giraffes browsed higher in the dry season compared to the wet season. Males spent more time browsing per tree compared to females in all three sites; however, browsing time in Mikumi was also affected by season, where giraffes had longer browsing bouts in the wet season compared to the dry season. We suggest that sexual differences in forage requirement and in foraging interacts with differences in tree chemistry and in competing herbivore communities between nutrient rich and nutrient poor savanna in shaping the sexual segregation.



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OX40: Structure and function – What questions remain?

Publication date: March 2017
Source:Molecular Immunology, Volume 83
Author(s): Jane Willoughby, Jordana Griffiths, Ivo Tews, Mark S. Cragg
OX40 is a type 1 transmembrane glycoprotein, reported nearly 30 years ago as a cell surface antigen expressed on activated T cells. Since its discovery, it has been validated as a bone fide costimulatory molecule for T cells and member of the TNF receptor family. However, many questions still remain relating to its function on different T cell sub-sets and with recent interest in its utility as a target for antibody-mediated immunotherapy, there is a growing need to gain a better understanding of its biology.Here, we review the expression pattern of OX40 and its ligand, discuss the structure of the receptor:ligand interaction, the downstream signalling it can elicit, its function on different T cell subsets and how antibodies might engage with it to provide effective immunotherapy.



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Enhancement of NK cell-mediated lysis of non-small lung cancer cells by nPKC activator, ingenol 3,20 dibenzoate

Publication date: March 2017
Source:Molecular Immunology, Volume 83
Author(s): Chenyuan Gong, Chao Yao, Zihang Xu, Zhongya Ni, Xiaowen Zhu, Lixin Wang, Xuewei Yan, Wuxiong Zhou, Shiguo Zhu
The IFN-γ production is crucial for NK cell-mediated lysis of cancer cells. Thus increasing the IFN-γ production by NK cells may be an ideal strategy to improve their tumoricidal effect. Since the focus on new drug development has shifted towards natural products, limited information is out there about natural products that enhance the IFN-γ production by NK cells. In this study, through a high-throughput screening, we have identified a natural product ingenol 3,20 dibenzoate (IDB), an activator of tumor suppressor protein kinase C (PKC) isozymes, could increase the IFN-γ production and degranulation by NK cells, especially when NK cells were stimulated by non-small lung cancer (NSCLC) cells. IDB also significantly enhanced the NK cell-mediated lysis of NSCLC cells. Furthermore, PKC inhibitor, sotrastaurin abrogated IDB-induced IFN-γ production, degranulation and cytotoxicity, but did not affect IFN-γ production by NK cells without IDB treatment and NSCLC cell stimulation. The IFN-γ neutralization reversed the IDB-induced enhancement of NK cell mediated killing. In conclusion, our study indicated that IDB enhanced NK cell-mediated lysis of NSCLC cells is dependent on specific PKC mediated IFN-γ production and degranulation. Thus, IDB may have a promising application in clinic for NK cell-based cancer immunotherapy.

Graphical abstract

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Anti-inflammatory effects of ononin on lipopolysaccharide-stimulated RAW 264.7 cells

Publication date: March 2017
Source:Molecular Immunology, Volume 83
Author(s): Lin Dong, Lei Yin, Yuanbin Zhang, Xueyan Fu, Jincai Lu
Increasing evidence has shown that ononin, a major isoflavone, has anti-inflammatory effects on lipopolysaccharide (LPS)-induced inflammation. However, the molecular mechanisms underlying the anti-inflammatory effects of ononin are still unclear. In the present study, we investigated these effects and the underlying mechanisms of ononin on LPS-induced inflammatory responses. Mouse RAW 264.7 cells were treated with 1μg/mL LPS and 5, 25, 50, 100 or 150μM ononin for 18h. Cell viability was assessed using MTT assays, and the production of nitric oxide (NO), prostaglandin E2 (PGE2) and the pro-inflammatory cytokines TNF-α, IL-1β and IL-6 in cultures was examined by Griess and ELISA analyses. qRT-PCR was performed to detect the mRNA expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2). Mitogen-activated protein kinases (MAPKs) and nuclear transcription factor Kappa-B (NF-κB) signalling pathway-related proteins were assessed by western blot assays. The results showed that cell viability was not significantly affected by up to 100μM ononin. The production of NO, PGE2 and the pro-inflammatory cytokines TNF-α, IL-1β and IL-6 in the cultures, the mRNA expression of two major inflammatory mediators, COX-2 and iNOS, and the expression of phosphorylated IκB-α, ERK, JNK, and p38 MAPKs proteins in LPS-treated cells were significantly increased. These changes could be reversed by treatment with ononin in a concentration-dependent manner (P<0.05). The results suggest that ononin has anti-inflammatory effects on LPS-induced inflammatory responses by inhibiting the NF-κB and MAPK pathways and may be a potential treatment for inflammation.

Graphical abstract

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The Effectiveness of the Braden Scale as a Tool for Identifying Nutrition Risk

Publication date: Available online 13 January 2017
Source:Journal of the Academy of Nutrition and Dietetics
Author(s): Wendy Phillips, Monica Hershey, Kate Willcutts, Janette Dietzler-Otte




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Using pupil size and heart rate to infer affective states during behavioral neurophysiology and neuropsychology experiments

Publication date: Available online 13 January 2017
Source:Journal of Neuroscience Methods
Author(s): Andrew R. Mitz, Ravi V. Chacko, Philip T. Putnam, Peter H. Rudebeck, Elisabeth A. Murray
BackgroundNonhuman primates (NHPs) are a valuable research model because of their behavioral, physiological and neuroanatomical similarities to humans. In the absence of language, autonomic activity can provide crucial information about cognitive and affective states during single-unit recording, inactivation and lesion studies. Methods standardized for use in humans are not easily adapted to NHPs and detailed guidance has been lacking.New MethodWe provide guidance for monitoring heart rate and pupil size in the behavioral neurophysiology setting by addressing the methodological issues, pitfalls and solutions for NHP studies. The methods are based on comparative physiology to establish a rationale for each solution. We include examples from both electrophysiological and lesion studies.ResultsSingle-unit recording, pupil responses and heart rate changes represent a range of decreasing temporal resolution, a characteristic that impacts experimental design and analysis. We demonstrate the unexpected result that autonomic measures acquired before and after amygdala lesions are comparable despite disruption of normal autonomic function.Comparison with Existing MethodsSpecies and study design differences can render standard techniques used in human studies inappropriate for NHP studies. We show how to manage data from small groups typical of NHP studies, data from the short behavioral trials typical of neurophysiological studies, issues associated with longitudinal studies, and differences in anatomy and physiology.ConclusionsAutonomic measurement to infer cognitive and affective states in NHP is neither off-the-shelf nor onerous. Familiarity with the issues and solutions will broaden the use of autonomic signals in NHP single unit and lesion studies.



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Prefrontal cortex-mediated executive function as assessed by Stroop task performance associates with weight loss among overweight and obese adolescents and young adults

Publication date: 15 March 2017
Source:Behavioural Brain Research, Volume 321
Author(s): Xia Xu, Zhang-Yan Deng, Qin Huang, Wei-Xia Zhang, Chang-zhu Qi, Jia-Ai Huang
People with cognitive deficits or executive dysfunction are often overweight or obese. Several human neuroimaging studies have found that executive function (EF) predicts food intake and weight gain; however, fewer studies have investigated the relationship between EF and weight loss. The Stroop task is a classic measure of EF that is used in many neuroimaging studies. In the present work, functional near infrared spectroscopy (fNIRS) data were collected during performance of the Stroop task from a sample of overweight or obese adolescents and young adults (n=31) who participated in a summer fitness and weight loss camp. We assessed the Stroop effect by interference in the reaction time (RT) to visual challenges, and by alterations in levels of oxygenated hemoglobin, as detected by fNIRS. In line with previous studies, we found that the Stroop effect was successfully induced by different visual task conditions among obese/overweight individuals. Moreover, our results reveal that better Stroop task performance is correlated with greater weight loss over a4-weekfitness intervention. Indeed, behavioral data demonstrated that reduced RT interference predicted a greater percentage of weight loss. Moreover, overweight/obese individuals with a greater hemodynamic response in the left ventrolateral and bilateral dorsolateral prefrontal cortex due to the Stroop effect lost more weight during the short-term fitness intervention than participants with lower levels of activation of these neural regions. Overall, our results support a role for prefrontal cortex-mediated EF in influencing food intake and weight loss outcomes in a population of a previously unstudied age.



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Editorial Board/Aims and Scope

Publication date: 20 January 2017
Source:Vaccine, Volume 35, Supplement 1





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Defining cases of severe pediatric diarrhea for an efficacy trial of an enterotoxigenic Escherichia coli (ETEC) vaccine: Report on an international workshop, Washington DC, March 2016

Publication date: 23 January 2017
Source:Vaccine, Volume 35, Issue 4
Author(s): Thomas F. Wierzba, Alexandra Bourgis
Enterotoxigenic Escherichia coli (ETEC) causes severe acute watery diarrhea. No ETEC vaccine is available but candidates are in development, including ETVAX, an oral, whole-cell inactivated vaccine. ETVAX is being tested in a descending-age trial in Bangladesh. If found safe and immunogenic, investigators may test it for efficacy in children. Like oral rotavirus vaccines, we expect that ETVAX will be most effective at decreasing the incidence of moderate-to-severe ETEC episodes. Thus, for an efficacy trial outcome, it will be necessary to triage patients into moderate-to-severe versus mild disease. A severity scale specific to ETEC does not exist. To develop this scale, PATH convened a committee of international experts for a two-day meeting to strategize on diagnostic scale development. The workshop began with four presentations. The first described existing scales, item selection, and issues related to validation, reliability, and ease of use. The other three presentations provided details on the following published scores: the DHAKA score, validated for use with Bangladeshi children seeking diarrhea treatment; a modified-Vesikari score for evaluating North American outpatient children with diarrhea; and the Community Diarrhea Assessment (CODA) score developed for passive-case surveillance of Peruvian children with diarrhea. Following the presentations and discussion, the committee made several recommendations including: modifying existing scores to make them ETEC-centric; evaluating scoring systems against an objective measure of dehydration (i.e., the percent change in a child's bodyweight following rehydration); and adding an item to the scale measuring ETEC effects on growth faltering. The committee also discussed using available data sets to evaluate scores, but was concerned that if investigators characterized patients using different procedures than prescribed by the score, the results would be difficult to interpret. Committee members suggested new data collection and recommended conducting studies in Sub-Saharan Africa. The study results would be presented for peer-review and to regulatory authorities.



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Moving beyond traditional valuation of vaccination: Needs and opportunities

Publication date: 20 January 2017
Source:Vaccine, Volume 35, Supplement 1
Author(s): David E. Bloom, Logan Brenzel, Daniel Cadarette, Jessica Sullivan
Economic evaluations of vaccination traditionally focus on a relatively narrow set of vaccine benefits, such as averted medical care costs among those who are immunized. In recent years, researchers have identified additional vaccination benefits that should be incorporated into economic evaluations in order to reflect vaccination's full value. Early efforts to estimate the magnitude of these broader benefits suggest that vaccination has been substantially undervalued, which has important implications for public and private vaccine policy and human health and welfare. More and better data will be required to advance this emerging line of research on the value of vaccination. The article discusses promising data sources and methods and research questions needing to be addressed.



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Interest in an Ebola vaccine among a U.S. national sample during the height of the 2014–2016 Ebola outbreak in West Africa

Publication date: 23 January 2017
Source:Vaccine, Volume 35, Issue 4
Author(s): Julia E. Painter, Ralph J. DiClemente, Michael E. von Fricken
To better understand the association between Ebola-related attitudes and interest in receiving an Ebola virus vaccine, a survey was administered to a U.S. national sample using GfK's KnowledgePanel®. Among participants (N=1417), 34.1% expressed interest in an Ebola vaccine for themselves. In the subset of participants with children aged 0–17 (N=410), 38.1% expressed interest in an Ebola vaccine for their child. In multivariable analyses, vaccine interest for oneself was associated with perceived susceptibility to Ebola (p=0.009), beliefs that the U.S. government should spend money to control Ebola (p=0.002), and beliefs Ebola posed a national threat (p=0.007). Vaccine interest for one's child was associated with perceived severity of Ebola (p=0.018) and beliefs that the U.S. government should spend money to control Ebola (p=0.003). Findings highlight the influence of personal and national threat beliefs on vaccine interest. Understanding the impact of threat beliefs may benefit vaccine campaign development during future pandemic threats.



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Negative impact of prior influenza vaccination on current influenza vaccination among people infected and not infected in prior season: A test-negative case-control study in Japan

Publication date: 23 January 2017
Source:Vaccine, Volume 35, Issue 4
Author(s): Nobuo Saito, Kazuhiro Komori, Motoi Suzuki, Kounosuke Morimoto, Takayuki Kishikawa, Takahiro Yasaka, Koya Ariyoshi
BackgroundAccumulating evidences indicate that repeated influenza vaccination has negative impact on the vaccine effectiveness (VE). However no published studies considered past influenza infection when assessing the VE of repeated vaccination.MethodsProspective surveillance was conducted from 2009 to 2012 at a community hospital on a small island in Japan. The study included all outpatients with an influenza-like illness (ILI) who attended the hospital, and a rapid diagnostic test (RDT) was used to diagnose influenza A/B infection. The VE of trivalent inactivated influenza vaccine (TIV) against medically attended influenza A (MA-fluA) was estimated using a test-negative case-control study design. The influence of TIV in the prior season on VE in the current season was investigated in the context of MA-fluA during the prior season.ResultsDuring the three influenza seasons, 5838 ILI episodes (4127 subjects) were analysed. Subjects who had an episode of MA-fluA in the prior season were at a significantly lower risk of MA-fluA in the current season (adjusted odds ratio: 0.38, 95% CI: 0.30–0.50). The overall adjusted VE was 28% (95% CI, 14–40). VE was substantially lower in subjects vaccinated in the prior season compared to those who had not been vaccinated in prior season (19%; 95% CI: 0–35 vs 46%; 95% CI: 26–60, test for interaction, P value <0.05). In subjects who did not have MA-fluA in the prior season showed the attenuation of VE due to repeated vaccination (13%; 95% CI: −7 to 30 vs 44%; 95% CI: 24–59, test for interaction, P<0.05). However this effect was not detected in subjects who had contracted MA-fluA in the prior season.ConclusionsNegative effects of repeated vaccination were significant among those without history of MA-fluA in the prior season.



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Planning and priority setting for vaccine development and immunization

Publication date: 20 January 2017
Source:Vaccine, Volume 35, Supplement 1
Author(s): Charles E. Phelps, Guruprasad Madhavan, Bruce Gellin
We review a sequence of strategic planning efforts over time in the United States, all involving processes to prioritize new vaccine candidates. The Institute of Medicine of the National Academies of Sciences, Engineering, and Medicine has been involved in three priority setting processes, each using different metrics and methodologies: infant mortality equivalents (1985–1986), cost-effectiveness (2000), and more recently, the implementation of a software system based on a broader multi-criteria systems approach that can include either of the earlier metrics among other various considerations (2015). The systems approach offers users the flexibility to select, combine, rank, weigh and evaluate different attributes representing their perspectives, assumptions, and particular needs. This approach also overcomes concerns relating to the previous single-metric ranking approaches that yielded lists that, once published, were static, and could not readily accommodate new information about emerging pathogens, new scientific advances, or changes in the costs and performance features of interventions. We discuss the rationale and reasoning behind the design of this multi-criteria decision support approach, stakeholder feedback about the tool, and highlight the potential advantages from using this expanded approach to better inform and support vaccine policies.



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Hospitalizations within 14days of vaccination among pediatric recipients of the live attenuated influenza vaccine, United States 2010–2012

Publication date: 23 January 2017
Source:Vaccine, Volume 35, Issue 4
Author(s): Alexander J. Millman, Sue Reynolds, Jonathan Duffy, Jufu Chen, Paul Gargiullo, Alicia M. Fry
BackgroundLive attenuated influenza vaccine (LAIV) is safe in healthy children ⩾2years. The original clinical trials excluded individuals with underlying conditions; however, post-marketing data suggest LAIV may be safe for these populations.MethodsWe analyzed MarketScan Commercial Claims Databases from 2010 to 2012 to describe hospitalizations within 14days of vaccination among LAIV recipients. We evaluated LAIV recipients aged 2–18years and defined underlying conditions by presence of inpatient or outpatient ICD-9 code during the previous calendar year. We excluded asthma and immunocompromising conditions. We defined risk windows as 1–7days and 8–14days after vaccination; the control period was 12–4days prior to and 15–23days after vaccination. We conducted a self-controlled case series analysis using a conditional Poisson regression model to estimate incidence-rate ratios (IRR).Results1,216,123 children aged 2–18years received LAIV from 2010 to 2012. 634 children met our inclusion criteria and were hospitalized during the observation period (12days prior to vaccination to 23days after vaccination). Of those hospitalized, 72 (11.4%) had non-asthma, non-immunocompromising underlying conditions. Children with non-asthma, non-immunocompromising underlying conditions had an all-cause hospitalization IRR of 1.1 (95% CI 0.6–2.0, p=0.83) in the 1–7day risk period and 0.9 (95% CI 0.4–1.7, p=0.67) in the 8–14day risk period. Children with no underlying conditions had an all-cause hospitalization IRR of 0.9 (0.8–1.2, p=0.60) in the 1–7day risk period and 1.1 (95% CI 0.9–1.3, p=0.53) in the 8–14day risk period. There were no differences in all-cause hospitalization risk in individuals with non-asthma, non-immunocompromising underlying conditions compared to those without underlying conditions in the 1–7day (p=0.88) or 8–14day (p=0.24) risk period.ConclusionsWe found no evidence of differences in post-LAIV hospitalization risk among children with non-asthma, non-immunocompromising underlying conditions compared to healthy children.



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Editorial Board/Aims and Scope

Publication date: 23 January 2017
Source:Vaccine, Volume 35, Issue 4





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Identification of amino acids in antigen-binding site of class II HLA proteins independently associated with hepatitis B vaccine response

Publication date: 23 January 2017
Source:Vaccine, Volume 35, Issue 4
Author(s): Aiko Sakai, Emiko Noguchi, Takashi Fukushima, Manabu Tagawa, Atsushi Iwabuchi, Masaki Kita, Keisuke Kakisaka, Akio Miyasaka, Yasuhiro Takikawa, Ryo Sumazaki
Background & aimsGenetic factors in class II human leukocyte antigen (HLA) have been reported to be associated with inter-individual variation in hepatitis B virus (HBV) vaccine response. However, the mechanism underlying the associations remains elusive. In particular, the broad linkage disequilibrium in HLA region complicates the localization of the independent effects of genetic variants. Thus, the present study aimed to identify the most probable causal variations in class II HLA loci involved in the immune response to HBV vaccine.MethodsWe performed a case-control study to assess whether HLA-DRB1, -DQB1, and -DPB1 4-digit alleles were associated with the response to primary HBV vaccination in 574 healthy Japanese students. To identify causative variants, we next assessed independently associated amino acid variants in these loci using conditional logistic regression analysis. Furthermore, to clarify the functional effects of these variants on HLA proteins, we performed computational structural studies.ResultsHLA-DRB1^∗01:01, HLA-DRB1^∗08:03, HLA-DQB1^∗05:01, and HLA-DPB1^∗04:02 were significantly associated with sufficient response, whereas HLA-DPB1^∗05:01 was associated with poor response. We then identified amino acids independently associated with sufficient response, namely, leucine at position 26 of HLA-DRβ1 and glycine-glycine-proline-methionine at positions 84–87 of HLA-DPβ1. These amino acids were located in antigen-binding pocket 4 of HLA-DR and pocket 1 of HLA-DP, respectively, which are important structures for selective binding of antigenic peptides. In addition, the detected variations in HLA-DP protein were responsible for the differences in the electrostatic potentials of the pocket, which can explain in part the sufficient/poor vaccine responses.ConclusionHLA-DRβ1 position 26 and HLA-DPβ1 positions 84–87 are independently associated with anti-HBs production against HBV vaccine. Our results suggest that HBsAg presentation through these HLA pocket structures plays an important role in the inter-individual variability of HBV vaccination.



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Achieving a “Grand Convergence” in global health by 2035

Publication date: 20 January 2017
Source:Vaccine, Volume 35, Supplement 1
Author(s): Adel Mahmoud
Historical evidence demonstrates the validity of the concept "Grand Convergence". The Lancet commission identified the major challenges facing low and lower middle income countries including the unfinished agenda, non-communicable diseases and injuries and an approach to funding and achieving these objectives along with progress towards universal health care. The role of vaccines is summarized as a major approach to accomplish a Grand Convergence in a generation.



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Passive antibodies derived from intramuscularly immunized toxoid fusion 3xSTaN12S-dmLT protect against STa+ enterotoxigenic Escherichia coli (ETEC) diarrhea in a pig model

Publication date: 23 January 2017
Source:Vaccine, Volume 35, Issue 4
Author(s): Rahul M. Nandre, Qiangde Duan, Yin Wang, Weiping Zhang
Enterotoxigenic Escherichia coli (ETEC) strains are among the most common causes of children's diarrhea and travelers' diarrhea. Developing effective vaccines against ETEC associated diarrhea becomes a top priority. ETEC heat-labile toxin (LT) and heat-stable toxin (STa) toxoid fusion 3xSTaN12S-dmLT was demonstrated recently to induce neutralizing antitoxin antibodies in intraperitoneally or subcutaneously immunized mice. However, whether antibodies derived from this toxoid fusion are protective against ETEC diarrhea has not been examined. In this study, we intramuscularly immunized pregnant gilts with toxoid fusion 3xSTaN12S-dmLT, challenged suckling piglets with a STa-positive ETEC strain, and assessed protective efficacy of passive acquire antitoxin antibodies against ETEC diarrhea. Data showed all three immunized gilts developed anti-STa IgG and IgA antibodies, and piglets born to the immunized dams acquired anti-STa and anti-LT antibodies. When challenged with a STa+ ETEC strain, none of the piglets born to the immunized dams developed watery diarrhea, with 20 piglets remained normal and the other 8 piglets developed mild diarrhea indicated with stained butt. In contrast, the control dams and born piglets had no anti-STa or anti-LT antibodies detected, and 26 out 32 piglets developed watery diarrhea after challenge of the STa+ ETEC strain. These results indicated that passive acquired anti-STa antibodies are protective against ETEC diarrhea, and suggested potential application of toxoid fusion 3xSTaN12S-dmLT in ETEC vaccine development.



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European strategy for vaccine development against infectious diseases

Publication date: 20 January 2017
Source:Vaccine, Volume 35, Supplement 1
Author(s): Line Matthiessen, Hannu Lång, Maria Klimathianaki, Finnian Hanrahan, Barbara Kerstiëns, Alessandra Martini, Ruxandra Draghia-Akli
Immunisation efforts save millions of lives every year, but vaccines hold the potential to deliver even greater health benefits for mankind. Vaccine research and development is highly complex, and it requires concerted public funding efforts to support. In this paper we discuss EU funding priorities and the resulting recent advancements in European vaccine research, and we lay out the EU strategy for aiding promising vaccine candidates to successfully reach the market.



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Viral vector vaccines protect cockatiels from inflammatory lesions after heterologous parrot bornavirus 2 challenge infection

Publication date: 23 January 2017
Source:Vaccine, Volume 35, Issue 4
Author(s): Solveig Runge, Marita Olbert, Christiane Herden, Sara Malberg, Angela Römer-Oberdörfer, Peter Staeheli, Dennis Rubbenstroth
Avian bornaviruses are causative agents of proventricular dilatation disease (PDD), a chronic neurologic and often fatal disorder of psittacines including endangered species. To date no causative therapy or immunoprophylaxis is available. Our previous work has shown that viral vector vaccines can delay the course of homologous bornavirus challenge infections but failed to protect against PDD when persistent infection was not prevented.The goal of this study was to refine our avian bornavirus vaccination and infection model to better represent natural bornavirus infections in order to achieve full protection against a heterologous challenge infection.We observed that parrot bornavirus 2 (PaBV-2) readily infected cockatiels (Nymphicus hollandicus) by combined intramuscular and subcutaneous injection with as little as 10^2.7foci-forming units (ffu) per bird, whereas a 500-fold higher dose of the same virus administered via peroral and oculonasal route did not result in persistent infection. These results indicated that experimental bornavirus challenge infections with this virus should be performed via the parenteral route.Prime-boost vaccination of cockatiels with Newcastle disease virus (NDV) and modified vaccinia virus Ankara (MVA) vectors expressing the nucleoprotein and phosphoprotein genes of PaBV-4 substantially blocked bornavirus replication following parenteral challenge infection with 10^3.5ffu of heterologous PaBV-2. Only two out of six vaccinated birds had very low viral levels detectable in a few organs. As a consequence, only one vaccinated bird developed mild PDD-associated microscopic lesions, while mock-vaccinated controls were not protected against PaBV-2 infection and inflammation.Our results demonstrate that NDV and MVA vector vaccines can protect against invasive heterologous bornavirus challenge infections and subsequent PDD. These vector vaccines represent a promising tool to combat avian bornaviruses in psittacine populations.



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Informing vaccine decision-making: A strategic multi-attribute ranking tool for vaccines—SMART Vaccines 2.0

Publication date: 20 January 2017
Source:Vaccine, Volume 35, Supplement 1
Author(s): Stacey Knobler, Karin Bok, Bruce Gellin
SMART Vaccines 2.0 software is being developed to support decision-making among multiple stakeholders in the process of prioritizing investments to optimize the outcomes of vaccine development and deployment. Vaccines and associated vaccination programs are one of the most successful and effective public health interventions to prevent communicable diseases and vaccine researchers are continually working towards expanding targets for communicable and non-communicable diseases through preventive and therapeutic modes. A growing body of evidence on emerging vaccine technologies, trends in disease burden, costs associated with vaccine development and deployment, and benefits derived from disease prevention through vaccination and a range of other factors can inform decision-making and investment in new and improved vaccines and targeted utilization of already existing vaccines. Recognizing that an array of inputs influences these decisions, the strategic multi-attribute ranking method for vaccines (SMART Vaccines 2.0) is in development as a web-based tool—modified from a U.S. Institute of Medicine Committee effort (IOM, 2015)—to highlight data needs and create transparency to facilitate dialogue and information-sharing among decision-makers and to optimize the investment of resources leading to improved health outcomes. Current development efforts of the SMART Vaccines 2.0 framework seek to generate a weighted recommendation on vaccine development or vaccination priorities based on population, disease, economic, and vaccine-specific data in combination with individual preference and weights of user-selected attributes incorporating valuations of health, economics, demographics, public concern, scientific and business, programmatic, and political considerations.Further development of the design and utility of the tool is being carried out by the National Vaccine Program Office of the Department of Health and Human Services and the Fogarty International Center of the National Institutes of Health. We aim to demonstrate the utility of SMART Vaccines 2.0 through the engagement of a community of relevant stakeholders and to identify a limited number of pilot projects to determine explicitly defined attribute preferences and the related data and model requirements that are responsive to user needs and able to improve the use of evidence for vaccine-related decision-making and consequential priorities of vaccination options.



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The economic impact of prenatal varicella immunity among pregnant women in Alberta

Publication date: 23 January 2017
Source:Vaccine, Volume 35, Issue 4
Author(s): Amrit Passi, Sabrina S. Plitt, Florence Y. Lai, Kimberley Simmonds, Carmen L. Charlton
In light of the changing epidemiology of varicella, we sought to examine varicella antibody levels in the prenatal population in the Canadian province of Alberta. All prenatal varicella screening tests performed between August 1, 2002 and February 2, 2014 (454,592) were included in this study. Test results, demographics and vaccination status were examined to identify varicella seroprevalence and correlates for being seronegative. An overall seroprevalence for varicella of 95.8% was found across all pregnancy screenings. Significant independent correlates of seronegativity included younger age (AOR: 4.72 (95% CI: 3.87–5.77) for <20years of age vs. >40years of age) and having immigrated to Alberta from Africa or Asia (AOR: 4.55 (95% CI: 4.10–5.05) and AOR: 5.83 (95%CI; 5.48–6.19), respectively). Women who were initially seronegative for varicella antibodies and who received both postnatal vaccination and post-vaccination prenatal screening (2566) were examined to assess seroconversion. 66.3% of women who were tested up to six months post-vaccination were seropositive, however only 36.9% of women tested after 36months were seropositive. Finally, 40.9% of all prenatal varicella specimens tested were deemed redundant, i.e. women had either a history of (1) ⩾2 doses of varicella vaccine, (2) varicella infection, or (3) a previous positive varicella serology. Eliminating this redundant screening could provide an estimated $96,000 in savings annually in laboratory and Public Health follow-up costs alone. As the number of women with vaccine-derived immunity through universal childhood vaccination increase in the prenatal population, screening methods may need to adapt to ensure varicella immunity is accurately conducted and assessed.



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Corrigendum to “Trends in childhood vaccine purchase costs in the US public sector: 1996–2014” [Vaccine 34 (2016) 4706–4711]

Publication date: 23 January 2017
Source:Vaccine, Volume 35, Issue 4
Author(s): Weiwei Chen, Mark Messonnier, Fangjun Zhou




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Introduction to the vaccine supplement

Publication date: 20 January 2017
Source:Vaccine, Volume 35, Supplement 1
Author(s): Rino Rappuoli




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What drivers will influence global immunizations in the era of grand convergence in global health?

Publication date: 20 January 2017
Source:Vaccine, Volume 35, Supplement 1
Author(s): Orin S. Levine
Recent projections suggest that by 2035 global health will look dramatically different than it does today. In what's called a 'grand convergence' the world is likely to be characterized by far more similarities than differences in the prevailing health and medical problems across populations. This manuscript considers how key drivers for vaccine use and uptake might change as a result of the grand convergence and how decisions taken now might anticipate those changes in ways that position immunizations to continue playing an important role in the future.



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Prioritizing vaccines for developing world diseases

Publication date: 20 January 2017
Source:Vaccine, Volume 35, Supplement 1
Author(s): Allan Saul, Katherine L. O'Brien
A major disparity in the burden of health will need to be addressed to achieve the "Grand Convergence" by 2035. In particular people living in low and middle income countries have a much higher burden of infectious diseases. Although vaccines have been very effective in reducing the global burden of infectious disease, there are no registered vaccines to address 60% of the current burden of infectious disease, especially in developing countries. Thus there is a pressing need for new vaccines and for prioritizing vaccine development given that resources for developing new vaccines are strictly limited. As part of the GLOBAL HEALTH 2035: Mission Grand Convergence meeting one working group assessed the SMART vaccine algorithm as a mechanism for prioritizing vaccine development for diseases of priority in the developing world. In particular, the working group considered which criteria in the standard SMART set were considered "key" criteria and whether other criteria should be considered, when prioritizing vaccines for this important set of countries.



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The role of the vaccines industry in Mission Grand Convergence

Publication date: 20 January 2017
Source:Vaccine, Volume 35, Supplement 1
Author(s): Jeffrey Almond, Donata Medaglini
The vast majority of vaccines used throughout the world are supplied by the private sector. It is essential therefore that the industry is closely engaged in future policy developments at a national and international level and is able to respond to the changing needs and priorities that may be required to ensure the success of Mission Grand Convergence. Uniquely, the major vaccine companies have the expertise and technical capacity to develop, produce and supply vaccines on a global scale. Through partnering with Governments, charities and NGOs, they must play a pivotal role in the Mission and, at the same time as agreeing on objectives that may not be entirely market driven, must be able to sustain their commercial obligations to shareholders. Similarly, small and medium sized companies, with the global investor market and government incentives that underpin and support them, also have a very important role to play; for example in innovation around a given disease and on technology, process and platform development across the whole value chain. The industry at large is therefore an essential player. Indeed Mission Grand Convergence can only succeed with the full and willing participation of the vaccines industry.



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NEIL1 is a candidate gene associated with common variable immunodeficiency in a patient with a chromosome 15q24 deletion

Publication date: Available online 14 January 2017
Source:Clinical Immunology
Author(s): Rosa Romano, Apostolos Zaravinos, Kyriaki Liadaki, Rozina Caridha, Johanna Lundin, Göran Carlsson, Jacek Winiarski, Qiang Pan-Hammarström, Lennart Hammarström
We report the first patient with an interstitial deletion of chromosome 15q24.1-q24.3 associated with common variable immunodeficiency (CVID). The 18-year old female patient's clinical and immunological phenotype was compared with 8 additional previously published patients with chr15q24 deletions. A CGH analysis estimated the deletion to be 3.767Mb in size (chr15: 74,410,916–78,178,418) and the result was confirmed using qRT-PCR. We defined an immune-related commonly deleted region (ICDR) within the chromosomal band 15q24.2, deleted in all four patients with different forms of antibody deficiencies. Mutations in the 14 genes within this ICDR were not identified in the remaining allele in our patient by WES and gene expression analyses showed haploinsufficiency of all the genes. Among these genes, we consider Nei Like DNA Glycosylase 1 (NEIL1) as a likely candidate gene due to its crucial role in B-cell activation and terminal differentiation.



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Hypoxia Inducible Factor-1α Inhibition Modulates Airway Hyperresponsiveness and Nitric Oxide Levels in a BALB/c Mouse Model of Asthma

Publication date: Available online 14 January 2017
Source:Clinical Immunology
Author(s): Carola Dewitz, Elisa McEachern, Stephanie Shin, Kathryn Akong, Dale G. Nagle, David H. Broide, Praveen Akuthota, Laura E. Crotty Alexander
Hypoxia inducible factor (HIF)-1α is a master regulator of inflammation and is upregulated in alveolar macrophages and lung parenchyma in asthma. HIF-1α regulates select pathways in allergic inflammation, and thus may drive particular asthma phenotypes. This work examines the role of pharmacologic HIF-1α inhibition in allergic inflammatory airway disease (AIAD) pathogenesis in BALB/c mice, which develop an airway hyperresponsiveness (AHR) asthma phenotype. Systemic treatment with HIF-1α antagonist YC-1 suppressed the increase in HIF-1α expression seen in control AIAD mice. Treatment with YC-1 also decreased AHR, blood eosinophilia, and allergic inflammatory gene expression: IL-5, IL-13, myeloperoxidase and iNOS. AIAD mice had elevated BAL levels of NO, and treatment with YC-1 eliminated this response. However, YC-1 did not decrease BAL, lung or bone marrow eosinophilia. We conclude that HIF-1α inhibition in different genetic backgrounds, and thus different AIAD phenotypes, decreases airway resistance and markers of inflammation in a background specific manner.Capsule SummaryAsthma is a common disease that can be difficult to control with current therapeutics. We describe how pharmacologic targeting of a specific transcription factor, HIF-1α, suppresses asthmatic airway reactivity and inflammation.

Graphical abstract

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Periosteum tissue engineering in an orthotopic in vivo platform

Publication date: March 2017
Source:Biomaterials, Volume 121
Author(s): J.G. Baldwin, F. Wagner, L.C. Martine, B.M. Holzapfel, C. Theodoropoulos, O. Bas, F.M. Savi, C. Werner, E.M. De-Juan-Pardo, D.W. Hutmacher
The periosteum plays a critical role in bone homeostasis and regeneration. It contains a vascular component that provides vital blood supply to the cortical bone and an osteogenic niche that acts as a source of bone-forming cells. Periosteal grafts have shown promise in the regeneration of critical size defects, however their limited availability restricts their widespread clinical application. Only a small number of tissue-engineered periosteum constructs (TEPCs) have been reported in the literature. A current challenge in the development of appropriate TEPCs is a lack of pre-clinical models in which they can reliably be evaluated.In this study, we present a novel periosteum tissue engineering concept utilizing a multiphasic scaffold design in combination with different human cell types for periosteal regeneration in an orthotopic in vivo platform. Human endothelial and bone marrow mesenchymal stem cells (BM-MSCs) were used to mirror both the vascular and osteogenic niche respectively. Immunohistochemistry showed that the BM-MSCs maintained their undifferentiated phenotype. The human endothelial cells developed into mature vessels and connected to host vasculature. The addition of an in vitro engineered endothelial network increased vascularization in comparison to cell-free constructs.Altogether, the results showed that the human TEPC (hTEPC) successfully recapitulated the osteogenic and vascular niche of native periosteum, and that the presented orthotopic xenograft model provides a suitable in vivo environment for evaluating scaffold-based tissue engineering concepts exploiting human cells.

Graphical abstract

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Controlling the 3D architecture of Self-Lifting Auto-generated Tissue Equivalents (SLATEs) for optimized corneal graft composition and stability

Publication date: March 2017
Source:Biomaterials, Volume 121
Author(s): Ricardo M. Gouveia, Elena González-Andrades, Juan C. Cardona, Carmen González-Gallardo, Ana M. Ionescu, Ingrid Garzon, Miguel Alaminos, Miguel González-Andrades, Che J. Connon
Ideally, biomaterials designed to play specific physical and physiological roles in vivo should comprise components and microarchitectures analogous to those of the native tissues they intend to replace. For that, implantable biomaterials need to be carefully designed to have the correct structural and compositional properties, which consequently impart their bio-function. In this study, we showed that the control of such properties can be defined from the bottom-up, using smart surface templates to modulate the structure, composition, and bio-mechanics of human transplantable tissues. Using multi-functional peptide amphiphile-coated surfaces with different anisotropies, we were able to control the phenotype of corneal stromal cells and instruct them to fabricate self-lifting tissues that closely emulated the native stromal lamellae of the human cornea. The type and arrangement of the extracellular matrix comprising these corneal stromal Self-Lifting Analogous Tissue Equivalents (SLATEs) were then evaluated in detail, and was shown to correlate with tissue function. Specifically, SLATEs comprising aligned collagen fibrils were shown to be significantly thicker, denser, and more resistant to proteolytic degradation compared to SLATEs formed with randomly-oriented constituents. In addition, SLATEs were highly transparent while providing increased absorption to near-UV radiation. Importantly, corneal stromal SLATEs were capable of constituting tissues with a higher-order complexity, either by creating thicker tissues through stacking or by serving as substrate to support a fully-differentiated, stratified corneal epithelium. SLATEs were also deemed safe as implants in a rabbit corneal model, being capable of integrating with the surrounding host tissue without provoking inflammation, neo-vascularization, or any other signs of rejection after a 9-months follow-up. This work thus paves the way for the de novo bio-fabrication of easy-retrievable, scaffold-free human tissues with controlled structural, compositional, and functional properties to replace corneal, as well as other, tissues.

Graphical abstract

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Novel salicylanilides from 4,5-dihalogenated salicylic acids: Synthesis, antimicrobial activity and cytotoxicity

Publication date: Available online 14 January 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Georgios Paraskevopoulos, Sara Monteiro, Rudolf Vosátka, Martin Krátký, Lucie Navrátilová, František Trejtnar, Jiřina Stolaříková, Jarmila Vinšová
Salicylanilides have proved their activity against tuberculosis (TB). One weak electron-withdrawing substituent is favored at the salicylic part, specially Cl or Br atoms at positions 4 or 5. On the other hand, the antimycobacterial activity of salicylanilides is negatively affected when a strong electron-withdrawing substituent (-NO2) is present at the same positions. Herein we describe the synthesis and characterization of novel salicylanilides possessing two weak electron-withdrawing groups (halogen atoms) at their salicylic part and compare their antitubercular activity with their monohalogenated analogues. All dihalogenated derivatives proved to possess antitubercular activity at a very narrow micromolar range (MIC= 1-4 μM), similar with their most active monohalogenated analogues. More importantly, the most active final molecules were further screened against multidrug resistant strains and found to inhibit their growth at the range of 0.5-4 μM.

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Farewell to Prof. Jens Overgaard

Publication date: Available online 13 January 2017
Source:Radiotherapy and Oncology
Author(s): Michael Baumann




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Identification of Fhit as a post-transcriptional effector of Thymidine Kinase 1 expression

Publication date: Available online 14 January 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Daniel L. Kiss, Catherine E. Waters, Iman M. Ouda, Joshua C. Saldivar, Jenna R. Karras, Zaynab A. Amin, Seham Mahrous, Teresa Druck, Ralf A. Bundschuh, Daniel R. Schoenberg, Kay Huebner
FHIT is a genome caretaker gene that is silenced in >50% of cancers. Loss of Fhit protein expression promotes accumulation of DNA damage, affects apoptosis and epithelial-mesenchymal transition, though molecular mechanisms underlying these alterations have not been fully elucidated. Initiation of genome instability directly follows Fhit loss and the associated reduced Thymidine Kinase 1 (TK1) protein expression. The effects on TK1 of Fhit knockdown and Fhit induction in the current study confirmed the role of Fhit in regulating TK1 expression. Changes in Fhit expression did not impact TK1 protein turnover or transcription from the TK1 promoter, nor steady-state levels of TK1 mRNA or turnover. Polysome profile analysis showed that up-regulated Fhit expression resulted in decreased TK1 RNA in non-translating messenger ribonucleoproteins and increased ribosome density on TK1 mRNA. Fhit does not bind RNA but its expression increased luciferase expression from a transgene bearing the TK1 5′-UTR. Fhit has been reported to act as a scavenger decapping enzyme, and a similar result with a mutant (H96) that binds but does not cleave nucleoside 5′,5′-triphosphates suggests the impact on TK1 translation is due to its ability to modulate the intracellular level of cap-like molecules. Consistent with this, cells expressing Fhit mutants with reduced activity toward cap-like dinucleotides exhibit DNA damage resulting from TK1 deficiency, whereas cells expressing wild-type Fhit or the H96N mutant do not. The results have implications for the mechanism by which Fhit regulates TK1 mRNA, and more broadly, for its modulation of multiple functions as tumor suppressor/genome caretaker.

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Protective effects of total flavonoids of Astragalus against adjuvant-induced arthritis in rats by regulating OPG/RANKL/NF-κB pathway

Publication date: March 2017
Source:International Immunopharmacology, Volume 44
Author(s): Xin-Yu Liu, Lu Xu, Ying Wang, Jin-Xia Li, Yu Zhang, Chong Zhang, Sha-Sha Wang, Xue-Mei Zhang
BackgroundAstragalus membranaceus Bunge is one of the oldest and most frequently used crude herbs in traditional Chinese medicine. The total flavonoids of Astragalus (TFA) are the main active components isolated from Astragalus membranaceus Bunge. Our recent study has shown its potential immunomodulatory and anti-inflammatory effects in vivo and in vitro. However, its anti-arthritic effects and mechanisms of action involved have not been elucidated. The aim of this study was to evaluate the protective effects and possible mechanisms of TFA on Freund's complete adjuvant (FCA)-induced arthritis in rats.MethodsWistar rats were intradermally injected FCA into the right hind metatarsal footpads to establish adjuvant-arthritic model. The rats were intragastrically administered daily with TFA at 25, 50 and 100mg/kg for 28days after FCA induction. Body weight, primary paw swelling, arthritis index, thymus and spleen indices were measured. The levels of serum tumor necrosis factor (TNF)-α, interleukin (IL)-1β, prostaglandin (PG)E2, osteoprotegerin (OPG) and receptor activator of nuclear factor-κB ligand (RANKL) were determined using ELISA. Histopathological changes and scores in joint tissues were examined using hematoxylin and eosin (H&E). The expression of nuclear factor (NF)-κB p65 in synovial tissues was assayed using immunohistochemical method.ResultsTFA significantly increased body weight, attenuated primary paw swelling and arthritis index, decreased thymus and spleen indices of rats induced by FCA. Furthermore, TFA significantly inhibited serum TNF-α, IL-1β, PGE2 and RANKL production, and promoted serum OPG production and OPG/RANKL ratio of rats induced by FCA. Histopathological examination indicated that TFA significantly attenuated inflammatory cell infiltration, synovial hyperplasia, pannus formation, and bone and cartilage damage. Immunohistochemical assay indicated that TFA inhibited NF-κB p65 expression in synovial tissues of rats induced by FCA.ConclusionsThese results suggest that TFA exerts potential protective effects against FCA-induced arthritis in rats by regulating OPG/RANKL/NF-κB pathway.



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Augmentation of humoral and cellular immunity in response to Tetanus and Diphtheria toxoids by supercritical carbon dioxide extracts of Hippophae rhamnoides L. leaves

Publication date: March 2017
Source:International Immunopharmacology, Volume 44
Author(s): Bindhya Jayashankar, Divya Singh, Himanshi Tanwar, KP Mishra, Swetha Murthy, Sudipta Chanda, Jigni Mishra, R Tulswani, K Misra, SB Singh, Lilly Ganju
Hippophae rhamnoides L. commonly known as Seabuckthorn (SBT), a wild shrub of family Elaegnacea, has extensively used for treating various ailments like skin diseases, jaundice, asthma, lung troubles. SBT leaves have been reported to possess several pharmacological properties including immunomodulatory, antioxidant, anti-inflammatory, antimicrobial and tissue regeneration etc. The present study was undertaken to evaluate the adjuvant property of supercritical carbon dioxide extracts (SCEs 300ET and 350ET) of SBT leaves in balb/c mice immunized with Tetanus and Diphtheria toxoids. The dynamic changes in the immune response were measured in terms of humoral and cell-mediated immune responses. We have seen the effect of SCEs on immunoglobulin subtypes and secondary immune response generation. In addition, the effect of SCEs on antigen specific cellular immunity was evaluated. Our results show that SCEs 300ET and 350ET significantly enhanced antibody titers in response to both TT and DT antigens. The secondary immune response generated was significantly increased in case of TT immunized animals. SCEs also enhanced cytokine levels (IFN-γ, IL-4, TNF-α and IL-1β) and increased lymphoproliferation. Besides, both SCEs did not show any toxic effects. Therefore, the study suggests that SCEs are safe and have potent immunostimulatory activity and hence, seems to be a promising balanced Th1 and Th2 directing immunological adjuvant for various veterinary as well as human vaccines.



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Investigations on the immunosuppressive activity of derivatives of mycophenolic acid in immature dendritic cells

Publication date: March 2017
Source:International Immunopharmacology, Volume 44
Author(s): Dorota Iwaszkiewicz-Grzes, Grzegorz Cholewinski, Agata Kot-Wasik, Piotr Trzonkowski, Krystyna Dzierzbicka
The main activity of mycophenolic acid 1 (MPA) and its analogs is the inhibition of proliferation of T cells. Here, we hypothesized that MPA and its conjugates inhibits also the activity of antigen-presenting cells (APC) including dendritic cells (DCs). We tested the effect of novel amino acid derivatives of MPA and conjugates of MPA with acridines/acridones on DCs by flow cytometry, ELISA and MLR assay. Both acridines/acridone derivatives could inhibit the maturation of DC, as shown by the decreased expression of B7 family receptors. It was confirmed in the mixed leucocyte reaction (MLR), in which T cells challenged with DCs pretreated with the analogs showed decreased proliferation and reduced cytokine secretion. The most interesting activity in this series of studies, that is, the suppression of CD86 receptor expression, decreased cytokine production and suppressed mixed leucocyte reaction, exhibited (mycophenoyl-N-3-propyl)-9-acridone-4-carboxamide ester 5a and (mycophenoyl-N-5-pentyl)-9-acridone-4-carboxamide ester 5b. These compounds reduced also the secretion of IL-2 and IL-15. In addition, they increased secretion of suppressive IL-10. Equally promising results were obtained for the N-mycophenoyl-D-glutamic acid 4b, which previously gave the highest value of selectivity. Acridone derivatives of MPA are therefore good immunosuppressive drug candidates for further testing.

Graphical abstract

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Transmembrane tumor necrosis factor-α promotes the recruitment of MDSCs to tumor tissue by upregulating CXCR4 expression via TNFR2

Publication date: March 2017
Source:International Immunopharmacology, Volume 44
Author(s): Hongping Ba, Baihua Li, Xiaoyan Li, Cheng Li, Anlin Feng, Yazhen Zhu, Jing Wang, Zhuoya Li, Bingjiao Yin
Myeloid-derived suppressor cells (MDSCs) accumulated in tumor sites promote immune evasion. We found that TNFR deficiency-induced rejection of transplanted tumor was accompanied with markedly decreased accumulation of MDSCs. However, the mechanism(s) behind this phenomenon is not completely understood. Here, we demonstrated that TNFR deficiency did not affect the amount of MDSCs in bone marrow (BM), but decreased accumulation of Gr-1⁺CD11b⁺ MDSCs in the spleen and tumor tissues. The chemotaxis of Tnfr^−/− MDSCs was prominently decreased in response to both tumor cell culture supernatants and tumor tissue homogenates from Tnfr^−/− and wild-type mice, indicating an effect of TNFR signaling on chemokine receptor expression in MDSCs. We used real-time PCR to detect gene expression for several chemokine receptors in MDSCs from BM and found that CXCR4 was the most affected molecule at the transcriptional level in Tnfr^−/− MDSCs. Neutralizing CXCR4 in wild-type MDSCs by a specific antibody blocked their chemotactic migration. Interestingly, it was tmTNF-α, but not sTNF-α, that induced CXCR4 expression in MDSCs. This effect of tmTNF-α was totally blocked in TNFR2^−/− but not in TNFR1^−/− MDSCs, and partially inhibited by PDTC or SB203580, an inhibitor of NF-κB or p38 MAPK pathway, respectively. Adoptive transfer of wild-type MDSCs restored MDSCs accumulation in tumors of Tnfr^−/− mice, but this could be partially blocked by treatment with a CXCR4 inhibitor AMD3100. Our data suggest that tmTNF-α upregulates CXCR4 expression that promotes chemotaxis of MDSCs to tumor, and give a new insight into a novel mechanism by which tmTNF-α facilitates tumor immune evasion.



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Oculomotor and Linguistic Processing Effects in Reading Dynamic Horizontally Scrolling Text.

Author: Harvey, Hannah; Godwin, Hayward J.; Fitzsimmons, Gemma; Liversedge, Simon P.; Walker, Robin

DOI: 10.1037/xhp0000329

Publication Date: POST AUTHOR CORRECTIONS, 12 January 2017

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The Dynamic Range of Response Set Activation During Action Sequencing.

Author: Behmer, Lawrence P. Jr.; Crump, Matthew J. C.

DOI: 10.1037/xhp0000335

Publication Date: POST AUTHOR CORRECTIONS, 12 January 2017

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Spoken Words Can Make the Invisible Visible-Testing the Involvement of Low-Level Visual Representations in Spoken Word Processing.

Author: Ostarek, Markus; Huettig, Falk

DOI: 10.1037/xhp0000313

Publication Date: POST AUTHOR CORRECTIONS, 12 January 2017

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Beyond Trial-by-Trial Adaptation: A Quantification of the Time Scale of Cognitive Control.

Author: Aben, Bart; Verguts, Tom; Van den Bussche, Eva

DOI: 10.1037/xhp0000324

Publication Date: POST AUTHOR CORRECTIONS, 12 January 2017

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Reaching Into Response Selection: Stimulus and Response Similarity Influence Central Operations.

Author: Wifall, Tim; Buss, Aaron T.; Farmer, Thomas A.; Spencer, John P.; Hazeltine, Eliot

DOI: 10.1037/xhp0000301

Publication Date: POST AUTHOR CORRECTIONS, 12 January 2017

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Higher-Order Cognitive Control in Dual Tasks: Evidence From Task-Pair Switching.

Author: Hirsch, Patricia; Nolden, Sophie; Koch, Iring

DOI: 10.1037/xhp0000309

Publication Date: POST AUTHOR CORRECTIONS, 12 January 2017

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Generalized Movement Representation in Haptic Perception.

Author: Dupin, Lucile; Hayward, Vincent; Wexler, Mark

DOI: 10.1037/xhp0000327

Publication Date: POST AUTHOR CORRECTIONS, 12 January 2017

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A Stroke Mimic: Methotrexate-induced Neurotoxicity in the Emergency Department

Publication date: Available online 13 January 2017
Source:The Journal of Emergency Medicine
Author(s): Patrick Rogers, Wilbur J. Pan, Richard A. Drachtman, Christopher Haines
BackgroundAcute lymphoblastic leukemia (ALL) is the most common form of childhood leukemia. The treatment of ALL involves multimodality therapy, and methotrexate (MTX) remains a mainstay of treatment. A complication of MTX therapy includes acute, subacute, and chronic neurotoxocity. Signs and symptoms may range from headaches, dizziness, and mood disorders to seizures and stroke-like symptoms.Case ReportAn 18-year-old woman with a history of ALL presented to the emergency department with acute onset of right-sided facial paralysis, right upper extremity flaccid paralysis, and right lower extremity weakness after receiving MTX therapy 3 days earlier. Diagnostic studies were unremarkable and the patient was treated with oral dextromethorphan for presumed MTX-induced neurotoxicity. The patient's symptoms began to improve within hours and she was discharged home within 48 hours with no neurologic deficits.Why Should an Emergency Physician Be Aware of This?Emergency physicians should be aware of this complication of MTX therapy given the sensitivity in regards to time with respect to cerebral vascular accidents. An awareness of this complication in the setting of the appropriate history and physical examination can lead to an accurate diagnosis and intervention and the avoidance of administering thrombolytics.



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Response to “Reassessing Claims of Non-inferiority of Daptomycin”

Publication date: Available online 13 January 2017
Source:The Journal of Emergency Medicine
Author(s): George J. Shaw, Christopher J. Lindsell




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Intermittent bilateral coherence in physiological and essential hand tremor

Publication date: Available online 14 January 2017
Source:Clinical Neurophysiology
Author(s): Soma Chakraborty, Jana Kopecká, Otakar Šprdlík, Martina Hoskovcová, Olga Ulmanová, Evžen Růžička, Martin Zapotocky
[Objective]To investigate the prevalence and the temporal structure of bilateral coherence in physiological (PT) and essential (ET) hand tremor.[Methods]Triaxial accelerometric recordings from both hands in 30 healthy subjects and 34 ET patients were analyzed using spectral coherence and wavelet coherence methods. In 12 additional healthy subjects, the relation between the hand tremor and the chest wall acceleration was evaluated using partial coherence analysis.[Results]The majority of both PT and ET subjects displayed significant bilateral coherence. While in PT, bilateral coherence was most frequently found in resting hand position (97% of subjects), in ET the prevalence was comparable for resting (54%) and postural (49%-57%) positions. In both PT and ET, epochs of strong coherence lasting several to a dozen seconds were separated by intervals of insignificant coherence. In PT, bilateral coherence at the main tremor frequency (8-12 Hz) was coupled with the ballistocardiac rhythm.[Conclusion]The oscillations of the two hands are intermittently synchronized in both PT and ET. We propose that in postural PT, bilateral coherence at the main tremor frequency arises from transient simultaneous entrainment of the left and right hand oscillations to ballistocardiac forcing.[Significance]Bilateral coherence of hand kinematics provides a sensitive measure of synchronizing influences on the left and right tremor oscillators.



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A Cross-Sectional Study of Colonization Rates with Methicillin-Resistant Staphylococcus aureus (MRSA) and Extended-Spectrum Beta-Lactamase (ESBL) and Carbapenemase-Producing Enterobacteriaceae in Four Swiss Refugee Centres.

A Cross-Sectional Study of Colonization Rates with Methicillin-Resistant Staphylococcus aureus (MRSA) and Extended-Spectrum Beta-Lactamase (ESBL) and Carbapenemase-Producing Enterobacteriaceae in Four Swiss Refugee Centres.

PLoS One. 2017;12(1):e0170251

Authors: Piso RJ, Käch R, Pop R, Zillig D, Schibli U, Bassetti S, Meinel D, Egli A

Abstract
BACKGROUND: The recent crisis of refugees seeking asylum in European countries challenges public health on many levels. Most refugees currently arrive from Syria, Afghanistan, or Eritrea. Data about multidrug resistant bacteria (MDR) prevalence are not present for these countries. However, when entering the European heath care systems, data about colonisation rates regarding highly resistant bacterial pathogens are important.
METHODS: We performed a cross-sectional screening in four Swiss refugee centres to determine the colonization rates for MRSA and ESBL- and carbapenemase-producing Enterobacteriaceae. We used pharyngeal, nasal, and inguinal swabs for MRSA and rectal swabs and urine for ESBL and carbapenemase screening using standard microbiological procedures. Whole genome sequencing (WGS) was used to determine the relatedness of MRSA isolates with high resolution due to a suspected outbreak.
RESULTS: 41/261(15.7%) refugees were colonized with MRSA. No differences regarding the country of origin were observed. However, in a single centre significantly more were colonized, which was confirmed to be a recent local outbreak. 57/241 (23.7%) refugees were colonized with ESBL with significantly higher colonisation in persons originating from the Middle East (35.1%, p<0.001). No carbapenemase producers were detected.
CONCLUSION: The colonisation rate of the refugees was about 10 times higher for MRSA and 2-5 times higher for ESBL compared to the Swiss population. Contact precaution is warranted for these persons if they enter medical care. In cases of infections, MRSA and ESBL-producing Enterobacteriaceae should be considered regarding antibiotic treatment choices.

PMID: 28085966 [PubMed - in process]

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Intestinal Bacterial Colonization in the First 2 Weeks of Life of Nigerian Neonates Using Standard Culture Methods.

Related Articles

Intestinal Bacterial Colonization in the First 2 Weeks of Life of Nigerian Neonates Using Standard Culture Methods.

Front Pediatr. 2016;4:139

Authors: Kigbu A, Orimadegun AE, Tongo OO, Odaibo GN, Olaleye DO, Akinyinka OO

Abstract
OBJECTIVE: The pattern and timing of development of intestinal microflora in Nigerian infants have been scarcely researched. This study was carried out to investigate the bacteria flora in the rectum of healthy neonates in Ibadan, Nigeria.
PATIENTS AND METHODS: In this hospital-based longitudinal study, rectal swabs of 70 neonates were taken within 6-12 h of birth (day 1) and subsequently on days 3, 9, and 14. Information collected included maternal sociodemographic characteristics, antibiotic use for the neonates, and type of feeding during the first 14 days of life. Identification and speciation of gram-negative isolates were done using the Analytical Profile Index 20E(®) and 20NE(®) as appropriate. Gram-positive bacteria were identified biochemically using the catalase and coagulase tests. Data were analyzed using descriptive statistics and Chi-square at p = 0.05.
RESULTS: Majority (92.9%) of the neonates were delivered vaginally with a median gestational age of 38 weeks (range = 34-42). On the first day of life, Escherichia coli was isolated more frequently from the rectal swabs of preterm (50.0%) than term (23.1%) neonates (p = 0.031). On day 3 of life, coagulase-negative staphylococcus was the most frequently isolated bacteria from the rectal swabs of nonasphyxiated (64.4%) compared with asphyxiated (27.3%) neonates' rectal swabs (p = 0.042). Staphylococcus aureus was the most frequently isolated bacteria from the rectal swabs of nonexclusively breastfed (66.7%) than exclusively breastfed (21.3%) neonates on day 14 (p = 0.004).
CONCLUSION: Staphylococcus aureus and Escherichia coli were the predominant isolates from the rectum of Nigerian neonates, and these isolates were influenced by breastfeeding and mild-moderate asphyxia. In all, bacterial diversity in the rectum increased as the neonates got older.

PMID: 28083526 [PubMed - in process]

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Data supporting the effects of lysozyme on mRNA and protein expression in a colonic epithelial scratch wound model

Publication date: April 2017
Source:Data in Brief, Volume 11
Author(s): Sarah K. Abey, Yuana Yuana, Paule V. Joseph, Natnael D. Kenea, Nicolaas H. Fourie, LeeAnne B. Sherwin, Gregory E. Gonye, Paul A. Smyser, Erin S. Stempinski, Christina M. Boulineaux, Kristen R. Weaver, Christopher K.E. Bleck, Wendy A. Henderson
Colonic epithelial health is implicated in a host of gastrointestinal (GI) diseases and disorders. Lysozyme is suspected to play a role in the ability of the epithelium to recover from injury (Abey et al., in press; Gallo, 2012; Rubio, 2014) [1–3]. Disrupted repair mechanisms may lead to delayed or ineffective recovery and disruptions to epithelial biology resulting in GI symptoms and altered barrier function (Peterson and Artis, 2014) [4]. The effect of lysozyme on the transcriptomic and proteomic profile of healthy colonic epithelial cells was investigated. Epithelial cells in culture were scratch wounded and treated with lysozyme. mRNA and protein profiles were simultaneously quantified in the same sample using a digital counting technology. Gene and protein expressions altered by the presence or absence of lysozyme are described in this article. Extensive statistical and bioinformatic analysis, and interpretation of the results can be found in "Lysozyme association with circulating RNA, extracellular vesicles, and chronic stress" (Abey et al., in press) [1].



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Temporal variations in early developmental decisions: an engine of forebrain evolution

Publication date: February 2017
Source:Current Opinion in Neurobiology, Volume 42
Author(s): H Bielen, S Pal, S Tole, C Houart
Tight control of developmental timing is pivotal to many major processes in developmental biology, such as patterning, fate specification, cell cycle dynamics, cell migration and connectivity. Temporal change in these ontogenetic sequences is known as heterochrony, a major force in the evolution of body plans and organogenesis. In the last 5 years, studies in fish and rodents indicate that heterochrony in signaling during early development generates diversity in forebrain size and complexity. Here, we summarize these findings and propose that, additionally to spatio-temporal tuning of neurogenesis, temporal and quantitative modulation of signaling events drive pivotal changes in shape, size and complexity of the forebrain across evolution, participating to the generation of diversity in animal behavior and emergence of cognition.



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Combination of Everolimus with Sorafenib for Solid Renal Tumors in Tsc2+/− Mice Is Superior to Everolimus Alone

Publication date: February 2017
Source:Neoplasia, Volume 19, Issue 2
Author(s): Jian Yang, Paulina A. Samsel, Kalin Narov, Ashley Jones, Daniel Gallacher, John Gallacher, Julian R. Sampson, Ming Hong Shen
Tuberous sclerosis (TSC) is an inherited tumor syndrome caused by mutations in TSC1 or TSC2 that lead to aberrant activation of mTOR and development of tumors in multiple organs including the kidneys. The mTOR inhibitors rapamycin and everolimus (rapalogs) have demonstrated clinical efficacy in treating TSC-associated tumors including renal angiomyolipomas. However, tumor responses are usually only partial, and regrowth occurs after drug withdrawal. TSC-associated tumors are highly vascular, and TSC patients with renal angiomyolipomas have elevated levels of circulating vascular endothelial growth factor (VEGF) A and VEGFD. Sorafenib inhibits multiple kinases including VEGF receptors and has been used to treat metastatic epithelioid angiomyolipoma in one case, but formal trials have not been undertaken. In this study, we investigated tumor angiogenesis and the therapeutic efficacy of everolimus in combination with sorafenib for renal tumors in Tsc2^+/− mice. We found that these tumors exhibited remarkably variable angiogenesis despite consistent aberrant activation of mTOR and increased expression of HIF1α and VEGFA. Treatment of 11-month-old Tsc2^+/− mice for 2 months with a combination of everolimus and sorafenib significantly reduced the number and size of solid renal tumors, whereas everolimus or sorafenib alone did not. These results suggest that inhibition of mTOR and multiple kinases including VEGF receptors using combination therapy could hold promise for the treatment of TSC-associated tumors that have responded inadequately to a rapalog alone.



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pH, Lactate, and Hypoxia: Reciprocity in Regulating High-Affinity Monocarboxylate Transporter Expression in Glioblastoma

Publication date: February 2017
Source:Neoplasia, Volume 19, Issue 2
Author(s): James P. Caruso, Brandon J. Koch, Philip D. Benson, Elsa Varughese, Michael D. Monterey, Amy E. Lee, Ajal M. Dave, Sam Kiousis, Andrew E. Sloan, Saroj P. Mathupala
Highly malignant brain tumors harbor the aberrant propensity for aerobic glycolysis, the excessive conversion of glucose to lactic acid even in the presence of ample tissue oxygen. Lactic acid is rapidly effluxed to the tumor microenvironment via a group of plasma-membrane transporters denoted monocarboxylate transporters (MCTs) to prevent "self-poisoning." One isoform, MCT2, has the highest affinity for lactate and thus should have the ability to respond to microenvironment conditions such as hypoxia, lactate, and pH to help maintain high glycolytic flux in the tumor. Yet, MCT2 is considered to not respond to hypoxia, which is counterintuitive. Its response to tumor lactate has not been reported. In this report, we experimentally identify the transcription initiation site/s for MCT2 in astrocytes (normal) and glioma (tumor). We then use a BACmid library to isolate a 4.2-kbp MCT2 promoter-exon I region and examine promoter response to glycolysis-mediated stimuli in glioma cells. Reporter analysis of nested-promoter constructs indicated response of MCT2 to hypoxia, pH, lactate, and glucose, the major physiological "players" that facilitate a tumor's growth and proliferation. Immunoblot analysis of native MCT2 expression under altered pH and hypoxia reflected the reporter data. The pH-mediated gene-regulation studies we describe are the first to record H⁺-based reporter studies for any mammalian system and demonstrate the exquisite response of the MCT2 gene to minute changes in tumor pH. Identical promoter usage also provides the first evidence of astrocytes harnessing the same gene regulatory regions to facilitate astrocyte-neuron lactate shuttling, a metabolic feature of normal brain.



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Integrating a street-canyon model with a regional Gaussian dispersion model for improved characterisation of near-road air pollution

Publication date: March 2017
Source:Atmospheric Environment, Volume 153
Author(s): Masoud Fallah-Shorshani, Maryam Shekarrizfard, Marianne Hatzopoulou
The development and use of dispersion models that simulate traffic-related air pollution in urban areas has risen significantly in support of air pollution exposure research. In order to accurately estimate population exposure, it is important to generate concentration surfaces that take into account near-road concentrations as well as the transport of pollutants throughout an urban region. In this paper, an integrated modelling chain was developed to simulate ambient Nitrogen Dioxide (NO2) in a dense urban neighbourhood while taking into account traffic emissions, the regional background, and the transport of pollutants within the urban canopy. For this purpose, we developed a hybrid configuration including 1) a street canyon model, which simulates pollutant transfer along streets and intersections, taking into account the geometry of buildings and other obstacles, and 2) a Gaussian puff model, which resolves the transport of contaminants at the top of the urban canopy and accounts for regional meteorology. Each dispersion model was validated against measured concentrations and compared against the hybrid configuration. Our results demonstrate that the hybrid approach significantly improves the output of each model on its own. An underestimation appears clearly for the Gaussian model and street-canyon model compared to observed data. This is due to ignoring the building effect by the Gaussian model and undermining the contribution of other roads by the canyon model. The hybrid approach reduced the RMSE (of observed vs. predicted concentrations) by 16%–25% compared to each model on its own, and increased FAC2 (fraction of predictions within a factor of two of the observations) by 10%–34%.



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Incontinence and psychological symptoms in individuals with Mowat-Wilson Syndrome

Publication date: Available online 13 January 2017
Source:Research in Developmental Disabilities
Author(s): Justine Niemczyk, Stewart Einfeld, David Mowat, Monika Equit, Catharina Wagner, Leopold Curfs, Alexander von Gontard
BackgroundMowat-Wilson Syndrome (MWS) is caused by deletion/mutation of the ZEB2 gene on chromosome 2q22. MWS is characterized by a distinctive facial appearance, severe intellectual disability and other anomalies, e.g. seizures and/or Hirschsprung disease (HSCR). Most individuals have a sociable demeanor, but one third show psychological problems.AimsThe aim was to investigate incontinence and psychological problems in MWS.Methods and procedures26 children (4–12 years), 13 teens (13–17 years) and 8 adults (>18years) were recruited through a MWS support group. The Parental Questionnaire: Enuresis/Urinary Incontinence, as well as the Developmental Behaviour Checklist (DBC) were completed by parents or care-givers.Outcomes and results97.7% of persons with MWS had incontinence (nocturnal enuresis 74.4%; daytime urinary incontinence 76.2%; fecal incontinence 81.4%). Incontinence remained high over age groups (children 95.8%, teens 100%, adults 100%). 46.2% of children, 25% of teens and 37.5% of adults exceeded the clinical cut-off on the DBC. The ability to use the toilet for micturition improved with age.Conclusions and implicationsMWS incontinence rates are very high. All had physical disabilities including anomalies of the genitourinary and gastrointestinal tract. Due to the high prevalence rates, a screening for incontinence and psychological problems in MWS is recommended.



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Acknowledgment to reviewers—2016

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Common characteristics of functional and adverse outcomes in acute lower-extremity trauma reconstruction

Abstract

Background

Injury to the lower extremity is one of the most common traumatic injuries encountered in both combat and civilian situations. Improvements in sterile technique, the use of antibiotics, bony fixation, and microvascular reconstruction have shifted the management paradigm from predominantly amputation to limb salvage. We reviewed acute lower-extremity reconstruction in a single suburban trauma center and identified common characteristics of functional and adverse outcomes.

Methods

The records of patients treated at a level I trauma center for lower-extremity injuries and requiring plastic surgery consultation or intervention were reviewed. Common demographic and clinical characteristics for three functional outcomes (range of motion, return to work, and ambulation) and three adverse outcomes (venous thromboembolism, rehospitalization, and operative revision) were compared.

Results

Of the 4039 patients treated for a lower-extremity traumatic injury over a 6-year period, 92 (2.3%) patients met the inclusion criteria. Severity of injury was a common determinant of outcome. On long-term follow-up, the majority of patients were ambulatory (n = 50), albeit frequently with some deficit in range of motion or gait disturbance. When modifiable characteristics were evaluated, an increased length of time to soft-tissue coverage was associated with both an increased incidence of venous thromboembolism and range-of-motion deficit.

Conclusions

Delayed definitive soft-tissue coverage of lower-extremity traumatic wounds is associated with thromboembolic events and range-of-motion deficits. Involvement of a plastic surgeon in a multi-disciplinary trauma team could expedite definitive wound coverage and improve clinical outcomes of lower-extremity trauma. Future research evaluating the impact of early plastic surgery involvement on outcome measures is necessary.

Level of Evidence: Level IV, risk/prognostic study

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