Cell-Type-Specific Epigenetic Editing at the Fosb Gene Controls Susceptibility to Social Defeat Stress.
Chronic social defeat stress regulates the expression of Fosb in the nucleus accumbens (NAc) to promote the cell-type-specific accumulation of ΔFosB in the two medium spiny neuron (MSN) subtypes in this region. ΔFosB is selectively induced in D1-MSNs in the NAc of resilient mice, and in D2-MSNs of susceptible mice. However, little is known about the consequences of such selective induction, particularly in D2-MSNs. This study examined how cell-type-specific control of the endogenous Fosb gene in NAc regulates susceptibility to social defeat stress. Histone post-translational modifications (HPTMs) were targeted specifically to Fosb using engineered zinc-finger proteins (ZFPs). Fosb-ZFPs were fused to either the transcriptional repressor, G9a, which promotes histone methylation or the transcriptional activator, p65, which promotes histone acetylation. These ZFPs were expressed in D1- vs D2-MSNs using Cre-dependent viral expression in the NAc of mice transgenic for Cre recombinase in these MSN subtypes. We found that stress susceptibility is oppositely regulated by the specific cell type and HPTM targeted. We report that Fosb-targeted histone acetylation in D2-MSNs or histone methylation in D1-MSNs promotes a stress-susceptible, depressive-like phenotype, while histone methylation in D2-MSNs or histone acetylation in D1-MSNs increases resilience to social stress as quantified by social interaction behavior and sucrose preference. This work presents the first demonstration of cell- and gene-specific targeting of histone modifications, which model naturally occurring transcriptional phenomena that control social defeat stress behavior. This epigenetic-editing approach, which recapitulates physiological changes in gene expression, reveals clear differences in the social defeat phenotype induced by Fosb gene manipulation in MSN subtypes.


The Projected Impact of a Neighborhood-scaled Green Infrastructure Retrofit.
Climate change and its related factors are increasing the frequency of hurricanes, coastal storms, and urban flooding. Recovery from disasters can be slow, with jurisdictions failing to build back better, wasting time and money without improving resilience to the next disaster. To help attenuate floods and mitigate their impacts, Low Impact Development (LID) and the incorporation of green infrastructure (GI) is gaining in popularity. LID installs more natural methods of absorbing, redirecting, retaining, and filtering water, through GI installations such as rain gardens, detention ponds, and the reduction of impervious surfaces. LID is, however, primarily implemented and evaluated only on a local scale; few studies have assessed the broader impacts of GI on a larger scale. In fact, most performance calculators that evaluate the effects of GI are only useful at the site scale. Further, most advocates of GI propose its use in new developments, without much attention to retrofitting existing, suburban development. This article seeks to determine what the potential effects of retrofitting an existing, suburban neighborhood with GI for flood protection at a larger scale could be, using Sugar Land, Texas, USA as a case site. First, low-impact facilities are proposed and schematically designed at a site scale for a typical single-family lot. The volume of rainfall that can be retained on site, due to each incorporated feature, is then derived using the Green Values National Storm Water Management Calculator. Using this data, the total volume of rainfall that could be retained if all residential sites in Sugar Land incorporate similar facilities is then projected. The result show that Sugar Land has the capacity to capture 56 billion liters of stormwater water annually if all residential properties use LID. Additional benefits of the use of GI include reduced heat (37%), improved aesthetics and property values (20%), increased recreational opportunities (18%), improved water quality (12%), improved air quality (5%), increased green collar jobs (4%), reduced damage from harmful gas emissions (3%), and increased energy savings (1%), thereby surpassing conventional storm water management techniques [1].


Machine Learning Assisted Approach for Finding Novel High Activity Agonists of Human Ectopic Olfactory Receptors.
Olfactory receptors (ORs) constitute the largest superfamily of G protein-coupled receptors (GPCRs). ORs are involved in sensing odorants as well as in other ectopic roles in non-nasal tissues. Matching of an enormous number of the olfactory stimulation repertoire to its counterpart OR through machine learning (ML) will enable understanding of olfactory system, receptor characterization, and exploitation of their therapeutic potential. In the current study, we have selected two broadly tuned ectopic human OR proteins, OR1A1 and OR2W1, for expanding their known chemical space by using molecular descriptors. We present a scheme for selecting the optimal features required to train an ML-based model, based on which we selected the random forest (RF) as the best performer. High activity agonist prediction involved screening five databases comprising ~23 M compounds, using the trained RF classifier. To evaluate the effectiveness of the machine learning based virtual screening and check receptor binding site compatibility, we used docking of the top target ligands to carefully develop receptor model structures. Finally, experimental validation of selected compounds with significant docking scores through in vitro assays revealed two high activity novel agonists for OR1A1 and one for OR2W1.


[Telematics equipment for poison control surveillance. Its applications in the health management of relevant chemical incidents].
Health management of major chemical incidents requires a close collaboration between rescuers (on the disaster site and in the emergency department) and the poison center. The study tested telematic technologies allowing telepresence and teleconsulting, a real time and continuous connection among health care personnel and toxicologists involved in the management of the emergency. The link between the poison center (PC) and the emergency department in the local hospital is provided by a ISDN operating video conferencing system, while the data transmission from the site of the accident to the PC is achieved with a personal computer and GSM cellular data transmission. Toxicological databases and risk assessment software are integrated in the system, to support information sharing. To test such instruments in operative nearly realistic conditions, the main phase of the study has implemented simulated chemical disasters in different locations in Italy. Instruments for telepresence and teleconsulting have been effectively utilized to evaluate from a remote location the scenario and the severity of the accident, by inspecting either specific details or the whole scene, to enable PC guiding the triage of the victims before and after hospitalization, to utilize and share data, such as intervention protocols or patient records, and to document all the activities. In summary, this experience shows that the telematic link allows the toxicologists of the poison center to rapidly understand the situation, and to correctly learn about the conditions of patients with the help of images. The results of this study indicate the valuable benefits of telematic instruments for the health care in case of major chemical disasters occurring in a remote geographical location or in an area which lacks local toxicological experts, where specialized expertise can be achieved by the use of telematic technologies.


The Challenge of Peat Substitution in Organic Seedling Production: Optimization of Growing Media Formulation through Mixture Design and Response Surface Analysis.
Peat replacement is an increasing demand in containerized and transplant production, due to the environmental constraints associated to peat use. However, despite the wide information concerning the use of alternative materials as substrates, it is very complex to establish the best materials and mixtures. This work evaluates the use of mixture design and surface response methodology in a peat substitution experiment using two alternative materials (green compost and palm fibre trunk waste) for transplant production of tomato (Lycopersicon esculentum Mill.); melon, (Cucumis melo L.); and lettuce (Lactuca sativa L.) in organic farming conditions. In general, the substrates showed suitable properties for their use in seedling production, showing the best plant response the mixture of 20% green compost, 39% palm fibre and 31% peat. The mixture design and applied response surface methodology has shown to be an useful approach to optimize substrate formulations in peat substitution experiments to standardize plant responses.


The protocol and design of a randomised controlled study on training of attention within the first year after acquired brain injury.
To describe the design of the study aiming to examine intensive targeted cognitive rehabilitation of attention in the acute (<4 months) and subacute rehabilitation phases (4-12 months) after acquired brain injury and to evaluate the effects on function, activity and participation (return to work). Within a prospective, randomised, controlled study 120 consecutive patients with stroke or traumatic brain injury were randomised to 20 hours of intensive attention training by Attention Process Training or by standard, activity based training. Progress was evaluated by Statistical Process Control and by pre and post measurement of functional and activity levels. Return to work was also evaluated in the post-acute phase. Primary endpoints were the changes in the attention measure, Paced Auditory Serial Addition Test and changes in work ability. Secondary endpoints included measurement of cognitive functions, activity and work return. There were 3, 6 and 12-month follow ups focussing on health economics. The study will provide information on rehabilitation of attention in the early phases after ABI; effects on function, activity and return to work. Further, the application of Statistical Process Control might enable closer investigation of the cognitive changes after acquired brain injury and demonstrate the usefulness of process measures in rehabilitation. The study was registered at ClinicalTrials.gov Protocol. NCT02091453, registered: 19 March 2014.


Reversible control of the chromium valence in chemically reduced Cr-doped SrTiO3 bulk powders.
The effect of chemical reduction by NaBH4 on the electronic structure of Cr-doped SrTiO3-δ bulk powders prepared by a solid-state reaction was systematically studied as a function of reduction temperature. Electron paramagnetic resonance (EPR) and diffuse reflectance spectroscopies (DRS) were utilized to monitor changes in the electronic structures of both intrinsic defects (oxygen vacancies and/or Ti(3+)) and extrinsic dopants (Cr(3+)) at different reduction temperatures. We identify the existence of two temperature regimes where changes occur within 30 min. The first temperature regime occurs between 300-375 °C and results in (1) reduction of oxygen-related surface defects, and (2) an increase in the concentration of Cr(3+) by over an order of magnitude, suggesting that EPR-silent Cr(4+) or Cr(6+) is being reduced to Cr(3+) by NaBH4. The second temperature regime occurs between 375-430 °C where we observe clear evidence of Ti(3+) formation by EPR spectroscopy that indicates chemical reduction of the SrTiO3 lattice. In addition, the oxygen-related surface defects observed in regime 1 are not formed in regime 2, but instead lattice oxygen vacancies (VO) are observed by EPR. The changes to the Cr-doped SrTiO3 electronic structure after chemical reduction in regime 1 are quantitatively reversible after aerobic annealing at 400 °C for 30 min. The internal oxygen vacancies formed during the higher temperature reductions in regime 2 require increased temperatures of at least 600 °C to be fully reoxidized in 30 min. The effect of these different oxygen-related defects on the EPR spectrum of substitutional Cr(3+) dopants is discussed. These results allow us to independently tune the dopant and host electronic structures of a technologically-relevant multifunctional material by a simple ex situ chemical perturbation.


Effect of Proanthocyanidin, Fluoride and Casein Phosphopeptide Amorphous Calcium Phosphate Remineralizing Agents on Microhardness of Demineralized Dentin.
The aim of this study was to evaluate the effect of dentin remineralization using proanthocyanidin (PA), fluoride varnish and casein phosphopeptide amorphous calcium phosphate (CPP-ACP) paste and their various combinations on microhardness of demineralized root dentin. One-hundred and twenty freshly extracted sound human premolars were selected and randomly divided into eight groups for dentin treatment as follows. C: Deionized water (control); PA: 6.5% PA solution; F: fluoride varnish (5% NaF, 22600 ppm fluoride); CP: CCP-ACP; PAF: 6.5% PA + fluoride varnish; PACP: 6.5% PA + CCP-ACP; FCP: fluoride varnish + CCP-ACP and PAFCP: 6.5% PA + fluoride varnish + CCP-ACP. All specimens were subjected to Vickers microhardness test (500 g, 10 seconds, 3 points). Data were analyzed using one-way ANOVA and Tukey's post hoc test. The significance level was set at 0.05. The mean and standard deviation (SD) values of Vickers hardness number (VHN) in groups C, PA, F, CP, PAF, PACP, FCP and PAFCP were 37.39±4.97, 38.68±4.62, 48.28±2.68, 41.91±3.32, 48.59±2.55, 53.34±2.57, 48.413±4.00 and 55.20±1.82, respectively. Pairwise comparisons of the groups revealed that there was no significant difference between groups C and PA, PA and CP, F and PAF, F and FCP, PAF and FCP, and PACP and FPACP (P>0.05); but significant differences were observed between other groups (P<0.05). The results of this study showed that the tested dentin treatments increased the microhardness of demineralized root dentin except for PA application.


Selenoproteins are essential for proper keratinocyte function and skin development.
Dietary selenium is known to protect skin against UV-induced damage and cancer and its topical application improves skin surface parameters in humans, while selenium deficiency compromises protective antioxidant enzymes in skin. Furthermore, skin and hair abnormalities in humans and rodents may be caused by selenium deficiency, which are overcome by dietary selenium supplementation. Most important biological functions of selenium are attributed to selenoproteins, proteins containing selenium in the form of the amino acid, selenocysteine (Sec). Sec insertion into proteins depends on Sec tRNA; thus, knocking out the Sec tRNA gene (Trsp) ablates selenoprotein expression. We generated mice with targeted removal of selenoproteins in keratin 14 (K14) expressing cells and their differentiated descendents. The knockout progeny had a runt phenotype, developed skin abnormalities and experienced premature death. Lack of selenoproteins in epidermal cells led to the development of hyperplastic epidermis and aberrant hair follicle morphogenesis, accompanied by progressive alopecia after birth. Further analyses revealed that selenoproteins are essential antioxidants in skin and unveiled their role in keratinocyte growth and viability. This study links severe selenoprotein deficiency to abnormalities in skin and hair and provides genetic evidence for the role of these proteins in keratinocyte function and cutaneous development.


Regulation of adipocyte 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) by CCAAT/enhancer-binding protein (C/EBP) β isoforms, LIP and LAP.
11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyses intracellular regeneration of active glucocorticoids, notably in liver and adipose tissue. 11β-HSD1 is increased selectively in adipose tissue in human obesity, a change implicated in the pathogenesis of metabolic syndrome. With high fat (HF)-feeding, adipose tissue 11β-HSD1 is down-regulated in mice, plausibly to counteract metabolic disease. Transcription of 11β-HSD1 is directly regulated by members of the CCAAT/enhancer binding protein (C/EBP) family. Here we show that while total C/EBPβ in adipose tissue is unaltered by HF diet, the ratio of the C/EBPβ isoforms liver-enriched inhibitor protein (LIP) and liver-enriched activator protein (LAP) (C/EBPβ-LIP:LAP) is increased in subcutaneous adipose. This may cause changes in 11β-HSD1 expression since genetically modified C/EBPβ((+/L)) mice, with increased C/EBPβ-LIP:LAP ratio, have decreased subcutaneous adipose 11β-HSD1 mRNA levels, whereas C/EBPβ(ΔuORF) mice, with decreased C/EBPβ-LIP:LAP ratio, show increased subcutaneous adipose 11β-HSD1. C/EBPβ-LIP:LAP ratio is regulated by endoplasmic reticulum (ER) stress and mTOR signalling, both of which are altered in obesity. In 3T3-L1 adipocytes, 11β-HSD1 mRNA levels were down-regulated following induction of ER stress by tunicamycin but were up-regulated following inhibition of mTOR by rapamycin. These data point to a central role for C/EBPβ and its processing to LIP and LAP in transcriptional regulation of 11β-HSD1 in adipose tissue. Down-regulation of 11β-HSD1 by increased C/EBPβ-LIP:LAP in adipocytes may be part of a nutrient-sensing mechanism counteracting nutritional stress generated by HF diet.


Organising primary health care for people with asthma: the patient's perspective.
The 1993 chronic disease management contract encourages United Kingdom general practices to implement a standardised package of care with an emphasis on regular visits to an asthma clinic. To explore the views of people with asthma about the organisation of asthma care in general practice. Semi-structured interviews with 20 patients registered with one practice with a nurse-run asthma clinic. The sample was selected to provide people with a wide range of ages and disease severity, and included parents of children. The age range of the interviewees was five to 87 years (parents of children were interviewed) and half of the interviewees had attended the asthma clinic at some time. In describing how they managed their asthma, people identified their medical care alongside other important factors, such as avoiding smoking and pollution, and a decision to seek medical help was made in the context of all of life's other priorities. People expressed diverse views about the organisation of care, describing how their needs changed over time and how they balanced up several factors in deciding what was best for them. These factors were encompassed by four themes: the accessibility of care, severity of asthma and dealing with uncertainty, self-knowledge and self-management, and expert knowledge and therapeutic relationships. Interviewees were evenly split between wishing to be seen regularly in the clinic and wishing only to attend when needing help. Patients required asthma services that allow individual choice and flexibility, and eight service objectives were identified that would cover most people's needs.


Characterization and treatment monitoring of inflammatory arthritis by photoacoustic imaging: a study on adjuvant-induced arthritis rat model.
Neovascularity also known as angiogenesis is an early feature of inflammatory arthritis disease. Therefore, identifying the development of neovascularity is one way to potentially detect and characterize arthritis. Laser-based photoacoustic imaging (PAI) is an emerging biomedical imaging modality which may aid in the detection of both early and continued development of neovascularity. In this work, we investigated the feasibility of PAI to measure angiogenesis, for the purpose of evaluating and monitoring inflammatory arthritis and responses to treatment. The imaging results on an arthritis rat model demonstrate that 1) there is noticeable enhancement in image intensities in the arthritic ankle joints when compared to the normal joints, and 2) there is noticeable decrease in image intensities in the arthritic ankle joints after treatment when compared to the untreated arthritic joints. In order to validate the findings from PAI, we performed positron emission tomography (PET) and histology on the same joints. The diameters of the ankle joints, as a clinical score of the arthritis, were also measured at each time point.


The Mediational Role of Cognitive Emotion Regulation Strategies in the Relationship of Ego-strength and Adjustment to Infertility in Women.
Infertility is considered as an intense and prolonged stressful experience. Despite of high prevalence of infertility and its emotional burden for couples and especially for women, the knowledge regarding psychological factors influencing adjustment to it is limited. The aim of the present study was to investigate the mediational role of cognitive emotion regulation strategies in the relationship of ego-strength and adjustment to infertility in women. A total number of 275 women with primary infertility referring to Valie-asr Reproductive Health Research Center (Tehran Imam Khomeini Hospital) participated in the present study. Data was collected via demographic information questionnaire, Ego-Strength Scale (ESS), Cognitive Emotion Regulation Questionnaire (CERQ) and Adjustment to Illness Scale (AIS). Data were analysed using Pearson correlation and path analysis methods Using SPSS (18) and LISREL (8.5) software. RESULTS indicated there are significant positive correlation between ego-strength and adjustment to infertility (r = 0.44, p < 0.01). Also Adjustment has significant positive correlation withadaptive emotion regulation strategies (r = 0.38, p < 0.01) and significant negative correlation with non-adaptive emotion regulation strategies (r = -0.43, p < 0.01). RESULTS of path analysis indicated emotion regulation strategies mediate the relationship of ego-strength and adjustment. These results can be helpful in making preventive policies, identifying high risk patients and planning psychological interventions.


Stiff skin syndrome: a case report.
Stiff skin syndrome (SSS) is a disease similar to scleroderma with an unknown etiology. Stone-hard areas of skin are observed from birth or in early childhood. In this article we describe a 15-year-old girl with skin hardening and limitation of movement. We diagnosed the case as SSS, of which we have not encountered a similar report in the Turkish literature.


Oxidative stress responses in human bronchial epithelial cells exposed to cigarette smoke and vapor from tobacco- and nicotine-containing products.
The use of novel tobacco- and nicotine-containing vapor products that do not combust tobacco leaves is on the rise worldwide. The emissions of these products typically contain lower numbers and levels of potentially harmful chemicals compared with conventional cigarette smoke. These vapor products may therefore elicit fewer adverse biological effects. We compared the effects of emissions from different types of such products, i.e., our proprietary novel tobacco vapor product (NTV), a commercially available heat-not-burn tobacco product (HnB), and e-cigarette (E-CIG), and a combustible cigarette in a human bronchial epithelial cell line. The aqueous extract (AqE) of the test product was prepared by bubbling the produced aerosol into medium. Cells were exposed to the AqEs of test products, and then glutathione oxidation, Nrf2 activation, and secretion of IL-8 and GM-CSF were examined. We found that all endpoints were similarly perturbed by exposure to each AqE, but the effective dose ranges were different between cigarette smoke and the tobacco- and nicotine-containing vapors. These results demonstrate that the employed assays detect differences between product exposures, and thus may be useful to understand the relative potential biological effects of tobacco- and nicotine-containing products.


Selection on age at reproduction in Drosophila melanogaster: female mating frequency as a correlated response.
We examined the effect of selection for age at reproduction on female mating frequency and fertility in female Drosophila melanogaster. Selection for increased age at reproduction (and hence increased lifespan) resulted in higher late life female mating frequencies, while females selected for younger ages at reproduction showed increased early life mating frequencies. These results indicate that the response to selection on age at reproduction has involved changes in the scheduling of female reproductive behavior.


Correlation between methylphenidate and ritalinic acid concentrations in oral fluid and plasma.
We studied the excretion profile of methylphenidate (MPH) and its metabolite ritalinic acid (RA) in oral fluid and plasma, the oral fluid-to-plasma (OF/P) drug ratio, and the variations of oral fluid pH after drug administration. We analyzed oral fluid and plasma samples, obtained from 8 healthy volunteers after ingestion of a single dose of 20 mg fast-release or extended-release MPH, for MPH and RA by LC-MS. We estimated the apparent pharmacokinetic parameters of MPH in plasma and oral fluid and calculated the OF/P ratio for each time interval. MPH and RA were detected in oral fluid. Whereas parent drug concentrations in oral fluid were an order of magnitude higher than those in plasma, the opposite was observed for RA. Oral fluid concentrations of MPH ranged between 0.5 and 466.7 microg/L and peaked at 0.5 h after administration of the fast-release formulation; they ranged between 0.7 and 89.5 microg/L and peaked at 2 h after administration of the extended-release formulation. Both formulations presented bimodal time-course curves for the OF/P ratio, ranging between 1.8 and 242.1 for the fast-release formulation and between 2.6 and 27.0 for extended-release. Oral fluid pH did not appear to be modified by the administration of the drug, and its influence on OF/P ratio did not affect the correlation of MPH between the 2 body fluids. The results obtained support the measurement of MPH in oral fluid as an alternative to plasma if the extended-release formulation is used.


Lipid Nanoparticles as a Shuttle for Anti-Adipogenic miRNAs to Human Adipocytes.
Obesity and type 2 diabetes are major health burdens for which no effective therapy is available today. One treatment strategy could be to balance the metabolic functions of adipose tissue by regulating gene expressions using miRNAs. Here, we have loaded two anti-adipogenic miRNAs (miR26a and miR27a) into a pegylated lipid nanoparticle (PEG-LNP) formulation by a single-step microfluidic-assisted synthesis step. For the miRNA-loaded LNPs, the following system properties were determined: particle size, zeta potential, miRNA complexation efficiency, and cytotoxicity. We have used a human preadipocyte cell line to address the transfection efficiency and biological effects of the miRNA candidates at the gene and protein level. Our findings revealed that the upregulation of miR27a in preadipocytes inhibits adipogenesis by the downregulation of PPARγ and the reduction of lipid droplet formation. In contrast, miR26a transfection in adipocytes induced white adipocyte browning detected as the upregulation of uncoupling protein 1 (UCP1) as a marker of non-shivering thermogenesis. We conclude that the selective delivery of miRNAs by PEG-LNPs to adipocytes could offer new perspectives for the treatment of obesity and related metabolic diseases.


Understanding and overcoming barriers to medication adherence: a review of research priorities.
Improving medication adherence has been identified as a crucial step towards improving health outcomes for patients with chronic disease and has provided the motivation for many changes in our health care system. Despite the volume of research done on this topic, however, we still lack important basic information about how to improve adherence in a cost-effective way. There is a need for a better understanding of what areas of research are most likely to produce advances that could be used by policymakers, providers, payers, or other stakeholders to generate real improvements in medication adherence. To address this, we developed a set of research priorities designed to improve understanding about whom to target for adherence interventions and which particular interventions to employ for specific subpopulations. To produce this research agenda, we synthesized information from the existing literature with a series of stakeholder interviews and expert panel meetings. We identified 6 key areas for research: (1) predicting nonadherence, (2) behavioral factors affecting nonadherence, (3) measuring the impact of nonadherence on health and cost outcomes, (4) effectiveness of existing interventions, (5) misaligned incentives between payers and providers, and (6) provider training and coordination of care. We provide detailed descriptions and example topics within each area. As the health care system continues to embrace reforms designed to improve the value of care, more and better information is needed to guide efforts designed to improve medication adherence. Addressing the topic areas identified here will be an important step towards accomplishing this goal.


Gas spectroscopy and optical path-length assessment in scattering media using a frequency-modulated continuous-wave diode laser.
Simultaneous assessment of the spectroscopic absorption signal of gas enclosed in a scattering medium and the corresponding optical path length of the probing light is demonstrated using a single setup. Sensitive gas absorption measurements are performed by a tunable diode laser using wavelength-modulation spectroscopy, while the path length is evaluated by the frequency-modulated cw technique commonly used in the field of telecommunication. Proof-of-principle measurements are demonstrated with water vapor as the absorbing gas and using polystyrene foam as an inhomogeneously scattering medium. The combination of these techniques opens up new possibilities for straightforward evaluation of gas presence and exchange in scattering media.


In situ cross-linked and highly carboxylated poly(vinyl alcohol) nanofibrous membranes for efficient adsorption of proteins.
Creating adsorptive materials for the fast, efficient, and high-throughput adsorption and purification of proteins is critical to meet the great demands for highly purified proteins, yet it has proven to be a highly challenging task. Here, we report that cross-linked and highly carboxylated poly(vinyl alcohol) (PVA) nanofibrous membranes were fabricated by a combination of electrospinning and the in situ graft polymerization of PVA and maleic anhydride (MAH) under mild conditions. Taking advantage of the large surface area available for protein binding, the highly tortuous porous structure, and the robust mechanical properties, the resultant PVA/MAH nanofibrous membranes exhibited a good integrated adsorption performance towards lysozyme, including a superior adsorption capacity of 177 mg g-1, fast adsorption equilibrium within 4 h, good selectivity, and good reversibility. Moreover, the saturation dynamic adsorption amount towards lysozyme reached 159 mg g-1 under 750 Pa driven solely by gravity, which conformed to the specified requirements for high adsorption capacity under relatively low pressure drops. Furthermore, the adsorption performance towards a protein mixture was analyzed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and the resultant PVA/MAH nanofibrous membranes retained excellent stability under depyrogenation conditions. The successful fabrication of such fascinating nanofibrous materials by using this simple and intriguing approach may provide new insights into the design and development of adsorptive materials for the purification of proteins with superior adsorption performance.


Activity of CD4-Pseudomonas exotoxin against cells expressing diverse forms of the HIV and SIV envelope glycoproteins.
CD4(178)-PE40 is a genetically engineered hybrid toxin containing a portion of human CD4 linked to the translocation and ADP-ribosylation domains of Pseudomonas exotoxin A. In vitro, the molecule has been shown to selectively kill cells expressing the envelope glycoproteins of human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV), and to inhibit HIV spread. In this report we examine the activity of the hybrid toxin against cells expressing diverse forms of the HIV and SIV envelope glycoproteins, encoded by recombinant vaccinia virus vectors. The activity of CD4(178)-PE40 was found to be unaffected by mutations in the HIV-1 or HIV-2 envelope glycoprotein genes, which prevent normal proteolytic processing of the corresponding gp160 precursor molecules. Cells expressing a mutant HIV-1 envelope glycoprotein lacking most of the cytoplasmic tail of the gp41 transmembrane subunit were also sensitive to the hybrid toxin. Most interestingly, HIV-1, HIV-2, and SIVmac envelope glycoprotein molecules known to have widely differing affinities for CD4 were found to be comparably effective at mediating sensitivity to CD4(178)-PE40. By virtue of its ability to kill infected cells, the hybrid toxin inhibited the spread of SIVmac in vitro. These results indicate that CD4(178)-PE40 is active against cells expressing HIV and SIV envelope glycoproteins with a diverse array of structural differences.


Blocking the monocyte chemoattractant protein-1/CCR2 chemokine pathway induces permanent survival of islet allografts through a programmed death-1 ligand-1-dependent mechanism.
Islet allografts are subject to rapid rejection through host cellular immune responses involving mononuclear cell recruitment and tissue injury. Interruption of leukocyte recruitment through chemokine receptor targeting is of therapeutic benefit in various experimental models, but little is known about the contribution of chemokine pathways to islet allograft rejection. We found that murine islets produce monocyte chemoattractant protein-1 (MCP-1; CCL2) in vitro and that islet allograft rejection was associated with intragraft expression of MCP-1 and its receptor, CCR2. We therefore investigated whether MCP-1 and CCR2 are required for the rejection of fully MHC-disparate islet allografts. Wild-type mice treated with blocking anti-MCP-1 mAb plus a brief, subtherapeutic course of rapamycin had long-term islet allograft survival, in contrast to the effect of treatment with either mAb or rapamycin alone. CCR2(-/-) mice treated with rapamycin also maintained islet allografts long-term. Both MCP/CCR2- and rapamycin-sensitive signals were required for maximal proliferation of alloreactive T cells, suggesting that MCP-1/CCR2 induce rejection by promoting alloreactive T cell clonal expansion and homing and migration. Prolonged islet allograft survival achieved by blockade of the MCP-1/CCR2 pathway plus rapamycin therapy was accompanied by a mononuclear cell infiltrate expressing the inhibitory receptor, programmed death-1 (PD-1), and its ligand (PD-L1, B7-H1), and prolongation of islet allograft survival was abrogated by anti-PD-L1 mAb therapy. These data show that the blockade of MCP-1 binding to CCR2 in conjunction with subtherapeutic immunosuppression can have profound effects on islet allograft survival and implicate the expression of the PD-1/PD-L1 pathway in the regulation of physiologic responses in vivo.


Conjugational recombination in resolvase-deficient ruvC mutants of Escherichia coli K-12 depends on recG.
ruvC mutants of Escherichia coli appear to lack an activity that resolves Holliday intermediates into recombinant products. Yet, these strains produce close to normal numbers of recombinants in genetic crosses. This recombination proficiency was found to be a function of recG. A "mini-kan" insertion in recG was introduced into ruvA, ruvB, and ruvC strains. Conjugational recombination was reduced by more than 100-fold in recG ruvA::Tn10, recG ruvB, and recG ruvC strains and by about 30-fold in a recG ruvA strain carrying a ruvA mutation that is not polar on ruvB. The double mutants also proved very deficient in P1 transduction and are much more sensitive to UV light than ruv single mutants. Since mutation of recG alone has very modest effects on recombination and sensitivity to UV, it is concluded that there is a functional overlap between the RecG and Ruv proteins. However, this overlap does not extend to circular plasmid recombination. The possibility that RecG provides a second resolvase that can substitute for Ruv is discussed in light of these findings.


Copper carbenes alkylate guanine chemoselectively through a substrate directed reaction.
Cu(i) carbenes derived from α-diazocarbonyl compounds lead to selective alkylation of the O6 position in guanine (O6-G) in mono- and oligonucleotides. Only purine-type lactam oxygens are targeted - other types of amides or lactams are poorly reactive under conditions that give smooth alkylation of guanine. Mechanistic studies point to N7G as a directing group that controls selectivity. Given the importance of O6-G adducts in biology and biotechnology we expect that Cu(i)-catalyzed O6-G alkylation will be a broadly used synthetic tool. While the propensity for transition metals to increase redox damage is well-appreciated, our results suggest that transition metals might also increase the vulnerability of nucleic acids to alkylation damage.


Moving research tools into practice: the successes and challenges in promoting uptake of classification tools.
In this paper, we present our experiences - both successes and challenges - in implementing evidence-based classification tools into clinical practice. We also make recommendations for others wanting to promote the uptake and application of new research-based assessment tools. We first describe classification systems and the benefits of using them in both research and practice. We then present a theoretical framework from Implementation Science to report strategies we have used to implement two research-based classification tools into practice. We also illustrate some of the challenges we have encountered by reporting results from an online survey investigating 58 Speech-language Pathologists' knowledge and use of the Communication Function Classification System (CFCS), a new tool to classify children's functional communication skills. We offer recommendations for researchers wanting to promote the uptake of new tools in clinical practice. Specifically, we identify structural, organizational, innovation, practitioner, and patient-related factors that we recommend researchers address in the design of implementation interventions. Roles and responsibilities of both researchers and clinicians in making implementations science a success are presented. Implications for rehabilitation Promoting uptake of new and evidence-based tools into clinical practice is challenging. Implementation science can help researchers to close the knowledge-to-practice gap. Using concrete examples, we discuss our experiences in implementing evidence-based classification tools into practice within a theoretical framework. Recommendations are provided for researchers wanting to implement new tools in clinical practice. Implications for researchers and clinicians are presented.


Palliative nursing care for the patient experiencing end-stage renal failure.
Caring for the patient with end-stage renal disease poses many challenges for the bedside nurse. Yet, how do we care for patients who continue to seek hemodialysis with a guarded prognosis? A discussion about palliative care and specific interventions used to help improve quality of life for the end-stage renal patient is provided. A case example accompanies this article, and highlights the interventions used successfully for one such patient.


Patch-clamp measurements of elementary chloride currents activated by the putative inhibitory transmitter GABA and glycine in mammalian spinal neurons.
Methods for measuring whole-cell and unitary Cl- currents in the soma membrane of cultured spinal cord neurons by the patch-clamp technique are described. To separate single channel Cl- currents activated by the two putative inhibitory transmitters GABA and glycine from other membrane currents, isotonic KCl pipette solutions are used for measurements on "cell-attached" membrane patches. To isolate unitary Cl- currents in "cell-free" membrane patches, symmetrical, isotonic Tris Cl- solutions are used in both the pipette and the bath. Single Cl- channels are opened following binding of two agonist molecules to their respective receptors. The gating behavior of single receptor-channel complexes is described in terms of the activation and desensitization mechanism suggested originally by del Castillo and Katz (1957) and Katz and Thesleff (1957).


Embryonic stem cells attenuate myocardial dysfunction and inflammation after surgical global ischemia via paracrine actions.
Stem cell treatment may positively influence recovery and inflammation after shock by multiple mechanisms, including the paracrine release of protective growth factors. Embryonic stem cells (ESCs) are understudied and may have greater protective power than adult bone marrow stem cells (BMSCs). We hypothesized that ESC paracrine protective mechanisms in the heart (decreased injury by enhanced growth factor-mediated reduction of proinflammatory cytokines) would be superior to the paracrine protective mechanisms of the adult stem cell population in a model of surgically induced global ischemia. Adult Sprague-Dawley rat hearts were isolated and perfused via Langendorff model. Hearts were subjected to 25 min of warm global ischemia and 40 min of reperfusion and were randomly assigned into one of four groups: 1) vehicle treated; 2) BMSC or ESC preischemic treatment; 3) BMSC or ESC postischemic treatment; and 4) BMSC- or ESC-conditioned media treatment. Myocardial function was recorded, and hearts were analyzed for expression of tissue cytokines and growth factors (ELISA). Additionally, ESCs and BMSCs in culture were assessed for growth factor production (ELISA). ESC-treated hearts demonstrated significantly greater postischemic recovery of function (left ventricular developed pressure, end-diastolic pressure, and maximal positive and negative values of the first derivative of pressure) than BMSC-treated hearts or controls at end reperfusion. ESC-conditioned media (without cells) also conferred cardioprotection at end reperfusion. ESC-infused hearts demonstrated increased VEGF and IL-10 production compared with BMSC hearts. ESC hearts also exhibited decreased proinflammatory cytokine expression compared with MSC hearts. Moreover, ESCs in cell culture demonstrated greater pluripotency than MSCs. ESC paracrine protective mechanisms in surgical ischemia are superior to those of adult stem cells.


Influence of the Fuzzy Function on the Estimation of the Fuzzy Sample Entropy with Fixed Tolerance Values for the Evaluation of Surface EMG Muscle Activity.
Fixed sample entropy (fSampEn) is a technique that has demonstrated superior performance to other amplitude estimators for assessing respiratory muscle electromyographic activity. This technique is based on the calculation of sample entropy (SampEn) using fixed tolerance thresholds. Fuzzy entropy (FuzzyEn) introduces an improvement to the SampEn algorithm based on the use of a fuzzy measure to evaluate the similarity between vectors. However, several fuzzy functions have been used to calculate the FuzzyEn, and not all of them allow an effective comparison with the SampEn calculation parameters. In the present work, an analysis of the different fuzzy functions previously used has been carried out and a new sigmoid fuzzy function for the calculation of FuzzyEn with fixed tolerance thresholds (fFuzzyEn) has been proposed. The results show that the proposed fuzzy function outperformed both fSampEn and previously proposed FuzzyEn-based algorithms. These results suggest that fFuzzyEn could improve the assessment of muscle activity providing potentially useful diagnostic information.Clinical Relevance- This sets out the appropriate use of the fuzzy function for the estimation of the fuzzy sample entropy with fixed tolerance thresholds (fFuzzyEn). The use of fFuzzyEn could improve methods for detecting the onset and offset of respiratory electromyographic (EMG) signals, as well as the assessment of EMG activation level.


Early intervention versus standard of care for mild idiopathic scoliosis: A case-controlled series based on SOSORT criteria evaluating the impact of a scoliosis activity suit.
In the present study, a group of adolescent patients diagnosed with mild adolescent idiopathic scoliosis wore a scoliosis activity suit instead of maintaining the recommended observation only strategy. These patients wore the scoliosis activity suit for up to 60 minutes twice daily while performing normal daily activities. These patients were followed through until end of growth. Their end of growth results were compared to a group of adolescent idiopathic scoliosis (AIS) patients who only participated in observation. The group who wore the scoliosis activity suit maintained their curve measurements through skeletal maturity, while the observation group saw their curves increase an average of 7 degrees. This study showed that a group of AIS patients were able to prevent their curves from progressing during growth, while those participating in an observation-only strategy saw their curves progress to beyond threshold where rigid brace prescription is recommended. These changes were statistically significant in intergroup comparison, as well as intragroup before and after comparison.


[Use of continuous high-volume hemofiltration in patients with sepsis and multiple organ dysfunction].
The paper gives the authors' experience in performing continuous high-volume hemofiltration in 38 patients with sepsis and multiple organ failure. The kinetics of proinflammatory cytokines and a number of plasma enzymes as markers of substances having a relatively high molecular mass was studied. The advantages of a procedure using an artificial kidney apparatus equipped with an on-line substituting fluid preparation system are described. The possibilities of correcting the parameters of homeostasis are the principles of maintenance of a hemostatic system in this group of patients during the procedure are presented. The drawbacks of this technique are also described.


Intra- and inter-instrument reliability of the actiwatch 4 accelerometer in a mechanical laboratory setting.
This study aimed to quantify the intra-and inter-instrument reliability of the Actiwatch 4 accelerometer (AW4) in a mechanical setting. Twenty seven AW4 were attached to an isokinetic dynamometer and subjected to angular acceleration for 30 min at 50 deg/sec representing moderate intensity (MPA condition) and 200 deg/sec representing vigorous intensity (VPA condition), with a repeat trial conducted. Reliability was assessed using coefficient of variation (CV), absolute percent error (APE), and intraclass correlation coefficients (ICC). Mean AW4 activity counts displayed acceptable reliability according to CV in both conditions (ConMPA: CVintra = 4.6%, APEintra = 6.6%, CVinter = 6.4%, APEinter = 5.2%; ConVPA: CVintra = 3.9%, APEintra = 5.6%, CVinter = 5.9%, APEinter = 4.7%). When counts were re-categorised into minutes of MPA and VPA, lower CV values were observed (ConMPA: CVintra = 3.2%, APEintra = 4.5%, CVinter = 4.3%, APEinter = 3.2%; ConVPA: CVintra = 0.0%, APEintra = 0.0%, CVinter = 0.0%, APEinter = 0.0%). When activity counts were re-categorised as minutes of MVPA, excellent reliability was observed (CVintra, APEintra, CVinter, and APEinter = 0.0%) in both conditions. Mean AW4 activity counts exhibit reliability statistics comparable to other accelerometers. Reliability is improved when activity counts are re-categorised as time spent in MPA and VPA, with greatest reliability obtained when counts are recategorised as time spent in MVPA. As MVPA is the subcomponent of physical activity most associated with health benefits it would appear that the AW4 is reliable for measuring time spent in this health enhancing intensity category, at least from testing in a mechanical laboratory setting.


Single-cell protein profiling defines cell populations associated with triple-negative breast cancer aggressiveness.
Triple-negative breast cancer (TNBC) is an aggressive and complex subtype of breast cancer that lacks targeted therapy. TNBC manifests characteristic, extensive intratumoral heterogeneity that promotes disease progression and influences drug response. Single-cell techniques in combination with next-generation computation provide an unprecedented opportunity to identify molecular events with therapeutic potential. Here, we describe the generation of a comprehensive mass cytometry panel for multiparametric detection of 23 phenotypic markers and 13 signaling molecules. This single-cell proteomic approach allowed us to explore the landscape of TNBC heterogeneity, with particular emphasis on the tumor microenvironment. We prospectively profiled freshly resected tumors from 26 TNBC patients. These tumors contained phenotypically distinct subpopulations of cancer and stromal cells that were associated with the patient's clinical status at the time of surgery. We further classified the epithelial-mesenchymal plasticity of tumor cells, and molecularly defined phenotypically diverse populations of tumor-associated stroma. Furthermore, in a retrospective tissue-microarray TNBC cohort, we showed that the level of CD97 at the time of surgery has prognostic potential.


The affective dimension of early-onset psychosis and its relationship with suicide.
The affective dimension has scarcely been studied in early-onset psychosis. Our aims were to investigate the prevalence and type of affective symptoms in the prodromal and acute phases of early-onset psychosis and to examine their relationship with suicide. We also sought to establish whether the presence of premorbid antecedents or the presence of affective symptoms during the prodromal and acute phase might predict a later diagnosis of bipolar disorder (BP) or schizophrenia (SZ). Participants were 95 youths, aged 9-17 years, experiencing a first episode of a psychotic disorder (FEP) according to DSM-IV criteria. Prodromal affective symptoms in the year prior to the onset of full-blown psychosis were assessed by means of the K-SADS. Affective symptoms during the acute episode were evaluated using the Hamilton Depression Rating Scale and the Young Mania Rating Scale. Suicidality was assessed during the acute episode and at 6 and 12 months. Half of the patients experienced affective symptoms during the prodrome, with depressive symptoms being the most frequently reported. During the acute episode, 23.2% presented depressive, 41.4% mixed and 18.9% manic symptoms. After logistic regression analysis, only the presence of depressive symptoms was significantly associated with suicidality during the 12 months following the FEP. Neither early premorbid antecedents nor the prevalence or type of affective symptoms during the FEP predicted a diagnosis of BP or SZ at 12 months. However, both depressive and manic prodromal symptoms were associated with a later diagnosis of BP. The FEP of both SZ and BP is preceded by an identifiable prodromal phase. Early detection programs should target young people at clinical risk for the extended psychosis phenotype. The high prevalence of affective symptoms during the early phases of psychosis may encourage clinicians to identify and treat them in order to prevent suicide behaviour.


Surveillance and Selective Treatment of Brugia malayi Filariasis Eleven Years after Stopping Mass Drug Administration in Belitung District, Indonesia.
Brugia malayi is the major cause of lymphatic filariasis (LF) in Indonesia. Zoophilic B. malayi was endemic in Belitung district, and mass drug administration (MDA) with diethylcarbamazine (DEC) and albendazole ceased after five annual rounds in 2010. The district passed three transmission assessment surveys (TAS) between 2011 and 2016. As part of the post-TAS3 surveillance of the national LF elimination program, we collected night blood samples for microfilaria (Mf) detection from 1,911 subjects more than 5 years of age in seven villages. A B. malayi Mf prevalence ranging from 1.7% to 5.9% was detected in five villages. Only 2 (5%) of the total 40 Mf-positive subjects were adolescents aged 18 and 19 years old, and 38 (95%) Mf-positive subjects were 21 years and older. Microfilarial densities in infected individuals were mostly low, with 60% of the subjects having Mf densities between 16 and 160 Mf/mL. Triple-drug treatment with ivermectin, DEC, and albendazole (IDA) was given to 36 eligible Mf-positive subjects. Adverse events were mostly mild, and treatment was well tolerated. One year later, 35 of the treated Mf-positive subjects were reexamined, and 33 (94%) had cleared all Mf, while the anti-Bm14 antibody prevalence remained almost unchanged. Results indicate that in B. malayi-endemic areas, post-TAS3 surveillance for Mf in the community may be needed to detect a potential parasite reservoir in adults. Selective treatment with IDA is highly effective in clearing B. malayi Mf and should be used to increase the prospects for LF elimination if MDA is reintroduced.


Blood Lactate And Lactate Clearance: Refined Biomarker And Prognostic Marker In Burn Resuscitation.
Adequate resuscitation of acute burn patients is important to ensure end organ perfusion and oxygenation. The ideal marker to the endpoint of burn resuscitation is still not established. We aimed to evaluate the role of blood lactate and lactate clearance in burn resuscitation and their association with mortality and sepsis in burn patients. The retrospective study included patients (18-50 years) with thermal and scald burns with total body surface area of 30% to 60% over a period of 9 months who had achieved target urine output of at least 0.5ml/kg/hr within 24 hours of resuscitation. Patients were divided based on their admission blood lactate levels (Group A < 2 mmol/L and Group B > 2 mmol/L). Group B was further subdivided into Group B1 in whom blood lactate levels reached less than 2 mmol/L within 24 hours of burn resuscitation and Group B2 in whom it did not. Total patients included were 203. Mortality (M) and sepsis (S) rates in subgroup B2 were higher (M=57.9%; S=43.5%) and rates in subgroup B1 (M=25.8%; S=27.4%) were comparable to Group A (M=27.8%; S=26.4%). Persistent lactic acidosis at 24 hours was independently associated with significantly increased mortality and sepsis. Our data suggests a correlation of blood lactate levels and lactate clearance within 24 hours of admission with mortality and sepsis related to burn injury.


The application of evidence-based practice to nonspeech oral motor treatments.
The purpose of this article is to help speech-language pathologists (SLPs) apply the principles of evidence-based practice (EBP) to nonspeech oral motor treatments (NSOMTs) in order to make valid, evidence-based decisions about NSOMTs and thus determine if they are viable treatment approaches for the management of communication disorders. A detailed description of EBP is provided, including levels of evidence for rating the quality of evidence. NSOMTs are described and a survey of the literature on NSOMTs is provided along with a determination of the level of evidence of each study reported. A systematic literature search was conducted using the electronic databases of MEDLINE and CINAHL (Cumulative Index to Nursing and Allied Health Literature) within an unrestricted time period. In addition, reference lists from identified articles were also reviewed. Ethical and fiscal issues related to EBP and NSOMTs, as well as clinical implications of EBP for the use of NSOMTs, are discussed. A total of 45 articles/reports were published between 1981 and 2006 in peer-reviewed and non-peer-reviewed journals. Most of the sources (25) relied on weak anecdotal evidence and opinions. Moreover, studies that employed stronger designs reported negative results for NSOMTs (i.e., evidence against the use of NSOMTs for modifying speech). Despite their use for many years and their popularity among some SLPs for the treatment of a wide variety of speech problems in children and adults, NSOMTs are controversial because sufficient evidence does not exist to support their effectiveness in improving speech. Moreover, limited evidence exists for the use of NSOMTs to facilitate nonspeech activities. Therefore, the available evidence does not support the continued use of NSOMTs as a standard treatment and they should be excluded from use as a mainstream treatment until there are further data. SLPs should consider the principles of EBP in making decisions about NSOMTs.


The timing of perinatal hypoxia/ischemia events in term neonates: a retrospective autopsy study. HSPs, ORP-150 and COX2 are reliable markers to classify acute, perinatal events.
The understanding of the cellular responses implicated in perinatal brain damages and the characterization of the various mechanisms involved might open new horizons for understanding the time of onset of a brain hypoxic-ischemic lesion and for effective therapeutic strategies. We performed an immunohistochemical investigation on brain and brainstem sections of 47 peripartum deaths. The gradation and localization of the expression of antibodies such as TNFalpha, IL-1beta, IL-6, HSPs, beta APP, anti-TrypH, GAP43, GFAP, COX2, ORP-150, could be correlated with an hypoxic-ischemic damage to document a significant correlation between response and the time of onset acute (</=8 hs) or non-acute (>/=8 hs </=48 hs). In non-acute cases HSP70 reaction was prominent in the neuron cytoplasm, while in acute cases a mild reaction was evident in sporadic fields. HSP90 exhibited a similar pattern of positivity as HSP70. In acute group, ORP150 expressed an intense reaction showing a granular pattern in the cytoplasm of the neurons in the cortex of the infarcted areas. In non-acute group the positive reaction was more intense in astrocytes and less extended in neurons. COX2 reaction exhibited the strongest positive reaction in the neuronal cell bodies of acute cases, while a immunolabeling was prominent in the glial cytoplasm in the non-acute cases. Chaperones HSP70 and 90, ORP-150 reaction, and COX2 protein, have provided very interesting results. These results would suggest to the clinicians to extend the differential diagnosis of a too large perinatal hypoxic-ischemic insult category to delineate a more accurate chronological judgement.


[Acute and chronic poisoning in extraction and processing of raw quartz and feldspar].
The authors showed relationships of technologic features, occupational hazards at workplaces with risks of acute and chronic poisoning among workers engaged into extraction and processing of raw quartz and feldspar. The authors determined directions of occupational diseases prophylaxis.


The horizontal-vertical illusion in photographs of concrete scenes with and without depth information.
On the basis of the hypothesis of misapplied constancy scaling, the perception of an abstract horizontal-vertical illusion figure embedded in photographs of natural scenes with depth cues is investigated. The effect is compared with that of a figure on photographs containing no depth information and with a figure on a neutral surface. It is shown that the magnitude of the illusion in the perspective scenes is greater than in the other two conditions. The results are considered compatible with a constancy theory of the illusion. Finally, the evidence for misapplied constancy scaling in the horizontal-vertical illusion in relation to a retinal theory is discussed.


The long non-coding RNA TP73-AS1 modulates HCC cell proliferation through miR-200a-dependent HMGB1/RAGE regulation.
P73 antisense RNA 1 T (non-protein coding), also known as TP73-AS1, is a long non-coding RNA (lncRNA) which is involved in cell proliferation and the development of tumors. However, the exact effects and molecular mechanisms of TP73-AS1 in hepatocellular carcinoma (HCC) progression are still unknown. The present study is aimed to investigate the detailed functions and the mechanism of TP73-AS1 in regulation of HCC cell proliferation. TP73-AS1 expression in HCC tissues and cell lines was determined using real-time PCR assays; the correlation of TP73-AS1 expression with clinicopathological features of HCC was analyzed. The functions of TP73-AS1 in regulation of HCC cell proliferation was evaluated using MTT and BrdU assays. The candidate upstream miRNAs of HMGB1 were screened using miRcode, miRWalk, miRanda and Target scan, verified using real-time PCR assays. The interaction between TP73-AS1 and miR-200a was confirmed using Luciferase report gene assays. The proten levels of HMGB1 signaling-related factors in response to co-processing TP73-AS1 knockdown and miR-200a inhibition were determined using Western blot assays and ELISA. Further, miR-200a, HMGB1 mRNA and RAGE mRNA and their correlations in HCC tissues were determined. TP73-AS1 was upregulated in HCC tissues and cell lines. High TP73-AS1 expression was correlated with worse clinicopathological features, poorer prognosis and shorter survival. Knockdown of TP73-AS1 inhibited the HCC proliferation and the expression levels of HMGB1, RAGE and NF-κB in HCC cells. By using online tools, we screened out several candidate upstream miRNAs of HMGB1, among which miR-200a overexpression inhibited HMGB1 mRNA expression the most significantly. By using luciferase assays, we confirmed that miR-200a could directly bind to TP73-AS1 and the 3'UTR of HMGB1; TP73-AS1 competed with HMGB1 for miR-200a binding. MiR-200a inhibition could up-regulate HMGB1, RAGE, NF-κB expression as well as NF-κB regulated cytokines levels, which could be partially restored by si-TP73-AS1. In HCC tissues, miR-200a was down-regulated while HMGB1 and RAGE were up-regulated; TP73-AS1 was inversely correlated with miR-200a, while positively correlated with HMGB1 and RAGE, respectively. Our data indicated that TP73-AS1 might be an oncogenic lncRNA that promoted proliferation of HCC and could be regarded as a therapeutic target in human HCC.


Erythropoietin in cancer: an update.
Erythropoietin (EPO) has long been recognized as the major hematopoietic cytokine regulating normal erythropoiesis. Moreover, there is a growing interest in the non-erythropoietic, tissue-protective effects of EPO. Because of its potential to correct anemia, EPO has been increasingly prescribed to cancer patients. However, although recombinant human Epo (rHuEPO) significantly reduces the risk for red blood cell transfusions in cancer patients, recent clinical studies have reported decreased survival and disease control following rHuEPO treatment in patients with different cancer types. The issue of EPOR expression in tumor cells is critical in this respect. The expression of EPOR in tumor cells raises the possibility that exogenous rHuEPO may directly influence tumor growth or sensitivity to chemo-radiation therapy. In addition, EPOR expression in endothelial cells suggests what potential effects EPO may have on tumor capillaries, such as the stimulation of angiogenesis. However, as experimental studies reveal, the overall direct effect of EPO-EPOR signaling on cancer progression and therapy is not a straightforward one. The current paper provides an update on the biology of EPO, and discusses its utility in the treatment of cancer patients.


A new 3-point bending traction method for restoring cervical lordosis and cervical manipulation: a nonrandomized clinical controlled trial.
To evaluate a new 3-point bending type of cervical traction. Nonrandomized controlled trial of prospective, consecutive patients compared with control subjects. Follow-up patient data were obtained at 3 and 15(1/2) months, and 8 1/10 months for controls. Data were collected at a spine clinic in Nevada. Volunteer subjects consisted of 30 patients and 24 controls. Subjects had cervicogenic pain (neck pain, headaches, arm pain, and/or numbness). Subjects were included if their Ruth Jackson radiographic stress lines measured less than 25 degrees but were excluded if they had suspected disk herniation or canal stenosis. All subjects completed the first follow-up examinations, and 25 of 30 patients completed the long-term follow-up examination. Spinal manipulation for pain and a new form of 3-point bending cervical traction to improve lordosis. Cervical manipulation was provided for the first 3 to 4 weeks of treatment. Traction treatment consisted of 3 to 5 sessions per week for 9 +/- 1 weeks. Besides pain visual analog scale (VAS) ratings, pre- and posttreatment lateral cervical radiographs were analyzed. Control subjects reported no change in the pain VAS ratings and had no statistically significant change in segmental or global radiographic alignment. For the traction group, VAS ratings were 4.3 pretreatment and 1.6 posttreatment. Traction group radiographic measurements showed statistically significant improvements (P <.008 in all instances of statistical significance), including anterior head weight bearing (improved 6.2mm), Cobb angle at C2-7 (improved 12.1 degrees ), and angle between posterior tangents at C2-7 (improved 14.2 degrees ). For the treatment group, at 15(1/2)-month follow-up, only minimal loss of C2-7 lordosis (3.5 degrees ) was observed. Sagittal cervical traction with transverse load at midneck (2-way cervical traction) combined with cervical manipulation can improve cervical lordosis in 8 to 10 weeks as indicated by increases in segmental and global cervical alignment. Magnitude of lordosis at C2-7 remained stable at long-term follow-up.


Induced pluripotent stem cell-derived brain organoids as potential human model system for chemotherapy induced CNS toxicity.
Neurotoxic phenomena are among the most common side effects of cytotoxic agents. The development of chemotherapy-induced polyneuropathy (CIPN) is a well-recognized adverse reaction in the peripheral nervous system, while changes of cognitive functions (post-chemotherapy cognitive impairment (PCCI)) are more diffuse and have only recently drawn scientific interest. PCCI in patients most often displays as short-term memory loss, reduced multitasking ability or deficits in language. Not least, due to a lack of preclinical human model systems, the underlying molecular mechanisms are poorly understood, and treatments are missing. We thus investigated whether induced pluripotent stem cell (iPSC)-derived brain organoids can serve as a human model system for the study of chemotherapy induced central nervous system toxicity. We robustly generated mature brain organoids from iPSC-derived neuronal precursor cells (NPC), which showed a typical composition with 1) dividing NPCs forming ventricle like structures 2) matured neurons and 3) supporting glial cells closer to the surface. Furthermore, upon stimulation the brain organoids showed functional signaling. When exposed to increasing concentrations of paclitaxel, a frequently used chemotherapy drug, we observed time dependent neurotoxicity with an EC50 of 153 nM, comparable to a published murine model system. Histological analysis after paclitaxel exposure demonstrated dose dependent apoptosis induction and reduced proliferation in the organoids with further Western blot analyses indicating the degradation of neuronal calcium sensor one protein (NCS-1) and activation of Caspase-3. We could also provide evidence that paclitaxel treatment negatively affects the pool of neuronal and astrocyte precursor cells as well as mature neurons. In summary our data suggests that human iPSC derived brain organoids are a promising preclinical model system to investigate molecular mechanisms underlying PCCI and to develop novel prevention and treatment strategies.


Proximal and distal colorectal cancer resection rates in the United States since widespread screening by colonoscopy.
Screening decreases colorectal cancer (CRC) incidence and mortality. Colonoscopy has become the most common CRC screening test in the United States, but the degree to which it protects against CRC of the proximal colon is unclear. We examined US trends in rates of resection for proximal vs distal CRC, which reflect CRC incidence, in the context of national CRC screening data, before and since Medicare's 2001 decision to pay for screening colonoscopy. We used the Nationwide Inpatient Sample, the largest US all-payer inpatient database, to estimate age-adjusted rates of resection for distal and proximal CRC, from 1993 to 2009, in adults. Temporal trends were analyzed using Joinpoint regression analysis. The rate of resection for distal CRC decreased from 38.7 per 100,000 persons (95% confidence interval [CI], 35.4-42.0) to 23.2 per 100,000 persons (95% CI, 20.9-25.5) from 1993 to 2009, with annual decreases of 1.2% (95% CI, 0.1%-2.3%) from 1993 to 1999, followed by larger annual decreases of 3.8% (95% CI, 3.3%-4.3%) from 1999 to 2009 (P < .001). In contrast, the rate of resection for proximal CRC decreased from 30.0 per 100,000 persons (95% CI, 27.4-32.5) to 22.7 per 100,000 persons (95% CI, 20.6-24.7) from 1993 to 2009, but significant annual decreases of 3.1% (95% CI, 2.3%-4.0%) occurred only after 2002 (P < .001). Rates of resection for CRC decreased for adults ages 50 years and older, but increased for younger adults. These findings support the hypothesis that population-level decreases in rates of resection for distal CRC are associated with screening, in general, and that implementation of screening colonoscopy, specifically, might be an important factor that contributes to population-level decreases in rates of resection for proximal CRC.


Inorganic anion transport in kidney and intestinal brush border and basolateral membranes.
The efflux of inorganic anions from purified brush border and basolateral membrane vesicles from dog kidney cortex was measured under equilibrium exchange conditions. Marked differences in temperature sensitivity and effects of inhibitors were found between the Cl and SO4 transport pathways and between the two types of membranes. SO4 transport in both brush border and basolateral membranes was markedly reduced by cooling, but significant inhibition by 4,4'-diisothiocyano-2,2'-disulfonic stilbene (DIDS) was only observed in basolateral vesicles. In contrast, Cl efflux from both types of vesicles was neither substantially inhibited by DIDS nor by lowering the temperature to 0 degrees C. Phosphate efflux from basolateral membrane vesicles was found to be only partially sensitive to DIDS. Attempts to label the stilbene-sensitive SO4 pathway in basolateral vesicles using [3H2]DIDS as a marker were unsuccessful due to the nonspecific labeling of many membrane components. The asymmetry in inorganic anion transport behavior exhibited by brush border and basolateral membrane vesicles from dog renal proximal tubule was also observed in equivalent vesicles prepared from rat small intestine.


Kinetic mechanism of pulmonary carbonyl reductase.
The kinetic mechanism of guinea-pig lung carbonyl reductase was studied at pH 7 in the forward reaction with five carbonyl substrates and NAD(P)H and in the reverse reaction with propan-2-ol and NAD(P)+. In each case the enzyme mechanism was sequential, and product-inhibition studies were consistent with a di-iso ordered bi bi mechanism, in which NAD(P)H binds to the enzyme first and NAD(P)+ leaves last and the binding of cofactor induces isomerization. The kinetic and binding studies of the cofactors and several inhibitors such as pyrazole, benzoic acid, Cibacron Blue and benzamide indicate that the cofactor and Cibacron Blue bind to the free enzyme whereas the other inhibitors bind to the binary and/or ternary complexes.


Kidney Function and Arterial Calcification in Major Vascular Beds.
Background The purpose of this study was to investigate the association between kidney function and arterial calcification in major vascular beds and to establish whether arterial calcification mediates the relation between kidney function measures and cardiovascular disease ( CVD ) incidence. Methods and Results In 2241 participants from the Rotterdam Study (mean age 69 years, 52% female), kidney function was assessed using the estimated glomerular filtration rate and urine albumin-to-creatinine ratio. All participants underwent noncontrast computed tomography to quantify the amount of arterial calcification in the coronary arteries, aortic arch, extracranial, and intracranial internal carotid arteries. We used linear regression models, adjusted for age, sex, and cardiovascular risk factors, to evaluate the association between kidney function and arterial calcification volume in the 4 vessel beds. Incidence rate of CVD was calculated in 3 groups of participants based on their kidney function and presence of arterial calcification. We conducted mediation analysis to evaluate whether arterial calcification mediates this association. We found that in age- and sex-adjusted models, lower estimated glomerular filtration rate and higher albumin-to-creatinine ratio were associated with larger calcification volumes in all 4 vascular beds. Adjusting for cardiovascular risk factors attenuated the effect estimates. CVD incidence was higher in participants with estimated glomerular filtration rate <60 mL/min per 1.73 m2 and presence of arterial calcification compared with individuals with estimated glomerular filtration rate >60 and no calcification. After adjusting for cardiovascular risk factors, arterial calcification did not mediate the association between kidney function measures and CVD incidence. Conclusions The association of impaired kidney function and larger volumes of arterial calcification is partly explained by cardiovascular risk factors. Arterial calcification does not mediate the association between kidney function and CVD beyond cardiovascular risk factors.


Surgical Technique of Vertebral Body Removal and Anterior Reconstruction in L5 Spondylectomy.
L5 spondylectomy for the treatment of spinal tumor is a technically demanding surgery because of the complex anatomy of major vessels, the obscurity of the posterior exposure from the iliac wings, and the increased comparative size of the L5 vertebral body. In this study, we present a surgical technique of L5 spondylectomy, vertebral body removal, and anterior reconstruction for a case with solitary spinal metastatic renal cell carcinoma (RCC). A 54-year-old man underwent right total nephrectomy for RCC one year ago. At the one-year postoperative follow-up, CT scan and MRI revealed a solitary L5 spinal metastasis. A two-stage posteroanterior approach was performed. To facilitate vertebral body removal, transverse processes were separated from the vertebral body by using the posterior approach. On the basis of the anterior approach, the vertebral body was removed via the interval space between the left common iliac vessels. Reconstruction was performed by using a liquid-nitrogen-frozen, tumor-bearing bone mixed with an autogenous bone graft in an expandable titanium cage. No intraoperative complications were observed. Postoperatively, the patient exhibited muscle weakness in the tibialis anterior and extensor hallucis longus bilaterally but improved with time. Seven months after the operation, the patient was able to walk independently. At the recent 2.5-year follow-up, the local recurrence of lesions was nonexistent. The bone graft had fused with the adjacent vertebrae. This report described a novel technique for L5 spondylectomy that can facilitate safe L5 vertebral body removal and demonstrated the effectiveness of liquid-nitrogen-frozen, tumor-bearing bone mixed with autogenous bone graft in anterior reconstruction both in terms of oncologic safety and biological healing.


Direct micromethod for diagnosis of acute and congenital Chagas' disease.
A microhematocrit concentration method (MH) for immediate diagnosis of Chagas' disease during the acute stage or in congenital cases was standardized. Parasitemia as low as 1,000 parasites per ml was detected, after centrifugation of six 50-microliters capillary tubes, by 10-min microscopic observation of each buffy coat spread between slide and cover glass. Operator's time was reduced by at least one-third when compared with a fresh blood observation (FB). In 12 of the 15 patients studied, diagnosis was performed in 4.9 +/- 3.08 min with MH, whereas 27.0 +/- 12.1 min were necessary when FB was used. In the three remaining patients whose FB results were negative, MH became positive after 13, 16, and 40 min. In our experience, FB proved to be more sensitive than previously reported. Suckling mouse inoculation also proved to be sensitive but, as in xenodiagnosis and in hemoculture, the delay in getting the final result was a limiting factor.


A model for inferring the voluntary and involuntary causes of residential segregation.
It is clear that both voluntary and involuntary forces normally contribute to the residential segregation existing between groups. For the most part, the contribution of each dimension has not been determined. Rather, researchers operate as if either one or the other force is operating. In the United States, for example, black-white segregation is assumed to be imposed by whites on blacks, as if the latter were themselves totally indifferent to the racial composition in their areas of residence. On the other hand, it is assumed that segregation between white ethnic groups is at present purely a voluntary matter. In an earlier period, it was assumed that their segregation was both voluntary (reflecting desires to be among copatriots) and involuntary (reflecting the imposition of restrictions on residential movement by other groups as well as economic forces). But it has not been possible for investigators to determine the relative importance of each factor. Using asymmetrical segregation indexes, a rudimentary procedure is proposed for determining the relative importance of voluntary and involuntary forces operating to generate a given level of segregation. Data based on Black, Anglo, and Spanish residential patterns are then considered in terms of the proposed model.


Gene expression profiling of Cecropin B-resistant Haemophilus parasuis.
Synthetically designed antimicrobial peptides (AMPs) present the potential of replacing antibiotics in the treatment of bacterial infections. However, microbial resistance to AMPs has been reported and little is known regarding the underlying mechanism of such resistance. The naturally occurring AMP cecropin B (CB) disrupts the anionic cell membranes of Gram-negative bacteria. In this study, CB resistance (CBR) was induced in Haemophilusparasuis SH0165 by exposing it to a series of CB concentrations. The CB-resistant H.parasuis strains CBR30 and CBR30-50 were obtained. The growth curves of SH0165 and CBR30 showed that CBR30 displayed lower growth rates than SH0165. The result of transmission electron microscopy showed cell membranes of the CB-resistant CBR30 and CBR30-50 were smoother than SH0165. Microarrays detected 257 upregulated and 254 downregulated genes covering 20 clusters of orthologous groups (COGs) of the CB-resistant CBR30 compared with SH0165 (>1.5-fold change, p < 0.05). Sixty genes were affected in CBR30-50 covering 18 COGs, with 28 upregulated and 32 downregulated genes. Under the COG function classification, the majority of affected genes in the CB-resistant CBR30 and CBR30-50 belong to the category of inorganic ion transport, amino acid transport, and metabolism. The microarray results were validated by real-time quantitative reverse transcription PCR. This study may provide useful guidance for understanding the molecular mechanism underlying H.parasuis resistance to CB.


[Scanning electron microscopy of resected ureters in children with ureterohydronephrosis].
Using scanning electron microscopy, various portions of the ureter in reflux and obstructive ureterohydronephrosis in children were evaluated. In the first case, architectonics of the distal portions is preserved, while in the second case connective tissue is proliferated. Differences in the structure of proximal and distal portions in both forms of ureterohydronephrosis consist in inflammatory changes and violation of the integrity of the epithelial lining, edema and infiltration of the underlying layers, especially the inner muscle layer of the distal portion. The wall of the ureter in proximal part is much thinner, especially the muscular and mucous layers.


Molecular mechanisms in 22q11 deletion syndrome.
It is now well recognized that as well as having a characteristic facial dysmorphology and a range of congenital abnormalities, individuals with chromosome 22q11 deletion syndrome (22q11DS) have a greatly increased risk of developing psychosis, in particular schizophrenia. The majority of deletions span a large 3Mb region at 22q11. However, the presence of affected individuals carrying smaller deletions have not been sufficient to satisfactorily reduce the critical region for the behavioral phenotype beyond a ~1.5Mb region that contains at least 28 genes. By having a shared genetic variant that greatly increases risk to psychosis, individuals with 22q11DS are a relatively homogeneous population to study psychiatric disease. Despite this, the large volume of research performed over the last 15 years suggest that the mechanism by which haploinsufficiency at 22q11 increases risk to psychiatric illness is likely to be complex and it remains uncertain why individuals carrying identical 22q11 deletions can present with such a wide range of neuropsychiatric phenotypes. This review will therefore consider the ways in which deletions at 22q11 are expected to increase risk to develop psychiatric disease by summarizing the work that has been done to investigate three of the most likely disease causing mechanisms: (a) gene dosage sensitivity; (b) unmasking of recessive alleles or functional polymorphism; and (c) position effect.


Area-specific differences in transmitter release in central catecholaminergic neurons of spontaneously hypertensive rats.
The link among blood pressure, sympathetic output, and brain neurons producing catecholamines is well documented. Nevertheless, their intrinsic properties and any alterations in signaling characteristics between normotensive and hypertensive phenotypes remain unknown. Here, we directly compared neurophysiological properties of catecholamine release of C1 and A2 neurons of the spontaneously hypertensive rat and Wistar rat in organotypic slices. C1 and A2 areas were studied because both are widely implicated in the pathophysiology of hypertension. Catecholaminergic neurons were visualized using viral vectors to express green fluorescent protein. Microamperometry revealed that C1 axonal varicosities of spontaneously hypertensive but not normotensive Wistar rats release a transmitter predominantly (approximately 86%) in very large quanta, comparable in catecholamine load to adrenal chromaffin granules. Because quantal size affects the spread of transmitter in the extracellular space, this may enhance the impact of C1 varicosities on their downstream targets and increase sympathetic drive in the hypertensive rat. Electrophysiological properties and Ca2+ handling were studied using patch clamp and confocal imaging. Although overall electrophysiological characteristics of C1 and A2 neurons were comparable between strains, the characteristic angiotensin-II-induced Ca2+ mobilization was reduced in A2 neurons of the spontaneously hypertensive rat. Because A2 neurons are a part of a homeostatic antihypertensive circuit, this could reduce their restraining influence on blood pressure. Thus, we have revealed an increased quantal size in C1 varicosities and a reduced responsiveness of A2 neurons of the spontaneously hypertensive rat to angiotensin II. Both effects could contribute to elevated sympathetic activity and blood pressure in the spontaneously hypertensive rat.


Lack of Association between Serum Cystatin C Levels and Coronary Artery Disease in Diabetic Patients.
Serum cystatin C level is a more sensitive marker of renal dysfunction than serum creatinine level. Serum cystatin C level was recently reported to predict the development of cardiovascular disease. This study was performed to evaluate whether the cystatin C level is associated with coronary artery disease (CAD), independent of diabetic nephropathy. We conducted a case-control study to assess the relationship between serum cystatin C level and coronary artery disease in diabetic patients. Among 460 diabetic patients, 38 diabetic patients had CAD. The control group consisted of 38 diabetic patients who were matched to cases by age, sex, and presence/absence of diabetic nephropathy. Serum cystatin C level was measured in stored samples. Serum cystatin C level was significantly higher in patients with diabetic nephropathy, both in CAD and non-CAD patients. However, serum cystatin C level did not differ between CAD and non-CAD patients, regardless of diabetic nephropathy. Serum cystatin C level is a marker of renal dysfunction, but not coronary artery disease, in diabetic patients.


The effect of fragmented cancer care and change in nurse staffing grade on cancer patient mortality.
Continuity of patient care ensures timely and appropriate care and is associated with better patient outcomes among cancer patients. However, the impact of nurse staffing grade changes on patient outcomes remains unknown. This retrospective cohort study aimed to evaluate the effect of fragmented care and changes in nurse staffing grade on the survival of colorectal cancer patients who underwent surgery. This study included 2228 newly diagnosed colorectal cancer patients. Fragmented care was defined as the receipt of treatment in multiple hospitals and was divided into three categories based on changes in nurse staffing grade. Five-year survival rates were used to evaluate the effect of fragmented care and nurse staffing grade on outcomes of cancer patients. Survival analysis was performed by adjusting for covariates using the Cox proportional hazards model for 5-year mortality. Approximately 18.5% of patients died within 5 years; the mortality rate during cancer treatment was higher in patients who received fragmented care, especially in those transferred to hospitals with fewer nurses. Patients who received fragmented care had shorter survival times, and those transferred to hospitals with fewer nurses had higher risks of 5-year mortality (hazard ratio: 1.625; 95% CI: [1.095, 2.412]). Transfers to hospitals with fewer nurses were associated with increased mortality rates in low-income patients, hospitals located in metropolitan and rural areas, and high-severity groups. Receipt of fragmented care and change in nurse staffing grade due to patients' transfer to different hospitals were associated with increased mortality rates in cancer patients, thus underlining the importance of ensuring continuity and quality of care. Patients from rural areas, from low-income families, and with high disease severity may have better outcomes if they receive treatment in well-staffed hospitals.


Diol responsive viscosity increase in a cetyltrimethylammonium bromide/sodium salicylate/3-fluorophenylboronic acid micelle system.
We report a novel smart micellar system utilising a phenylboronic acid (PBA) derivative whose viscosity increases on adding diol compounds such as sugar or sugar alcohol. We prepared a typical worm-like micelle (WLM) system in 100 mM cetyltrimethylammonium bromide (CTAB)/70 mM sodium salicylate (NaSal), which showed high zero-shear viscosity (η 0). Upon the addition of 20 mM 3-fluorophenylboronic acid (3FPBA) to the WLM system, η 0 decreased by 1/300 that of the system without 3FPBA. Furthermore, upon the addition of 1.12 M fructose (Fru) and 1.12 M sorbitol (Sor) to the CTAB/NaSal/3FPBA system, η 0 increased by 50-fold and 30-fold, respectively. 19F NMR spectral results of the systems using 4-fluorosalicylic acid (FSal) instead of NaSal demonstrated that the FSal/3FPBA-complex interacts with CTAB. Moreover, the addition of sugar or sugar alcohol to the micellar system leads to a decrease in the amount of FSal/3FPBA-complex interacting with CTA+ and an increase in the amount of 3FPBA/Fru or Sor-complex, which does not interact with CTA+. These changes in molecular interactions induce the elongation of the WLMs and increase the viscosity of the system. This system utilises the competitive cyclic ester bond between the NaSal/3FPBA and 3FPBA/sugar or sugar alcohol to induce viscosity changes.


Dual-Resonance Nanostructures for Color Downconversion of Colloidal Quantum Emitters.
We present a dual-resonance nanostructure made of a titanium dioxide (TiO2) subwavelength grating to enhance the color downconversion efficiency of CdxZn1-xSeyS1-y colloidal quantum dots (QDs) emitting at ∼530 nm when excited with a blue light at ∼460 nm. A large mode volume can be created within the QD layer by the hybridization of the grating resonances and waveguide modes, resulting in large absorption and emission enhancements. Particularly, we achieved polarized light emission with a maximum photoluminescence enhancement of ∼140 times at a specific angular direction and a total enhancement of ∼34 times within a 0.55 numerical aperture (NA) of the collecting objective. The enhancement encompasses absorption, Purcell and outcoupling enhancements. We achieved a total absorption of 35% for green QDs with a remarkably thin color conversion layer of ∼400 nm. This work provides a guideline for designing large-volume cavities for absorption/fluorescence enhancement in microLED display, detector, or photovoltaic applications.


Adenovirus-mediated overexpression of IRS-1 interacting domains abolishes insulin-stimulated mitogenesis without affecting glucose transport in 3T3-L1 adipocytes.
Activated insulin receptor (IR) interacts with its substrates, IRS-1, IRS-2, and Shc via the NPXY motif centered at Y960. This interaction is important for IRS-1 phosphorylation. Studies using the yeast two-hybrid system and sequence identity analysis between IRS-1 and IRS-2 have identified two putative elements, the PTB and SAIN domains, between amino acids 108 and 516 of IRS-1 that are sufficient for receptor interaction. However, their precise function in mediating insulin's bioeffects is not understood. We expressed the PTB and SAIN domains of IRS-1 in HIRcB fibroblasts and 3T3-L1 adipocytes utilizing replication-defective adenoviral infection to investigate their role in insulin signalling. In both cell types, overexpression of either the PTB or the SAIN protein caused a significant decrease in insulin-induced tyrosine phosphorylation of IRS-1 and Shc proteins, IRS-1-associated phosphatidylinositol 3-kinase (PI 3-K) enzymatic activity, p70s6k activation, and p44 and p42 mitogen-activated protein kinase (MAPK) phosphorylation. However, epidermal growth factor-induced Shc and MAPK phosphorylation was unaffected by the overexpressed proteins. These findings were associated with a complete inhibition of insulin-stimulated cell cycle progression. In 3T3-L1 adipocytes, PTB or SAIN expression extinguished IRS-1 phosphorylation with a corresponding 90% decrease in IRS-1-associated PI 3-K activity. p70s6k is a downstream target of PI 3-K, and insulin-stimulated p70s6k was inhibited by PTB or SAIN expression. Interestingly, overexpression of either PTB or SAIN protein did not affect insulin-induced AKT activation or insulin-stimulated 2-deoxyglucose transport, even though both of these bioeffects are inhibited by wortmannin. Thus, interference with the IRS-1-IR interaction inhibits insulin-stimulated IRS-1 and Shc phosphorylation, PI 3-K enzymatic activity, p70s6k activation, MAPK phosphorylation and cell cycle progression. In 3T3-L1 adipocytes, interference with the IR-IRS-1 interaction did not cause inhibition of insulin-stimulated AKT activation or glucose transport. These results indicate a bifurcation or subcompartmentalization of the insulin signalling pathway whereby some targets of PI 3-K (i.e., p70s6k) are dependent on IRS-1-associated PI 3-K and other targets (i.e., AKT and glucose transport) are not. IR-IRS-1 interaction is not essential for insulin's effect on glucose transport, and alternate, or redundant, pathways exist in these cells.


Outcomes measurement in pain management: issues of disease complexity and uncertain outcomes.
Pain is a complex disease process. Pain management requires an interdisciplinary rather than a multidisciplinary clinical intervention, interdisciplinary because the factors that may affect pain intensity and duration occur simultaneously. A particular problem exits when measuring outcomes from chronic diseases, disorders, and impairments because neither a cure nor death is a likely outcome. The clinical and psychosocial determinates of pain complicate the assessment of level of pain and the measurement of pain management outcomes. The major obstacle to assessing change from a pain intervention is the lack of a gold standard. Because we have no gold standard for better functional health, our evaluation of the responsiveness of health status measures regarding pain management will continue to be plagued with the question "responsive to what"?


[Significance of the arrest of pulmonary circulation in the genesis of postperfusion pulmonary complications in open heart surgery].
The purpose of the work is to elucidate the importance of pulmonary circulation arrest during extracorporeal circulation in the development of microcirculatory disorders in the pulmonary tissue. Experiments showed that temporary arrest of pulmonary circulation under conditions of extracorporeal circulation is attended by the development of ischemia of the respiratory pulmonary tissue. The systemic blood flow in the arterio-arterial anastomoses between the pulmonary and bronchial arteries is incapable of providing the pulmonary tissue with blood. Ischemia of the parenchyma leads to disorders in the microvessels of the organ, the manifestation of which in the ischemic and postischemic, periods is determined by the duration of the pathologic effect. The data gained indicate the importance of developing methods for the prevention and treatment of ischemic and postischemic pulmonary microcirculatory disorders and determining the safe terms of pulmonary artery ischemia.


Nucleolar and Spindle Associated Protein 1 (NUSAP1) Inhibits Cell Proliferation and Enhances Susceptibility to Epirubicin In Invasive Breast Cancer Cells by Regulating Cyclin D Kinase (CDK1) and DLGAP5 Expression.
BACKGROUND Differentially expressed genes (DEGs) of IBC were selected from the Gene Expression Omnibus (GEO) chip data: GSE21422 and GSE21974. Network analysis of the DEGs and IBC-related genes was performed in STRING database to find the core gene. Thus, this study aimed to determine the role of NUSAP1 in invasive breast cancer (IBC) and to investigate its effect on drug susceptibility to epirubicin (E-ADM). MATERIAL AND METHODS The mRNA expression of NUSAP1 was determined by quantitative polymerase chain reaction (q-PCR). The protein expression was detected by Western blotting. Cell growth and growth cycle were detected by MTT assay and flow cytometry, respectively. Cell migration and invasion were tested by Transwell assay. RESULTS Through use of gene network analysis, we found that NUSAP1 interacts with IBC-related genes. NUSAP1 presented high expression in IBC tissue samples and MCF-7 cells. NUSAP1 overexpression promoted the growth, migration, and invasion of MCF-7 cells. While NUSAP1 gene silencing downregulated the expression of genes associated with cell cycle progression in G2/M phase, cyclin D kinase (CDK1) and DLGAP5 arrested cells in G2/M phase and significantly inhibited the growth, migration, and invasion of MCF-7 cells. si-NUSAP1 increased the susceptibility of MCF-7 cells to E-ADM-induced apoptosis. CONCLUSIONS Our study provides evidence that downregulation of NUSAP1 can inhibit the proliferation, migration, and invasion of IBC cells by regulating CDK1 and DLGAP5 expression and enhances the drug susceptibility to E-ADM.


Comparison of electronic brachytherapy and Mohs micrographic surgery for the treatment of early-stage non-melanoma skin cancer: a matched pair cohort study.
High-dose-rate electronic brachytherapy (EBT) provides a non-surgical treatment option for non-melanoma skin cancer (NMSC). This matched-pair cohort study compared the outcomes of treatment with EBT to those of Mohs micrographic surgery (MMS) in patients with NMSC. At four treatment centers, patients treated with EBT were case matched to patients treated with MMS based on retrospectively-collected patient age, lesion size, location and type, and year of treatment. Follow-up data were prospectively collected and included local recurrence, toxicities, cosmesis, and patient-reported outcomes. The 369 patients (188 in the EBT treatment group and 181 in the MMS treatment group) had 416 lesions (208 in the EBT group and 208 in the MMS group), including 226 basal cell carcinomas (BCC) and 190 squamous cell carcinomas (SCC). Most patients were Caucasian (98.9% and 99.5%) and male (65.4% and 66.3%) of median age 80.7 (range: 61-98) (EBT) and 76.8 (range: 51-98) years (MMS). Most lesions were size > 1 cm and ≤ 2 cm, and located on the head. At mean 3.4 years post-treatment, 99.5% of EBT, and 100.0% of MMS-treated lesions were free of recurrence (p = ns). One recurrence was noted in the EBT group. Physicians rated cosmesis as "excellent" or "good" in 97.6% of EBT-treated lesions, and 95.7% of MMS-treated lesions. This matched-pair cohort study supports the use of EBT as an effective non-surgical treatment option for NMSC with equivalent recurrence rates and cosmetic outcomes to MMS in appropriately-selected patients with early stage NMSC at extended follow-up.


Shyness, Preference for Solitude, and Adolescent Internalizing: The Roles of Maternal, Paternal, and Best-Friend Support.
The researchers examined differential outcomes related to two distinct motivations for withdrawal (preference for solitude and shyness) as well as the possibility that support from important others (mothers, fathers, and best friends) attenuate any such links. Adolescents (159 males, 171 females) reported on their motivations to withdraw, internalizing symptoms, and relationship quality in eighth grade, as well as their anxiety and depression in ninth grade. Using structural equation modeling, the authors found that maternal support weakened the association between shyness and internalizing problems; friend support weakened the association between preference for solitude and depression; and friend support strengthened the association between shyness and depression. Results suggest that shy adolescents may not derive the same benefits from supportive friendships as their typical peers.