Factors Contributing to the Spread of Odontogenic Infections: A prospective pilot study.
Spreading odontogenic infections (SOI) are the commonest type of serious infections encountered in the orofacial region. A prospective multi-centre study was conducted in the West of Scotland to investigate the contributing role of social, systemic and microbial factors in the pathogenesis of SOI. Twenty-five patients with severe odontogenic infections were recruited over a period of six months. At admission, clinical assessment included temperature rise, haematological and biochemical investigations. Demographic data, social and past medical histories were obtained. Microbiology samples were collected to identify causative microorganisms and the clinical management of each infection was recorded. Most infections were associated with teeth or roots. Eighty percent of the patients were tobacco smokers and 72% came from deprived areas. Five patients were intravenous drug users, four admitted chronic alcohol abuse, six had underlying systemic disorders and two were at high risk of malnutrition. A raised C-reactive protein at admission was a useful indicator of the severity of infection. Inappropriate prior antibiotic treatment in the absence of surgical drainage was common. Microbiology results showed a predominance of strict anaerobes, notably anaerobic streptococci, Prevotella and Fusobacterium species. SOIs remain surprisingly common and our present pilot study showed a particular association with social deprivation and tobacco smoking. Further elucidation of the role of malnutrition in SOI would be of interest. Molecular characterisation of the microflora associated with SOI may help to highlight whether bacterial factors play a role in converting a localised dentoalveolar abscess into a serious, spreading odontogenic infection.


Role of surface composition in morphological evolution of GaAs nano-dots with low-energy ion irradiation.
The surface chemistry of GaAs (100) with 50-keV Ar+ ion beam irradiation at off-normal incidence has been investigated in order to elucidate the surface nano-structuring mechanism(s). Core level and valence band studies of the surface composition were carried out as a function of fluences, which varied from 1 × 1017 to 7 × 1017 ions/cm2. Core-level spectra of samples analyzed by X-ray photoelectron spectroscopy confirmed the Ga enrichment of the surface resulting in bigger sized nano-dots. Formation of such nano-dots is attributed to be due to the interplay between preferential sputtering and surface diffusion processes. Valence band measurement shows that the shift in the Fermi edge is higher for Ga- rich, bigger sized nano-dots due to the partial oxide formation of Ga. 'One-dimensional power spectral density' extracted from atomic force micrographs also confirms the significant role of surface diffusion in observed nano-structuring.


Management of a Septic Open Abdomen Patient with Spontaneous Jejunal Perforation after Emergent C/S with Confounding Factor of Mild Acute Pancreatitis.
Introduction. We report the management of a septic Open Abdomen (OA) patient by the help of negative pressure therapy (NPT) and abdominal reapproximation anchor (ABRA) system in pregnant woman with spontaneous jejunal perforation after emergent cesarean section (C/S) with confounding factor of mild acute pancreatitis (AP). Presentation of Case. A 29-year-old and 34-week pregnant woman with AP underwent C/S. She was arrested after anesthesia induction and responded to cardiopulmonary resuscitation (CPR). There were only ash-colored serosanguinous fluid within abdomen during C/S. After C/S, she was transferred to intensive care unit (ICU) with vasopressor support. On postoperative 1st day, she underwent reoperation due to fecal fluid coming near the drainage. Leakage point could not be identified exactly and operation had to be deliberately abbreviated due to hemodynamic instability. NPT was applied. Two days later source control was provided by conversion of enteroatmospheric fistula (EAF) to jejunostomy. ABRA was added and OA was closed. No hernia developed at 10-month follow-up period. Conclusion. NPT application in septic OA patient may gain time to patient until adequate source control could be achieved. Using ABRA in conjunction with NPT increases the fascial closure rate in infected OA patient.


Variable heat shock response model for medical laser procedures.
According to the standard Arrhenius relation, tissue damage is linearly dependent on the duration of exposure to elevated temperatures and exponentially dependent on the temperature itself. However, recently published measurements of damage threshold temperatures at extremely short exposure times (commonly present during laser treatments) exhibit a shift to temperatures that are higher than what would normally be expected from a single-process Arrhenius model. A novel variable heat shock (VHS) response model was developed that takes into account the observed deviation from the single-process Arrhenius relation, by assuming that the cell viability can be described as the combined effect of two biochemical processes that dominate cell survival characteristics at very short and very long exposure times. The potential implications of the VHS model are explored theoretically through an example of non-ablative laser resurfacing. The VHS model shows that under the appropriate conditions, very high temperature heat shocks can be generated within the superficial epithelium tissue layer without causing irreversible tissue damage. A mechanism of action for tissue regeneration by means of non-ablative resurfacing with the Er:YAG laser is proposed, which involves indirect triggering of tissue regeneration through intense heat shock to the epithelia, in addition to the tissue regeneration mechanism by means of direct thermal injury to deeper lying connective tissues.


Aspergillus versicolor Inhalation Triggers Neuroimmune, Glial, and Neuropeptide Transcriptional Changes.
Increasing evidence associates indoor fungal exposure with deleterious central nervous system (CNS) health, such as cognitive and emotional deficits in children and adults, but the specific mechanisms by which it might impact the brain are poorly understood. Mice were exposed to filtered air, heat-inactivated Aspergillus versicolor (3 × 105 spores), or viable A. versicolor (3 × 105 spores) via nose-only inhalation exposure 2 times per week for 1, 2, or 4 weeks. Analysis of cortex, midbrain, olfactory bulb, and cerebellum tissue from mice exposed to viable A. versicolor spores for 1, 2, and 4 weeks revealed significantly elevated pro-inflammatory (Tnf and Il1b) and glial activity (Gdnf and Cxc3r1) gene expression in several brain regions when compared to filtered air control, with the most consistent and pronounced neuroimmune response 48H following the 4-week exposure in the midbrain and frontal lobe. Bulk RNA-seq analysis of the midbrain tissue confirmed that 4 weeks of A. versicolor exposure resulted in significant transcriptional enrichment of several biological pathways compared to the filtered air control, including neuroinflammation, glial cell activation, and regulation of postsynaptic organization. Upregulation of Drd1, Penk, and Pdyn mRNA expression was confirmed in the 4-week A. versicolor exposed midbrain tissue, highlighting that gene expression important for neurotransmission was affected by repeated A. versicolor inhalation exposure. Taken together, these findings indicate that the brain can detect and respond to A. versicolor inhalation exposure with changes in neuroimmune and neurotransmission gene expression, providing much needed insight into how inhaled fungal exposures can affect CNS responses and regulate neuroimmune homeostasis.


Cannabidiol restores intestinal barrier dysfunction and inhibits the apoptotic process induced by Clostridium difficile toxin A in Caco-2 cells.
Clostridium difficile toxin A is responsible for colonic damage observed in infected patients. Drugs able to restore Clostridium difficile toxin A-induced toxicity have the potential to improve the recovery of infected patients. Cannabidiol is a non-psychotropic component of Cannabis sativa, which has been demonstrated to protect enterocytes against chemical and/or inflammatory damage and to restore intestinal mucosa integrity. The purpose of this study was to evaluate (a) the anti-apoptotic effect and (b) the mechanisms by which cannabidiol protects mucosal integrity in Caco-2 cells exposed to Clostridium difficile toxin A. Caco-2 cells were exposed to Clostridium difficile toxin A (30 ng/ml), with or without cannabidiol (10-7-10-9 M), in the presence of the specific antagonist AM251 (10-7 M). Cytotoxicity assay, transepithelial electrical resistence measurements, immunofluorescence analysis and immunoblot analysis were performed in the different experimental conditions. Clostridium difficile toxin A significantly decreased Caco-2 cells' viability and reduced transepithelial electrical resistence values and RhoA guanosine triphosphate (GTP), bax, zonula occludens-1 and occludin protein expression, respectively. All these effects were significantly and concentration-dependently inhibited by cannabidiol, whose effects were completely abolished in the presence of the cannabinoid receptor type 1 (CB1) antagonist, AM251. Cannabidiol improved Clostridium difficile toxin A-induced damage in Caco-2 cells, by inhibiting the apoptotic process and restoring the intestinal barrier integrity, through the involvement of the CB1 receptor.


Early nasogastric tube feeding in optimising treatment for hyperemesis gravidarum: the MOTHER randomised controlled trial (Maternal and Offspring outcomes after Treatment of HyperEmesis by Refeeding).
Hyperemesis gravidarum (HG), or intractable vomiting during pregnancy, is the single most frequent cause of hospital admission in early pregnancy. HG has a major impact on maternal quality of life and has repeatedly been associated with poor pregnancy outcome such as low birth weight. Currently, women with HG are admitted to hospital for intravenous fluid replacement, without receiving specific nutritional attention. Nasogastric tube feeding is sometimes used as last resort treatment. At present no randomised trials on dietary or rehydration interventions have been performed. Small observational studies indicate that enteral tube feeding may have the ability to effectively treat dehydration and malnutrition and alleviate nausea and vomiting symptoms. We aim to evaluate the effectiveness of early enteral tube feeding in addition to standard care on nausea and vomiting symptoms and pregnancy outcomes in HG patients. The MOTHER trial is a multicentre open label randomised controlled trial ( www.studies-obsgyn.nl/mother ). Women ≥ 18 years hospitalised for HG between 5 + 0 and 19 + 6 weeks gestation are eligible for participation. After informed consent participants are randomly allocated to standard care with intravenous rehydration or early enteral tube feeding in addition to standard care. All women keep a weekly diary to record symptoms and dietary intake until 20 weeks gestation. The primary outcome will be neonatal birth weight. Secondary outcomes will be the 24-h Pregnancy Unique Quantification of Emesis and nausea score (PUQE-24), maternal weight gain, dietary intake, duration of hospital stay, number of readmissions, quality of life and side-effects. Also gestational age at birth, placental weight, umbilical cord plasma lipid concentration and neonatal morbidity will be evaluated. Analysis will be according to the intention to treat principle. With this trial we aim to clarify whether early enteral tube feeding is more effective in treating HG than intravenous rehydration alone and improves pregnancy outcome. NTR4197 . Date of registration: October 2(nd) 2013.


Clinical resistance to crenolanib in acute myeloid leukemia due to diverse molecular mechanisms.
FLT3 mutations are prevalent in AML patients and confer poor prognosis. Crenolanib, a potent type I pan-FLT3 inhibitor, is effective against both internal tandem duplications and resistance-conferring tyrosine kinase domain mutations. While crenolanib monotherapy has demonstrated clinical benefit in heavily pretreated relapsed/refractory AML patients, responses are transient and relapse eventually occurs. Here, to investigate the mechanisms of crenolanib resistance, we perform whole exome sequencing of AML patient samples before and after crenolanib treatment. Unlike other FLT3 inhibitors, crenolanib does not induce FLT3 secondary mutations, and mutations of the FLT3 gatekeeper residue are infrequent. Instead, mutations of NRAS and IDH2 arise, mostly as FLT3-independent subclones, while TET2 and IDH1 predominantly co-occur with FLT3-mutant clones and are enriched in crenolanib poor-responders. The remaining patients exhibit post-crenolanib expansion of mutations associated with epigenetic regulators, transcription factors, and cohesion factors, suggesting diverse genetic/epigenetic mechanisms of crenolanib resistance. Drug combinations in experimental models restore crenolanib sensitivity.


Can the learning curve of totally endoscopic robotic mitral valve repair be short-circuited?
A concern with the initiation of totally endoscopic robotic mitral valve repair (TERMR) programs has been the risk for the learning curve. To minimize this risk, we initiated a TERMR program with a defined team and structured learning approach before clinical implementation. A dedicated team (two surgeons, one cardiac anesthesiologist, one perfusionist, and two nurses) was trained with clinical scenarios, simulations, wet laboratories, and "expert" observation for 3 months. This team then performed a series of TERMRs of varying complexity. Thirty-two isolated TERMRs were performed during the first programmatic year. All operations included mitral valve repair, left atrial appendage exclusion, and annuloplasty device implantation. Additional procedures included leaflet resection, neochordae insertion, atrial ablation, and papillary muscle shortening. Longer clamp times were associated with number of neochordae (P < 0.01), papillary muscle procedures (P < 0.01), and leaflet resection (P = 0.06). Sequential case number had no impact on cross-clamp time (P = 0.3). Analysis of nonclamp time demonstrated a 71.3% learning percentage (P < 0.01; ie, 28.7% reduction in nonclamp time with each doubling of case number). There were no hospital deaths or incidences of stroke, myocardial infarction, unplanned reoperation, respiratory failure, or renal failure. Median length of stay was 4 days. All patients were discharged home. Totally endoscopic robotic mitral valve repair can be safely performed after a pretraining regimen with emphasis on experts' current practice and team training. After a pretraining regimen, cross-clamp times were not subject to learning curve phenomena but were dependent on procedural complexity. Nonclamp times were associated with a short learning curve.


Developmental stability and human violence.
Developmental stability (the precision with which genotypes are translated into phenotypes under physically stressful developmental conditions), is a major source of phenotypic and behavioural variation, yet researchers have largely ignored its potential role in the ontogeny of individual propensities toward human aggression and violence. In this study, we measured fluctuating asymmetry of the body and administered aggression and fighting history questionnaires to 229 college students (139 female and 90 male undergraduates). Among males, but not females, fluctuating asymmetry correlated negatively and significantly with the participants' number of fights and propensity to escalate agonistic encounters to physical violence. Principal components analyses and scree tests suggested that two psychometric factors underlie observed correlations between self-report measures of aggressive tendencies. The first factor, 'aggressive negative affect', reflected verbal aggression and hostility toward others, while the second factor, 'self-assessed fighting ability', reflected physical violence and a tendency to win fights. The two factors correlated minimally. For both males and females, the second factor correlated with number of fights while the first factor did not. Fluctuating asymmetry did not significantly correlate with either factor for either sex, but for both sexes, psychometric intelligence (IQ) correlated positively with the first factor.


(99m)Tc-sestamibi scanning in thyroid nodules with nondiagnostic cytology.
Our aim in this study was to assess the relevance of (99m)Tc-sestaMIBI (MIBI) scan in the diagnostic evaluation of thyroid nodules with nondiagnostic cytology. In all, 74 patients with a single nodule and repeatedly nondiagnostic ultrasound-guided fine-needle aspiration cytology (US-FNAC) were enrolled. In all cases thyroid nodules were cold in (99m)Tc-pertechnetate (Tc) scans. Thyroid scans were also acquired 30 and 120 minutes after intravenous administration of MIBI. Nodules that concentrate MIBI were considered as positive (ie, suspicious for malignancy). Histologic findings were obtained after surgery in all patients. No differences occurred in early and late MIBI images. None of 63 patients with a negative MIBI scan had a final histologic diagnosis of malignancy (ie, no false-negative results). Two patients with a final histologic diagnosis of papillary thyroid carcinoma (PTC) and 1 with follicular thyroid carcinoma (FTC) had a positive MIBI scan. Eight patients with a final histologic diagnosis of benign lesions (3 with follicular adenomas) also had MIBI-positive scans. The sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) were, respectively, 100%, 88%, 89%, 27%, and 100%. A negative MIBI scan in a cold nodule accurately excludes malignancy when US-FNAC is reported as nondiagnostic. This avoids the need for more invasive diagnostic procedures (ie, surgery) and positively influences the cost-effectiveness profile. A MIBI scan may be performed by acquiring images 30 minutes after tracer administration alone. Histology is still necessary to distinguish benign from malignant disease in a MIBI-positive nodule but unnecessary surgery could have been reduced from 71 to 8 cases in our series.


Use of SMS-Based Surveys in the Rapid Response to the Ebola Outbreak in Liberia: Opening Community Dialogue.
During an emerging health crisis like the 2014 Ebola outbreak in West Africa, communicating with communities to learn from them and to provide timely information can be a challenge. Insight into community thinking, however, is crucial for developing appropriate communication content and strategies and for monitoring the progress of the emergency response. In November 2014, the Health Communication Capacity Collaborative partnered with GeoPoll to implement a Short Message Service (SMS)-based survey that could create a link with affected communities and help guide the communication response to Ebola. The ideation metatheory of communication and behavior change guided the design of the survey questionnaire, which produced critical insights into trusted sources of information, knowledge of transmission modes, and perceived risks-all factors relevant to the design of an effective communication response that further catalyzed ongoing community actions. The use of GeoPoll's infrastructure for data collection proved a crucial source of almost-real-time data. It allowed for rapid data collection and processing under chaotic field conditions. Though not a replacement for standard survey methodologies, SMS surveys can provide quick answers within a larger research process to decide on immediate steps for communication strategies when the demand for speedy emergency response is high. They can also help frame additional research as the response evolves and overall monitor the pulse of the situation at any point in time.


A supervised visual model for finding regions of interest in basal cell carcinoma images.
This paper introduces a supervised learning method for finding diagnostic regions of interest in histopathological images. The method is based on the cognitive process of visual selection of relevant regions that arises during a pathologist's image examination. The proposed strategy emulates the interaction of the visual cortex areas V1, V2 and V4, being the V1 cortex responsible for assigning local levels of relevance to visual inputs while the V2 cortex gathers together these small regions according to some weights modulated by the V4 cortex, which stores some learned rules. This novel strategy can be considered as a complex mix of "bottom-up" and "top-down" mechanisms, integrated by calculating a unique index inside each region. The method was evaluated on a set of 338 images in which an expert pathologist had drawn the Regions of Interest. The proposed method outperforms two state-of-the-art methods devised to determine Regions of Interest (RoIs) in natural images. The quality gain with respect to an adaptated Itti's model which found RoIs was 3.6 dB in average, while with respect to the Achanta's proposal was 4.9 dB.


AltitudeOmics: Red Blood Cell Metabolic Adaptation to High Altitude Hypoxia.
Red blood cells (RBCs) are key players in systemic oxygen transport. RBCs respond to in vitro hypoxia through the so-called oxygen-dependent metabolic regulation, which involves the competitive binding of deoxyhemoglobin and glycolytic enzymes to the N-terminal cytosolic domain of band 3. This mechanism promotes the accumulation of 2,3-DPG, stabilizing the deoxygenated state of hemoglobin, and cytosol acidification, triggering oxygen off-loading through the Bohr effect. Despite in vitro studies, in vivo adaptations to hypoxia have not yet been completely elucidated. Within the framework of the AltitudeOmics study, erythrocytes were collected from 21 healthy volunteers at sea level, after exposure to high altitude (5260 m) for 1, 7, and 16 days, and following reascent after 7 days at 1525 m. UHPLC-MS metabolomics results were correlated to physiological and athletic performance parameters. Immediate metabolic adaptations were noted as early as a few hours from ascending to >5000 m, and maintained for 16 days at high altitude. Consistent with the mechanisms elucidated in vitro, hypoxia promoted glycolysis and deregulated the pentose phosphate pathway, as well purine catabolism, glutathione homeostasis, arginine/nitric oxide, and sulfur/H2S metabolism. Metabolic adaptations were preserved 1 week after descent, consistently with improved physical performances in comparison to the first ascendance, suggesting a mechanism of metabolic memory.


Genetic interactions of modifier genes and modifiable alleles in Drosophila melanogaster.
We have examined the effects of mutations in the six allele-specific modifier genes su(Hw), e(we), su(f), su(s), su(wa), and su(pr) on the expression of 18 modifiable alleles, situated at 11 loci. Ten of the modifiable alleles are associated with insertions of the gypsy retrotransposon and the others include alleles associated with insertions of copia and 412. We tested or retested 90 of the 108 possible combinations and examined the expression of modifiable alleles in flies mutant for pairs of modifier genes in various heterozygous and homozygous configurations. Our principal findings are: (1) a screen of 40,000 mutagenized X chromosomes yielded three new mutations in known modifier genes, but revealed no new modifier genes; (2) the modification effects of different mutations in a given modifier gene were qualitatively similar; (3) each of the six modifiers suppressed some modifiable alleles, enhanced others, and had no noticeable effect on still others; (4) the modifier genes could be placed in four classes, according to their effects on the gypsy-insertion alleles; and (5) the effects of mutations in different modifier genes combined additively. Implications of these results for models of modifier gene action are discussed.


Regulation of hematopoietic stem cell behavior by the nanostructured presentation of extracellular matrix components.
Hematopoietic stem cells (HSCs) are maintained in stem cell niches, which regulate stem cell fate. Extracellular matrix (ECM) molecules, which are an essential part of these niches, can actively modulate cell functions. However, only little is known on the impact of ECM ligands on HSCs in a biomimetic environment defined on the nanometer-scale level. Here, we show that human hematopoietic stem and progenitor cell (HSPC) adhesion depends on the type of ligand, i.e., the type of ECM molecule, and the lateral, nanometer-scaled distance between the ligands (while the ligand type influenced the dependency on the latter). For small fibronectin (FN)-derived peptide ligands such as RGD and LDV the critical adhesive interligand distance for HSPCs was below 45 nm. FN-derived (FN type III 7-10) and osteopontin-derived protein domains also supported cell adhesion at greater distances. We found that the expression of the ECM protein thrombospondin-2 (THBS2) in HSPCs depends on the presence of the ligand type and its nanostructured presentation. Functionally, THBS2 proved to mediate adhesion of HSPCs. In conclusion, the present study shows that HSPCs are sensitive to the nanostructure of their microenvironment and that they are able to actively modulate their environment by secreting ECM factors.


Quality of care of patients with non-small-cell lung cancer: a report of a performance improvement initiative.
Lung cancer is the leading cause of cancer deaths in the United States. In recent years, significant advancements have been made in the molecular characterization of tumors, and the availability of new agents to treat non-small-cell lung cancer has increased. Despite these achievements, optimal care of patients with this condition remains less than ideal. Although national quality measures and guideline recommendations provide the necessary framework for patient care, routine self-assessment of adherence to these measures is required for physician practice improvement. To this end, a performance improvement initiative that met national continuing medical education standards was designed. Focusing on non-small-cell lung cancer patient care, oncologists underwent a three-step process that included a self-assessment of predetermined performance measures, the development and implementation of an actionable plan for improvement, and a second round of assessment to measure practice change. A total of 440 unique patient charts were reviewed by 22 practicing oncologists. Participants demonstrated high baseline performance levels of established quality measures, such as inclusion of the patient's pathology report and assessment of smoking history. Significant gains were observed in the areas of supportive care, including assessment of the patient's emotional well-being and the use of molecular markers in diagnostic and treatment decision making. Data from this study support the value of performance improvement initiatives to help increase physician delivery of evidence-based care to patients.


Dropout from Internet-based treatment for psychological disorders.
The purpose of this review was to present an in-depth analysis of literature identifying the extent of dropout from Internet-based treatment programmes for psychological disorders, and literature exploring the variables associated with dropout from such programmes. A comprehensive literature search was conducted on PSYCHINFO and PUBMED with the keywords: dropouts, drop out, dropout, dropping out, attrition, premature termination, termination, non-compliance, treatment, intervention, and program, each in combination with the key words Internet and web. A total of 19 studies published between 1990 and April 2009 and focusing on dropout from Internet-based treatment programmes involving minimal therapist contact were identified and included in the review. Dropout ranged from 2 to 83% and a weighted average of 31% of the participants dropped out of treatment. A range of variables have been examined for their association with dropout from Internet-based treatment programmes for psychological disorders. Despite the numerous variables explored, evidence on any specific variables that may make an individual more likely to drop out of Internet-based treatment is currently limited. This review highlights the need for more rigorous and theoretically guided research exploring the variables associated with dropping out of Internet-based treatment for psychological disorders.


A New Tool for Public Health Opinion to Give Insight Into Telemedicine: Twitter Poll Analysis.
Telemedicine draws on information technologies in order to enable the delivery of clinical health care from a distance. Twitter is a social networking platform that has 316 million monthly active users with 500 million tweets per day; its potential for real-time monitoring of public health has been well documented. There is a lack of empirical research that has critically examined the potential of Twitter polls for providing insight into public health. One of the benefits of utilizing Twitter polls is that it is possible to gain access to a large audience that can provide instant and real-time feedback. Moreover, Twitter polls are completely anonymized. The overall aim of this study was to develop and disseminate Twitter polls based on existing surveys to gain real-time feedback on public views and opinions toward telemedicine. Two Twitter polls were developed utilizing questions from previously used questionnaires to explore acceptance of telemedicine among Twitter users. The polls were placed on the Twitter timeline of one of the authors, which had more than 9300 followers, and the account followers were asked to answer the poll and retweet it to reach a larger audience. In a population where telemedicine was expected to enjoy big support, a significant number of Twitter users responding to the poll felt that telemedicine was not as good as traditional care. Our results show the potential of Twitter polls for gaining insight into public health topics on a range of health issues not just limited to telemedicine. Our study also sheds light on how Twitter polls can be used to validate and test survey questions.


Okazaki fragment processing: modulation of the strand displacement activity of DNA polymerase delta by the concerted action of replication protein A, proliferating cell nuclear antigen, and flap endonuclease-1.
DNA polymerase (pol) delta is essential for both leading and lagging strand DNA synthesis during chromosomal replication in eukaryotes. Pol delta has been implicated in the Okazaki fragment maturation process for the extension of the newly synthesized fragment and for the displacement of the RNA/DNA segment of the preexisting downstream fragment generating an intermediate flap structure that is the target for the Dna2 and flap endonuclease-1 (Fen 1) endonucleases. Using a single-stranded minicircular template with an annealed RNA/DNA primer, we could measure strand displacement by pol delta coupled to DNA synthesis. Our results suggested that pol delta alone can displace up to 72 nucleotides while synthesizing through a double-stranded DNA region in a distributive manner. Proliferating cell nuclear antigen (PCNA) reduced the template dissociation rate of pol delta, thus increasing the processivity of both synthesis and strand displacement, whereas replication protein A (RP-A) limited the size of the displaced fragment down to 20-30 nucleotides, by generating a "locked" flap DNA structure, which was a substrate for processing of the displaced fragment by Fen 1 into a ligatable product. Our data support a model for Okazaki fragment processing where the strand displacement activity of DNA polymerase delta is modulated by the concerted action of PCNA, RP-A and Fen 1.


Results of a Dutch national and subsequent international expert meeting on interconception care.
Introduction: The potential value of preconception care and interconception care is increasingly acknowledged, but delivery is generally uncommon. Reaching women for interconception care is potentially easier than for preconception care, however the concept is still unfamiliar. Expert consensus could facilitate guidelines, policies and subsequent implementation. A national and subsequent international expert meeting were organized to discuss the term, definition, content, relevant target groups, and ways to reach target groups for interconception care.Methods: We performed a literature study to develop propositions for discussion in a national expert meeting in the Netherlands in October 2015. The outcomes of this meeting were discussed during an international congress on preconception care in Sweden in February 2016. Both meetings were recorded, transcribed and subsequently reviewed by participants.Results: The experts argued that the term, definition, and content for interconception care should be in line with preconception care. They discussed that the target group for interconception care should be "all women who have been pregnant and could be pregnant in the future and their (possible) partners". In addition, they opted that any healthcare provider having contact with the target group should reach out and make every encounter a potential opportunity to promote interconception care.Discussion: Expert discussions led to a description of the term, definition, content, and relevant target groups for interconception care. Opportunities to reach the target group were identified, but should be further developed and evaluated in policies and guidelines to determine the optimal way to deliver interconception care.


The geographical dynamics of global R&D collaboration networks in robotics: Evidence from co-patenting activities across urban areas worldwide.
The focus of this study is on the geography of robotics Research and Development (R&D) activities. The objectives are, first, to identify hotspots in robotics R&D worldwide, and second, to characterise structures and dynamics of global robotics R&D collaboration networks through detailed geographical lenses of global urban areas. We use patents as marker for R&D activities, and accordingly focus on technologically oriented R&D, drawing on information from patents applied for between 2002 and 2016. We employ an appropriate search strategy to identify relevant robotics patents based on detailed levels of the Cooperative Patent Classification (CPC) and assign patents to more than 900 global urban areas based on the inventor addresses. The co-patent networks are examined from a Social Network Analysis (SNA) perspective by means of robotics co-patents, contributing to a global network where urban areas are the nodes inter-linked by joint inventive activities recorded in robotics patents. Global SNA measures illustrate structures and dynamics of the network as a whole, while local measures indicate the specific positioning and roles of urban areas in the network. The results are original in characterising the global spatial emergence of this generic new industry, highlighting prominent urban hotspots in terms of specialisation in robotics R&D, pointing to a global shift reflected by the increasing role of emerging economies, in particular China. The global robotics R&D has grown significantly both in total patenting and also in terms of R&D collaboration activities between urban areas. Also, for the networks, growth is not equally distributed, but is rather characterised by significant spatial shifts, both in terms of cities declining or climbing up the specialisation ranking, but even more in terms of the spatial network structure.


An International Multi-Institutional Validation of Age 55 Years as a Cutoff for Risk Stratification in the AJCC/UICC Staging System for Well-Differentiated Thyroid Cancer.
Age is a critical factor in outcome for patients with well-differentiated thyroid cancer. Currently, age 45 years is used as a cutoff in staging, although there is increasing evidence to suggest this may be too low. The aim of this study was to assess the potential for changing the cut point for the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) staging system from 45 years to 55 years based on a combined international patient cohort supplied by individual institutions. A total of 9484 patients were included from 10 institutions. Tumor (T), nodes (N), and metastasis (M) data and age were provided for each patient. The group was stratified by AJCC/UICC stage using age 45 years and age 55 years as cutoffs. The Kaplan-Meier method was used to calculate outcomes for disease-specific survival (DSS). Concordance probability estimates (CPE) were calculated to compare the degree of concordance for each model. Using age 45 years as a cutoff, 10-year DSS rates for stage I-IV were 99.7%, 97.3%, 96.6%, and 76.3%, respectively. Using age 55 years as a cutoff, 10-year DSS rates for stage I-IV were 99.5%, 94.7%, 94.1%, and 67.6%, respectively. The change resulted in 12% of patients being downstaged, and the downstaged group had a 10-year DSS of 97.6%. The change resulted in an increase in CPE from 0.90 to 0.92. A change in the cutoff age in the current AJCC/UICC staging system from 45 years to 55 years would lead to a downstaging of 12% of patients, and would improve the statistical validity of the model. Such a change would be clinically relevant for thousands of patients worldwide by preventing overstaging of patients with low-risk disease while providing a more realistic estimate of prognosis for those who remain high risk.


Evaluation of commonly used antimicrobial interventions for fresh beef inoculated with Shiga toxin-producing Escherichia coli serotypes O26, O45, O103, O111, O121, O145, and O157:H7.
Although numerous antimicrobial interventions targeting Escherichia coli O157:H7 have been developed and implemented to decontaminate meat and meat products during the harvesting process, the information on efficacy of these interventions against the so-called Big Six non-O157 Shiga toxin-producing E. coli (STEC) strains is limited. Prerigor beef flanks (160) were inoculated to determine if antimicrobial interventions currently used by the meat industry have a similar effect in reducing non-O157 STEC serogroups O26, O45, O103, O111, O121, and O145 compared with E. coli O157:H7. A high (10(4) CFU/cm(2)) or a low (10(1) CFU/cm(2)) inoculation of two cocktail mixtures was applied to surfaces of fresh beef. Cocktail mixture 1 was composed of O26, O103, O111, O145, and O157, while cocktail mixture 2 was composed of O45, O121, and O157. The inoculated fresh beef flanks were subjected to spray treatments by the following four antimicrobial compounds: acidified sodium chlorite, peroxyacetic acid, lactic acid, and hot water. High-level inoculation samples were enumerated for the remaining bacteria populations after each treatment and compared with the untreated controls, while low-level inoculation samples were chilled for 48 h at 4°C before enrichment, immunomagnetic separation, and isolation. Spray treatments with hot water were the most effective, resulting in mean pathogen reductions of 3.2 to 4.2 log CFU/cm(2), followed by lactic acid. Hot water and lactic acid also were the most effective interventions with the low-level inoculation on surfaces of fresh beef flanks after chilling. Peroxyacetic acid had an intermediate effect, while acidified sodium chlorite was the least effective in reducing STEC levels immediately after treatment. Results indicate that the reduction of non-O157 STEC by antimicrobial interventions on fresh beef surfaces were at least as great as for E. coli O157:H7. However, the recovery of these low inoculation levels of pathogens indicated that there is no single intervention to eliminate them.


Geographical distribution and spatio-temporal patterns of hospitalization due to dengue infection at a leading specialist hospital in Malaysia.
Increasing numbers of dengue infection worldwide have led to a rise in deaths due to complications caused by this disease. We present here a cross-sectional study of dengue patients who attended the Emergency and Trauma Department of Ampang Hospital, one of Malaysia's leading specialist hospitals. The objective was to search for potential clustering of severe dengue, in space and/or time, among the annual admissions with the secondary objective to describe the spatio-temporal pattern of all dengue cases admitted to this hospital. The dengue status of the patients was confirmed serologically with the geographic location of the patients determined by residency, but not more specific than the street level. A total of 1165 dengue patients were included in the analysis using SaTScan software. The mean age of these patients was 27.8 years, with a standard deviation of 14.2 years and an age range from 1 to 77 years, among whom 54 (4.6%) were cases of severe dengue. A cluster of general dengue cases was identified occurring from October to December in the study year of 2015 but the inclusion of severe dengue in that cluster was not statistically significant (P=0.862). The standardized incidence ratio was 1.51. General presence of dengue cases was, however, detected to be concentrated at the end of the year, which should be useful for hospital planning and management if this pattern holds.


Usage of the Terms Prostitution, Sex Work, Transactional Sex, and Survival Sex: Their Utility in HIV Prevention Research.
This article considers the terms prostitution, sex work, transactional sex, and survival sex, the logic of their deployment and utility to research concerned with people who are paid for sex, and HIV. The various names for paid sex in HIV research are invested in strategically differentiated positionings of people who receive payment and emphasize varying degrees of choice. The terminologies that seek to distinguish a range of economically motivated paid sex practices from sex work are characterized by an emphasis on the local and the particular, efforts to evade the stigma attached to the labels sex worker and prostitute, and an analytic prioritizing of culture. This works to bestow cultural legitimacy on some locally specific forms of paid sex and positions those practices as artifacts of culture rather than economy. This article contends that, in HIV research in particular, it is necessary to be cognizant of ways the deployment of alternative paid sex categories relocates and reinscribes stigma elsewhere. While local identity categories may be appropriate for program implementation, a global category is necessary for planning and funding purposes and offers a purview beyond that of isolated local phenomena. We argue that "sex work" is the most useful global term for use in research into economically motivated paid sex and HIV, primarily because it positions paid sex as a matter of labor, not culture or morality.


What can experimental studies of bias tell us about real-world group disparities?
This article questions the widespread use of experimental social psychology to understand real-world group disparities. Standard experimental practice is to design studies in which participants make judgments of targets who vary only on the social categories to which they belong. This is typically done under simplified decision landscapes and with untrained decision-makers. For example, to understand racial disparities in police shootings, researchers show pictures of armed and unarmed Black and White men to undergraduates and have them press "shoot" and "don't shoot" buttons. Having demonstrated categorical bias under these conditions, researchers then use such findings to claim that real-world disparities are also due to decision-maker bias. I describe three flaws inherent in this approach, flaws which undermine any direct contribution of experimental studies to explaining group disparities. First, the decision landscapes used in experimental studies lack crucial components present in actual decisions (missing information flaw). Second, categorical effects in experimental studies are not interpreted in light of other effects on outcomes, including behavioral differences across groups (missing forces flaw). Third, there is no systematic testing of whether the contingencies required to produce experimental effects are present in real-world decisions (missing contingencies flaw). I apply this analysis to three research topics to illustrate the scope of the problem. I discuss how this research tradition has skewed our understanding of the human mind within and beyond the discipline and how results from experimental studies of bias are generally misunderstood. I conclude by arguing that the current research tradition should be abandoned.


Improving antibiotic use through behaviour change: a systematic review of interventions evaluated in low- and middle-income countries.
Antibiotic resistance (ABR) has been identified as a critical threat to global health at the highest policy fora. A leading cause of ABR is the inappropriate use of antibiotics by both patients and healthcare providers. Although countries around the world have committed to developing and implementing national action plans to tackle ABR, there is a considerable gap in evidence about effective behaviour change interventions addressing inappropriate use of antibiotics in low- and middle-income countries (LMICs), where ABR is growing at an alarming rate. We conducted a systematic review to synthesize evidence about the effectiveness and cost-effectiveness of behaviour change interventions to reduce inappropriate use of antibiotics in LMICs. Three databases were searched using a set of predefined search terms and exclusion criteria. The search identified 43 relevant articles. A narrative synthesis of results was conducted using the Behaviour Change Wheel framework to categorize intervention components. The majority of the reviewed studies were set in lower-middle-income or low-income countries located in Sub-Saharan Africa or East Asia and the Pacific. Twenty-four articles evaluated multi-faceted interventions over a period of 12 months or less. Despite the widespread use of antibiotics in the community, interventions were primarily implemented in public health facilities, targeting health professionals such as doctors, nurses, and other allied medical staff. Although education for providers was the most widely used strategy for influencing antibiotic use, it was shown to be most effective when used in conjunction with training or other enabling and supportive measures to nudge behaviour. Six articles included an evaluation of costs of interventions and found a reduction in costs in inpatient and outpatient settings, and one article found a training and guidelines implementation-based intervention to be highly cost-effective. However, the small number of articles conducting an economic evaluation highlights the need for such analyses to be conducted more frequently to support priority setting in resource-constrained environments.


Nationwide comprehensive gastro-intestinal cancer cohorts: the 3P initiative.
The increasing sub-classification of cancer patients due to more detailed molecular classification of tumors, and limitations of current trial designs, require innovative research designs. We present the design, governance and current standing of three comprehensive nationwide cohorts including pancreatic, esophageal/gastric, and colorectal cancer patients (NCT02070146). Multidisciplinary collection of clinical data, tumor tissue, blood samples, and patient-reported outcome (PRO) measures with a nationwide coverage, provides the infrastructure for future and novel trial designs and facilitates research to improve outcomes of gastrointestinal cancer patients. All patients aged ≥18 years with pancreatic, esophageal/gastric or colorectal cancer are eligible. Patients provide informed consent for: (1) reuse of clinical data; (2) biobanking of primary tumor tissue; (3) collection of blood samples; (4) to be informed about relevant newly identified genomic aberrations; (5) collection of longitudinal PROs; and (6) to receive information on new interventional studies and possible participation in cohort multiple randomized controlled trials (cmRCT) in the future. In 2015, clinical data of 21,758 newly diagnosed patients were collected in the Netherlands Cancer Registry. Additional clinical data on the surgical procedures were registered in surgical audits for 13,845 patients. Within the first two years, tumor tissue and blood samples were obtained from 1507 patients; during this period, 1180 patients were included in the PRO registry. Response rate for PROs was 90%. The consent rate to receive information on new interventional studies and possible participation in cmRCTs in the future was >85%. The number of hospitals participating in the cohorts is steadily increasing. A comprehensive nationwide multidisciplinary gastrointestinal cancer cohort is feasible and surpasses the limitations of classical study designs. With this initiative, novel and innovative studies can be performed in an efficient, safe, and comprehensive setting.


Subxiphoid single incision thoracoscopic surgery approach for thymectomy: a case report.
Thoracic surgery is rapidly evolving with minimally invasive strategies now dominating. Thymectomy has traditionally been performed through a sternotomy, but more recently video-assisted thoracoscopic surgery (VATS) approaches have become increasingly popular. To further minimise surgical impact, the uniportal subxiphoid VATS technique has recently been described, using a muscle sparing incision that avoids intercostal nerve injury. A potential advantage that makes this approach particularly suited to thymectomy includes the ability to access both sides of the chest with a single incision. There is also the potential for reduced post-operative pain and chronic thoracostomy neuralgia. Here we describe the management of a patient with thymoma, reporting our procedure and technique for performing uniportal subxiphoid VATS thymectomy.


Synchronization of medial temporal lobe and prefrontal rhythms in human decision making.
Optimal decision making requires that we integrate mnemonic information regarding previous decisions with value signals that entail likely rewards and punishments. The fact that memory and value signals appear to be coded by segregated brain regions, the hippocampus in the case of memory and sectors of prefrontal cortex in the case of value, raises the question as to how they are integrated during human decision making. Using magnetoencephalography to study healthy human participants, we show increased theta oscillations over frontal and temporal sensors during nonspatial decisions based on memories from previous trials. Using source reconstruction we found that the medial temporal lobe (MTL), in a location compatible with the anterior hippocampus, and the anterior cingulate cortex in the medial wall of the frontal lobe are the source of this increased theta power. Moreover, we observed a correlation between theta power in the MTL source and behavioral performance in decision making, supporting a role for MTL theta oscillations in decision-making performance. These MTL theta oscillations were synchronized with several prefrontal sources, including lateral superior frontal gyrus, dorsal anterior cingulate gyrus, and medial frontopolar cortex. There was no relationship between the strength of synchronization and the expected value of choices. Our results indicate a mnemonic guidance of human decision making, beyond anticipation of expected reward, is supported by hippocampal-prefrontal theta synchronization.


A safety rule approach to surveillance and eradication of biological invasions.
Uncertainty about future spread of invasive organisms hinders planning of effective response measures. We present a two-stage scenario optimization model that accounts for uncertainty about the spread of an invader, and determines survey and eradication strategies that minimize the expected program cost subject to a safety rule for eradication success. The safety rule includes a risk standard for the desired probability of eradication in each invasion scenario. Because the risk standard may not be attainable in every scenario, the safety rule defines a minimum proportion of scenarios with successful eradication. We apply the model to the problem of allocating resources to survey and eradicate the Asian longhorned beetle (ALB, Anoplophora glabripennis) after its discovery in the Greater Toronto Area, Ontario, Canada. We use historical data on ALB spread to generate a set of plausible invasion scenarios that characterizes the uncertainty of the beetle's extent. We use these scenarios in the model to find survey and tree removal strategies that minimize the expected program cost while satisfying the safety rule. We also identify strategies that reduce the risk of very high program costs. Our results reveal two alternative strategies: (i) delimiting surveys and subsequent tree removal based on the surveys' outcomes, or (ii) preventive host tree removal without referring to delimiting surveys. The second strategy is more likely to meet the stated objectives when the capacity to detect an invader is low or the aspirations to eradicate it are high. Our results provide practical guidelines to identify the best management strategy given aspirational targets for eradication and spending.


Maintaining live discussion in two-stage open peer review.
Open peer review has been proposed for a number of reasons, in particular, for increasing the transparency of the article selection process for a journal, and for obtaining a broader basis for feedback to the authors and for the acceptance decision. The review discussion may also in itself have a value for the research community. These goals rely on the existence of a lively review discussion, but several experiments with open-process peer review in recent years have encountered the problem of faltering review discussions. The present article addresses the question of how lively review discussion may be fostered by relating the experience of the journal Electronic Transactions on Artificial Intelligence (ETAI) which was an early experiment with open peer review. Factors influencing the discussion activity are identified. It is observed that it is more difficult to obtain lively discussion when the number of contributed articles increases, which implies difficulties for scaling up the open peer review model. Suggestions are made for how this difficulty may be overcome.


Follow-up of participants in a preschool hearing screening program in child care centres.
As part of its response to the Ontario Ministry of Health recommendation that communication disorders in preschool children be identified, the Hamilton-Wentworth Department of Public Health Services performed hearing screening tests on all preschool children in child care centres. Parents of children who had failed the hearing screening test were recommended to take their child to their family physician for further assessment. Out of 1,844 children tested between September 1990 and February 1991, 35 children failed the pure-tone audiometry test administered by nurses. A telephone follow-up interview determined that 26 children with screening test failures had received some medical follow-up. Eight children had a confirmed hearing problem; of these, five were newly diagnosed with a hearing problem, all resulting from fluid build-up in the middle ear. Three children were treated, with two having improved hearing. Of the two children not treated, one was reported to have improved hearing. As with other recently reported preschool hearing screening programs, this study raises doubts about the usefulness of such programs.


Nurses' Use of Positive Deviance When Encountering Electronic Health Records-Related Unintended Consequences.
As organizations adopt electronic health records (EHRs), nurses frequently encounter system barriers and difficulty performing role expectations. This article describes nurses' experiences with unintended consequences emerging from the use of an EHR. In some situations, nurses were positively deviant when encountering unintended consequences relating to EHRs to accomplish patient care or protect patient safety. Nurses engaged in work-arounds to provide patient care when the EHR did not meet their needs, sometimes in positively deviant ways. Qualitative data were collected from 5 open-ended questions at the end of a quantitative survey. Analysis included coding of responses and organization of processes in line with the triangle model, a human factors framework, to identify overarching themes. Five themes emerged: (1) User support after implementation of EHR; (2) User satisfaction with EHR; (3) Communication for patient care, quality, and safety; (4) Effort to complete tasks; and (5) Areas for improvement. Nurses' ability to adopt positive deviance as they experience unintended consequences offers opportunities for organizations to engage nursing perspectives in improving the EHR and engineer it to be more resilient to nursing work.


Use of RE-AIM to develop a multi-media facilitation tool for the patient-centered medical home.
Much has been written about how the medical home model can enhance patient-centeredness, care continuity, and follow-up, but few comprehensive aids or resources exist to help practices accomplish these aims. The complexity of primary care can overwhelm those concerned with quality improvement. The RE-AIM planning and evaluation model was used to develop a multimedia, multiple-health behavior tool with psychosocial assessment and feedback features to facilitate and guide patient-centered communication, care, and follow-up related to prevention and self-management of the most common adult chronic illnesses seen in primary care. The Connection to Health Patient Self-Management System, a web-based patient assessment and support resource, was developed using the RE-AIM factors of reach (e.g., allowing input and output via choice of different modalities), effectiveness (e.g., using evidence-based intervention strategies), adoption (e.g., assistance in integrating the system into practice workflows and permitting customization of the website and feedback materials by practice teams), implementation (e.g., identifying and targeting actionable priority behavioral and psychosocial issues for patients and teams), and maintenance/sustainability (e.g., integration with current National Committee for Quality Assurance recommendations and clinical pathways of care). Connection to Health can work on a variety of input and output platforms, and assesses and provides feedback on multiple health behaviors and multiple chronic conditions frequently managed in adult primary care. As such, it should help to make patient-healthcare team encounters more informed and patient-centered. Formative research with clinicians indicated that the program addressed a number of practical concerns and they appreciated the flexibility and how the Connection to Health program could be customized to their office. This primary care practice tool based on an implementation science model has the potential to guide patients to more healthful behaviors and improved self-management of chronic conditions, while fostering effective and efficient communication between patients and their healthcare team. RE-AIM and similar models can help clinicians and media developers create practical products more likely to be widely adopted, feasible in busy medical practices, and able to produce public health impact.


Defining osteoarthritis of the hip for epidemiologic studies.
The authors compared seven radiologic indices of hip osteoarthritis to establish which provided the best definition of the disease for epidemiologic purposes. Hip joints were assessed from intravenous urograms taken in a British hospital between 1982 and 1987 in 1,315 men aged 60-75 years. The indices examined were an overall qualitative grading of osteoarthritis, four measures of joint space, the maximum thickness of subchondral sclerosis, and the size of the largest osteophyte. Minimal joint space (i.e., the shortest distance between the femoral head margin and the acetabulum) was the index most strongly associated with other radiologic features of osteoarthritis. Among a subset of 759 men who answered a questionnaire about symptoms, the overall qualitative grading, minimal joint space, and thickness of subchondral sclerosis were the radiologic indices most predictive of hip pain. Within- and between-observer repeatability were tested in a subset of 50 subjects. Measures of joint space were more reproducible than other indices. These data suggest that, at least in men, minimal joint space is the best radiologic criterion of hip osteoarthritis for use in epidemiologic studies.


Effects of pyrethroid insecticides in urban runoff on Chinook salmon, steelhead trout, and their invertebrate prey.
Pyrethroid insecticides can affect salmonids either indirectly through toxicity to their prey or directly by toxicity to the fish themselves. In support of a study on pyrethroid impacts to Chinook salmon and steelhead trout in the American River (Sacramento, California, USA), 96-h median effective concentration (EC50) and median lethal concentration (LC50) values for the pyrethroid bifenthrin were determined for taxa not traditionally used for toxicity testing but of interest as salmonid prey, including a chironomid, caddisflies, mayflies, and stoneflies. A laboratory was constructed on the banks of the American River to expose macroinvertebrates, Chinook salmon, and steelhead trout to flow-through river water containing urban runoff during storm events. Bifenthrin from urban runoff was found in river water following 5 rain events, reaching 14.6 ng/L. Mortality to the exposed salmonids was not observed, and sublethal effects were not seen in vitellogenin or sex steroid levels. Indirect effects via toxicity to salmonid prey are possible. Mortality to Hyalella azteca, a potential prey, was observed in every event tested, and peak bifenthrin concentrations were comparable to the 96-h EC50 of the caddisfly, Hydropsyche sp., the most important prey species on a biomass basis for American River Chinook salmon. The other invertebrates tested had EC50s exceeding bifenthrin concentrations seen in the American River, though could potentially be at risk at concentrations previously reported in smaller urban tributaries. Environ Toxicol Chem 2015;34:649-657. © 2014 SETAC.


Resveratrol regulates pathologic angiogenesis by a eukaryotic elongation factor-2 kinase-regulated pathway.
Abnormal angiogenesis is central to the pathophysiology of diverse disease processes including cancers, ischemic and atherosclerotic heart disease, and visually debilitating eye disease. Resveratrol is a naturally occurring phytoalexin that has been demonstrated to ameliorate and decelerate the aging process as well as blunt end organ damage from obesity. These effects of resveratrol are largely mediated by members of the sirtuin family of proteins. We demonstrate that resveratrol can inhibit pathological angiogenesis in vivo and in vitro by a sirtuin-independent pathway. Resveratrol inhibits the proliferation and migration of vascular endothelial cells by activating eukaryotic elongation factor-2 kinase. The active kinase in turn phosphorylates and inactivates elongation factor-2, a key mediator of ribosomal transfer and protein translation. Functional inhibition of the kinase by gene deletion in vivo or RNA as well as pharmacological inhibition in vitro is able to completely reverse the effects of resveratrol on blood vessel growth. These studies have identified a novel and critical pathway that promotes aberrant vascular proliferation and one that is amenable to modulation by pharmacological means. In addition, these results have uncovered a sirtuin-independent pathway by which resveratrol regulates angiogenesis.


Proteomic analysis of the SH2 domain-containing leukocyte protein of 76 kDa (SLP76) interactome in resting and activated primary mast cells [corrected].
We report the first proteomic analysis of the SLP76 interactome in resting and activated primary mouse mast cells. This was made possible by a novel genetic approach used for the first time here. It consists in generating knock-in mice that express signaling molecules bearing a C-terminal tag that has a high affinity for a streptavidin analog. Tagged molecules can be used as molecular baits to affinity-purify the molecular complex in which they are engaged, which can then be studied by mass spectrometry. We examined first SLP76 because, although this cytosolic adapter is critical for both T cell and mast cell activation, its role is well known in T cells but not in mast cells. Tagged SLP76 was expressed in physiological amounts and fully functional in mast cells. We unexpectedly found that SLP76 is exquisitely sensitive to mast cell granular proteases, that Zn(2+)-dependent metalloproteases are especially abundant in mast cells and that they were responsible for SLP76 degradation. Adding a Zn(2+) chelator fully protected SLP76 in mast cell lysates, thereby enabling an efficient affinity-purification of this adapter with its partners. Label-free quantitative mass spectrometry analysis of affinity-purified SLP76 interactomes uncovered both partners already described in T cells and novel partners seen in mast cells only. Noticeably, molecules inducibly recruited in both cell types primarily concur to activation signals, whereas molecules recruited in activated mast cells only are mostly associated with inhibition signals. The transmembrane adapter LAT2, and the serine/threonine kinase with an exchange factor activity Bcr were the most recruited molecules. Biochemical and functional validations established the unexpected finding that Bcr is recruited by SLP76 and positively regulates antigen-induced mast cell activation. Knock-in mice expressing tagged molecules with a normal tissue distribution and expression therefore provide potent novel tools to investigate signalosomes and to uncover novel signaling molecules in mast cells.


Therapeutic and pharmacological studies of tetrachloro(d,l-trans)1,2-diaminocyclohexane platinum (IV) (tetraplatin), a new platinum analogue.
Tetrachloro(d,l-trans)1,2-diaminocyclohexane platinum (IV) (tetraplatin), a new platinum analogue, showed greater therapeutic efficacy after i.p. administration than either cis-dichlorodiammineplatinum (II) (cisplatin) or cis-diammine-1,1-cyclobutanedicarboxylate platinum (II) (carboplatin) in mice bearing i.p. implanted L1210 leukemia. At an optimal dose of 5.7 mg/kg/injection given as a single dose on days 1, 5, and 9, tetraplatin increased the median life span over controls by more than 566% with 5 of 8 long-term (50-day) survivors. In contrast, cisplatin at the same optimal dose increased survival by 186% with 2 of 8 long-term survivors, and carboplatin at an optimal dose of 75.6 mg/kg/injection increased survival by only 120% with no long-term survivors. Tetraplatin also was more effective than cisplatin when treatment was delayed until days 3, 7, and 11 after i.p. implant. A combination of tetraplatin and Adriamycin in mice bearing i.p. implanted L1210 leukemia produced more long-term survivors over a wider range of doses than could be achieved with either drug alone. Tetraplatin at 5.7 mg/kg/injection and Adriamycin at 3 mg/kg/injection on days 1, 5, and 9 increased survival by more than 566% with 8 of 8 50-day survivors. Using the same treatment schedule, combinations of tetraplatin with either cisplatin, carboplatin, daunomycin, or 5-fluorouracil did not produce therapeutic efficacy greater than that seen with tetraplatin alone. The in vitro cellular uptake of platinum by L1210 cells at 37 degrees C was about 4-fold higher after exposure to tetraplatin compared to cisplatin following a 2-h incubation at the two concentrations examined (2.5 and 5 micrograms/ml). Comparative pharmacological studies were performed in rats at a single dose of 3 mg/kg i.v. The t1/2 beta for total platinum in plasma was 29.10 h (7.47 h for unbound platinum) after the administration of tetraplatin and 23.70 h (13.09 h for unbound platinum) after cisplatin. By 48 h the urinary excretion of platinum after tetraplatin and cisplatin was 30.1% and 41.4%, respectively. Tissue distribution of platinum was similar after either complex. Thus, tetraplatin has similar pharmacological properties to cisplatin and like cisplatin is a candidate for combination chemotherapy. However, tetraplatin may be superior to cisplatin in some therapeutic situations based on its greater efficacy against selected tumors.


Optimization of the switch-on and switch-off transition in a commercial laser.
The response of a Class B laser to a rapid change in one of its parameters is known to be accompanied by delay and ringing. It has been theoretically and numerically shown that the transition can be modified by using adequate functional shapes for the control parameter (e.g., the laser pump) in order to steer the laser from one point of operation to another. Here we experimentally show the implementation of these ideas in a commercial device: a semiconductor laser. We establish a procedure for optimizing a controlled switch-on and switch-off and obtain a clean, fast, and reliable square pulse, either in a single shot or in a repetitive sequence. The generality of this procedure promises a wide field of application for a variety of laser systems.


Treatment of unruptured cerebral aneurysms in California.
The impact of endovascular therapy on treatment outcomes of unruptured cerebral aneurysms has not been studied in a defined geographic area. All primary diagnoses of unruptured aneurysms were retrieved from a statewide database of hospital discharges in California from January 1990 through December 1998. Admissions for initial treatment and all follow-up care were combined to reflect the entire course of therapy. An adverse outcome was defined as an in-hospital death or discharge to nursing home or rehabilitation hospital at any point during the treatment course. Multivariable analyses were performed with generalized estimating equations with adjustment for age, sex, ethnicity, source of admission, year of treatment, hospital volume, and clustering of observations at institutions. A total of 2069 patients were treated for unruptured aneurysms. Adverse outcomes were more frequent in the 1699 patients treated with surgery (25%) than in those treated with endovascular therapy (10%; P:<0.001). The difference persisted after multivariable adjustment (surgery versus endovascular therapy: odds ratio for adverse outcomes, 3.1; 95% CI, 2.5 to 4.0; P:<0.001). Adverse outcomes declined from 1991 to 1998 in patients treated with endovascular therapy (P:<0.005) but not for surgery. In-hospital deaths occurred in 3.5% of surgical cases and 0.5% of endovascular cases (P:=0.003), and the difference remained significant after adjustment (odds ratio, 6.3; 95% CI, 3.5 to 11.4; P:<0.001). Total length of stay and hospital charges were greater in surgical cases (both P:<0.001). Results were similar in a confirmatory analysis focusing on treatment differences between institutions. Institutional treatment volume was also associated with outcome but did not account for the differences between surgery and endovascular therapy. In California, endovascular therapy of unruptured aneurysms is associated with less risk of adverse outcomes and in-hospital death, lower hospital charges, and shorter hospital stays compared with surgery. Differences between therapies became more distinct through the years. Uncontrolled differences in prognosis of patients receiving endovascular therapy and surgery cannot be ruled out in this study of discharge abstracts.


Non-paying partnerships and its association with HIV risk behavior, program exposure and service utilization among female sex workers in India.
In India, HIV prevention programs have focused on female sex workers' (FSWs') sexual practices vis-à-vis commercial partners leading to important gains in HIV prevention. However, it has become apparent that further progress is contingent on a better understanding of FSWs' sexual risks in the context of their relationships with non-paying partners. In this paper, we explored the association between FSWs' non-paying partner status, including cohabitation and HIV risk behaviors, program exposure and utilization of program services. We used data from the cross-sectional Integrated Behavioral and Biological Assessment (IBBA) survey (2009-2010) conducted among 8,107 FSWs in three high priority states of India- Maharashtra, Andhra Pradesh and Tamil Nadu. Multiple logistic regression was used to examine the association between non-paying partner and cohabitation status of FSWs with HIV risk behaviors, program exposure and utilization of program services. FSWs reporting a non-paying partner were more likely to be exposed to and utilize HIV prevention resources than those who did not have a non-paying partner. Analyses revealed that FSWs reporting a non-cohabiting non-paying partner were more likely to be exposed to HIV prevention programs (adjusted OR: 1.7, 95% CI: 1.3-2.1), attend meetings (adjusted OR: 1.5, 95% CI: 1.2-1.8), and visit a sexually transmitted infections clinic at least twice in the last six months (adjusted OR: 1.6, 95% CI: 1.3-1.9) as compared to those reporting no non-paying partner. That said, FSWs with a non-paying partner rarely used condoms consistently and were more vulnerable to HIV infection because of being street-based (p<0.001) and in debt (p<0.001). FSWs with cohabiting partners were more likely to be exposed to HIV prevention program and utilize services, suggesting that this program was successful in reaching vulnerable groups. However, this subgroup was unlikely to use condoms consistently with their non-paying partners and was more vulnerable, being street based and in debt. The next generation of HIV prevention interventions in India should focus on addressing relationship factors like risk communication and condom negotiation, including specific vulnerabilities like indebtedness and street based solicitation among women in sex work.


Brief periods of monocular deprivation in kittens: effects of delay prior to physiological study.
1. Brief periods of selective visual exposure in 4-wk postnatal kittens can cause pronounced alterations in striate cortex. The processes underlying these changes may be similar to those of other short-term neural events such as memory or learning, and attempts have been made to link these areas. In particular, it has been reported that the effects of selective visual exposures are consolidated if a delay is interposed between rearing and physiological study. 2. We have tested this notion directly. Normally reared kittens were monocularly occluded for 8 or 24 h on postnatal day 29. Half of the 8-h and of the 24-h groups were tested physiologically immediately following monocular exposure, while the other halves were recorded after an intervening session of 8 or 48 h, respectively, during which the kittens were kept in darkness. 3. Extracellular responses of cortical neurons were analyzed, and primary attention was paid to absolute and relative interocular response strengths of each cell. Ocular dominance distributions from all kittens were significantly abnormal, but invariably, effects were less extensive for those who had experienced a period of dark rearing prior to physiological study. 4. These results are clearly at odds with the idea that the effects of monocular deprivation were consolidated by allowing a period of delay between exposure and physiological recording. On the contrary, during the time the kittens spent in darkness, it appears that some functional recovery of binocular pathways occurred. 5. To explore the minimal period of monocular occlusion that could cause cortical disruption, we studied an additional group of normally reared kittens that were occluded for only 4 h on postnatal day 29. Effects for this group were small but ocular dominance patterns were significantly abnormal. 6. An alternative procedure was used for the delay period between 24-h monocular occlusion and physiological study. Prior to recording, these kittens spent 48 h in a normally illuminated colony. Ocular dominance histograms were normal, indicating that complete recovery had occurred from the initial monocular deprivation. 7. Histological reconstructions were made to estimate effects in different cortical laminae, but conclusions must be tentative because of small samples. In the group that had been monocularly occluded for 4 h and then recorded, inactivation of binocular pathways was most apparent in layers IV and V. This results suggest that the process deprivation disconnection during monocular deprivation occurs frist in these layers. Findings from the groups in which a delay was imposed between monocular exposure and recording indicate that functional binocular recovery occurs frist in layer IV and above and last in layer VI.


Insulin and insulin-like growth factor (somatomedin) receptors on cloned rat pituitary tumor cells.
Specific receptors for insulin and the somatomedin peptides insulin-like growth factors I and II (IGF-I and IGF-II) have been characterized on three separate cloned strains of rat pituitary tumor cells (GH3, GH1, and GC). Binding of 125I-labeled peptides was time, temperature, and pH dependent for all three cell lines. Specific binding of [125I]insulin, which was extremely low in normal rat adenohypophyseal cells, was demonstrable for all three lines, with the Kd for the high affinity receptor ranging from 10(-10) to 4 X 10(-10) M/liter. A specific high affinity IGF-I receptor was also identified, with a Kd of approximately 10(-9) M/liter. IGF-II and insulin were, respectively, 10% and 1% as potent as IGF-I in competing for this receptor. When [125I]insulin and [125I]IGF-I were cross-linked to GH3 cells with disuccinimidyl suberate, followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, both receptors were found to have an apparent mol wt greater than 300,000 in the unreduced state, with subunits of apparent mol wt 125,000 after reduction. A third discrete receptor, which bound [125I]IGF-II, was also identified on all three cell lines. IGF-I was only 10% as potent as IGF-II at displacing [125I]IGF-II, and insulin was virtually unreactive. When [125I]IGF-II was cross-linked to GH3 cells and analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, two receptors were identified. One had an apparent mol wt of 205,000 unreduced and 250,000 upon reduction, and presumably represents the type II receptor. Additionally, a band was observed at an apparent mol wt greater than 300,000 unreduced and 125,000 upon reduction, probably representing IGF-II binding to the IGF-I or insulin receptor. The presence of specific high affinity receptors for insulin, IGF-I, and IGF-II in these transformed cell lines is consistent with previous observations in normal rat and human pituitary cells and suggests a role for these peptides in the modulation of pituitary function.


Patterns of genetic structuring in the coral Pocillopora damicornis on reefs in East Africa.
Studies of population genetic structures provide an indication of direction and magnitude of larval transport and hence are an important component in the assessment of the ability of reefs to recover from severe disturbance. This paper reports data on population genetic structures in the coral Pocillopora damicornis from 26 reefs in Kenya and Tanzania. Gene flow among reefs was found to be variable, with a significant overall genetic subdivision (FST = 0.023 +/- 0.004 SE; p < 0.001), however, only 34% of all pairwise population comparisons showed significant differentiation. Panmixia could not be rejected between reefs separated by as much as 697 km, while other sites, separated by only a single kilometre, were found to be significantly differentiated. An analysis of molecular variance indicated that population genetic differentiation was significant only at the smaller spatial scale (< 10 km), whereas panmixia could not be rejected between groups of samples separated by over 100 km. Estimates of contemporary gene flow showed similar results, with numbers of first generation migrants within each population ranging from 0 to 4 (~5% of the total number of colonies sampled) and likely dispersal distances ranging between 5 and 500 km. This study showed that population differentiation in P. damicornis varied over spatial scales and that this variability occurred at both evolutionary and ecological time scales. This paradox is discussed in light of stochastic recruitment and small scale population structures found in other species of coral. The study also identifies potential source reefs, such as those within Mnemba Conservation area near Zanzibar and genetically isolated reefs such as those within Malindi Marine National Park and Reserve in northern Kenya.


Effect of ion concentration changes in the limited extracellular spaces on sarcolemmal ion transport and Ca2+ turnover in a model of human ventricular cardiomyocyte.
We have developed a computer model of human cardiac ventricular myocyte (CVM), including t-tubular and cleft spaces with the aim of evaluating the impact of accumulation-depletion of ions in restricted extracellular spaces on transmembrane ion transport and ionic homeostasis in human CVM. The model was based on available data from human CVMs. Under steady state, the effect of ion concentration changes in extracellular spaces on [Ca2+]i-transient was explored as a function of critical fractions of ion transporters in t-tubular membrane (not documented for human CVM). Depletion of Ca2+ and accumulation of K+ occurring in extracellular spaces slightly affected the transmembrane Ca2+ flux, but not the action potential duration (APD90). The [Ca2+]i-transient was reduced (by 2%-9%), depending on the stimulation frequency, the rate of ion exchange between t-tubules and clefts and fractions of ion-transfer proteins in the t-tubular membrane. Under non-steady state, the responses of the model to changes of stimulation frequency were analyzed. A sudden increase of frequency (1-2.5 Hz) caused a temporal decrease of [Ca2+] in both extracellular spaces, a reduction of [Ca2+]i-transient (by 15%) and APD90 (by 13 ms). The results reveal different effects of activity-related ion concentration changes in human cardiac t-tubules (steady-state effects) and intercellular clefts (transient effects) in the modulation of membrane ion transport and Ca2+ turnover.


Advances in single quantum dot-based nanosensors.
Single-molecule detection provides a simple and ultrasensitive platform to quantify target molecules by simply counting the individual fluorescence signals. Quantum dots (QDs) are novel semiconductor nanocrystals with distinct characteristics of high brightness, large Stokes shift and broad absorption spectra, high molar extinction coefficients, high quantum yield, good photostability and long fluorescence lifetime. The combination of single-molecule detection with QDs enables the development of single QD-based nanosensors with extremely high sensitivity. Single QD-based nanosensors may be divided into two categories based on single QD burst coincidence detection and single QD-fluorescence resonance energy transfer (FRET) detection, and have significant advantages of high signal-to-noise ratio, high sensitivity, rapidity, and low sample consumption. The single QD-based nanosensors have the capability of directly detecting low-abundance species without the need for nucleic acid amplification, and may elucidate a variety of biological and biochemical phenomena in real time using single QD tracking. In this review, we summarize the recent advances in single QD-based nanosensors and their applications for sensitive detection of DNAs, microRNAs, proteins, enzymes, small molecules and viruses. We highlight the challenges and future direction of single QD-based nanosensors as well.


Metabolic and endocrinologic complications in beta-thalassemia major: a multicenter study in Tehran.
ABSTRACT : BACKGROUND : The combination of transfusion and chelation therapy has dramatically extended the life expectancy of thalassemic patients. The main objective of this study is to determine the prevalence of prominent thalassemia complications. METHODS : Two hundred twenty patients entered the study. Physicians collected demographic and anthropometric data and the history of therapies as well as menstrual histories. Patients have been examined to determine their pubertal status. Serum levels of 25(OH) D, calcium, phosphate, iPTH were measured. Thyroid function was assessed by T3, T4 and TSH. Zinc and copper in serum were determined by flame atomic absorption spectrophotometry. Bone mineral density (BMD) measurements at lumbar and femoral regions have been done using dual x-ray absorptiometry. The dietary calcium, zinc and copper intakes were estimated by food-frequency questionnaires. RESULTS : Short stature was seen in 39.3% of our patients. Hypogonadism was seen in 22.9% of boys and 12.2% of girls. Hypoparathyroidism and primary hypothyroidism was present in 7.6% and 7.7% of the patients. About 13 % of patients had more than one endocrine complication with mean serum ferritin of 1678 +/- 955 micrograms/lit. Prevalence of lumbar osteoporosis and osteopenia were 50.7% and 39.4%. Femoral osteoporosis and osteopenia were present in 10.8% and 36.9% of the patients. Lumbar BMD abnormalities were associated with duration of chelation therapy. Low serum zinc and copper was observed in 79.6% and 68% of the study population respectively. Serum zinc showed significant association with lumbar but not femoral BMD. In 37.2% of patients serum levels of 25(OH) D below 23 nmol/l were detected. CONCLUSION : High prevalence of complications among our thalassemics signifies the importance of more detailed studies along with therapeutic interventions.


Capsaicin pretreatment attenuates suppression of food intake by cholecystokinin.
Capsaicin, the pungent principal in red pepper, has been shown to damage small-diameter peptide-containing sensory neurons. Suppression of feeding by cholecystokinin octapeptide (CCK OP) was attenuated after systemic pretreatment with capsaicin. Capsaicin pretreatment did not attenuate suppression of food intake by intragastric preloads. Pretreatment of rats with microgram quantities of capsaicin injected into the fourth ventricle, near the sites of vagal afferent termination, also attenuated CCK OP-induced suppression of food intake. These results suggest that the satiety-inducing effects of CCK OP are mediated, at least in part, by capsaicin-sensitive afferent neurons.


Genetic versus chemoprotective activation of Nrf2 signaling: overlapping yet distinct gene expression profiles between Keap1 knockout and triterpenoid-treated mice.
Loss of NF-E2-related factor 2 (Nrf2) signaling increases susceptibility to acute toxicity, inflammation and carcinogenesis in mice due to the inability to mount adaptive responses. In contrast, disruption of Keap1 (a cytoplasmic modifier of Nrf2 turnover) protects against these stresses in mice, although inactivating mutations in Keap1 have been identified recently in some human cancers. Global characterization of Nrf2 activation is important to exploit this pathway for chemoprevention in healthy, yet at-risk individuals and also to elucidate the consequences of hijacking the pathway in Keap1-mutant human cancers. Liver-targeted conditional Keap1-null, Albumin-Cre:Keap1((flox/-)) (CKO) mice provide a model of genetic activation of Nrf2 signaling. By coupling global gene expression analysis of CKO mice with analysis of pharmacologic activation using the synthetic oleanane triterpenoid 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im), we are able to gain insight into pathways affected by Nrf2 activation. CDDO-Im is an extremely potent activator of Nrf2 signaling. CKO mice were used to identify genes modulated by genetic activation of Nrf2 signaling. The CKO response was compared with hepatic global gene expression changes in wild-type mice treated with CDDO-Im at a maximal Nrf2 activating dose. The results show that genetic and pharmacologic activation of Nrf2 signaling modulates pathways beyond detoxication and cytoprotection, with the largest cluster of genes associated with lipid metabolism. Genetic activation of Nrf2 results in much larger numbers of detoxication and lipid metabolism gene changes. Additionally, analysis of pharmacologic activation suggests that Nrf2 is the primary mediator of CDDO-Im activity, though other cell-signaling targets are also modulated following an oral dose of 30 micromol/kg.


B7-1/CD80-transduced tumor cells elicit better systemic immunity than wild-type tumor cells admixed with Corynebacterium parvum.
Tumor cells genetically modified by transduction of B7 (B7-1/CD80), a natural ligand for the T-cell costimulatory molecules CD28 and CTLA-4, can elicit potent tumor immunity, and they can be effective for treatment of established cancers in animal models. In this study, three tumor lines, the EL4 lymphoma, the P815 mastocytoma, and the MCA102 sarcoma were transduced with recombinant retrovirus containing the murine B7 gene, and their potency to induce systemic immunity protective against challenge with wild-type tumor was compared to that of the same tumor cells admixed with the commonly used adjuvant Corynebacterium parvum. While admixture of tumor cells with C. parvum resulted in complete regression of tumors in syngeneic mice, it did not induce protective immunity against a subsequent challenge of wild-type cells from any of the 3 tumors tested. In contrast, B7-transduced EL4 and P815 tumors regressed locally and induced a potent systemic immunity to wild-type tumors and a higher level of cytotoxic T-cell activity than did tumor cells admixed with C. parvum. No systemic immunity was induced by B7-transduced nonimmunogenic MCA102 sarcoma cells. Our results demonstrate that immunogenic tumor cells transduced with the B7 gene are superior to tumor cells mixed with C. parvum for the induction of systemic tumor immunity.


Study of the Microstructure Evolution of Low-pH Cements Based on Ordinary Portland Cement (OPC) by Mid- and Near-Infrared Spectroscopy, and Their Influence on Corrosion of Steel Reinforcement.
Low-pH cements are designed to be used in underground repositories for high level waste. When they are based on Ordinary Portland Cements (OPC), high mineral admixture contents must be used which significantly modify their microstructure properties and performance. This paper evaluates the microstructure evolution of low-pH cement pastes based on OPC plus silica fume and/or fly ashes, using Mid-Infrared and Near-Infrared spectroscopy to detect cement pastes mainly composed of high polymerized C-A-S-H gels with low C/S ratios. In addition, the lower pore solution pH of these special cementitious materials have been monitored with embedded metallic sensors. Besides, as the use of reinforced concrete can be required in underground repositories, the influence of low-pH cementitious materials on steel reinforcement corrosion was analysed. Due to their lower pore solution pH and their different pore solution chemical composition a clear influence on steel reinforcement corrosion was detected.


Nitrate-induced and in situ electrochemical activation synthesis of oxygen deficiencies-rich nickel/nickel (oxy)hydroxide hybrid films for enhanced electrocatalytic water splitting.
Hydrogen produced by electrochemical water splitting offers a hopeful and renewable solution for addressing the global energy crisis; however, development of highly efficient non-noble-metal electrocatalysts remains a big challenge. Herein, we report a facile strategy to fabricate oxygen deficiencies-rich nickel/nickel (oxy)hydroxide hybrid films as efficient electrocatalysts for water splitting by in situ oxygen evolution reaction (OER) activation. Under OER conditions, the originally deposited Ni films from the ethaline-based deep eutectic solvent (DES) undergo a structural rearrangement with a phase transformation in the oxidation state from Ni(ii) to Ni(iii) at the surface. The change is coupled with an increase in oxygen deficiencies and a pronounced defective precursor is induced by the addition of nitrate ions, providing structural disordering and boosting the intrinsic activity of the catalyst, which strongly enhances the water splitting performance.


Preoperative embolization of intracranial meningiomas: efficacy, technical considerations, and complications.
Preoperative embolization for intracranial meningiomas offers potential advantages for safer and more effective surgery. However, this treatment strategy has not been examined in a large comparative series. The purpose of this study was to review our experience using preoperative embolization to understand the efficacy, technical considerations and complications of this technique. We performed a retrospective review of patients undergoing intracranial meningioma resection at our institution (March 2001 to December 2012). Comparisons were made between embolized and nonembolized patients, including patient and tumor characteristics, embolization method, operative blood loss, complications, and extent of resection. Logistic regression analyses were used to identify factors predictive of operative blood loss and extent of resection. Preoperatively, 224 patients were referred for embolization, of which 177 received embolization. No complications were seen in 97.1%. There were no significant differences in operative duration, extent of resection, or complications. Estimated blood loss was higher in the embolized group (410 versus 315 mL, P=.0074), but history of embolization was not a predictor of blood loss in multivariate analysis. Independent predictors of blood loss included decreasing degree of tumor embolization (P=.037), skull base location (P=.005), and male sex (P=.034). Embolization was not an independent predictor of gross total resection. Preoperative embolization is a safe option for selected meningiomas. In our series, embolization did not alter the operative duration, complications, or degree of resection, but the degree of embolization was an independent predictor of decreased operative blood loss.


Alterations in antibody-dependent cellular cytotoxicity during the course of HIV-1 infection. Humoral and cellular defects.
HIV-1-specific cell-mediated cytotoxicity (CMC) is a form of antibody-dependent cellular cytotoxicity (ADCC) in which HIV-1-specific antibodies arm NK cells directly to become cytotoxic for targets bearing HIV-1 antigenic determinants. This non-MHC-restricted cytotoxic activity is present in early stages of disease and declines markedly with disease progression. To understand the cellular and humoral factors contributing to the reduction in this activity, the conditions under which maximal arming of cells occurs was examined in vitro. With the use of a large patient cohort, a strong positive correlation was found between the capacity of a serum to direct lysis in standard ADCC assays and its ability to arm NK cells. Patients with minimal HIV-1-specific ADCC-directing antibodies exhibited low levels of CMC and were unable to arm normal effector cells in vitro. The lack of sufficient ADCC-directing antibodies was found to be one cause of defective CMC in some patients. Unlike asymptomatics, only a weak positive correlation was found between arming and ADCC with sera from AIDS patients, indicating that a factor other than absolute HIV-1 specific antibody titer was responsible for decreased CMC in this patient population. Another group of patients was found to have diminished CMC despite the presence of antibodies in the serum that were fully capable of arming normal effector cells to become cytotoxic for gp120-expressing targets. When compared with those of normal individuals, lymphocytes from seropositive patients mediated significantly reduced levels of cytotoxicity in ADCC and arming assays with the use of a high titered HIV-1-specific serum. In both assay systems, the magnitude and frequency of dysfunction in antibody-dependent cytolysis was found to be greater among AIDS patients than among asymptomatic individuals. The demonstration of both cellular and humoral defects in the ability of seropositive individuals to manifest ADCC reactivities strongly suggests that HIV-1 infection may significantly compromise the effectiveness of this potentially important cytolytic reactivity in vivo.