Postoperative cognitive dysfunction: an acute approach for the development of novel treatments for neuroinflammation.
Inflammation within the central nervous system (CNS; neuroinflammation) is a major contributor to lasting symptoms of traumatic brain injury and stroke, and likely has a casual role Alzheimer's disease (AD) and other neurodegenerative conditions. Therapeutic modulation of the immune processes that initiate and maintain neuroinflammation is of growing scientific interest but neuroinflammatory drug development is hampered by limited reliability and availability of neuroimaging or other biomarkers in humans. Better means of establishing drug efficacy on human neuroinflammation would have great value in accelerating the development of neuroinflammatory compounds for many clinical indications. Here, we discuss the use of postoperative cognitive decline (POCD), which is hypothesised to have a neuroinflammatory basis, as an acute indication to demonstrate the efficacy of novel neuroinflammatory drugs.


Multimodal Regulation of Cardiac Myocyte Proliferation.
Efficient cardiac regeneration is closely associated with the ability of cardiac myocytes to proliferate. Fetal or neonatal mouse hearts containing proliferating cardiac myocytes regenerate even extensive injuries, whereas adult hearts containing mostly post-mitotic cardiac myocytes have lost this ability. The same correlation is seen in some homoiotherm species such as teleost fish and urodelian amphibians leading to the hypothesis that cardiac myocyte proliferation is a major driver of heart regeneration. Although cardiomyocyte proliferation might not be the only prerequisite to restore full organ function after cardiac damage, induction of cardiac myocyte proliferation is an attractive therapeutic option to cure the injured heart and prevent heart failure. To (re)initiate cardiac myocyte proliferation in adult mammalian hearts, a thorough understanding of the molecular circuitry governing cardiac myocyte cell cycle regulation is required. Here, we review the current knowledge in the field focusing on the withdrawal of cardiac myocytes from the cell cycle during the transition from neonatal to adult stages.


Phase I trial of a novel diphtheria toxin/granulocyte macrophage colony-stimulating factor fusion protein (DT388GMCSF) for refractory or relapsed acute myeloid leukemia.
Patients with relapsed or refractory acute myeloid leukemia have a poor prognosis. We tested the safety and efficacy of a diphtheria fusion protein [diphtheria toxin (DT)388 granulocyte-macrophage colony-stimulating factor (GMCSF)] directed against the GMCSF receptor that is strongly expressed by leukemic blasts. DT388GMCSF fusion protein containing the catalytic and translocation domains of DT388 fused to human GMCSF was administered in an interpatient dose escalation trial by 15 min i.v. infusion daily for up to 5 days. The maximal tolerated dose was 4 microg/kg/day. The dose-limiting toxicity was liver injury and occurred at the 4.5-5-microg/kg/day dose level. Among nine treated patients at these doses, one patient developed liver failure, and one patient had transient hepatic encephalopathy. There was a positive correlation between peak serum DT388GMCSF levels and serum aspartate aminotransferase (P = 0.0002). DT388GMCSF did not damage hepatic cell lines in vitro; however, DT388GMCSF binds macrophages and induces cytokine release in vitro. Among the treated patients, we observed an early elevation in serum levels of interleukin (IL)-18 and a later rise in IL-8 but no significant changes in IL-1beta, IL-6, IFNgamma, macrophage inflammatory protein-1alpha, tumor necrosis factor alpha or IL-12. The IL-18 elevations occurred before elevations of liver enzymes and correlated with peak aspartate aminotransferase levels (P = 0.005). Of the 31 patients who were resistant to chemotherapy, 1 had a complete remission and 2 had partial remissions; all 3 of these patients were treated at or above the maximal tolerated dose, all 3 responding patients had baseline marrow blast percentage of <30%, whereas only 6 of the nonresponding 28 patients had less than 30% marrow blasts. Five of these six patients were treated with subtherapeutic doses. Eight (42%) of 19 patient courses at <4 microg/kg/day and 8 (40%) of 20 patient courses at 4-5 microg/kg/day showed marrow blast reductions at day 12. Patients with higher pretreatment anti-DT388GMCSF levels had significantly lower peak DT388GMCSF levels (P = 0.0001). DT388GMCSF can produce complete and partial remissions in patients with chemotherapy-resistant acute myeloid leukemia, but methods to prevent liver injury are needed before more widespread application of this novel agent.


Implementing an acceptance and commitment therapy group protocol with veterans using VA's stepped care model of pain management.
The purpose of the current study was to replicate and extend previous findings; further demonstrating the effectiveness of an ACT outpatient, group-based treatment for Veterans who suffer from mixed idiopathic, chronic, non-cancer pain. This course of treatment utilized the VA's Stepped Care Model of Pain Management as a framework. A sample of 50 Veterans who participated in an ACT for chronic pain group intervention was evaluated after completing a pain health education program at a Midwestern VA Medical Center between February 16, 2010 and November 9, 2010. All participants completed a standard set of pre- and post-intervention measures. Paired-samples t tests were conducted to evaluate the impact of the manualized intervention on Veterans' scores. The current study found a significant difference in measures of pain interference, illness-focused coping, and global distress upon completion of the intervention. Findings suggest that ACT is an effective treatment for Veterans with chronic pain as a secondary consultative service.


Survival of cells after intra-articular transplantation of fresh allografts of the patellar and anterior cruciate ligaments. DNA-probe analysis in a goat model.
The fate of donor cells in fresh allografts of the patellar and anterior cruciate ligaments was assessed after transplantation of the allografts as substitutes for the anterior cruciate ligament in goats. DNA-probe analysis was used to distinguish between the DNA of individual goats. Donor DNA was completely replaced by recipient DNA in both the transplanted patellar and anterior cruciate ligaments within a four-week period. Simultaneous full-thickness skin transplants in the same animals were not rejected during the interval of rapid loss of donor DNA from the allografts. The absence of rejection of the skin grafts at the one-week interval suggests that no pre-existing antibody associated with an immune reaction was responsible for the rapid loss of DNA in the allografts.


Preparation of uniformly labelled 13C- and 15N-plants using customised growth chambers.
Stable isotopically labelled organisms have found wide application in life science research including plant physiology, plant stress and defense as well as metabolism related sciences. Therefore, the reproducible production of plant material enriched with stable isotopes such as 13C and 15N is of considerable interest. A high degree of enrichment (> 96 atom %) with a uniformly distributed isotope (global labelling) is accomplished by a continuous substrate supply during plant growth/cultivation. In the case of plants, 13C-labelling can be achieved by growth in 13CO2(g) atmosphere while global 15N-labelling needs 15N- containing salts in the watering/nutrient solution. Here, we present a method for the preparation of 13C and 15N-labelled plants by the use of closed growth chambers and hydroponic nutrient supply. The method is exemplified with durum wheat. In total, 330 g of globally 13C- and 295 g of 15N-labelled Triticum durum wheat was produced during 87 cultivation days. For this, a total of 3.88 mol of 13CO2(g) and 58 mmol of 15N were consumed. The degree of enrichment was determined by LC-HRMS and ranged between 96 and 98 atom % for 13C and 95-99 atom % for 15N, respectively. Additionally, the isotopically labelled plant extracts were successfully used for metabolome-wide internal standardisation of native T.durum plants. Application of an isotope-assisted LC-HRMS workflow enabled the detection of 652 truly wheat-derived metabolites out of which 143 contain N. A reproducible cultivation which makes use of climate chambers and hydroponics was successfully adapted to produce highly enriched, uniformly 13C- and 15N-labelled wheat. The obtained plant material is suitable to be used in all kinds of isotope-assisted research. The described technical equipment and protocol can easily be applied to other plants to produce 13C-enriched biological samples when the necessary specific adaptations e.g. temperature and light regime, as well as nutrient supply are considered. Additionally, the 15N-labelling method can also be carried out under regular glasshouse conditions without the need for customised atmosphere.


Quantification of ricinine in rat and human urine: a biomarker for ricin exposure.
Ricin is a toxalbumin derived from the castor bean plant, Ricinus communis. Ricinine is an alkaloid (3-cyano-4-methoxy-N-methyl-2-pyridone) that shares a common plant source with ricin, and its presence in urine infers ricin exposure. A new quantification method for ricinine was developed that uses solid-phase extraction to prepare 1-mL urine samples (81% recovery) for a 5-min, isocratic high-performance liquid chromatography method, followed by electrospray ionization tandem mass spectrometry. Protonated molecular ions were selected in the multiple reaction monitoring mode and quantified by isotope dilution with (13)C(6)-labelled ricinine as the internal reference. Urine pools enriched with ricinine at two concentrations were characterized as quality control materials and then used to validate the method. The method limit of quantification was 0.083 ng/mL, even with a confirmation ion of low relative abundance. Ricinine was stable in human urine when heated at 90 degrees C for 1 h, and during storage at 25 degrees C and 5 degrees C for 3 weeks. The method was applied to an animal exposure study, a crude ricin preparation scheme, and a forensic analysis. These studies show that ricinine can be measured in rat urine at least 48 h after exposure. Ricinine is present in crude preparations of ricin, and it can be found in human urine after a lethal exposure to ricin.


Pramlintide an Adjunct to Insulin Therapy: Challenges and Recent progress in delivery.
Dysregulation of various glucoregulatory hormones lead to failure of insulin monotherapy in patients with diabetes mellitus due to various reasons, including severe hypoglycaemia, glycaemic hypervariability, and an increased risk of microvascular complications. However, Pramlintide an adjunct to insulin therapy, enhances glucagon suppression and thereby offers improved glycaemic control. Clinical studies have shown that Pramlintide improves glycaemic control, reduces postprandial glucose excursions, and promotes weight loss in patients with type 1 and type 2 diabetes. Although clinical benefits of Pramlintide are well reported, there still exists a high patient resistance for the therapy as separate injections for Pramlintide and insulin are required to be administered. While marketed insulin formulations generally demonstrate a peak action in 60-90 min, Pramlintide elicits its peak concentration at around 20-30 min after administration. Thus, owing to the significant differences in pharmacokinetics of exogenously administered Pramlintide and insulin, the therapy fails to elicit its action otherwise produced by the endogenous hormones. Hence, strategies such as delaying the release of Pramlintide by using inorganic polymers like silica, synthetic polymers like polycaprolactone and lipids have been employed. Also, approaches like non-covalent conjugation, polyelectrolyte complexation and use of amphiphilic excipients for co-delivery of Insulin and Pramlintide have been explored to address the issues with Pramlintide delivery and improve patient adherence to the therapy. This approach may usher a new era of diabetes management, offering patients multiple options to tailor their treatment and improve their quality of life. Significance Statement To our knowledge, this is the first report that summarizes various challenges in Insulin and Pramlintide co-delivery and strategies to overcome them. The paper also provides deeper insights into various novel formulation strategies for Pramlintide that could further broaden the readers understanding of peptide co-delivery.


A longitudinal examination of the relation between parental expressed emotion and externalizing behaviors in children and adolescents with autism spectrum disorder.
The current study explored the longitudinal relation between parental expressed emotion, a well-established predictor of symptom relapse in various other disorders (e.g., schizophrenia) with externalizing behaviors in 84 children, ages 8-18 (at Time 2), with autism spectrum disorder (ASD). It was found that parental expressed emotion, specifically criticism/hostility at Time 1, significantly related to a change in externalizing behaviors from Time 1 to Time 2, even after controlling for Time 1 family income, ASD symptom severity, parental distress, and parenting practices. That is, higher levels of parental criticism/hostility at Time 1 predicted higher levels of child externalizing behaviors at Time 2. However, the reverse was not found. This finding of a unidirectional relation has important clinical implications.


Selamectin is a potent substrate and inhibitor of human and canine P-glycoprotein.
The transport of the antiparasitic agents, ivermectin, selamectin and moxidectin was studied in human intestinal epithelial cell monolayers (Caco-2) and canine peripheral blood lymphocytes (PBL). Both models expressed the mdr1-coded 170 kDa ATP-binding cassette (ABC) transporter P-glycoprotein (P-gp). Fluxes of the P-gp substrate rhodamine-123 (Rh-123) across Caco-2 monolayers showed that ivermectin and selamectin acted as potent P-gp inhibitors with IC50 values of 0.1 microm. In contrast, moxidectin was a weaker P-gp inhibitor with an IC50 of 10 microm. The transport of radiolabelled ivermectin, selamectin and moxidectin through Caco-2 monolayers showed that ivermectin, selamectin and moxidectin were P-gp substrates with secretory/absorptive ratios of 7.5, 4.7 and 2.6 respectively. Secretory transport of [3H]-ivermectin and [3H]-selamectin was blocked by the P-gp inhibitor, verapamil. Ivermectin and selamectin inhibited the efflux of Rh-123 from PBL and the concentration of inhibition was similar to that of verapamil. In contrast, moxidectin did not have a significant effect on Rh-123 efflux from PBL. The data suggest that ivermectin and selamectin are potent P-gp substrates, while moxidectin is a weak one.


Efficacy of diflunisal versus acetaminophen with codeine in controlling mild to moderate pain after arthroscopy.
An open, randomized clinical study was performed to evaluate the efficacy of diflunisal versus acetaminophen with codeine in patients who underwent outpatient arthroscopy of the knee. Twenty patients were randomly assigned to each treatment group. Nineteen patients in each group successfully completed the study, which consisted of both objective and subjective evaluations. The results showed equal efficacy between the two drugs. However, a larger percentage of patients viewed diflunisal as providing good to excellent results overall compared with acetaminophen with codeine.


[Antioxidant micronutrients and human pathology].
The harmful oxidation by free radicals has been implicated in the pathogenesis of many illnesses, including, as the most significant from the epidemiological standpoint, cardiovascular disease and cancer. This paper reviews the physio-pathological foundations of this relationship and describes the possible usefulness of anti-oxidant therapy in these and other conditions.


Assessment of mean transit time in the engrafted lung with 133Xe lung ventilation scintigraphy improves diagnosis of bronchiolitis obliterans syndrome in living-donor lobar lung transplant recipients.
Staging of bronchiolitis obliterans syndrome (BOS) following lung transplantation is based on declines in forced expiratory volume in 1 s (FEV(1)). The aim of this study was to evaluate the usefulness of (133)Xe ventilation scintigraphy in the early detection of BOS following living-donor lobar lung transplantation (LDLLT), to compare (133)Xe washout imaging with computed tomography (CT) findings for early detection of BOS following LDLLT, and to evaluate (133)Xe washout imaging by quantitative analyses. Subjects comprised 30 double-lung recipients and 1 single-lung recipient, who had undergone LDLLT at our institution and survived more than 1 year. Clinically diagnosed BOS developed in six recipients. Declines in graft function were evaluated using a combination of three methods, namely, dynamic spirometry, high-resolution CT (HRCT), and (133)Xe ventilation scintigraphy. Findings for all transplanted lungs were compared between CT and (133)Xe washout imaging. (133)Xe washout imaging was assessed using mean transit time (MTT) of bi-and unilateral lungs. Correlations between MTT of bilateral lungs and FEV(1)% were evaluated. Differences in MTT between BOS and non-BOS lungs, and between non-BOS and donor lungs were also evaluated on unilateral lungs. Appropriate cut-off values of MTT of unilateral lungs were set for the diagnosis of BOS. In all six BOS cases, prolonged-washout images of engrafted lungs revealed early-phase BOS with declines from baseline FEV(1), whereas only one BOS case could be detected using early CT findings of BO (bronchodilatation, decrease in number and size of pulmonary vessels, thickening of septal lines, and volume reduction). A significant correlation was identified between MTT and FEV(1)% (r = -0.346, P < 0.0001). MTT of unilateral lungs was significantly longer in BOS lungs than in non-BOS lungs (P < 0.0001). The cut-off MTT of unilateral lungs for the diagnosis of BOS was set at 64.77 s. Our data show that (133)Xe washout imaging offers excellent potential for early detection of BOS compared with early CT findings. Using (133)Xe washout imaging and MTT with radioactive tracer offers a noninvasive indication of selective ventilatory function in engrafted lungs following LDLLT. MTT appears useful for identifying BOS following LDLLT and allows quantitative evaluation of graft function in unilateral lungs.


Dammarane-type glycosides from Gynostemma pentaphyllum.
Fifteen new dammarane glycosides (1-15), together with four known compounds, gypenosides IV, VIII, LXXI, and XLIX, were isolated from the MeOH extract of the aerial parts of Gynostemma pentaphyllum. Their structures were elucidated by 1D and 2D NMR spectra interpretation as well as by chemical degradation.


An integrated community-based outpatient therapeutic feeding programme for severe acute malnutrition in rural Southern Ethiopia: Recovery, fatality, and nutritional status after discharge.
A scaled up and integrated outpatient therapeutic feeding programme (OTP) brings the treatment of severely malnourished children closer to the community. This study assessed recovery from severe acute malnutrition (SAM), fatality, and acute malnutrition up to 14 weeks after admission to a programme integrated in the primary health care system. In this cohort study, 1,048 children admitted to 94 OTPs in Southern Ethiopia were followed for 14 weeks. Independent anthropometric measurements and information on treatment outcome were collected at four home visits. Only 32.7% (248/759) of children with SAM on admission fulfilled the programme recovery criteria at the time of discharge (i.e., gained 15% in weight, or oedema, if present at admission, was resolved at discharge). Of all children admitted to the programme for whom nutritional assessment was done 14 weeks later, 34.6% (321/928) were severely malnourished, and 37.5% (348/928) were moderately malnourished; thus, 72.1% were acutely malnourished. Of the children, 27/982 (2.7%) had died by 14 weeks, of whom all but one had SAM on admission. Children with severe oedema on admission had the highest fatality rate (12.0%, 9/75). The median length of admission to the programme was 6.6 weeks (interquartile range: 5.3, 8.4 weeks). Despite children participating for the recommended duration of the programme, many children with SAM were discharged still acutely malnourished and without reaching programme criteria for recovery. For better outcome of OTP, constraints in service provision by the health system as well as challenges of service utilization by the beneficiaries should be identified and addressed.


Biomedical Potentialities of Taraxacum officinale-based Nanoparticles Biosynthesized Using Methanolic Leaf Extract.
In the present study, the potential of methanolic leaf extract of Taraxacum officinale plant as a function of bio-inspired green synthesis for the fabrication of silver nanoparticles (AgNPs) has been explored. The bio-reduction of aqueous silver nitrate (AgNO3) solution was confirmed by visually detecting the color change from pale yellow to blackish-brown. Maximum absorbance was observed at 420 nm due to the presence of characteristic surface Plasmon resonance of nano silver by UV-visible spectroscopy. The role of various functional groups in the bio-reduction of silver and chemical transformation was verified by Fourier transform infrared spectroscopy (FTIR). Scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDX) predict the shape (rocky, flack type, ellipsoidal, etc.), size (68 nm) and elemental composition (Ag as a major constituent) of the biosynthesized AgNPs, respectively. Transmission electron microscopy (TEM) analysis further corroborated the morphology of the AgNPs. Color mapping and atomic force microscopy (AFM) confirmed the nano-sized topography. The dynamic light scattering (DLS) showed the charge, stability, and size of the AgNPs. The generated AgNPs presented potential antibacterial activities against Gram-positive and Gram-negative bacterial strains including Staphylococcus aureus, Escherichia coli, and Haemophilus influenzae. The biosynthesized AgNPs also showed antiproliferative activity against MCF-7 breast cancer cell line in a dosedependent manner. In conclusion, results clearly indicate that biosynthesized AgNPs could be used as effective nano drug for treating infectious diseases caused by multidrug resistant bacterial strains in the near future.


Augmentation Strategies in Electroconvulsive Therapy: A Synthesis.
Over the past four decades, a variety of pharmacological augmentation strategies have been used in electroconvulsive therapy (ECT). Their goal has been to enhance therapeutic effects and seizure manifestations, or to minimize cognitive effects. Although they are not intended to affect outcome or other clinical parameters, medications taken during ECT may also impact on safety and efficacy. There is a large literature in epileptology on how pharmacologic agents affect seizure physiology. We review the clinical literature on augmentation strategies in ECT, with a synopsis of relevant preclinical studies, and seek to relate the pharmacological effects on seizure parameters to critical clinical variables in ECT.


Hemorrhage during warfarin therapy associated with cotrimoxazole and other urinary tract anti-infective agents: a population-based study.
Some antibiotic agents, including cotrimoxazole, inhibit the metabolism of warfarin sodium and possibly increase the risk of hemorrhage. We examined the risk of upper gastrointestinal (UGI) tract hemorrhage in older patients receiving warfarin in combination with antibiotics commonly used to treat urinary tract infection, with a focus on cotrimoxazole. This population-based, nested case-control study using health care databases in Ontario, Canada, between April 1, 1997, and March 31, 2007, identified residents 66 years or older who were continuously treated with warfarin. Cases were hospitalized with UGI tract hemorrhage. For each case, we selected up to 10 age- and sex-matched control subjects. We calculated adjusted odds ratios (aORs) for exposure to cotrimoxazole, amoxicillin trihydrate, ampicillin trihydrate, ciprofloxacin hydrochloride, nitrofurantoin, and norfloxacin within 14 days before the UGI tract hemorrhage. We identified 134 637 patients receiving warfarin, of whom 2151 cases were hospitalized for UGI tract hemorrhage. Cases were almost 4 times more likely than controls to have recently received cotrimoxazole (aOR, 3.84; 95% confidence interval [CI], 2.33-6.33). Treatment with ciprofloxacin was also associated with increased risk (aOR, 1.94; 95% CI, 1.28-2.95), but no significant association was observed with amoxicillin or ampicillin (1.37; 0.92-2.05), nitrofurantoin (1.40; 0.71-2.75), or norfloxacin (0.38; 0.12-1.26). Compared with amoxicillin or ampicillin, cotrimoxazole prescription was associated with an almost 3-fold risk (ratio of ORs, 2.80; 95% CI, 1.48-5.32). Among older patients receiving warfarin, cotrimoxazole is associated with a significantly higher risk of UGI tract hemorrhage than other commonly used antibiotics. Whenever possible, clinicians should prescribe alternative antibiotics in patients receiving warfarin.


Growth factors and transcription factors in oligodendrocyte development.
O-2A progenitor cells, the precursors of oligodendrocytes in the central nervous system (CNS), probably originate in the subventricular germinal zones of the developing CNS, and subsequently migrate away from there to populate the rest of the CNS with oligodendrocytes. We are trying to understand how the O-2A progenitor cells interact with their changing environment as they migrate, and how this influences each stage of their development into mature, myelinating oligodendrocytes. In this article we summarize evidence that platelet-derived growth factor (PDGF) is important for stimulating O-2A progenitor cell proliferation in vivo, and describe our efforts to map the distribution of PDGF and its receptors in the developing rat CNS by in situ hybridization and immunohistochemistry. These studies suggest that, in the CNS, PDGF alpha-receptor subunits may be restricted to O-2A lineage cells that have started to migrate away from the subventricular zones towards their final destinations. Many neurons express the A and/or B chains of PDGF, and astrocytes express the A chain, but it is not yet clear which of these cell types might be the major source of PDGF for O-2A lineage cells in vivo. O-2A progenitor cells can be purified and maintained in a proliferating state in vitro by culturing in the presence of PDGF and bFGF. Under these conditions, the POU transcription factor SCIP/Tst-1 is expressed at a high level; when oligodendrocyte differentiation is initiated by withdrawing the growth factors, SCIP/Tst-1 mRNA is rapidly down-regulated, followed by a decline in SCIP/Tst-1 protein and sequential activation of myelin-specific genes.(ABSTRACT TRUNCATED AT 250 WORDS)


Study and modeling of the distribution process of some phenolic compounds between the solid and liquid phases.
The article presents the results related to the study of distribution of biologically active substances from the plant raw material between solid and liquid phases. The aim of this study is to develop theoretical bases of the extraction process in the equilibrium state by the example of study and modeling of the distribution process of biologically active substances from Eucalyptus viminalis leaves. In these studies, we used ground plant raw material of E. viminalis leaves with particle fraction of 0.1-0.5 mm; and ethanol with concentration 80% ±1% v/v was used as an extractant. Qualitative and quantitative analyses were carried out by reversed phase high-performance liquid chromatography with rutin, chlorogenic acid, and euglobal standards equivalent to spissum extract of chlorophyllipt of the State Pharmacopoeia of Ukraine. A hypothesis has been suggested that Henry's adsorption law and the law of conservation of matter play a fundamental role in this process. The experimental data are described well by the suggested equation with high value of determination coefficient R 2 =0.99. At the same time, F-test and the significance of coefficients in equations satisfy the statistic condition, which means that the current hypothesis about the adsorption mechanism of distribution of biologically active substances in the extraction system is not refuted. The results of these studies demonstrate good agreement of experimental data and theoretical model based on Henry's adsorption law and mass balance. The numerical values of constants in the model suggested have been calculated.


CariesCare practice guide: consensus on evidence into practice.
This CariesCare practice guide is derived from the International Caries Classification and Management System (ICCMS) and provides a structured update for dentists to help them deliver optimal caries care and outcomes for their patients. This '4D cycle' is a practice-building format, which both prevents and controls caries and can engage patients as long-term health partners with their practice. CariesCare International (CCI™) promotes a patient-centred, risk-based approach to caries management designed for dental practice. This comprises a health outcomes-focused system that aims to maintain oral health and preserve tooth structure in the long-term. It guides the dental team through a four-step process (4D system), leading to personalised interventions: 1st D: Determine Caries Risk; 2nd D: Detect lesions, stage their severity and assess their activity status; 3rd D: Decide on the most appropriate care plan for the specific patient at that time; and then, finally, 4th D: Do the preventive and tooth-preserving care which is needed (including risk-appropriate preventive care; control of initial non-cavitated lesions; and conservative restorative treatment of deep dentinal and cavitated caries lesions). CariesCare International has designed this practice-friendly consensus guide to summarise best practice as informed by the best available evidence. Following the guide should also increase patient satisfaction, involvement, wellbeing and value, by being less invasive and more health-focused. For the dentist it should also provide benefits at the professional and practice levels including improved medico-legal protection.


Saikosaponin-d Inhibits the Hepatoma Cells and Enhances Chemosensitivity Through SENP5-Dependent Inhibition of Gli1 SUMOylation Under Hypoxia.
Chemosensitivity is one of the key factors affecting the therapeutic effect on cancer, but the clinical application of corresponding drugs is rare. Hypoxia, a common feature of many solid tumors, including hepatocellular carcinoma (HCC), has been associated with resistance to chemotherapy in part through the activation of the Sonic Hedgehog (SHh) pathway. Hypoxia has also been associated with the increased SUMOylation of multiple proteins, including GLI family proteins, which are key mediators of SHh signaling, and has become a promising target to develop drug-resistant drugs for cancer treatment. However, there are few target drugs to abrogate chemotherapy resistance. Saikosaponin-d (Ssd), one of the main bioactive components of Radix bupleuri, has been reported to exert multiple biological effects, including anticancer activity. Here, we first found that Ssd inhibits the malignant phenotype of HCC cells while increasing their sensitivity to the herpes simplex virus thymidine kinase/ganciclovir (HSVtk/GCV) drug system under hypoxia in vitro and in vivo. Furthermore, we had explored that GLI family activation and extensive protein SUMOylation were characteristics of HCC cells, and hypoxia could activate the SHh pathway and promote epithelial-mesenchymal transition (EMT), invasion, and chemosensitivity in HCC cells. SUMOylation is required for hypoxia-dependent activation of GLI proteins. Finally, we found that Ssd could reverse the effects promoted by hypoxia, specifically active sentrin/small ubiquitin-like modifier (SUMO)-specific protease 5 (SENP5), a SUMO-specific protease, in a time- and dose-dependent manner while inhibiting the expression of SUMO1 and GLI proteins. Together, these findings confirm the important role of Ssd in the chemoresistance of liver cancer, provide some data support for further understanding the molecular mechanisms of Ssd inhibition of malignant transformation of HCC cells, and provide a new perspective for the application of traditional Chinese medicine in the chemical resistance of liver cancer.


Shared probe design and existing microarray reanalysis using PICKY.
Large genomes contain families of highly similar genes that cannot be individually identified by microarray probes. This limitation is due to thermodynamic restrictions and cannot be resolved by any computational method. Since gene annotations are updated more frequently than microarrays, another common issue facing microarray users is that existing microarrays must be routinely reanalyzed to determine probes that are still useful with respect to the updated annotations. PICKY 2.0 can design shared probes for sets of genes that cannot be individually identified using unique probes. PICKY 2.0 uses novel algorithms to track sharable regions among genes and to strictly distinguish them from other highly similar but nontarget regions during thermodynamic comparisons. Therefore, PICKY does not sacrifice the quality of shared probes when choosing them. The latest PICKY 2.1 includes the new capability to reanalyze existing microarray probes against updated gene sets to determine probes that are still valid to use. In addition, more precise nonlinear salt effect estimates and other improvements are added, making PICKY 2.1 more versatile to microarray users. Shared probes allow expressed gene family members to be detected; this capability is generally more desirable than not knowing anything about these genes. Shared probes also enable the design of cross-genome microarrays, which facilitate multiple species identification in environmental samples. The new nonlinear salt effect calculation significantly increases the precision of probes at a lower buffer salt concentration, and the probe reanalysis function improves existing microarray result interpretations.


Reconstruction of Mohs Defects Located in the Head and Neck.
Defects following Mohs micrographic surgery (MMS) can range in size from small defects requiring linear closure to large defects needing flap coverage. Reconstruction is dependent on defect size and facial aesthetic unit involvement. The aim of this study was to review the types of facial reconstruction per aesthetic unit involvement and describe their outcomes. All data were retrieved for patients ≥18 years who underwent multidisciplinary treatment including dermatological MMS and plastic surgical reconstruction at a single tertiary hospital center (2001-2017). Patient characteristics, tumor pathology, surgical specifics, reconstructive modalities, and surgical outcomes were analyzed. A total of 418 patients were included. Patients were predominantly White, non-Hispanic (97%) and female (58%) with a mean age of 60 ± 13.9 years. Tumor pathology was predominantly basal cell carcinoma in 73% of all cases followed by squamous cell carcinoma in 14%. The nasal aesthetic unit was mostly affected (50%). Local advancement flaps and different types of grafts were used in 51% and 25% of reconstructions, respectively. Complications were observed in 3% and local cancer recurrence in 4% of the patients. Scar revision was needed in 6% of the patients. Reconstruction of facial defects after Mohs micrographic surgery can be challenging due to its technical complexity and aesthetic implications. There were differences in complications in reconstructions performed within the same day versus 1 week, with a majority of complications occurring within same-day Mohs reconstructions. A multidisciplinary structured approach, which incorporates patient-reported outcomes, may be needed to optimize surgical results.


Cell-mediated mutagenicity in Chinese hamster V79 cells of dibenzopyrenes and their bay-region fluorine-substituted derivatives.
The polycyclic aromatic hydrocarbons dibenzo(a,i)pyrene and dibenzo(a,h)pyrene, each of which possesses two bay regions, and their bay-region difluorinated derivatives were tested for mutagenicity for ouabain and 6-thioguanine resistance in Chinese hamster V79 cells. Since V79 cells do not metabolize polycyclic aromatic hydrocarbons, mutagenesis was tested in both the presence and the absence of golden hamster embryo cells capable of metabolizing polycyclic aromatic hydrocarbons. Neither of the dibenzopyrenes nor their fluorinated derivatives were mutagenic in the absence of the golden hamster embryo cells. In the presence of these cells (cell-mediated assay), both dibenzopyrenes were mutagenic, whereas the difluorinated derivatives, 2,10-difluorodibenzo-(a,i)pyrene and 3,10-difluorodibenzo(a,h)pyrene, either were inactive or exhibited (on a dose basis) a weak response. However, the mutagenicity of the dibenzopyrenes was eliminated when they were coincubated with 7,8-benzoflavone, a mixed-function oxidase inhibitor. The results suggest that metabolic oxidation of these polycyclic aromatic hydrocarbons at the bay region (presumably to diol-epoxides) is required for a mutagenic response in the cell-mediated assay.


Use of cyclooxygenase inhibitors and risk of melanoma in high-risk patients.
Results from in vitro and animal studies suggest that cyclooxygenase (COX) inhibitors may reduce the risk of melanoma, but among humans, the evidence remains limited. In a pilot retrospective cohort, to determine the relationship between the use of COX inhibitors and the incidence, recurrence, and metastases of melanoma in high-risk patients. Reviewing computerized records at the Miami Veterans Affairs Medical Center, we retrospectively examined the association between COX inhibitor use and melanoma incidence, recurrence, and metastases in high-risk subjects: white subjects previously diagnosed with melanoma (1996-2003). We evaluated three potential outcomes: new melanoma diagnosis, recurrence of a previous melanoma, and melanoma metastasis. Eighty-three subjects with melanoma were included. There was one metastasis among 28 subjects prescribed COX inhibitors, whereas four new melanomas (7.3%), two melanoma recurrences, and six metastases (10.9%) occurred among 55 patients not prescribed COX inhibitors. Although no individual outcomes measures reached statistical significance, combining the three measures, these were significantly lower in users of COX inhibitors compared with nonusers (1 vs 12; p = .05). After adjustment for age and tumor depth of invasion, COX inhibitor users had significantly lower rates of melanoma outcome measures (odds ratio 0.08; 95% confidence interval 0.01-0.77; p = .03). Potential exists for chemoprevention of melanoma among high-risk patients.


Isolation and characterization of a Clo DF13::Tn901 plasmid mutant with thermosensitive control of DNA replication.
After nitrosoguanidine mutagenesis, a mutant Escherichia coli strain harboring the Clo DF13::Tn901 plasmid pJN03 was isolated that is thermosensitive (Ts) for growth at 43 degrees C. The mutation responsible for this thermosensitive phenotype resides on the pJN03 plasmid genome. Cells harboring the pJN03 cop-1(Ts) plasmid mutant showed a large increase in plasmid copy number at 43 degrees C accompanied by an increase in the synthesis of plasmid-specified gene products like cloacin DF13 and beta-lactamase. The pJN03 cop-1(Ts) mutant showed uncontrolled plasmid DNA replication at the nonpermissive temperature. Analysis of plasmid deletions showed that the mutation is located in the Clo DF13 map interval from 0 to 12% or 29 to 45%. This implies that native cloacin DF13 and the Clo DF13-specified polypeptides B, C, D, E, and G are not involved in the pleiotropic phenotype of the plasmid mutant pJN03 cop-1(Ts).


Chronic alcohol ingestion exacerbates skeletal muscle myopathy in HIV-1 transgenic rats.
Separately, chronic alcohol ingestion and HIV-1 infection are associated with severe skeletal muscle derangements, including atrophy and wasting, weakness, and fatigue. One prospective cohort study reported that 41% of HIV-infected patients met the criteria for alcoholism, however; few reports exist on the co-morbid effects of these two disease processes on skeletal muscle homeostasis. Thus, we analyzed the atrophic effects of chronic alcohol ingestion in HIV-1 transgenic rats and identified alterations to several catabolic and anabolic factors. Relative plantaris mass, total protein content, and fiber cross-sectional area were reduced in each experimental group compared to healthy, control-fed rats. Alcohol abuse further reduced plantaris fiber area in HIV-1 transgenic rats. Consistent with previous reports, gene levels of myostatin and its receptor activin IIB were not increased in HIV-1 transgenic rat muscle. However, myostatin and activin IIB were induced in healthy and HIV-1 transgenic rats fed alcohol for 12 weeks. Catabolic signaling factors such as TGFβ1, TNFα, and phospho-p38/total-p38 were increased in all groups compared to controls. There was no effect on IL-6, leukemia inhibitory factor (LIF), cardiotrophin-1 (CT-1), or ciliary neurotrophic factor (CNTF) in control-fed, transgenic rats. However, the co-morbidity of chronic alcohol abuse and HIV-1-related protein expression decreased expression of the two anabolic factors, CT-1 and CNTF. Consistent with previous reports, alcohol abuse accentuated skeletal muscle atrophy in an animal model of HIV/AIDS. While some catabolic pathways known to drive alcoholic or HIV-1-associated myopathies were also elevated in this co-morbid model (e.g., TGFβ1), consistent expression patterns were not apparent. Thus, specific alterations to signaling mechanisms such as the induction of the myostatin/activin IIB system or reductions in growth factor signaling via CT-1- and CNTF-dependent mechanisms may play larger roles in the regulation of muscle mass in alcoholic, HIV-1 models.


Killing of gram-negative bacteria by lactoferrin and lysozyme.
Although lactoferrin has antimicrobial activity, its mechanism of action is not full defined. Recently we have shown that the protein alters the Gram-negative outer membrane. As this membrane protects Gram-negative cells from lysozyme, we have studied whether lactoferrin's membrane effect could enhance the antibacterial activity of lysozyme. We have found that while each protein alone is bacteriostatic, together they can be bactericidal for strains of V. cholerae, S. typhimurium, and E. coli. The bactericidal effect is dose dependent, blocked by iron saturation of lactoferrin, and inhibited by high calcium levels, although lactoferrin does not chelate calcium. Using differing media, the effect of lactoferrin and lysozyme can be partially or completely inhibited; the degree of inhibition correlating with media osmolarity. Transmission electron microscopy shows that E. coli cells exposed to lactoferrin and lysozyme at 40 mOsm become enlarged and hypodense, suggesting killing through osmotic damage. Dialysis chamber studies indicate that bacterial killing requires direct contact with lactoferrin, and work with purified LPS suggests that this relates to direct LPS-binding by the protein. As lactoferrin and lysozyme are present together in high levels in mucosal secretions and neutrophil granules, it is probable that their interaction contributes to host defense.


Common childhood bacterial infections.
Children with infectious diseases are commonly encountered in primary care settings. Identification of the subset of patients with bacterial infections is key in guiding the best possible management. Clinicians frequently care for children with infections of the upper respiratory tract, including acute otitis media, otitis externa, sinusitis, and pharyngitis. Conjunctivitis is not an uncommon reason for office visits. Bacterial pneumonia, urinary tract infections, and gastroenteritis are regularly seen. Over the last decade, a growing number of children have had infections of the skin and soft tissue, driven by the increased prevalence of infections caused by methicillin-resistant Staphylococcus aureus. The following review addresses the epidemiology and risk factors for specific infections and examines the clinical presentation and selection of appropriate diagnostic methods in such conditions. Methods to prevent these bacterial infections and recommendations for follow-up are suggested. Management of these infections requires that antimicrobial agents be used in a judicious manner in the outpatient setting. Such antibiotic therapy is recommended using both available clinical evidence and review of disease-specific treatment guidelines.


Tuft Cell Formation Reflects Epithelial Plasticity in Pancreatic Injury: Implications for Modeling Human Pancreatitis.
Chronic pancreatitis, a known risk factor for the development of pancreatic ductal adenocarcinoma (PDA), is a serious, widespread medical condition characterized by inflammation, fibrosis, and acinar to ductal metaplasia (ADM). ADM is a cell type transdifferentiation event where pancreatic acinar cells become ductal-like under conditions of injury or oncogenic mutation. Here, we show that chronic pancreatitis and ADM in genetically wild type mice results in the formation of a significant population of chemosensory tuft cells. Transcriptomic analyses of pancreatitis tuft cells identify expression of inflammatory mediators, consistent with a role for tuft cells in injury progression and/or resolution. Though similar to tuft cell populations in other organs and disease systems, we identified a number of key differences that suggest context-specific tuft cell functions. We evaluated seven different mouse strains for tuft cell formation in response to chronic injury and identified significant heterogeneity reflecting varying proclivity for epithelial plasticity between strains. These results have interesting implications in the role of epithelial plasticity and heterogeneity in pancreatitis and highlight the importance of mouse strain selection when modeling human disease.


NADPH oxidase and cardiac failure.
Increases in oxidative stress in the heart play an important role in mediating hypertrophy, apoptosis, fibrosis, mitochondrial dysfunction, and the consequent development of heart failure. Although it has been widely believed that electron leakage from the mitochondrial electron transport chain is the primary source of oxidative stress in the failing heart, increasing lines of evidence suggest that enzymes which produce reactive oxygen species may also contribute to it. NADPH oxidases are transmembrane enzymes dedicated to producing superoxide (O(2)(-)) by transferring an electron from NAD(P)H to molecular oxygen. Nox4 is a major NADPH oxidase isoform expressed in the heart. Nox4 is localized primarily at mitochondria in cardiac myocytes, and upregulation of Nox4 hypertrophic stimuli enhances O(2)(-) production, apoptosis, and mitochondrial dysfunction, thereby playing an important role in mediating cardiac dysfunction. Since Nox4 could be a key molecule mediating oxidative stress and pathological hypertrophy, it may serve as an important target of heart failure treatment. In this review, the importance of NADPH oxidases as sources of increased oxidative stress in the failing heart and the role of Nox4 in mediating growth and death of cardiac myocytes are discussed.


LmbE proteins from Bacillus cereus are de-N-acetylases with broad substrate specificity and are highly similar to proteins in Bacillus anthracis.
The genomes of Bacillus cereus and its closest relative Bacillus anthracis each contain two LmbE protein family homologs: BC1534 (BA1557) and BC3461 (BA3524). Only a few members of this family have been biochemically characterized including N-acetylglucosaminylphosphatidyl inositol (GlcNAc-PI), 1-D-myo-inosityl-2-acetamido-2-deoxy-alpha-D-glucopyranoside (GlcNAc-Ins), N,N'-diacetylchitobiose (GlcNAc(2)) and lipoglycopeptide antibiotic de-N-acetylases. All these enzymes share a common feature in that they de-N-acetylate the N-acetyl-D-glucosamine (GlcNAc) moiety of their substrates. The bc1534 gene has previously been cloned and expressed in Escherichia coli. The recombinant enzyme was purified and its 3D structure determined. In this study, the bc3461 gene from B. cereus ATCC14579 was cloned and expressed in E. coli. The recombinant enzymes BC1534 (EC 3.5.1.-) and BC3461 were biochemically characterized. The enzymes have different molecular masses, pH and temperature optima and broad substrate specificity, de-N-acetylating GlcNAc and N-acetylchito-oligomers (GlcNAc(2), GlcNAc(3) and GlcNAc(4)), as well as GlcNAc-1P, N-acetyl-D-glucosamine-1 phosphate; GlcNAc-6P, N-acetyl-D-glucosamine-6 phosphate; GalNAc, N-acetyl-D-galactosamine; ManNAc, N-acetyl-D-mannosamine; UDP-GlcNAc, uridine 5'-diphosphate N-acetyl-D-glucosamine. However, the enzymes were not active on radiolabeled glycol chitin, peptidoglycan from B. cereus, N-acetyl-D-glucosaminyl-(beta-1,4)-N-acetylmuramyl-L-alanyl-D-isoglutamine (GMDP) or N-acetyl-D-GlcN-Nalpha1-6-D-myo-inositol-1-HPO(4)-octadecyl (GlcNAc-I-P-C(18)). Kinetic analysis of the activity of BC1534 and BC3461 on GlcNAc and GlcNAc(2) revealed that GlcNAc(2) is the favored substrate for both native enzymes. Based on the recently determined crystal structure of BC1534, a mutational analysis identified functional key residues, highlighting their importance for the catalytic mechanism and the substrate specificity of the enzyme. The catalytic efficiencies of BC1534 variants were significantly decreased compared to the native enzyme. An alignment-based tree places both de-N-acetylases in functional categories that are different from those of other LmbE proteins.


Morphological and quantitative comparison between infectious and non-infectious forms of influenza virus.
Electron microscopic study has revealed the morphological entity responsible for the rise in viral hemagglutinin observed in brains of mice after intracerebral inoculation of non-neurotropic strains of influenza virus. This rise in hemagglutinin, although dependent on inoculation of fully infectious virus, is not associated with an increase in infectious titer. The hemagglutinating principle is functionally similar to the "incomplete" influenza virus which can be obtained from chick embryos by serial egg-to-egg transfer of undiluted, infected allantoic fluid according to the method of von Magnus. A method has been described which facilitates selective adsorption of viral particles recovered from organ extracts on saponine-lysed ghosts of fowl erythrocytes. This procedure has been utilized in studying the morphology of non-infectious, hemagglutinating virus from chorio-allantoic membranes or mouse brains and in comparing these two forms with each other and with ordinary, infectious (standard) influenza virus. Standard virus isolated from allantoic fluids or membranes of infected eggs was found to contain uniform particles of predominantly spherical shape with smooth surface and even density, resembling those described by others. The appearance of such particles was not affected by the procedure of extraction and concentration used. In contrast, non-infectious, hemagglutinating virus obtained either from allantoic sacs ("undiluted passages") or from mouse brain was pleomorphic and seemed to consist of disintegrating particles. The majority appeared flattened and bag-like and had a rough, granular surface and reduced, uneven density. 37 per cent of the non-infectious particles isolated from mouse brain infected with the non-neurotropic strain WS had diameters in excess of 170 mmicro, as compared with only 2 per cent of the particles of the parent strain itself. Regardless of whether or not the contrast in appearance of standard and of non-infectious particles was due to differing resistance to the preparatory treatment, it indicated the existence of basic structural differences between the two types of virus. Correlation of particle counts with hemagglutinin titers has shown that the non-infectious virus obtained from mouse brain is, unit for unit, an equivalent counterpart of standard virus derived from infected eggs. The end-point of hemagglutination in a pattern test corresponds for both forms to that dilution at which the ratio virus particles/red cells approaches one. The quantitative data based on particle counts support the assumption that non-infectious virus arises in mouse brain as a product of viral multiplication.


Sex Differences in the Diagnosis, Management, and Outcomes of Suspected Non-ST-Elevation Acute Coronary Syndromes Meeting Rapid Rule-Out Criteria.
(1) Background: patients who meet current rapid rule-out criteria for myocardial infarction (MI) are considered low risk, yet their management remains nebulous, especially among women. We aimed to examine sex differences in the diagnosis, management, and outcomes of patients meeting the rapid rule-out criteria. (2) Methods: by simulating application of the rapid rule-out MI criteria, we analyzed consecutively triaged men and women with suspected NSTE-ACS who had high-sensitivity cardiac troponin T (hs-cTnT) values that met criteria (n = 11,477), in particular, those who were admitted (n = 3775). (3) Results: men constituted ~55% of triaged patients who met the rule-out criteria, whether admitted or discharged. Men were more likely to be admitted (33.7% vs. 31.9%, p = 0.04), more commonly with hs-cTnT values between level of detection (LOD, 5 ng/ml) and the 99th percentile (59.4% of all admissions vs. 40.5% for women), whereas women were more likely to be admitted with values < level of blank (LOB, 3 ng/mL; 22.9% vs. 9.2% for men). Thirty-day mortality (1 man and 1 woman) and in-hospital MI (9 men vs. 1 woman) were uncommon among admitted patients, yet resource utilization during 3-4 hospitalization days was substantial for both sexes, with men undergoing coronary angiography (6.8% vs. 2.9%) and revascularization (3.4% vs. 1.1%) more commonly. Long-term survival for both men and women, whether admitted or discharged, was significantly worse for hs-cTnT values between LOD and the 99th percentile, even after adjusting for age and cardiovascular comorbidities. (4) Conclusions: reporting actual hs-cTnT values < 99th percentile allows for better risk stratification, especially for women, possibly closing the sex gap.


Dual effects of the antioxidant agents probucol and carvedilol on proliferative and fatty lesions in hypercholesterolemic rabbits.
The in vivo direct antiatherogenic activity of the antioxidant probucol (200 mg/kg per day) or the beta-blocker with antioxidant properties carvedilol (10 and 20 mg/kg per day) was tested in the same animal in two different types of atherosclerotic lesion (proliferative and fatty lesions) induced in cholesterol-fed rabbits (1%). Drugs were given daily mixed with standard diet for 8 weeks; body weight and plasma lipid profile were not different among groups throughout the study. Aortic fatty lesions were induced by cholesterol feeding (n = 25 in each group) and their extent expressed as % of aorta inner surface covered by plaques was significantly reduced by both drugs (28.2+/-9.6%, P <0.05, 19.9+/-6.2%, P <0.01 for low- and high-dose carvedilol, respectively; 22.3+/-7.6%, P <0.01 for probucol, versus 41.6+/-10.7% in control rabbits). Proliferative lesions were obtained by positioning a hollow silastic collar around one carotid artery 6 weeks after dietary and drug treatments started (n = 5 in each group). The neointimal formation, mostly composed by myocytes, was determined by measuring cross-sectional thickness ratio of intimal (I) and medial (M) tissue of fixed arteries. In untreated animals, collared arteries resulted in a significant neointimal cell accumulation compared to the sham (1.10+/-0.14 versus 0.02+/-0.01) without change in medial thickness. I/M ratio was reduced by about 50% in animals treated with probucol (0.51+/-0.1) and carvedilol (0.66+/-0.21 and 0.52+/-0.1 in the low- and high-dose group, respectively). Total plasma TBARS were more than 50% lower in both probucol- and high-dose carvedilol-treated rabbits. Results show that pharmacological pretreatment with antioxidants directly inhibits early atherogenic processes, representing a potentially useful approach in the prevention of atherosclerosis.


Epidemiological impact and cost-effectiveness of introducing vaccination against serogroup B meningococcal disease in France.
Despite its low incidence in France, invasive serogroup B meningococcal disease remains a public health concern. A new vaccine against the disease, Bexsero(®), has been licensed in the EU. We studied the epidemiological impact and cost-effectiveness of routine vaccination using Bexsero(®) in order to inform the decision-making process regarding its potential inclusion in the vaccination schedule. A multi-generational Markov model was used. Time horizon was set to 100 years. Five vaccination strategies were evaluated: infants at 3, 5, 6 and 13 months, toddlers at 13, 15 and 27 months and adolescents at 15 years provided 2 doses one month apart. A booster dose at 15 years old and a catch-up for 15 years old subjects during the first 15 years of the programme were added to the infant and toddler strategies. Costs per QALY gained were computed from a restricted societal perspective including direct costs only. Herd immunity was simulated in an alternative base-case scenario and sensitivity analyses. In the base-case analysis without herd immunity and with all cohorts vaccinated, at € 40 per vaccine dose, routine infant vaccination would provide the lowest cost per QALY gained (€ 380,973) despite only preventing 18% of cases. Under the assumption of herd immunity, the adolescent vaccination would provide the lowest cost per QALY gained (€ 135,902) preventing 24% of cases. Infant vaccination with a late booster and catch-up would prevent 51% of cases with a cost of € 188,511 per QALY gained. Given current meningococcal epidemiology in France and the available data on the protection provided by Bexsero(®), our modelling work showed that routine vaccination against serogroup B meningococcal disease is not cost-effective.


Consequences of cathodal stimulation for behavior: when does it help and when does it hurt performance?
Cathodal Transcranial Direct Current Stimulation (C-tDCS) has been reported, across different studies, to facilitate or hinder performance, or simply to have no tangible effect on behavior. This discrepancy is most prominent when C-tDCS is used to alter a cognitive function, questioning the assumption that cathodal stimulation always compromises performance. In this study, we aimed to study the effect of two variables on performance in a simple cognitive task (letter Flanker), when C-tDCS was applied to the left prefrontal cortex (PFC): (1) the time of testing relative to stimulation (during or after), and (2) the nature of the cognitive activity during stimulation in case of post-tDCS testing. In three experiments, we had participants either perform the Flanker task during C-tDCS (Experiment 1), or after C-tDCS. When the Flanker task was administered after C-tDCS, we varied whether during stimulation subjects were engaged in activities that posed low (Experiment 2) or high (Experiment 3) demands on the PFC. Our findings show that the nature of the task during C-tDCS has a systematic influence on the outcome, while timing per se does not.


Outcome of traumatic hyphema.
One hundred and twenty-seven cases of traumatic hyphema are reviewed and discussed according to a definite system of grading. Grade iii hyphemas have definitely a poorer prognosis than Grade ii and Grade i hyphemas. Rebleeding occurs more frequently when there is a delay in treatment but does not appear to affect the outcome of a traumatic hyphema. Blood staining of the cornea could be avoided by an adequate treatment started immediately after the trauma, thus decreasing the percentage of blindness following a traumatic hyphema.


Feasibility of the EORTC/NCIC Trial Protocol in a Neurosurgical Outpatient Unit: The Case for Neurosurgical Neuro-Oncology.
With the publication of the European Organization for Research and Treatment of Cancer/National Cancer Information Center (EORTC/NCIC) trial, concomitant radiochemotherapy followed by intermittent chemotherapy became the new treatment standard for patients with primary glioblastoma. Eight years after widespread introduction of this protocol, it is of interest to investigate whether this new standard has been established in daily neuro-oncologic practice. We were particularly interested in its practicality within a neurosurgical neuro-oncologic setting. We analyzed primary glioblastoma patients diagnosed between 2005 and 2013 treated at our center according to the EORTC/NCIC trial. Parameters associated with treatment performance (interruption of radiotherapy, concomitant chemotherapy and intermittent chemotherapy, total number of cycles, and side effects) were retrospectively analyzed and compared with the available data from the EORTC/NCIC trial. In this single-center retrospective study, we identified 189 patients (116 men, 73 women; median age: 62 years) who were treated according to the EORTC/NCIC trial protocol. A total of 176 patients received cytoreductive surgery; 13 patients had stereotactic biopsy only (EORTC/NCIC trial: 239 patients and 48 patients, respectively). Radiotherapy had to be interrupted in 9 patients (5%) (EORTC/NCIC trial: 15 patients [5%]) and concomitant chemotherapy in 26 patients (14%) (EORTC/NCIC trial: 37 patients [13%]). In 156 patients (83%), adjuvant TMZ chemotherapy was initiated (6 median temozolomide [TMZ] cycles; range: 1-30). In the EORTC/NCIC trial, 223 patients (47%) received the intermittent chemotherapy protocol (median: 3 cycles; range: 1-7). Overall, 97 patients (62%) completed 6 TMZ cycles (EORTC/NCIC-trial: 105 patients [47%]); dose escalation to 200 mg/qm at the second cycle was performed in 91 patients (58%) (versus 149 patients [67%]). Intermittent TMZ therapy was discontinued in 59 patients (38%) (versus 118 patients [53%]). Median overall survival in our patient cohort was 19 months (versus 14.6 months); median time to progression was 9 months (versus 6.9 months). Comparison between the feasibility of the treatment protocol established by the EORTC/NCIC trial (performed within the setting of a prospective randomized trial) and the daily routine in a dedicated neurosurgical neuro-oncologic department demonstrates that the protocol is suitable for daily practice within a neurosurgical unit.


Antioxidant action of Vaccinium myrtillus extract on human low density lipoproteins in vitro: initial observations.
Oxidative modifications of low density lipoproteins (LDL) are now recognised as one of the major processes in atherogenesis. Various drugs, as well as a number of natural products, have been proposed to inhibit such processes. Among the naturally-occurring constituents of plants which appear to possess antioxidant activity are polyphenolic compounds such as flavonoids. The aqueous extract of Vaccinium myrtillus is rich in such molecules. In this report, we describe the in vitro antioxidative potential of this extract on human LDL. The copper-induced oxidative modification of these lipoproteins was assessed using 1) measurement of oxidative resistance as determined by the lag-phase preceding conjugated diene formation; 2) quantification of the amount of lipoperoxides and thiobarbituric acid-reactive substances generated, and measurement of the modification in the net negative electrical charge of the lipoproteins, over a 7-hour time course experiment. Trace amounts of V myrtillus extract (15 to 20 micrograms/mL) induce statistically significant changes in the oxidation behaviour of LDL, which include 1) prolongation of the lag-phase of conjugated diene production (P < 0.01); 2) reduction in the formation of lipoperoxides and of thiobarbituric acid-reactive substances up to 7 hours and especially between 1 and 5 hours (P < 0.01); and 3) inhibition of modification in the net negative charge of LDL. These results demonstrate that V myrtillus extract exerts potent protective action on LDL particles during in vitro copper-mediated oxidation. Calculation of IC50 values indicates that, on a molar basis, this extract may indeed be more potent than either ascorbic acid or butylated hydroxytoluene in the protection of LDL particles from oxidative stress.


[The sympatry of closely related species of ixodid ticks and its possible role in the parasitic systems of natural foci of transmissible diseases].
Sympatry of the following pairs (or groups) of closely related species in the territory of the former Soviet Union amd some neighbouring countries has been revealed as a result of a revision of the fam. Ixodidae: I. persulcatus-I. ricinus, I. persulcatus-I. pavlovskyi, I. crenulatus-I. kaiseri, Dermacentor marginatus-D. silvarum-D. ushakovae, D. ushakovae-D. niveus, D. pavlovskyi-D. montanus, Rhipicephalus turanicus-R. sanguineus, R. turanicus-R. rossicus, R. turanicus-R. pumilio, R. rossicus-R. pumilio. Biotope and host relationships of sympatric species, as well as seasons of parasitizing have been described on the basis of the field researches conducted by the author, the collections of the Zoological Institute, Russian Academy of Sciences, and the publications substantiated by collection materials studied by the author. Hypothetic ways of the paleogenesis of each sympatric area and geological age have been considered. The recent sympatric area for I. persulcatus-I. ricinus (fig. 1) is of Holocene age (max. 8.000-10.000 years). During that period approximately 1600-2000 sympatric generations could have been realized. Some recent sympatric areas (I. persulcatus-I. pavlovskyi, and some species of other genera) are of Pleistocene and even Pliocene age (2-10 million years). In these areas the number of realized sympatric generations must have been much higher. Several variants of joint simultaneous and successive feeding on one and the same host individual have been established for stages of life cycles of sympatric species of ticks. Contacts of this kind could have created canals for multiple oscillatory exchange of pathogenic taxa (species, genospecies, strains) in a few or many thousands of sympatric generations of closely related vectors. Thus, the same taxon of a pathogen may be subject to different influence of ixodid vectors in sympatric area and in the area of separate habitat of close species of vectors.


Oil-Immersion Flow Imaging Microscopy for Quantification and Morphological Characterization of Submicron Particles in Biopharmaceuticals.
Flow imaging microscopy (FIM) is widely used to analyze subvisible particles starting from 2 μm in biopharmaceuticals. Recently, an oil-immersion FIM system emerged, the FlowCam Nano, designed to enable the characterization of particle sizes even below 2 μm. The aim of our study was to evaluate oil-immersion FIM (by using FlowCam Nano) in comparison to microfluidic resistive pulse sensing and resonant mass measurement for sizing and counting of particles in the submicron range. Polystyrene beads, a heat-stressed monoclonal antibody formulation and a silicone oil emulsion, were measured to assess the performance on biopharmaceutical relevant samples, as well as the ability to distinguish particle types based on instrument-derived morphological parameters. The determination of particle sizes and morphologies suffers from inaccuracies due to a low image contrast of small particles and light-scattering effects. The ill-defined measured volume impairs an accurate concentration determination. Nevertheless, FlowCam Nano in its current design complements the limited toolbox of submicron particle analysis of biopharmaceuticals by providing particle images in a size range that was previously not accessible with commercial FIM instruments.


Will Infant Hepatitis B Vaccination Protect Into Adulthood?: Extended Canadian Experience After a 2-, 4- and 6-month Immunization Schedule.
Hepatitis B virus (HBV) vaccination programs generally target infants to prevent chronic HBV infection and/or preadolescents to reduce transmission in adulthood. To assess whether infant HBV immunization can potentially accomplish both objectives, we measured residual immunity 10-16 years after vaccination in Canadian children. A prospective, parallel group, single center study enrolled adolescents given HBV vaccine at 2, 4 and 6 months of age. Exclusion criteria included prior HBV infection and additional vaccinations. At follow-up anti-HBs testing, participants were 10-11 or 15-16 years old; those with <12 mIU/mL anti-HBs by the assay used were challenged with HBV vaccine to assess immune memory-based responsiveness. A total of 137 tested participants were 10-11 and 213 were 15-16 years old, respectively; none had evidence of prior HBV infection. At baseline, 78% of younger and 64% of older participants had <12 mIU/mL anti-HBs (P = 0.006) and were challenged with vaccine: 103/106 (97.2%) younger and 123/135 (91.1%) older participants developed ≥12 mIU/mL anti-HBs (P = 0.06), with geometric mean antibody concentration of 590 (95% confidence interval: 473-737) and 319 mIU/mL (95% confidence interval: 229-445; P = 0.004), respectively. Immune memory loss may have occurred in 3 younger (2.2%) and 12 older children (5.6%; P = 0.06) who were nonresponsive to first but not second vaccine challenge. After HBV vaccination at 2, 4 and 6 months of age, most adolescents had little or no residual antibody but nearly all responded to HBV challenge, confirming immune memory persistence. However, anamnestic responses were weaker in 15- to 16-year olds and lost in some. Booster responses in 10- to 11-year olds were vigorous in comparison. Extended evaluation of protection is warranted.


The origin of a new fin skeleton through tinkering.
Adipose fins are positioned between the dorsal and caudal fins of many teleost fishes and primitively lack skeleton. In at least four lineages, adipose fins have evolved lepidotrichia (bony fin rays), co-opting the developmental programme for the dermal skeleton of other fins into this new territory. Here I provide, to my knowledge, the first description of lepidotrichia development in an adipose fin, characterizing the ontogeny of the redtail catfish, Phractocephalus hemioliopterus. Development of these fin rays differs from canonical lepidotrich development in the following four ways: skeleton begins developing in adults, not in larvae; rays begin developing at the fin's distal tip, not proximally; the order in which rays ossify is variable, not fixed; and lepidotrichia appear to grow both proximally and distally, not exclusively proximodistally. Lepidotrichia are often wavy, of irregular thickness and exhibit no regular pattern of segmentation or branching. This skeleton is among the most variable observed in a vertebrate appendage, offering a unique opportunity to explore the basis of hypervariation, which is generally assumed to reflect an absence of function. I argue that this variation reflects a lack of canalization as compared with other, more ancient lepidotrichs and suggest developmental context can affect the morphology of serial homologues.


Behavior problems and children's academic achievement: A test of growth-curve models with gender and racial differences.
The aim of this study was to examine the longitudinal association between externalizing and internalizing behavior and children's academic achievement, particularly in terms of whether these variables varied as a function of gender and race. Data pertaining to externalizing and internalizing behavior, academic achievement, gender, and race from three waves of the Child Development Supplement of the Panel Study of Income Dynamics (N = 2028) were used. Results indicate that behavior problems had a negative relationship with academic performance and some of these associations endured over time. Externalizing behavior impacted reading scores more negatively for females compared to males at baseline, but the impact of externalizing behavior on long-term reading outcomes did not vary by gender. Externalizing behavior impacted reading scores more negatively for Black children than White children at multiple points in time. Differences between males, females, Black, and White children concerning behavior and achievement are explained. Implications, limitations, and ideas for future research are also presented.


[Vertical migrations of hungry imagoes of the tick Dermacentor marginatus].
The ticks of D. marginatus display activity at a temperature of 3 to 16 C and relative humidity of 20 to 75%. At a low temperature higher than 19 C their activity is inhibited throughout the whole autumn period at any time of the day. Active appearance of ticks on the stems of vegetation was recorded at 8C and higher in August and the first decade of September (in the morning 16%, in the day time 7.5% and in the evening 74% of ticks become active). As a rule the most high percentage of ticks (56 to 85%) recorded from upper parts of stems was observed in August and first decade of September at evening hours at 12 to 17 C and relative humidity of 50 to 70%.


The role of same-sex mentorship and organizational support in encouraging women to pursue surgery.
While women represent approximately half of all medical students, only 38% of general surgery residents are women. The objective of this study is to explore how access to mentors and organizational support affects career choices. In June of 2016, a survey was sent to medical students at a single institution (n = 472). Questions utilized a 5-point Likert scale. A two-sample t-test was used to evaluate data. A total of 160 students participated in the survey. Among MS1/MS2 students, women were more likely to rank same-sex role models as a positive influence (mean 3.1 vs. 2.4; p < 0.05). Similar results were seen among MS3/MS4 students (mean 3.6 vs. 2.5; p < 0.05). More women ranked the presence of organizations that support women in surgery as being important (mean 4.6 vs. 4.1; p < 0.05). Exposure to same-sex mentors was highly rated among female participants. These findings encourage the creation of national mentorship programs. Early involvement in organizations can positively influence career choice. Addressing gaps in mentorship opportunities and widening accessibility to national organizations are important in reducing barriers.


The shear modulus of lower-leg muscles correlates to intramuscular pressure.
Shear wave elastography (SWE) is emerging as an innovative tool to evaluate muscle properties and function. It has been shown to correlate with both passive and active muscle forces, and is sensitive to physiological processes and pathological conditions. Similarly, intramuscular pressure (IMP) is an important parameter that changes with passive and active muscle contraction, body position, exercise, blood pressure, and several pathologies. Therefore, the objective of this study was to quantify the dependency of shear modulus within the lower-leg muscles on IMP in healthy individuals. Nineteen healthy individuals (age: Mean age ± SD, 23.84 ± 6.64 years) were recruited. Shear modulus was measured using ultrasound SWE on the tibialis anterior (TA) and peroneus longus (PL) muscles using pressure cuff inflation around the thigh at 40 mmHg, 80 mmHg, and 120 mmHg. Changes in IMP were verified using a catheter connected to a blood pressure monitor. It was found that IMP was correlated to TA and PL shear modulus (spearman's rank correlation = 0.99 and 0.99, respectively). Applying a gradual increase of cuff pressure from 0 to 120 mmHg increased the shear modulus of the TA and PL muscles from 15.83 (2.46) kPa to 21.88 (4.33) kPa and from 9.64 (1.97) kPa to 12.88 (5.99) kPa, respectively. These results demonstrate that changes of muscle mechanical properties are dependent on IMP. This observation is important to improve interpretation of ultrasound elastograms and to potentially use it as a biomarker for more accurate diagnosis of pathologies related to increased IMP.


[Treatment and prevention phantom pain syndrome in mine-explosive injuries].
Phantom pain syndrome significantly impairs the quality of life and effectiveness of surgical treatment after limb amputations. The authors consider possible strategies for treatment and prevention in elective surgical intervention and mine-explosive injuries.


Abnormal NF-kappa B function characterizes human type 1 diabetes dendritic cells and monocytes.
Dendritic cell (DC) differentiation is abnormal in type 1 diabetes mellitus (T1DM). However, the nature of the relationship between this abnormality and disease pathogenesis is unknown. We studied the LPS response in monocytes and monocyte-derived DCs isolated from T1DM patients and from non-T1DM controls. In T1DM patients, late LPS-mediated nuclear DNA binding by RelA, p50, c-Rel, and RelB was impaired as compared with type 2 DM, rheumatoid arthritis, and healthy subjects, associated with impaired DC CD40 and MHC class I induction but normal cytokine production. In TIDM monocytes, RelA and RelB were constitutively activated, and the src homology 2 domain-containing protein tyrosine phosphatase (SHP-1), a negative regulator of NF-kappaB, was overexpressed. Addition of sodium stibogluconate, a SHP-1 inhibitor, to DCs differentiating from monocyte precursors restored their capacity to respond to LPS in approximately 60% of patients. The monocyte and DC NF-kappaB response to LPS is thus a novel phenotypic and likely pathogenetic marker for human T1DM. SHP-1 is at least one NF-kappaB regulatory mechanism which might be induced as a result of abnormal inflammatory signaling responses in T1DM monocytes.


Effect of particle size based separation of milled corn stover on AFEX pretreatment and enzymatic digestibility.
Particle size and compositional variance are found to have a substantial influence on ammonia fiber explosion (AFEX) pretreatment and enzymatic hydrolysis of lignocellulosic biomass. Corn stover was milled and fractionated into particle sizes of varying composition. The larger particle size fractions (rich in corn cob and stalk portions) were found to be more recalcitrant to hydrolysis compared to the smaller size fractions (rich in leaves and husk portion). Electron spectroscopy for chemical analysis (ESCA) and Fourier transform infrared spectroscopy (FTIR) were used for biomass surface and bulk compositional analysis, respectively. The ESCA results showed a 15-30% decrease in the O/C (oxygen to carbon) ratio after the pretreatment indicating an increase in the hydrophobic nature of biomass surface. FTIR results confirmed cleavage of the lignin-carbohydrate complex (LCC) for the AFEX-treated fractions. The spectroscopic results indicate the extraction of cleaved lignin phenolic fragments and other cell wall extractives to the biomass surface upon AFEX. Water washing of AFEX-treated fractions removed some of the hydrophobic extractives resulting in a 13% weight loss (dry weight basis). Phenolic content of wash stream was evaluated by the modified Prussian blue (MPB) method. Removal of ligno-phenolic extractives from the AFEX-treated biomass by water washing vastly improved the glucan conversion as compared to the unwashed samples. Reduction in substrate particle size was found to affect the AFEX process and rate of hydrolysis as well. Implications of the stover particle size, composition, and inhibitory role of the phenolic fragments on an integrated biorefinery are discussed.


Can Artificial Ecosystems Enhance Local Biodiversity? The Case of a Constructed Wetland in a Mediterranean Urban Context.
Constructed wetlands (CW) are considered a successful tool to treat wastewater in many countries: their success is mainly assessed observing the rate of pollution reduction, but CW can also contribute to the conservation of ecosystem services. Among the many ecosystem services provided, the biodiversity of CW has received less attention. The EcoSistema Filtro (ESF) of the Molentargius-Saline Regional Natural Park is a constructed wetland situated in Sardinia (Italy), built to filter treated wastewater, increase habitat diversity, and enhance local biodiversity. A floristic survey has been carried out yearly 1 year after the construction of the artificial ecosystem in 2004, observing the modification of the vascular flora composition in time. The flora of the ESF accounted for 54% of the whole Regional Park's flora; alien species amount to 12%; taxa of conservation concern are 6%. Comparing the data in the years, except for the biennium 2006/2007, we observed a continuous increase of species richness, together with an increase of endemics, species of conservation concern, and alien species too. Once the endemics appeared, they remained part of the flora, showing a good persistence in the artificial wetland. Included in a natural park, but trapped in a sprawling and fast growing urban context, this artificial ecosystem provides multiple uses, by preserving and enhancing biodiversity. This is particularly relevant considering that biodiversity can act as a driver of sustainable development in urban areas where most of the world's population lives and comes into direct contact with nature.


Carbon nanotube/polysulfone soft composites: preparation, characterization and application for electrochemical sensing of biomarkers.
Multi-walled carbon nanotube/polysulfone soft composites (MWCNT/PSf) prepared via phase inversion are a novel platform for electrochemical and electroanalytical purposes with practical applications in the design of screen-printed electrodes for electrochemical sensing. We present here a thorough characterization of the morphological, physical, chemical and electrochemical properties of this material. These composites constitute a robust mesoporous network with high specific surface area, which is beneficial for trapping bioanalytes and increasing the electrochemical sensitivity. We highlight the advantages of these soft composites by comparing them with analogous graphite composites.


Antitumor effects of a novel small molecule targeting PCNA chromatin association in prostate cancer.
Proliferating cell nuclear antigen (PCNA) plays an essential role in DNA replication and repair. Tumor cells express high levels of PCNA, identifying it as a potentially ideal target for cancer therapy. Previously, we identified nine compounds termed PCNA inhibitors (PCNA-Is) that bind directly to PCNA, stabilize PCNA trimer structure, reduce chromatin-associated PCNA, and selectively inhibit tumor cell growth. Of these compounds, PCNA-I1 is most potent. The purposes of this study were to further investigate the effects of targeting PCNA chromatin association on DNA damage and cytotoxicity and to evaluate the therapeutic potential of PCNA-I1 against tumors in mice. Given the important roles of tumor suppressor p53 in regulating sensitivity of tumor cells to chemotherapeutics, we performed studies in two human prostate cancer cell lines differing in p53 expression: LNCaP cells (wild-type p53) and PC-3 cells (p53-null). PCNA-I1 induced DNA damage and apoptosis in both LNCaP and PC-3 cells and enhanced DNA damage and apoptosis triggered by cisplatin. PCNA-I1 also induced autophagy in PC-3 cells. A short-term pretreatment with PCNA-I1 reduced colony formation by 50% in both cell lines. These data suggest that, unlike many other cytotoxic drugs, the effects of PCNA-I1 on tumor cells do not depend on expression of p53. Intravenous administrations of PCNA-I1 significantly retarded growth of LNCaP tumors of in nude mice without causing detectable effects on mouse body weight and hematology profiles. These data provide proof of concept that targeting PCNA chromatin association could be a novel and effective therapeutic approach for treatment of cancer.


Learning control for batch thermal sterilization of canned foods.
A control technique based on Reinforcement Learning is proposed for the thermal sterilization of canned foods. The proposed controller has the objective of ensuring a given degree of sterilization during Heating (by providing a minimum temperature inside the cans during a given time) and then a smooth Cooling, avoiding sudden pressure variations. For this, three automatic control valves are manipulated by the controller: a valve that regulates the admission of steam during Heating, and a valve that regulate the admission of air, together with a bleeder valve, during Cooling. As dynamical models of this kind of processes are too complex and involve many uncertainties, controllers based on learning are proposed. Thus, based on the control objectives and the constraints on input and output variables, the proposed controllers learn the most adequate control actions by looking up a certain matrix that contains the state-action mapping, starting from a preselected state-action space. This state-action matrix is constantly updated based on the performance obtained with the applied control actions. Experimental results at laboratory scale show the advantages of the proposed technique for this kind of processes.


Enzymatic Degradation of DNA Probed by In Situ X-ray Scattering.
Label-free in situ X-ray scattering from protein spherical nucleic acids (Pro-SNAs, consisting of protein cores densely functionalized with covalently bound DNA) was used to elucidate the enzymatic reaction pathway for the DNase I-induced degradation of DNA. Time-course small-angle X-ray scattering (SAXS) and gel electrophoresis reveal a two-state system with time-dependent populations of intact and fully degraded DNA in the Pro-SNAs. SAXS shows that in the fully degraded state, the DNA strands forming the outer shell of the Pro-SNA were completely digested. SAXS analysis of reactions with different Pro-SNA concentrations reveals a reaction pathway characterized by a slow, rate determining DNase I-Pro-SNA association, followed by rapid DNA hydrolysis. Molecular dynamics (MD) simulations provide the distributions of monovalent and divalent ions around the Pro-SNA, relevant to the activity of DNase I. Taken together, in situ SAXS in conjunction with MD simulations yield key mechanistic and structural insights into the interaction of DNA with DNase I. The approach presented here should prove invaluable in probing other enzyme-catalyzed reactions on the nanoscale.


Unique features of head and neck malignancies which relate to their management.
The unique features of head and neck malignancies which relate to their management have resulted in the development of a surgical specialty group for which training criteria have been established. Head and neck tumors are uniquely sensitivity to radiotherapy which provides the surgeon with an alternate method of therapy. They are easily visible and palpable so that the results of therapy can be readily assessed and appropriate treatment protocols developed. Tumors of the head and neck interfere with vital function and present major problems of reconstruction both for cosmetic and functional purposes. Patients with head and neck tumors are remarkably prone to develop second primary malignancies and to have other major physical problems which must be considered. The proper management of head and neck tumors requires a dedicated, knowledgeable team of physicians, nurses, and related personnel working under ideal conditions which allow for the consideration of all the factors uniquely related to malignant disease in the area.


A Comparative Evaluation of Gait between Children with Autism and Typically Developing Matched Controls.
Anecdotal reports suggest children with autism spectrum disorder (ASD) ambulate differently than peers with typical development (TD). Little empirical evidence supports these reports. Children with ASD exhibit delayed motor skills, and it is important to determine whether or not motor movement deficits exist during walking. The purpose of the study was to perform a comprehensive lower-extremity gait analysis between children (aged 5-12 years) with ASD and age- and gender-matched-samples with TD. Gait parameters were normalized to 101 data points and the gait cycle was divided into seven sub-phases. The Model Statistic procedure was used to test for statistical significance between matched-pairs throughout the entire gait cycle for each parameter. When collapsed across all participants, children with ASD exhibited large numbers of significant differences (p < 0.05) throughout the gait cycle in hip, knee, and ankle joint positions as well as vertical and anterior/posterior ground reaction forces. Children with ASD exhibited unique differences throughout the gait cycle, which supports current literature on the heterogeneity of the disorder. The present work supports recent findings that motor movement differences may be a core symptom of ASD. Thus, individuals may benefit from therapeutic movement interventions that follow precision medicine guidelines by accounting for individual characteristics, given the unique movement differences observed.


Design and Evaluation of Sensor Housing for Boundary Layer Profiling Using Multirotors.
Traditional configurations for mounting Temperature-Humidity (TH) sensors on multirotor Unmanned Aerial Systems (UASs) often suffer from insufficient radiation shielding, exposure to mixed and turbulent air from propellers, and inconsistent aspiration while situated in the wake of the UAS. Descent profiles using traditional methods are unreliable (when compared to an ascent profile) due to the turbulent mixing of air by the UAS while descending into that flow field. Consequently, atmospheric boundary layer profiles that rely on such configurations are bias-prone and unreliable in certain flight patterns (such as descent). This article describes and evaluates a novel sensor housing designed to shield airborne sensors from artificial heat sources and artificial wet-bulbing while pulling air from outside the rotor wash influence. The housing is mounted above the propellers to exploit the rotor-induced pressure deficits that passively induce a high-speed laminar airflow to aspirate the sensor consistently. Our design is modular, accommodates a variety of other sensors, and would be compatible with a wide range of commercially available multirotors. Extensive flight tests conducted at altitudes up to 500 m Above Ground Level (AGL) show that the housing facilitates reliable measurements of the boundary layer phenomena and is invariant in orientation to the ambient wind, even at high vertical/horizontal speeds (up to 5 m/s) for the UAS. A low standard deviation of errors shows a good agreement between the ascent and descent profiles and proves our unique design is reliable for various UAS missions.


Antioxidant and Antimicrobial Evaluation and Chemical Investigation of Rosa gallica var. aegyptiaca Leaf Extracts.
Rosa gallica var. aegyptiaca is a species of flowering plant belonging to the Rosaceae family that plays an important role as a therapeutic agent for the treatment of specific types of cancer, microbial infections, and diabetes mellitus. This work presents the first report on the evaluation of the antioxidant and antimicrobial potential along with the phytochemical analysis of Rosa gallica var. aegyptiaca leaves. Five leaf extracts of hexane, chloroform, methanol, hydromethanol 80%, and water were prepared. Assessment of antioxidant activity was carried out via DPPH radical scavenging assay. Antimicrobial activity against five foodborne pathogenic bacteria-including Listeria monocytogenes, Bacillus subtilis, Staphylococcus aureus, Escherichia coli, and Salmonella enteritidis-and the fungus Candida albicans, was examined using the disc diffusion method. Total phenolic content and total flavonoid content were determined using the Folin-Ciocalteu reagent and aluminum chloride methods, respectively. Isolation, identification, and quantification of phenolic compounds were performed using HPLC-DAD analysis. Amongst the five leaf extracts that were investigated, hydromethanol 80% extract possessed the highest extraction yield, antioxidant activity, total phenolic content, and antimicrobial activity against all tested microbial strains. Moreover, this extract furnished six active phenolic compounds: gallic acid (1), (+) catechin (2), chlorogenic acid (3), (-) epicatechin (4), quercetin-3-O-α-d-(glucopyranoside) (5), and quercetin (6). This study provides an alternative utilization of R. gallica var. aegyptiaca leaves as a readily accessible source of natural antioxidants and antimicrobials in the food and pharmaceutical industries.


A fast and efficient method to compensate for brain shift for tumor resection therapies measured between preoperative and postoperative tomograms.
In this paper, an efficient paradigm is presented to correct for brain shift during tumor resection therapies. For this study, high resolution preoperative (pre-op) and postoperative (post-op) MR images were acquired for eight in vivo patients, and surface/subsurface shift was identified by manual identification of homologous points between the pre-op and immediate post-op tomograms. Cortical surface deformation data were then used to drive an inverse problem framework. The manually identified subsurface deformations served as a comparison toward validation. The proposed framework recaptured 85% of the mean subsurface shift. This translated to a subsurface shift error of 0.4 +/- 0.4 mm for a measured shift of 3.1 +/- 0.6 mm. The patient's pre-op tomograms were also deformed volumetrically using displacements predicted by the model. Results presented allow a preliminary evaluation of correction both quantitatively and visually. While intraoperative (intra-op) MR imaging data would be optimal, the extent of shift measured from pre- to post-op MR was comparable to clinical conditions. This study demonstrates the accuracy of the proposed framework in predicting full-volume displacements from sparse shift measurements. It also shows that the proposed framework can be extended and used to update pre-op images on a time scale that is compatible with surgery.


Two autonomous myc oncogenes in avian carcinoma virus OK10.
The oncogenic avian retrovirus OK10 has the genetic structure gag-delta pol-myc-delta-env. The myc sequence is transduced from a cellular gene, proto-myc, while gag, pol, and env are essential retrovirus genes. By analogy with other directly oncogenic retroviruses, the specific myc sequence of OK10 is thought to be essential for transforming function. However, unlike the specific sequences of all other transforming retroviruses that encode unique transforming proteins, the myc sequence of OK10 encodes two potential transforming proteins, p58 and p200. p200 is translated from the gag-delta pol-myc region of genomic RNA, while p58 is thought to be translated from the gag leader and the open reading frame of myc via a subgenomic mRNA. In this paper, we ask whether both myc genes of OK10 are autonomous transforming genes. By differentially inactivating the p200 myc gene of OK10 provirus in vitro and analyzing transforming function in quail embryo cells, it was found that mutants expressing only p58 transformed like wild-type OK10. Further, it was shown that p58 with and without the gag leader had transforming function and that p58 of wild-type OK10 is initiated from the gag leader. Mutants expressing only p200 were also transforming but less efficiently than mutants that express only p58. A mutant OK10 virus in which the native frameshift of retroviruses between gag and pol was deleted expressed a shortened p200 (delta p200). Although this virus expressed more delta p200 than wild-type OK10 did, it transformed cells less efficiently. It follows that OK10 expresses two autonomous transforming genes, which is unique among retroviruses with onc genes.


Proteins that mask the nuclear binding sites of the avian oviduct progesterone receptor.
The binding of a steroid receptor to specific nuclear sites (i.e., nuclear acceptor sites) represents the immediate event preceding the steroid regulation of gene transcription. How the same steroid receptor regulates different genes in different tissues is unknown. Since a major fraction of the nuclear acceptor sites for a variety of steroid receptors has been reported to be masked in the chromatins of a variety of tissues, the differential expression of the nuclear acceptor sites may explain this regulation of different genes. In the avian oviduct, the removal of a subfraction of chromosomal non-histone proteins, termed CP-2, results in the unmasking of the nuclear acceptor sites for the progesterone receptor (PR). Further, the extent of masking of these nuclear acceptor sites for PR has been reported to vary during cytodifferentiation of the avian oviduct. This paper describes a method for the reconstitution of the masking of PR nuclear acceptor sites in the avian oviduct chromatin using a partially purified chromosomal protein fraction (CP-2b). The reannealling of the CP-2b fraction to unmasked avian oviduct chromatin (termed nucleoacidic protein or NAP) results in the "remasking" of about the same number of nuclear acceptor sites for PR as found in intact chromatin. Because some of the PR acceptor sites on the NAP cannot be remasked, these sites either must be protected from masking or not be recognized by the masking proteins. The masking activity apparently involves only protein(s) because the unmasking of acceptor sites can be achieved with protease but not ribonuclease activities and because the dissociated masking activity is destroyed only by proteases. The masking appears to be reversible because the reconstituted masked sites can again be unmasked. Preliminary purification and characterization of the masking activity in fraction CP-2b by molecular sieve chromatography indicate a heterogeneity of size with the activity eluting in a molecular weight range of from 60 000 to greater than 150 000. Whether the masking proteins prevent the binding of the progesterone receptor by directly binding the acceptor sites or by binding neighboring domains to condense the chromatin is unknown. It is speculated that the masking of acceptor sites may be responsible in part for determining the tissue-specific gene expression induced by steroids and/or may play a role in the unresponsiveness of certain human tumors containing steroid receptors.