Letter to the editor: Genetics and the archaeology of ancient Israel.
This letter is a call for DNA testing on ancient skeletal materials from the southern Levant to begin a database of genetic information of the inhabitants of this crossroads region. In this region, during the Iron I period traditionally dated to circa 1200-1000 BCE, archaeologists and biblical historians view the earliest presence of a group that called itself Israel. They lived in villages in the varied hill countries of the region, contemporary with urban settlements in the coastal plains, inland valleys, and central hill country attributed to varied indigenous groups collectively called Canaanite. The remnants of Egyptian imperial presence in the region lasted until around 1150 BCE, postdating the arrival of an immigrant group from the Aegean called the Philistines circa 1175 BCE. The period that follows in the southern Levant is marked by the development of territorial states throughout the region, circa 1000-800 BCE. These patrimonial kingdoms, including the United Kingdom of Israel and the divided kingdoms of northern Israel and Judah, coalesced varied peoples under central leadership and newly founded administrative and religious bureaucracies. Ancient DNA testing will give us a further refined understanding of the individuals who peopled the region of the southern Levant throughout its varied archaeological and historic periods and provide scientific data that will support, refute, or nuance our sociohistoric reconstruction of ancient group identities. These social identities may or may not map onto genetic data, but without sampling of ancient DNA we may never know. A database of ancient DNA will also allow for comparisons with modern DNA samples collected throughout the greater region and the Mediterranean littoral, giving a more robust understanding of the long historical trajectories of regional human genetics and the genetics of varied ancestral groups of today's Jewish populations and other cultural groups in the modern Middle East and Mediterranean.


Rationale and design of a multicentre, randomized, placebo-controlled trial of mirabegron, a Beta3-adrenergic receptor agonist on left ventricular mass and diastolic function in patients with structural heart disease Beta3-left ventricular hypertrophy (Beta3-LVH).
Progressive left ventricular (LV) remodelling with cardiac myocyte hypertrophy, myocardial fibrosis, and endothelial dysfunction plays a key role in the onset and progression of heart failure with preserved ejection fraction. The Beta3-LVH trial will test the hypothesis that the β3 adrenergic receptor agonist mirabegron will improve LV hypertrophy and diastolic function in patients with hypertensive structural heart disease at high risk for developing heart failure with preserved ejection fraction. Beta3-LVH is a randomized, placebo-controlled, double-blind, two-armed, multicentre, European, parallel group study. A total of 296 patients will be randomly assigned to receive either mirabegron 50 mg daily or placebo over 12 months. The main inclusion criterion is the presence of LV hypertrophy, that is, increased LV mass index (LVMi) or increased wall thickening by echocardiography. The co-primary endpoints are a change in LVMi by cardiac magnetic resonance imaging and a change in LV diastolic function (assessed by the E/e' ratio). Secondary endpoints include mirabegron's effects on cardiac fibrosis, left atrial volume index, maximal exercise capacity, and laboratory markers. Two substudies will evaluate mirabegron's effect on endothelial function by pulse amplitude tonometry and brown fat activity by positron emission tomography using 17F-fluorodeoxyglucose. Morbidity and mortality as well as safety aspects will also be assessed. Beta3-LVH is the first large-scale clinical trial to evaluate the effects of mirabegron on LVMi and diastolic function in patients with LVH. Beta3-LVH will provide important information about the clinical course of this condition and may have significant impact on treatment strategies and future trials in these patients.


Gravity Spy: integrating advanced LIGO detector characterization, machine learning, and citizen science.
With the first direct detection of gravitational waves, the advanced laser interferometer gravitational-wave observatory (LIGO) has initiated a new field of astronomy by providing an alternative means of sensing the universe. The extreme sensitivity required to make such detections is achieved through exquisite isolation of all sensitive components of LIGO from non-gravitational-wave disturbances. Nonetheless, LIGO is still susceptible to a variety of instrumental and environmental sources of noise that contaminate the data. Of particular concern are noise features known as glitches, which are transient and non-Gaussian in their nature, and occur at a high enough rate so that accidental coincidence between the two LIGO detectors is non-negligible. Glitches come in a wide range of time-frequency-amplitude morphologies, with new morphologies appearing as the detector evolves. Since they can obscure or mimic true gravitational-wave signals, a robust characterization of glitches is paramount in the effort to achieve the gravitational-wave detection rates that are predicted by the design sensitivity of LIGO. This proves a daunting task for members of the LIGO Scientific Collaboration alone due to the sheer amount of data. In this paper we describe an innovative project that combines crowdsourcing with machine learning to aid in the challenging task of categorizing all of the glitches recorded by the LIGO detectors. Through the Zooniverse platform, we engage and recruit volunteers from the public to categorize images of time-frequency representations of glitches into pre-identified morphological classes and to discover new classes that appear as the detectors evolve. In addition, machine learning algorithms are used to categorize images after being trained on human-classified examples of the morphological classes. Leveraging the strengths of both classification methods, we create a combined method with the aim of improving the efficiency and accuracy of each individual classifier. The resulting classification and characterization should help LIGO scientists to identify causes of glitches and subsequently eliminate them from the data or the detector entirely, thereby improving the rate and accuracy of gravitational-wave observations. We demonstrate these methods using a small subset of data from LIGO's first observing run.


Isolation and purification of rat liver morphine UDP-glucuronosyltransferase.
A UDP-glucuronosyltransferase (UDPGT) isoenzyme capable of morphine glucuronidation has been purified to apparent homogeneity and partially characterized from hepatic microsomes of female Wistar rats which have low 3 alpha-hydroxysteroid UDPGT. A rapid and sensitive assay was developed to quantify morphine glucuronide formation using 14C-UDP-glucuronic acid and reverse phase C-18 minicolumns whereby radioactive glucuronides were differentially eluted from 14C-UDP-glucuronic acid. Trisacryl-DEAE and chromatofocusing chromatographic procedures were employed to separate and purify morphine UDPGT in the presence of exogenous phosphatidylcholine. The addition of phospholipid was necessary to stabilize UDPGT activities throughout the purification procedures. Morphine UDPGT was isolated to apparent homogeneity and displayed a pl of 7.9 upon chromatofocusing. A monomeric molecular weight of 56,000 was obtained. The purified enzyme reacted with morphine but not with 4-hydroxybiphenyl, p-nitrophenol, testosterone, androsterone, estrone, bilirubin, 4-aminobiphenyl, or alpha-naphthylamine. The MgCl2 requirement for maximal expression of morphine glucuronidation was higher for the purified enzyme than for solubilized and intact microsomes. Codeine competitively inhibits morphine glucuronidation with an apparent Ki of 1.1 mM with the purified morphine UDPGT. 4-Hydroxybiphenyl UDPGT was separated from morphine UDPGT using a chromatofocusing procedure for Emulgen 911-solubilized microsomes. An apparent pl value of 5.5 was obtained for this protein. Based on this work we conclude that morphine and 4-hydroxybiphenyl can react with separate UDPGT isoforms.


Acetylcholinesterase plays a non-neuronal, non-esterase role in organogenesis.
Acetylcholinesterase (AChE) is crucial for degrading acetylcholine at cholinergic synapses. In vitro studies suggest that, in addition to its role in nervous system signaling, AChE can also modulate non-neuronal cell properties, although it remains controversial whether AChE functions in this capacity in vivo Here, we show that AChE plays an essential non-classical role in vertebrate gut morphogenesis. Exposure of Xenopus embryos to AChE-inhibiting chemicals results in severe defects in intestinal development. Tissue-targeted loss-of-function assays (via microinjection of antisense morpholino or CRISPR-Cas9) confirm that AChE is specifically required in the gut endoderm tissue, a non-neuronal cell population, where it mediates adhesion to fibronectin and regulates cell rearrangement events that drive gut lengthening and digestive epithelial morphogenesis. Notably, the classical esterase activity of AChE is dispensable for this activity. As AChE is deeply conserved, widely expressed outside of the nervous system, and the target of many environmental chemicals, these results have wide-reaching implications for development and toxicology.


A lack of experience-dependent plasticity after more than a decade of recovered sight.
In 2000, monocular vision was restored to M. M., who had been blind between the ages of 3 and 46 years. Tests carried out over 2 years following the surgery revealed impairments of 3-D form, object, and face processing and an absence of object- and face-selective blood-oxygen-level-dependent responses in ventral visual cortex. In the present research, we reexamined M. M. to test for experience-dependent recovery of visual function. Behaviorally, M. M. remains impaired in 3-D form, object, and face processing. Accordingly, we found little to no evidence of the category-selective organization within ventral visual cortex typically associated with face, body, scene, or object processing. We did observe remarkably normal object selectivity within lateral occipital cortex, consistent with M. M.'s previously reported shape-discrimination performance. Together, these findings provide little evidence for recovery of high-level visual function after more than a decade of visual experience in adulthood.


Geographic distribution and serologic and genomic characterization of Morro Bay virus, a newly recognized bunyavirus.
More than 75,000 immature mosquitoes in three genera were collected from coastal California, reared to the adult stage, and tested for virus by plaque assay in Vero cell cultures. Twenty-six strains of Morro Bay (MB) virus, a newly recognized member of the California (CAL) serogroup, were isolated from Aedes squamiger, a pestiferous salt marsh mosquito species restricted to intertidal salt marshes in coastal California and Baja California. The geographic distribution of the isolates was 10 from San Luis Obispo County, one each from Santa Barbara and Orange Counties, and 14 from San Diego County. No virus isolations were made from 23,157 Ae. squamiger collected north of San Luis Obispo County (midpoint in the geographic range of this species in California). Thus, MB virus infection in Ae. squamiger appears to be restricted to the southern range of this species in California. Serum dilution neutralization tests indicated that MB virus represents a novel subtype of the California encephalitis (CE) serotype within the CAL serogroup. Comparative analyses of genomic sequence data from four geographically distinct MB virus isolates indicated that the isolates are genetically similar to each other and distinct from other CE serotype bunyaviruses. Phylogenetic analysis of nucleocapsid protein gene sequence data indicated that MB virus represents a distinct lineage within the CE serotype and thus supports the serologic classification of MB virus as a distinct CAL serogroup virus.


Development of a Bioinformatics Framework for Identification and Validation of Genomic Biomarkers and Key Immunopathology Processes and Controllers in Infectious and Non-infectious Severe Inflammatory Response Syndrome.
Sepsis is defined as dysregulated host response caused by systemic infection, leading to organ failure. It is a life-threatening condition, often requiring admission to an intensive care unit (ICU). The causative agents and processes involved are multifactorial but are characterized by an overarching inflammatory response, sharing elements in common with severe inflammatory response syndrome (SIRS) of non-infectious origin. Sepsis presents with a range of pathophysiological and genetic features which make clinical differentiation from SIRS very challenging. This may reflect a poor understanding of the key gene inter-activities and/or pathway associations underlying these disease processes. Improved understanding is critical for early differential recognition of sepsis and SIRS and to improve patient management and clinical outcomes. Judicious selection of gene biomarkers suitable for development of diagnostic tests/testing could make differentiation of sepsis and SIRS feasible. Here we describe a methodologic framework for the identification and validation of biomarkers in SIRS, sepsis and septic shock patients, using a 2-tier gene screening, artificial neural network (ANN) data mining technique, using previously published gene expression datasets. Eight key hub markers have been identified which may delineate distinct, core disease processes and which show potential for informing underlying immunological and pathological processes and thus patient stratification and treatment. These do not show sufficient fold change differences between the different disease states to be useful as primary diagnostic biomarkers, but are instrumental in identifying candidate pathways and other associated biomarkers for further exploration.


How television moved a nation: media, change and Indigenous rights.
This article examines the role of television in Australia's 1967 referendum, which is widely believed to have given rights to Aboriginal and Torres Strait Islander peoples. It presents an analysis of archival television footage to identify five stories that moved the nation: Australia's shame, civil rights and global connections, admirable activists, 'a fair go' and consensus. It argues that television shaped the wider culture and opened a channel of communication that allowed Indigenous activists and everyday people to speak directly to non-Indigenous people and other First Nations people throughout the land for the first time. The referendum narrative that television did so much to craft and promote marks the shift from an older form of settler nationalism that simply excluded Indigenous people, to an ongoing project that seeks to recognise, respect and 'reaccredit' the nation-state through incorporation of Indigenous narratives. We conclude that whereas television is understood to have 'united' the nation in 1967, 50 years later seismic shifts in media and society have made the quest for further constitutional reform on Indigenous rights and recognition more sophisticated, diffuse, complex and challenging.


High-frequency EEG activity at the start of seizures.
Frequencies above 35-40 Hz are poorly visualized on conventional EEG scalp recordings. We investigated frequency components up to 150 Hz in digitally recorded EEGs of seizures in five patients with implanted subdural grids, as part of their evaluation for epilepsy surgery. Amplifier bandpass was set from 0.1 to 300 Hz, and EEG was digitized at 2,000 samples per second. Seizures with electrodecremental patterns at the start showed a significant increase in spectral power above 35 Hz, with a twofold increase in the 40-50-Hz range, and up to a fivefold increase in the 80-120-Hz portion of the spectrum. Activity above 40 Hz could represent summed action potentials, harmonics of synaptic potentials or transient sharp components of synaptic potentials. High-frequency increases were largely localized to the region of the seizure focus. Grid sites remote from the focus did not show significant energy in the EEG band above 40 Hz at baseline, nor at time of seizure onset. Our findings suggest that high-frequency recordings may be of use in localizing seizure foci.


A multi-omics digital research object for the genetics of sleep regulation.
With the aim to uncover the molecular pathways underlying the regulation of sleep, we recently assembled an extensive and comprehensive systems genetics dataset interrogating a genetic reference population of mice at the levels of the genome, the brain and liver transcriptomes, the plasma metabolome, and the sleep-wake phenome. To facilitate a meaningful and efficient re-use of this public resource by others we designed, describe in detail, and made available a Digital Research Object (DRO), embedding data, documentation, and analytics. We present and discuss both the advantages and limitations of our multi-modal resource and analytic pipeline. The reproducibility of the results was tested by a bioinformatician not implicated in the original project and the robustness of results was assessed by re-annotating genetic and transcriptome data from the mm9 to the mm10 mouse genome assembly.


Updating and correction.
The current editions of two books edited by William T. Golden, Science Advice to the President and Science and Technology Advice to the President, Congress, and Judiciary, published this year by AAAS Press, are now being distributed by Transaction Publishers, New Brunswick, NJ 08903, at the prices $22.95 and $27.95 (paper), respectively, and are no longer available from AAAS. A related work, Golden's 1991 compilation Worldwide Science and Technology Advice to the Highest Levels of Government, originally published by Pergamon Press, is also being distributed by Transaction Publishers, at $25.95. For more information about the books see Science 1 July, p. 127. In the review of K. S. Thorne's Black Holes and Time Warps (13 May, p. 999-1000), the captions and illustrations on p. 1000 were mismatched. The correct order of the captions is (i) "A heavy rock..."; (ii) "Cosmic radio waves..."; and (iii) "The trajectories in space...."


Host nutrition-based approach for biotechnological production of the antifungal cyclic lipopeptide jagaricin.
In today's, society multi-resistant pathogens have become an emerging threat, which makes the search for novel anti-infectives more urgent than ever. A promising class of substances are cyclic lipopeptides like the antifungal jagaricin. Jagaricin is formed by the bacterial mushroom pathogen Janthinobacterium agaricidamnosum. It has shown antifungal activity against human pathogenic fungi like Candida albicans and Aspergillus fumigatus. In addition, jagaricin is nearly non-toxic for plants, which makes it a promising agent for agricultural applications. Cyclic lipopeptides formed by microorganisms originate from their secondary metabolism. This makes it very challenging to determine the inducing factor for product formation, especially for unknown microbial systems like J. agaricidamnosum. In the presented study, a biotechnological process for jagaricin formation was developed, investigating impact factors like the medium, oxygen availability, and phosphate. For this reason, experiments were conducted on microtiter plate, shake flask, and stirred tank bioreactor level. Ultimately, a final maximum jagaricin concentration of 251 mg L-1 (15.5 mgJagaricin∙gCDW-1) could be achieved, which is an increase of approximately 458 % in comparison to previous results in standard glucose medium. This concentration allows the production of significantly higher amounts of jagaricin and enables further experiments to investigate the potential of this substance.


Shoulder resurfacing.
Resurfacing is a type of shoulder arthroplasty that involves replacing the humeral joint surface with a metal covering, or cap, thus preserving the bone of the proximal part of the humerus. If the glenoid is also replaced, a current conventional polyethylene glenoid replacement prosthesis or an interposed soft-tissue graft is used. The potential advantages of humeral resurfacing, as compared with conventional shoulder arthroplasty, are: (1) no osteotomy is performed (and thus the head-shaft angle does not have to be addressed); (2) minimal bone resection; (3) a short operative time; (4) a low prevalence of humeral periprosthetic fractures; and (5) ease of revision to a conventional total shoulder replacement, if needed. Outcomes of surface replacement arthroplasty have been comparable with those of arthroplasties with a stemmed prosthesis in numerous short and mid-term follow-up studies. Future studies are required to assess the long-term outcomes of humeral resurfacing and to evaluate alternative surface bearing materials, especially on the glenoid side. Resurfacing appears to be a viable option for shoulder replacement, especially in young patients.


Biocatalytic conversion of avermectin to 4''-oxo-avermectin: improvement of cytochrome p450 monooxygenase specificity by directed evolution.
Discovery of the CYP107Z subfamily of cytochrome P450 oxidases (CYPs) led to an alternative biocatalytic synthesis of 4''-oxo-avermectin, a key intermediate for the commercial production of the semisynthetic insecticide emamectin. However, under industrial process conditions, these wild-type CYPs showed lower yields due to side product formation. Molecular evolution employing GeneReassembly was used to improve the regiospecificity of these enzymes by a combination of random mutagenesis, protein structure-guided site-directed mutagenesis, and recombination of multiple natural and synthetic CYP107Z gene fragments. To assess the specificity of CYP mutants, a miniaturized, whole-cell biocatalytic reaction system that allowed high-throughput screening of large numbers of variants was developed. In an iterative process consisting of four successive rounds of GeneReassembly evolution, enzyme variants with significantly improved specificity for the production of 4''-oxo-avermectin were identified; these variants could be employed for a more economical industrial biocatalytic process to manufacture emamectin.


Incomplete sulphomucin-secreting intestinal metaplasia for gastric cancer. Preliminary data from a prospective study from three centres.
A joint prospective long term study of gastric biopsies has been undertaken to survey intestinal metaplasia Types I, II, and III in terms of their incidence, distribution and value in the selection of high risk cancer patients. This study is based on protocols agreed between three centres for endoscopy, histological interpretation, and mucin histochemistry. The results on the first 1350 gastric biopsies examined during 1981-1982 are presented. Intestinal metaplasia was found in 267 biopsies (20%), being common in association with carcinoma (71%), less so in benign conditions such as gastric ulcer (39%), and chronic gastritis (24%), but rare in 'normal' (3%). Type I intestinal metaplasia was predominant (73%) in all the biopsies with intestinal metaplasia and was most common in benign conditions, 70% in gastric ulcer and 76% in chronic gastritis. Type III intestinal metaplasia (incomplete sulphomucin-secreting intestinal metaplasia) was recorded in only 9.8% of all the biopsies with intestinal metaplasia and had a higher incidence in carcinoma (35%), than in benign conditions (7%) (p less than 0.0001). These results suggest that intestinal metaplasia types may have different malignant potential and their identification may be useful in screening patients for early detection of cancer.


The diagnosis and management of antibiotic allergy in children: Systematic review to inform a contemporary approach.
Adverse drug reactions (ADRs) to antibiotics are commonly reported among children, with some representing genuine drug allergies. Accurate diagnostic tests are required. Drug provocation testing (DPT) is accepted as the gold standard investigation among children with suspected antibiotic allergy. We conducted this review to ascertain the strength of current evidence for using DPT as the first-line investigation for suspected antibiotic allergy among children. Medline was searched in June 2014 for publications investigating antibiotic allergy among children. 865 publications were retrieved and 76 studies selected. ADRs are most common among children of 0-4 years, however only some reveal drug allergies. The best evidence demonstrates that around 0.21% of general paediatric outpatients demonstrate positive antibiotic intradermal (ID) testing or DPTs, while 6.8% of children attending emergency departments for suspected β-lactam allergy may fulfil DPT reactions. Four studies used DPT-based protocols to investigate suspected antibiotic allergy, with two of these conducting ID testing and DPTs across all participants. β-lactam and clarithromycin ID testing had sensitivities of 66.7% and 75%, with positive predictive values of 36% and 33%, respectively, when compared with DPT data. Our literature review found four (6%) publications that performed DPTs to subjects' index antibiotic across all participants. No rigorous evidence supports using skin prick, ID or in vitro diagnostic testing; indeed, the testing regimens, extracts and positivity criteria used are inconsistent. We recommend that suspected non-serious antibiotic allergy should be primarily investigated using DPT-based clinical protocols. Data examining their safety, acceptability and diagnostic performance are required.


Identification of a Ca2(+)-dependent cell-cell adhesion molecule in endothelial cells.
Confluent cultures of aortic endothelial cells contain two different cell-cell adhesion mechanisms distinguished by their requirement for calcium during trypsinization and adhesion. A hybridoma clone was isolated producing a monoclonal antibody Ec6C10, which inhibits Ca2(+)-dependent adhesion of endothelial cells. There was no inhibition of Ca2(+)-independent adhesion of endothelial cells and only a minor effect on Ca2(+)-dependent adhesion of smooth muscle cells. Immunoblotting analysis shows that the antibody Ec6C10 recognizes a protein in endothelial but not epithelial cells with an apparent molecular weight of 135,000 in reducing conditions and 130,000 in non-reducing conditions. Monoclonal antibody Ec6C10 reacts with an antigen at the cell surface as shown by indirect immunofluorescence of confluent endothelial cells in a junctional pattern outlining the cobblestone morphology of the monolayer. Removal of extracellular calcium increased the susceptibility of the antigen recognized by antibody Ec6C10 to proteolysis by trypsin. The role of the Ca2(+)-dependent cell adhesion molecule in organization of the dense peripheral microfilament band in confluent endothelial cells was examined by adjusting the level of extracellular calcium to modulate cell-cell contact. Addition of the monoclonal antibody Ec6C10 at the time of the calcium switch inhibited the extent of formation of the peripheral F-actin band. These results suggest an association between cell-cell contact and the peripheral F-actin band potentially through the Ca2(+)-dependent CAM.


Safety and efficacy of ureteral access sheaths.
The ureteral access sheath (UAS) was introduced as a means of passing a flexible ureteroscope. Although the device was initially lauded for its ability to facilitate ureteroscopic access, passage was difficult and risked ureteral injury, and the UAS fell out of favor until the development of a new generation of devices that was easier to insert. The UAS should be advanced under fluoroscopy over a stiff guidewire, and the surgeon should ensure copious hydration of all inner and outer surfaces. Use of the UAS is purported to improve irrigant flow and visibility. The UAS can induce transient ureteral ischemia and promote an acute inflammatory response, but it also prevents potentially harmful elevations in intrarenal pressure. Unequivocal data are not yet available to suggest that UAS use during ureteroscopy protects or harms the upper urinary tract. The UAS also has the potential to improve stone-free rates by allowing passive egress or active retrieval of fragments. A large prospective study is needed to unequivocally determine if UAS use is superior in terms of stone-free rates. Cost studies reported to favor UAS use, although a formal cost-effectiveness analysis has not been performed. Further study is needed before routine use of the UAS can be recommended.


Approximate robust policy iteration using multilayer perceptron neural networks for discounted infinite-horizon Markov decision processes with uncertain correlated transition matrices.
We study finite-state, finite-action, discounted infinite-horizon Markov decision processes with uncertain correlated transition matrices in deterministic policy spaces. Existing robust dynamic programming methods cannot be extended to solving this class of general problems. In this paper, based on a robust optimality criterion, an approximate robust policy iteration using a multilayer perceptron neural network is proposed. It is proven that the proposed algorithm converges in finite iterations, and it converges to a stationary optimal or near-optimal policy in a probability sense. In addition, we point out that sometimes even a direct enumeration may not be applicable to addressing this class of problems. However, a direct enumeration based on our proposed maximum value approximation over the parameter space is a feasible approach. We provide further analysis to show that our proposed algorithm is more efficient than such an enumeration method for various scenarios.


Increased circulating endothelial progenitor cells and improved short-term outcomes in acute non-cardioembolic stroke after hyperbaric oxygen therapy.
Acute ischemic stroke is a leading cause of mortality and long-term disability, and profiles of endothelial progenitor cells (EPCs) reflect the degree of endothelial impairment. This study tested the hypothesis that hyperbaric oxygen therapy (HBOT) both improves the clinical short-term outcomes and increases the number of circulating EPCs and antioxidant capacity. The numbers of circulating EPCs [CD133+/CD34+ (%), KDR+/CD34+ (%)], biomarkers for oxidative stress (thiols and thiobarbituric acid-reactive substances), and clinical scores (National Institutes of Health Stroke Scale [NIHSS], Barthel index [BI], and modified Rankin Scale [MRS]) were prospectively evaluated in 25 patients with acute non-cardioembolic stroke under HBOT at two time points (pre- and post-HBOT). The biomarkers and clinical scores were compared with those of 25 age- and sex-matched disease controls. The numbers of KDR+/CD34+ (%) in the HBOT group following HBOT increased significantly, whereas the numbers of CD133+/CD34+ (%) also showed a tendency to increase without statistical significance. The mean high-sensitivity C-reactive protein levels showed significant decrease post-HBOT follow-up in the HBOT group. The changes in KDR+/CD34+EPC (%) numbers were positively correlated with changes in clinical outcomes scores (BI, NIHSS, and MRS) in the HBOT group. Based on the results of our study, HBOT can both improve short-term clinical outcomes and increase the number of circulating EPCs in patients with acute non-cardioembolic stroke.


Effects of miglustat treatment in a patient affected by an atypical form of Tangier disease.
Tangier disease (TD) is a rare autosomal recessive disorder, resulting from mutations in the ATP binding cassette transporter (ABCA1) gene. The deficiency of ABCA1 protein impairs high density lipoprotein (HDL) synthesis and cholesterol esters trafficking. A 58 year-old female, presenting with complex clinical signs (splenomegaly, dysarthria, dysphagia, ataxia, tongue enlargement, prurigo nodularis, legs lymphedema, pancytopenia and bone marrow foam cells), was misdiagnosed as Niemann-Pick C (NPC) and treated with miglustat (300 mg/day), normalizing neurological symptoms and improving skin lesions and legs lymphedema. Subsequently filipin-staining and molecular analysis for NPC genes were negative. Lipid profiling showed severe deficiency of HDL, 2 mg/dl (n.v. 45-65) and apoAI, 5.19 mg/dl (n.v. 110-170), suggesting TD as a probable diagnosis. Molecular analysis of ABCA1 gene showed the presence of a novel homozygous deletion (c.4464-486_4698 + 382 Del). Miglustat treatment was then interrupted with worsening of some neurological signs (memory defects, slowing of thought processes) and skin lesions. Treatment was restarted after 7 months with neurological normalization and improvement of skin involvement. These results suggest miglustat as a possible therapeutic approach in this untreatable disease. The mechanisms by which miglustat ameliorates at least some clinical manifestations of TD needs to be further investigated.


Dynamics of adolescents' smartphone use and well-being are positive but ephemeral.
Well-being and smartphone use are thought to influence each other. However, previous studies mainly focused on one direction (looking at the effects of smartphone use on well-being) and considered between-person effects, with self-reported measures of smartphone use. By using 2548 assessments of well-being and trace data of smartphone use collected for 45 consecutive days in 82 adolescent participants (Mage = 13.47, SDage = 1.62, 54% females), the present study disentangled the reciprocal and individual dynamics of well-being and smartphone use. Hierarchical Bayesian Continuous Time Dynamic Models were used to estimate how a change in frequency and duration of smartphone use predicted a later change in well-being, and vice versa. Results revealed that (i) when participants used the smartphone frequently and for a longer period, they also reported higher levels of well-being; (ii) well-being positively predicted subsequent duration of smartphone use; (iii) usage patterns and system dynamics showed heterogeneity, with many subjects showing reciprocal effects close to zero; finally, (iv) changes in well-being tend to persist longer than changes in the frequency and duration of smartphone use.


Inspiratory muscle training in patients with cystic fibrosis.
Little information is available about the effects of inspiratory muscle training in patients with cystic fibrosis (CF). In this study the effects of inspiratory-threshold loading in patients with CF on strength and endurance of the inspiratory muscles, pulmonary function, exercise capacity, dyspnoea and fatigue were evaluated. Sixteen patients were assigned to one of two groups using the minimization method: eight patients in the training group and eight patients in the control group. The training was performed using an inspiratory-threshold loading device. Patients were instructed to use the threshold trainer 20 min a day, 5 days a week for 6 weeks. Patients in the training group trained at inspiratory threshold loads up to 40% of maximal static inspiratory pressure (Pimax) and patients in the control group got 'sham' training at a load of 10% of Pimax. No significant differences were found among the two groups in gender, age, weight, height, pulmonary function, exercise capacity, inspiratory-muscle strength and inspiratory-muscle endurance before starting the training programme. Mean (SD) age in the control group was 19 (5.5) years, mean (SD) age in the training group was 17 (5.2) years. Mean FEV1 in both groups was 70% predicted, mean inspiratory-muscle strength in both groups was above 100% predicted. All patients except one, assigned to the training group, completed the programme. After 6 weeks of training, mean inspiratory-muscle endurance (% Pimax) in the control group increased from 50% to 54% (P = 0.197); in the training group mean inspiratory muscle endurance (% Pimax) increased from 49% to 66% (P = 0.003). Statistical analysis showed that the change in inspiratory-muscle endurance (% Pimax) in the training group was significantly higher than in the control group (P = 0.012). After training, in the training group there was a tendency of improvement in Pimax with an increase from 105 to 123% predicted, which just fell short of statistical significance (P = 0.064). After training no significant differences were found in changes from baseline in pulmonary function, exercise capacity, dyspnoea and fatigue. It is concluded that low-intensity inspiratory-threshold loading at 40% of Pimax was sufficient to elicit an increased inspiratory-muscle endurance in patients with CF.


Capacitance variation induced by microfluidic two-phase flow across insulated interdigital electrodes in lab-on-chip devices.
Microfluidic two-phase flow detection has attracted plenty of interest in various areas of biology, medicine and chemistry. This work presents a capacitive sensor using insulated interdigital electrodes (IDEs) to detect the presence of droplets in a microchannel. This droplet sensor is composed of a glass substrate, patterned gold electrodes and an insulation layer. A polydimethylsiloxane (PDMS) cover bonded to the multilayered structure forms a microchannel. Capacitance variation induced by the droplet passage was thoroughly investigated with both simulation and experimental work. Olive oil and deionized water were employed as the working fluids in the experiments to demonstrate the droplet sensor. The results show a good sensitivity of the droplet with the appropriate measurement connection. This capacitive droplet sensor is promising to be integrated into a lab-on-chip device for in situ monitoring/counting of droplets or bubbles.


What is Bowenwork®? A systematic review.
The objectives of this study were to systematically review the literature available on the complementary approach to healing known as Bowenwork(®) and to examine reported research methods. To the authors' knowledge, an exhaustive search of the computerized databases from the known scientific community on all available published literature on Bowenwork(®) was conducted. Databases included Medline Ovid, PubMed, PsychINFO, and CINAHL(®). The literature search included English language studies (1985-September 5, 2009) using the following search terms: Bowen Technique, Bowen Therapy, Bowtech, and Bowenwork(®). In addition, a hand search of individual journals noted to publish complementary and alternative medicine articles was done (1997-2009). Abstracts of all studies were reviewed. Studies were included if (1) they referenced the original Bowenwork, (2) provided health-related outcomes, and (3) provided quantitative or qualitative data. Excluded articles included testimonials, duplicates, unrelated topics, literature reviews, articles lacking verifiable sources, and studies from proprietary resources. Of the 309 citations obtained, only 15 articles met the inclusion criteria (randomized clinical trial, n=1; quasi-experimental, n=2; mixed methods, n=3; cross-sectional, n=2; case study, n=7). Over half of these studies (53%) reported that Bowenwork was effective for pain reduction and 33% reported improved mobility. In addition, several studies (n=5) reported the effectiveness of Bowenwork(®) on the relief of symptoms experienced by persons living with a chronic illness, such as multiple sclerosis. Bowenwork(®) may provide a noninvasive and affordable complementary approach to improvements in health. This intervention may offer improvements in pain reduction for various conditions such as frozen shoulder and migraines. While Bowenwork is recognized internationally, scientific evidence is not well documented. Further research is needed to systematically test this modality, before widespread recommendations can be given.


Clinical Benefits of Memantine Treatment for Alzheimer's Disease in the Okayama Memantine Study II (OMS II).
The clinical benefits of memantine, depending on the baseline cognitive and affective conditions in real world dementia clinics, have not been completely examined. We performed the "Okayama Memantine Study II (OMS II)" to retrospectively evaluate the clinical effects of memantine monotherapy (n = 38) in Alzheimer's disease (AD) patients using seven batteries to assess dementia at the baseline, at 3, 6, and 12 months. Additionally, we divided 163 AD patients treated with memantine into two subgroups depending on the baseline cognitive score of the Mini-Mental State Examination (MMSE): the MMSE <15 group (n = 36) and the baseline MMSE ≥15 group (n = 127). We also analyzed 71 AD patients based on the baseline behavioral and psychological symptoms of dementia (BPSD) severity using Abe's BPSD score (ABS). Memantine monotherapy maintained cognitive functions until 6 months of treatment, but showed a decrease at 12 months ( *p < 0.05 versus baseline). However, memantine monotherapy greatly improved BPSD symptoms until 12 months ( *p < 0.05, **p < 0.01) and maintained other affective functions as well as the activity of daily living. Memantine treatment showed similar effects, regardless of the baseline cognitive functions, but showed better effects on ABS for higher baseline cognitive functions. Memantine treatment greatly improved ABS depending on baseline BPSD severity. Our present OMS II showed that memantine monotherapy improved BPSD until 12 months. The higher baseline cognitive subgroup (MMSE ≥15) and the worse baseline BPSD subgroup were expected to show better effects with memantine.


Effects of Arp2 and Arp3 nucleotide-binding pocket mutations on Arp2/3 complex function.
Contributions of actin-related proteins (Arp) 2 and 3 nucleotide state to Arp2/3 complex function were tested using nucleotide-binding pocket (NBP) mutants in Saccharomyces cerevisiae. ATP binding by Arp2 and Arp3 was required for full Arp2/3 complex nucleation activity in vitro. Analysis of actin dynamics and endocytosis in mutants demonstrated that nucleotide-bound Arp3 is particularly important for Arp2/3 complex function in vivo. Severity of endocytic defects did not correlate with effects on in vitro nucleation activity, suggesting that a critical Arp2/3 complex function during endocytosis may be structural rather than catalytic. A separate class of Arp2 and Arp3 NBP mutants suppressed phenotypes of mutants defective for actin nucleation. An Arp2 suppressor mutant increased Arp2/3 nucleation activity. Electron microscopy of Arp2/3 complex containing this Arp2 suppressor identified a structural change that also occurs upon Arp2/3 activation by nucleation promoting factors. These data demonstrate the importance of Arp2 and Arp3 nucleotide binding for nucleating activity, and Arp3 nucleotide binding for maintenance of cortical actin cytoskeleton cytoarchitecture.


The UNITE database for molecular identification of fungi: handling dark taxa and parallel taxonomic classifications.
UNITE (https://unite.ut.ee/) is a web-based database and sequence management environment for the molecular identification of fungi. It targets the formal fungal barcode-the nuclear ribosomal internal transcribed spacer (ITS) region-and offers all ∼1 000 000 public fungal ITS sequences for reference. These are clustered into ∼459 000 species hypotheses and assigned digital object identifiers (DOIs) to promote unambiguous reference across studies. In-house and web-based third-party sequence curation and annotation have resulted in more than 275 000 improvements to the data over the past 15 years. UNITE serves as a data provider for a range of metabarcoding software pipelines and regularly exchanges data with all major fungal sequence databases and other community resources. Recent improvements include redesigned handling of unclassifiable species hypotheses, integration with the taxonomic backbone of the Global Biodiversity Information Facility, and support for an unlimited number of parallel taxonomic classification systems.


Altered protein secretion of Chlamydia trachomatis in persistently infected human endocervical epithelial cells.
Chlamydia trachomatis is the most common bacterial infection of the human reproductive tract globally; however, the mechanisms underlying the adaptation of the organism to its natural target cells, human endocervical epithelial cells, are not clearly understood. To secure its intracellular niche, C. trachomatis must modulate the host cellular machinery by secreting virulence factors into the host cytosol to facilitate bacterial growth and survival. Here we used primary human endocervical epithelial cells and HeLa cells infected with C. trachomatis to examine the secretion of bacterial proteins during productive growth and persistent growth induced by ampicillin. Specifically, we observed a decrease in secretable chlamydial protease-like activity factor (CPAF) in the cytosol of host epithelial cells exposed to ampicillin with no evident reduction of CPAF product by C. trachomatis. In contrast, the expression of CopN and Tarp was downregulated, suggesting that C. trachomatis responds to ampicillin exposure by selectively altering the expression of secretable proteins. In addition, we observed a greater accumulation of outer-membrane vesicles from C. trachomatis in persistently infected cells. Taken together, these results suggest that the regulation of both gene expression and the secretion of chlamydial virulence proteins is involved in the adaptation of the bacteria to a persistent infection state in human genital epithelial cells.


Demographic characteristics and perceived health status of users of folk therapies in Taiwan.
This study examined the prevalence of folk therapy use among Taiwanese adults and factors associated with such use. The data used in this study were from the 2001 National Health Interview Survey in Taiwan, which utilized a multistaged stratified systematic sampling scheme. Included in the current analysis were 11,290 individuals from 20 to 65 years. Only 1.3% of those surveyed were classified as users of folk therapy. Users of folk therapies were older (p = 0.002), had higher annual incomes (p < 0.001), and experienced more health problems (p = 0.006) than nonusers. The two groups were comparable in the areas of marital status, employment status, gender, and educational level. Users had lower scores in the physical functioning (p < 0.001), role physical (p = 0.041), general health perception (p = 0.002), and bodily pain (p < 0.001) domains of the Medical Outcome Studies 36-Item Short-Form Health Survey. The two groups were not significantly different regarding the utilization and satisfaction with conventional medical resources and the domain scores of the brief version of the World Health Organization Quality of Life (QOL) questionnaire. Less than 2% of adult Taiwanese population reported relying primarily on folk therapies for their common physical discomfort. Users of folk therapies are older, have higher incomes, and have more health problems and poorer health-related QOL, but they neither make more frequent use of conventional medical services nor are they dissatisfied with the available services.


Falsehood on the move. The Aztec children and science in the second half of the 19th century.
Allegedly kidnapped from a secret city in Central America, the "Aztec children" began a showman's career in the early-1850s. They died around 1900, after being observed by countless pathologists and ethnologists from Europe and the US. Most of the literature on the "Aztec children" has emphasized racial theories, the imperial gaze, and the character of "ethnological shows", where monstrosity and ethnicity were practically synonymous. Less attention has been paid to the fact that scientists continuously insisted that the case was false, an argument that instead of debunking the myth of the "Aztec children", contributed to establishing the "Aztecs" as "a matter of fact". In examining the case of the "Aztec children", this essay aims to explore what can be called the shifting nature or elusiveness of falsehood.


X-linked ichthyosis with hypogonadism: not always Kallmann's syndrome.
We describe two males with congenital ichthyosis secondary to steroid sulphatase deficiency who also manifested delayed puberty with biochemical features of hypogonadotrophic hypogonadism. In the first patient a history of cryptorchidism and the clinical findings of anosmia, micropenis and bimanual synkinesis suggested a contiguous gene syndrome, comprising X-linked Kallmann's syndrome and X-linked ichthyosis. An X-Y chromosomal translocation involving the Xp22.3 locus was identified; deletions of the STS locus and of exons 10-14 of the KAL locus were subsequently demonstrated. The second patient was euosmic and, although the STS locus was deleted in association with a pericentric inversion involving Xp22.3, no deletions were detected at the KAL locus. Clinically, he was felt to have constitutionally delayed puberty rather than hypogonadotropic hypogonadism and this diagnosis was substantiated by his subsequent development.


Differences in hemodynamic response to metaboreflex activation between obese patients with metabolic syndrome and healthy subjects with obese phenotype.
Patients suffering from obesity and metabolic syndrome (OMS) manifest a dysregulation in hemodynamic response during exercise, with an exaggerated systemic vascular increase. However, it is not clear whether this is the consequence of metabolic syndrome per se or whether it is due to concomitant obesity. The aim of the present investigation was to discover whether OMS and noncomplicated obesity resulted in different hemodynamic responses during the metaboreflex. Twelve metabolically healthy but obese subjects (MHO; 7 women), 13 OMS patients (5 women), and 12 normal age-matched controls (CTL; 6 women) took part in this study. All participants underwent a postexercise muscle ischemia protocol to evaluate the metaboreflex activity. Central hemodynamics were evaluated by impedance cardiography. The main result shows an exaggerated increase in systemic vascular resistance from baseline during the metaboreflex in the OMS patients as compared with the other groups (481.6 ± 180.3, -0.52 ± 177.6, and -60.5 ± 58.6 dynes·s(-1)·cm(-5) for the OMS, the MHO, and the CTL groups, respectively; P < 0.05). Moreover, the MHO subjects and the CTL group showed an increase in cardiac output during the metaboreflex (288.7 ± 325.8 and 703.8 ± 276.2 ml/m increase with respect to baseline), whereas this parameter tended to decrease in the OMS group (-350 ± 236.5 ml/m). However, the blood pressure response, which tended to be higher in the OMS patients, was not statistically different between groups. The results of the present investigation suggest that OMS patients have an exaggerated vasoconstriction in response to metaboreflex activation and that this fact is not due to obesity per se.


Acute gangrene of the scrotum and penis in four hematologic patients. The usefulness of hyperbaric oxygen therapy in one case.
We describe four cases of Fournier's gangrene complicating the postchemotherapy aplastic phase (polymorphonuclear cells [PMN] less than 500/microliter) in three patients with acute leukemia and one patient with non-Hodgkin's lymphoma. Blood and local cultures from two patients contained Pseudomonas aeruginosa, and local cultures from another patient grew both P. aeruginosa and Proteus rettgeri. Early recognition and aggressive antibiotic and surgical treatment with granulocyte recovery were fundamental factors in resolution of the gangrene in three of the four patients. Hyperbaric oxygen therapy, never reported in hematologic patients, was also very useful in one patient in whom the clinical course was particularly acute.


Increased resistance of Bt aspens to Phratora vitellinae (Coleoptera) leads to increased plant growth under experimental conditions.
One main aim with genetic modification (GM) of trees is to produce plants that are resistant to various types of pests. The effectiveness of GM-introduced toxins against specific pest species on trees has been shown in the laboratory. However, few attempts have been made to determine if the production of these toxins and reduced herbivory will translate into increased tree productivity. We established an experiment with two lines of potted aspens (Populus tremula×Populus tremuloides) which express Bt (Bacillus thuringiensis) toxins and the isogenic wildtype (Wt) in the lab. The goal was to explore how experimentally controlled levels of a targeted leaf beetle Phratora vitellinae (Coleoptera; Chrysomelidae) influenced leaf damage severity, leaf beetle performance and the growth of aspen. Four patterns emerged. Firstly, we found clear evidence that Bt toxins reduce leaf damage. The damage on the Bt lines was significantly lower than for the Wt line in high and low herbivory treatment, respectively. Secondly, Bt toxins had a significant negative effect on leaf beetle survival. Thirdly, the significant decrease in height of the Wt line with increasing herbivory and the relative increase in height of one of the Bt lines compared with the Wt line in the presence of herbivores suggest that this also might translate into increased biomass production of Bt trees. This realized benefit was context-dependent and is likely to be manifested only if herbivore pressure is sufficiently high. However, these herbivore induced patterns did not translate into significant affect on biomass, instead one Bt line overall produced less biomass than the Wt. Fourthly, compiled results suggest that the growth reduction in one Bt line as indicated here is likely due to events in the transformation process and that a hypothesized cost of producing Bt toxins is of subordinate significance.


Iron deficiency and child and maternal health.
Iron deficiency is most commonly found in women of reproductive age and infants worldwide, but the influence of maternal iron deficiency on infant development is underexplored. The objective was to examine the relation between maternal iron status and mother-child interactions in a randomized, double-blind, intervention trial conducted in South Africa. Women were recruited into the study from a health clinic at 6-8 wk postpartum and were classified as either iron-deficient anemic (IDA) or iron-sufficient after blood analysis. IDA mothers received iron supplements of 125 mg FeSO(4) (IDA-Fe; n = 34) or placebo (IDA-PL; n = 30) daily from 10 wk to 9 mo postpartum. The control group (n = 31) consisted of iron-sufficient mothers. Free-play mother-child interaction sessions were videotaped in the clinic at 10 wk (n = 80) and 9 mo (n = 66) postpartum and coded per the Emotional Availability Scales (4 maternal scales: sensitivity, structuring, nonintrusiveness, and nonhostility; 2 infant scales: responsiveness and involvement). At 10 wk, scores for maternal sensitivity and child responsiveness were significantly greater in the control group than in the IDA groups (P = 0.028 and 0.009, respectively). At 9 mo, the control and IDA-Fe groups no longer differed. These 2 groups scored significantly better on the maternal sensitivity, structuring, and nonhostility scales and on the child responsiveness scale than did the IDA-PL group (P = 0.007-0.032), whose iron status remained low. These data indicate that maternal iron deficiency negatively affects mother-child interactions and that iron supplementation protects against these negative effects.


Heme: a novel inducer of MCP-1 through HO-dependent and HO-independent mechanisms.
This study examined the effect of hemin on the expression of heme oxygenase-1 (HO-1) and monocyte chemoattractant protein-1 (MCP-1) in immortalized rat proximal tubular epithelial cells (IRPTCs). Hemin elicited a dose- and time-dependent induction of HO-1 and MCP-1 mRNA. HO activity contributed to MCP-1 mRNA expression at early time points (4-6 h) because inhibition of HO activity by zinc protoporphyrin (ZnPP) prevented hemin-induced expression of MCP-1 mRNA. Catalytically active intracellular iron was markedly increased in hemin-treated IRPTCs and contributed to the induction of HO-1 and MCP-1 mRNA because an iron chelator blocked hemin-induced upregulation of both genes, whereas a cell-permeant form of iron directly induced these genes. N-acetylcysteine completely blocked hemin-induced expression of HO-1 and MCP-1 mRNA, thereby providing added evidence for redox regulation of expression of these genes. The redox-sensitive transcription factor NF-kappaB was recruited in hemin-induced upregulation of MCP-1 because two different compounds that abrogate the activation of NF-kappaB (TPCK and BAY 11-7082) completely blocked hemin-induced upregulation of MCP-1 mRNA. In contrast to this HO-mediated induction of MCP-1 through redox-sensitive, iron-dependent, and NF-kappaB-involved pathways observed after 4-6 h, hemin also elicited a delayed induction of MCP-1 at 18 h through HO-independent pathways. We conclude that hemin is a potent inducer of MCP-1 in IRPTCs: HO-dependent, heme-degrading pathways lead to an early, robust, and self-remitting induction of MCP-1, whereas HO-independent mechanisms lead to a delayed expression of MCP-1.


Selective ex vivo photothermal nano-therapy of solid liver tumors mediated by albumin conjugated gold nanoparticles.
We have used albumin (BSA) bound to gold nanoparticles (GNPs) as active vectors to target liver cells. Our incentive to develop an original model of living liver cancer sprang from the ethical drawbacks that hindered the assessment of the selective character and the therapeutic capacity of these nano-biosystems in cancer patients. Ex vivo-perfused liver specimens were obtained from hepatocellular carcinoma patients similarly to the surgical technique of transplantation. Albumin bound to GNPs was inoculated intra-arterially onto the resulting specimen and determined the specific delivery of the nano-bioconjugate into the malignant tissue by means of the capillary bed. The extent of necrosis was considerable following laser therapy and at the same time surrounding parenchyma was not seriously affected. The selective photothermal ablation of the malignant liver tissue was obtained after the selective accumulation of BSA bound to GNPs into tumor cells following ex-vivo intra-vascular perfusion.


Avoidable errors in the modelling of outbreaks of emerging pathogens, with special reference to Ebola.
As an emergent infectious disease outbreak unfolds, public health response is reliant on information on key epidemiological quantities, such as transmission potential and serial interval. Increasingly, transmission models fit to incidence data are used to estimate these parameters and guide policy. Some widely used modelling practices lead to potentially large errors in parameter estimates and, consequently, errors in model-based forecasts. Even more worryingly, in such situations, confidence in parameter estimates and forecasts can itself be far overestimated, leading to the potential for large errors that mask their own presence. Fortunately, straightforward and computationally inexpensive alternatives exist that avoid these problems. Here, we first use a simulation study to demonstrate potential pitfalls of the standard practice of fitting deterministic models to cumulative incidence data. Next, we demonstrate an alternative based on stochastic models fit to raw data from an early phase of 2014 West Africa Ebola virus disease outbreak. We show not only that bias is thereby reduced, but that uncertainty in estimates and forecasts is better quantified and that, critically, lack of model fit is more readily diagnosed. We conclude with a short list of principles to guide the modelling response to future infectious disease outbreaks.


Microglia and astrocytes attenuate the replication of the oncolytic vaccinia virus LIVP 1.1.1 in murine GL261 gliomas by acting as vaccinia virus traps.
Oncolytic virotherapy is a novel approach for the treatment of glioblastoma multiforme (GBM) which is still a fatal disease. Pathologic features of GBM are characterized by the infiltration with microglia/macrophages and a strong interaction between immune- and glioma cells. The aim of this study was to determine the role of microglia and astrocytes for oncolytic vaccinia virus (VACV) therapy of GBM. VACV LIVP 1.1.1 replication in C57BL/6 and Foxn1(nu/nu) mice with and without GL261 gliomas was analyzed. Furthermore, immunohistochemical analysis of microglia and astrocytes was investigated in non-, mock-, and LIVP 1.1.1-infected orthotopic GL261 gliomas in C57BL/6 mice. In cell culture studies virus replication and virus-mediated cell death of GL261 glioma cells was examined, as well as in BV-2 microglia and IMA2.1 astrocytes with M1 or M2 phenotypes. Co-culture experiments between BV-2 and GL261 cells and apoptosis/necrosis studies were performed. Organotypic slice cultures with implanted GL261 tumor spheres were used as additional cell culture system. We discovered that orthotopic GL261 gliomas upon intracranial virus delivery did not support replication of LIVP 1.1.1, similar to VACV-infected brains without gliomas. In addition, recruitment of Iba1(+) microglia and GFAP(+) astrocytes to orthotopically implanted GL261 glioma sites occurred already without virus injection. GL261 cells in culture showed high virus replication, while replication in BV-2 and IMA2.1 cells was barely detectable. The reduced viral replication in BV-2 cells might be due to rapid VACV-induced apoptotic cell death. In BV-2 and IMA 2.1 cells with M1 phenotype a further reduction of virus progeny and virus-mediated cell death was detected. Application of BV-2 microglial cells with M1 phenotype onto organotypic slice cultures with implanted GL261 gliomas resulted in reduced infection of BV-2 cells, whereas GL261 cells were well infected. Our results indicate that microglia and astrocytes, dependent on their activation state, may preferentially clear viral particles by immediate uptake after delivery. By acting as VACV traps they further reduce efficient virus infection of the tumor cells. These findings demonstrate that glia cells need to be taken into account for successful GBM therapy development.


Sterlizing and packaging males of Anopheles Albimanus Wiedemann for field release.
Technology was developed for sterilizing and packaging as many as 1 million male Anopheles albimanus Wiedemann per day for field release. The average sterility produced in the males during a 1.5-year period was 98.9%. Mortality due to transport of the males in specially developed cages averaged 4.5% for 72-hour-old adults and 2.5% for 24-hour-old adults. The average mortality due to transport and field exposure of pupae was 1.2 to 9.8%, depending on the technique used.


Protein-passivated Fe(3)O(4) nanoparticles: low toxicity and rapid heating for thermal therapy.
Thermotherapy is a promising technique for the minimally invasive elimination of solid tumors. Here we report the fabrication of protein-coated iron oxide NPs (12 nm core) for use as thermal therapeutic agents. These albumin-passivated NPs are stable under physiological conditions, with rapid heating and cell killing capacity upon alternating magnetic field (AMF) exposure. The mode of action is specific: no measurable cytotoxicity was observed for the particle without AMF or for AMF exposure without the particle.


Imatinib plasma levels are correlated with clinical benefit in patients with unresectable/metastatic gastrointestinal stromal tumors.
PURPOSE To study the pharmacokinetics (PK) of imatinib (IM) in patients with advanced GI stromal tumors (GISTs) treated in a randomized phase II study and to explore the potential relationship between IM plasma levels and long-term clinical outcomes. PATIENTS AND METHODS Patients were randomly assigned to receive IM at 400 mg versus 600 mg daily. IM plasma levels were analyzed in a subset of patients (n = 73) for whom PK data on day 1 and at steady-state (SS, day 29) were available. IM PK was evaluated using a population PK approach. The relationship between IM plasma exposure and clinical outcome was explored by grouping patients into quartiles according to IM trough concentration (C(min)). The clinical outcome parameters evaluated include overall objective benefit rate (OOBR; complete response plus partial response plus stable disease) time to progression (TTP), and KIT genotyping. Results IM PK exposure showed a high inter-patient variability, and clinical outcomes were correlated with IM trough levels at SS. The median TTP was 11.3 months for patients in the lowest C(min) quartile (Q1, < 1,110 ng/mL) compared with more than 30 months for Q2 to Q4 (P = .0029). OOBR was also inferior in Q1 patients. In patients with GIST with KIT exon 11 mutations (n = 39), the OOBR was 67% for Q1 patients versus 100% for all others (P = .001). CONCLUSION In patients with advanced GIST, IM trough levels at SS were associated with clinical benefit. Patients with IM C(min) below 1,100 ng/mL showed a shorter TTP and lower rate of clinical benefit (OOBR). Further studies are justified to test whether monitoring IM plasma levels might optimize clinical outcomes for patients with GIST.


Assessment of Parasitic Activity of Fusarium Strains Obtained from a Heterodera schachtii-Suppressive Soil.
This study assessed the potential impact of various Fusarium strains on the population development of sugarbeet cyst nematodes. Fungi were isolated from cysts or eggs of Heterodera schachtii Schmidt that were obtained from a field suppressive to that nematode. Twenty-six strains of Fusarium spp. were subjected to a phylogenic analysis of their rRNA-ITS nucleotide sequences. Seven genetically distinct Fusarium strains were evaluated for their ability to influence population development of H. schachtii and crop performance in greenhouse trials. Swiss chard (Beta vulgaris) seedlings were transplanted into fumigated field soil amended with a single fungal strain at 1,000 propagules/g soil. One week later, the soil was infested with 250 H. schachtii J2/100 cm(3) soil. Parasitized eggs were present in all seven Fusarium treatments at 1,180 degree-days after fungal infestation. The percentage of parasitism ranged from 17 to 34%. Although the most efficacious F. oxysporum strain 471 produced as many parasitized eggs as occurred in the original suppressive soil, none of the Fusarium strains reduced the population density of H. schachtii compared to the conducive check. This supports prior results that Fusarium spp. were not the primary cause of the population suppression of sugarbeet cyst nematodes at this location.


Human peripheral blood-derived CD31+ cells have robust angiogenic and vasculogenic properties and are effective for treating ischemic vascular disease.
This study aimed to determine if CD31 is a novel marker of a circulating angio-vasculogenic cell population and to establish the cells' therapeutic effects on experimental ischemia. Emerging evidence suggested that therapeutic mechanisms underlying various bone marrow-derived cells are due to paracrine effects. Furthermore, the vasculogenic potential of these cells is under debate. CD31 is a well-known marker for endothelial cells but is also expressed in a fraction of peripheral blood (PB) mononuclear cells. CD31(+) cells were isolated from human PB by magnetic-activated cell sorting. The gene expression profile was examined by deoxyribonucleic acid microarray and real-time reverse transcriptase polymerase chain reaction. Various in vitro endothelial differentiation or vasculogenic assays were conducted. Finally, cells were directly implanted into a mouse hind limb ischemia model to test angiogenic-vasculogenic and therapeutic effects. Fluorescent-activated cell sorter analysis revealed that PB-CD31(+) cells exhibited endothelial and hematopoietic stem/progenitor markers. CD31(+) cells had higher levels of expression of proangiogenic genes on microarray and real-time reverse transcriptase polymerase chain reaction and generated higher numbers of endothelial progenitor cells than CD31(-) cells did. CD31(+) cells spontaneously formed vascular tubelike structures and exhibited an endothelial cell phenotype in vitro. In a hind limb ischemia model, CD31(+) cell transplantation augmented blood perfusion and prevented limb loss. Both angiogenic cytokines and capillary density were increased, suggesting CD31(+) cells augmented neovascularization. CD31 is a novel marker that designates circulating angiogenic and vasculogenic cells. These cells are easily isolated from human PB and thus are a novel candidate for treatment of ischemic cardiovascular disease.


Maternal touch and infant affect in the Still Face Paradigm: A cross-cultural examination.
Touch between mother and infant plays an important role in development starting from birth. Cross-cultural differences surrounding rearing practices have an influence on parent-infant interaction, including types of touch used and the development of emotional regulation. This study was designed to investigate maternal touch and infant emotional regulation in infant-mother dyads from Ecuador (n=25) and Hispanic dyads from the United States (US) (n=26). Mothers and their 4-month-old full-term infants participated in the Still Face Paradigm. Second-by-second coding of maternal touch and infant affect was completed. Overall the analyses showed that Ecuadorian mothers used more nurturing and accompaniment touch and less attention seeking touch than US Hispanic mothers during the pre-stressor (baseline) episode. Lagged multilevel models were used to investigate the effect of the different types of touch on infant emotional regulation in the groups for the episodes. The data suggest that playful touch had a significant increase in infant affect, whereas accompaniment and attention-seeking touch had a significant decrease in infant affect. Overall, this study provides support for the role of touch in mother-infant synchronicity in relation to infant's emotional regulation. Identifying touch that is more calming is important to foster emotional regulation in infancy, which can have important implications for development.


The Relationship Between End-of-Treatment Alcohol Use and Subsequent Healthcare Costs: Do Heavy Drinking Days Predict Higher Healthcare Costs?
A challenge for evaluating alcohol treatment efficacy is determining what constitutes a "good" outcome or meaningful improvement. Abstinence at the end of treatment is an unambiguously good outcome; however, a focus on abstinence ignores the potential benefits of patients reducing their drinking to less problematic levels. Patients may be drinking at low-risk levels at the end of treatment but may be high-functioning and impose few social costs. In this study, we estimate the relationship between drinking at the end of COMBINE treatment and subsequent healthcare costs with an emphasis on heavy and nonheavy drinking levels. Indicators of heavy drinking days (HDDs; 5+ drinks for men, 4+ for women) and nonheavy drinking days (non-HDDs) during the last 30 days of COMBINE treatment were constructed for 748 patients enrolled in the COMBINE Economic Study. Generalized linear models were used to model total costs following COMBINE treatment as a function of drinking indicators. Different model specifications analyzed alternative counts of HDDs (e.g., 1 HDD and 2 to 30 HDDs), and groups having Both non-HDDs and HDDs. Patients with HDDs had 66.4% (p < 0.01) higher healthcare costs than those who were abstinent. Having more than 2 HDDs was associated with the highest costs (75.9%, p < 0.01). Patients with non-HDDs had costs that were not significantly different than abstainers, even if they also had HDDs. However, those with HDDs only had costs 91.7% higher than abstainers (p < 0.01). Having HDDs at the end of treatment is associated with higher costs. Patients who had Only HDDs at the end of treatment had worse subsequent outcomes than those who had Both non-HDDs and HDDs. These findings offer new context for evaluating treatment outcomes and provide new information on the association of drinking with consequences.


An empirical analysis of overlap publication in Chinese language and English research manuscripts.
There are a number of sound justifications for publishing nearly identical information in Chinese and English medical journals, assuming several conditions are met. Although overlap publication is perceived as undesirable and ethically questionable in Europe and North America, it may serve an important function in some regions where English is not the native tongue. There is no empirical data on the nature and degree of overlap publication in English and Chinese language journals. A random sample of 100 English manuscripts from Chinese institutions was selected from PubMed. Key words and institutions were searched in the China National Knowledge Infrastructure, a comprehensive Chinese language research database. Unacknowledged overlap was a priori defined according to International Committee of Medical Journal Editor (ICMJE) guidelines following examination by two individuals. 19% (95% CI 11-27) of English manuscripts from Chinese institutions were found to have substantial overlap with Chinese published work based on full text examination. None of the manuscripts met all of the criteria established by the ICMJE for an acknowledged overlap publication. Individual-level, journal-level, and institutional factors seem to influence overlap publication. Manuscripts associated with an institution outside of China and with more than one institution were significantly less likely to have substantial overlap (p<0.05). Overlap publication was common in this context, but instances of standard ICMJE notations to acknowledge this practice were rare. This research did not cite the identified overlap manuscripts with the hope that these empirical data will inform journal policy changes and structural initiatives to promote clearer policies and manuscripts.


Blood does not buy goodwill: allowing culling increases poaching of a large carnivore.
Quantifying environmental crime and the effectiveness of policy interventions is difficult because perpetrators typically conceal evidence. To prevent illegal uses of natural resources, such as poaching endangered species, governments have advocated granting policy flexibility to local authorities by liberalizing culling or hunting of large carnivores. We present the first quantitative evaluation of the hypothesis that liberalizing culling will reduce poaching and improve population status of an endangered carnivore. We show that allowing wolf (Canis lupus) culling was substantially more likely to increase poaching than reduce it. Replicated, quasi-experimental changes in wolf policies in Wisconsin and Michigan, USA, revealed that a repeated policy signal to allow state culling triggered repeated slowdowns in wolf population growth, irrespective of the policy implementation measured as the number of wolves killed. The most likely explanation for these slowdowns was poaching and alternative explanations found no support. When the government kills a protected species, the perceived value of each individual of that species may decline; so liberalizing wolf culling may have sent a negative message about the value of wolves or acceptability of poaching. Our results suggest that granting management flexibility for endangered species to address illegal behaviour may instead promote such behaviour.


A 3-tier classification of cerebral arteriovenous malformations. Clinical article.
The authors propose a 3-tier classification for cerebral arteriovenous malformations (AVMs). The classification is based on the original 5-tier Spetzler-Martin grading system, and reflects the treatment paradigm for these lesions. The implications of this modification in the literature are explored. Class A combines Grades I and II AVMs, Class B are Grade III AVMs, and Class C combines Grades IV and V AVMs. Recommended management is surgery for Class A AVMs, multimodality treatment for Class B, and observation for Class C, with exceptions to the latter including recurrent hemorrhages and progressive neurological deficits. To evaluate whether combining grades is warranted from the perspective of surgical outcomes, the 3-tier system was applied to 1476 patients from 7 surgical series in which results were stratified according to Spetzler-Martin grades. Pairwise comparisons of individual Spetzler-Martin grades in the series analyzed showed the fewest significant differences (p < 0.05) in outcomes between Grades I and II AVMs and between Grades IV and V AVMs. In the pooled data analysis, significant differences in outcomes were found between all grades except IV and V (p = 0.38), and the lowest relative risks were found between Grades I and II (1.066) and between Grades IV and V (1.095). Using the pooled data, the predictive accuracies for surgical outcomes of the 5-tier and 3-tier systems were equivalent (receiver operating characteristic curve area 0.711 and 0.713, respectively). Combining Grades I and II AVMs and combining Grades IV and V AVMs is justified in part because the differences in surgical results between these respective pairs are small. The proposed 3-tier classification of AVMs offers simplification of the Spetzler-Martin system, provides a guide to treatment, and is predictive of outcome. The revised classification not only simplifies treatment recommendations; by placing patients into 3 as opposed to 5 groups, statistical power is markedly increased for series comparisons.


Comprehensive overview of computer-based health information tailoring: a systematic scoping review.
To explore the scope of the published literature on computer-tailoring, considering both the development and the evaluation aspects, with the aim of identifying and categorising main approaches and detecting research gaps, tendencies and trends. Original researches from any country and healthcare setting. Patients or health consumers with any health condition regardless of their specific characteristics. A systematic scoping review was undertaken based on the York's five-stage framework outlined by Arksey and O'Malley. Five leading databases were searched: PubMed, Scopus, Science Direct, EBSCO and IEEE for articles published between 1990 and 2017. Tailoring concept was investigated for three aspects: system design, information delivery and evaluation. Both quantitative (ie, frequencies) and qualitative (ie, theme analysis) methods have been used to synthesis the data. After reviewing 1320 studies, 360 articles were identified for inclusion. Two main routes were identified in tailoring literature including public health research (64%) and computer science research (17%). The most common facets used for tailoring were sociodemographic (73 %), target behaviour status (59%) and psycho-behavioural determinants (56%), respectively. The analysis showed that only 13% of the studies described the tailoring algorithm they used, from which two approaches revealed: information retrieval (12%) and natural language generation (1%). The systematic mapping of the delivery channel indicated that nearly half of the articles used the web (57%) to deliver the tailored information; printout (19%) and email (10%) came next. Analysis of the evaluation approaches showed that nearly half of the articles (53%) used an outcome-based approach, 44% used process evaluation and 3% assessed cost-effectiveness. This scoping review can inform researchers to identify the methodological approaches of computer tailoring. Improvements in reporting and conduct are imperative. Further research on tailoring methodology is warranted, and in particular, there is a need for a guideline to standardise reporting.


Clinical evaluation of commercial nucleic acid amplification tests in patients with suspected sepsis.
Sepsis is a serious medical condition requiring timely administered, appropriate antibiotic therapy. Blood culture is regarded as the gold standard for aetiological diagnosis of sepsis, but it suffers from low sensitivity and long turnaround time. Thus, nucleic acid amplification tests (NAATs) have emerged to shorten the time to identification of causative microbes. The aim of the present study was to evaluate the clinical utility in everyday practice in the emergency department of two commercial NAATs in patients suspected with sepsis. During a six-week period, blood samples were collected consecutively from all adult patients admitted to the general emergency department for suspicion of a community-onset sepsis and treated with intravenous antibiotics. Along with conventional blood cultures, multiplex PCR (Magicplex™) was performed on whole blood specimens whereas portions from blood culture bottles were used for analysis by microarray-based assay (Prove-it™). The aetiological significance of identified organisms was determined by two infectious disease physicians based on clinical presentation and expected pathogenicity. Among 382 episodes of suspected sepsis, clinically relevant microbes were detected by blood culture in 42 episodes (11%), by multiplex PCR in 37 episodes (9.7%), and by microarray in 32 episodes (8.4%). Although moderate agreement with blood culture (kappa 0.50), the multiplex PCR added diagnostic value by timely detection of 15 clinically relevant findings in blood culture-negative specimens. Results of the microarray corresponded very well to those of blood culture (kappa 0.90), but were available just marginally prior to blood culture results. The use of NAATs on whole blood specimens in adjunct to current culture-based methods provides a clinical add-on value by allowing for detection of organisms missed by blood culture. However, the aetiological significance of findings detected by NAATs should be interpreted with caution as the high analytical sensitivity may add findings that do not necessarily corroborate with the clinical diagnosis.


A Chemoproteomic Strategy for Direct and Proteome-Wide Covalent Inhibitor Target-Site Identification.
Despite recent clinical successes for irreversible drugs, potential toxicities mediated by unpredictable modification of off-target cysteines represents a major hurdle for expansion of covalent drug programs. Understanding the proteome-wide binding profile of covalent inhibitors can significantly accelerate their development; however, current mass spectrometry strategies typically do not provide a direct, amino acid level readout of covalent activity for complex, selective inhibitors. Here we report the development of CITe-Id, a novel chemoproteomic approach that employs covalent pharmacologic inhibitors as enrichment reagents in combination with an optimized proteomic platform to directly quantify dose-dependent binding at cysteine-thiols across the proteome. CITe-Id analysis of our irreversible CDK inhibitor THZ1 identified dose-dependent covalent modification of several unexpected kinases, including a previously unannotated cysteine (C840) on the understudied kinase PKN3. These data streamlined our development of JZ128 as a new selective covalent inhibitor of PKN3. Using JZ128 as a probe compound, we identified novel potential PKN3 substrates, thus offering an initial molecular view of PKN3 cellular activity. CITe-Id provides a powerful complement to current chemoproteomic platforms to characterize the selectivity of covalent inhibitors, identify new, pharmacologically addressable cysteine-thiols, and inform structure-based drug design programs.


Perioperative Rehabilitation in Operable Lung Cancer Patients (PROLUCA): A Feasibility Study.
Introduction Surgical resection in patients with non-small cell lung cancer (NSCLC) may be associated with significant morbidity, functional limitations, and decreased quality of life. Objectives The safety and feasibility of a preoperative and early postoperative rehabilitation program in patients operated for NSCLC was determined in a nonhospital setting, with focus on high-intensity interval exercise. Methods Forty patients with biopsy-proven NSCLC stages I to IIIa referred for surgical resection at the Department of Cardiothoracic Surgery RT, Rigshospitalet, University of Copenhagen, were randomly assigned to 1 of 4 groups (3 intervention groups and 1 control group). The preoperative intervention consisted of a home-based exercise program, while the postoperative exercise program comprised a supervised group exercise program involving resistance and high-intensity interval cardiorespiratory exercise 2 hours weekly for 12 weeks combined with individual counseling. The study endpoints were inclusion rate, adherence, and number of adverse events. Results Forty patients (of 124 screened; 32%) were included and randomized into the 4 groups. The postoperative exercise was completed by 73% of the patients randomized to this intervention. No adverse events were observed, indicating that the early postoperative exercise program is safe. The preoperative home-based exercise program was not feasible due to interfering diagnostic procedures and fast-track surgery that left only 1 to 2 weeks between diagnosis and surgery. Conclusion The early postoperative exercise program for patients with NSCLC was safe and feasible, but in a fast-track set up, a preoperative home-based exercise program was not feasible for this population.


Where do they go and how do they get there? Older adults' travel behaviour in a highly walkable environment.
Mobility-the ability to move about in one's neighbourhood and maintain independence-is essential for older adults' wellbeing. Neighbourhood environments support or hinder mobility especially as health declines and physical vulnerability increases with age. Linkages between mobility and planning and policy are key to designing age-friendly neighbourhoods with destinations that encourage older adults to get out and be physically active. We describe the mobility of older adults who live in a highly walkable neighbourhood. Specifically, we address the questions of 'where do older adults go?' (destinations) and 'how they get there?' (travel mode, physical activity). We recruited older adults (age 60+) who live in Vancouver's downtown core, an area acknowledged to be highly walkable (Walk Score(®): 94-97/100), and who leave their houses most days of the week. Participants (n = 184) recorded travel in diaries and wore an ActiGraph GT3X + accelerometer for 7 days during September to October 2012. We classified reported destinations according to the North American Industry Classification System, and analysed mobility [trip rates (overall and walking), steps, moderate to vigorous physical activity (MVPA)] and associations between travel and physical activity-related mobility measures. Key destinations were grocery stores (13.6% of trips), restaurants (7.2%), malls/marketplaces (5.5%), and others' homes (5.4%). Participants made 4.6 (std: 2.5) one-way trips/day, took 7910.1 (3871.1) steps/day, and accrued 39.2 (32.9) minutes/day of MVPA. Two-thirds of trips were by active modes (62.8% walk, 3.2% bike) and 22.4% were by car. Trip rates were significantly associated with physical activity outcomes. Older adults living in highly walkable neighbourhoods were very mobile and frequently used active transportation. Travel destinations signify the importance of nearby commercial and social opportunities, even in a highly walkable environment. The high rates of active travel and physical activity in a walkable neighbourhood suggest that when provided compelling destinations, community dwelling older adults walk more and may achieve health benefits through daily travel.


Mutability of Y-chromosomal microsatellites: rates, characteristics, molecular bases, and forensic implications.
Nonrecombining Y-chromosomal microsatellites (Y-STRs) are widely used to infer population histories, discover genealogical relationships, and identify males for criminal justice purposes. Although a key requirement for their application is reliable mutability knowledge, empirical data are only available for a small number of Y-STRs thus far. To rectify this, we analyzed a large number of 186 Y-STR markers in nearly 2000 DNA-confirmed father-son pairs, covering an overall number of 352,999 meiotic transfers. Following confirmation by DNA sequence analysis, the retrieved mutation data were modeled via a Bayesian approach, resulting in mutation rates from 3.78 × 10(-4) (95% credible interval [CI], 1.38 × 10(-5) - 2.02 × 10(-3)) to 7.44 × 10(-2) (95% CI, 6.51 × 10(-2) - 9.09 × 10(-2)) per marker per generation. With the 924 mutations at 120 Y-STR markers, a nonsignificant excess of repeat losses versus gains (1.16:1), as well as a strong and significant excess of single-repeat versus multirepeat changes (25.23:1), was observed. Although the total repeat number influenced Y-STR locus mutability most strongly, repeat complexity, the length in base pairs of the repeated motif, and the father's age also contributed to Y-STR mutability. To exemplify how to practically utilize this knowledge, we analyzed the 13 most mutable Y-STRs in an independent sample set and empirically proved their suitability for distinguishing close and distantly related males. This finding is expected to revolutionize Y-chromosomal applications in forensic biology, from previous male lineage differentiation toward future male individual identification.


A natural experiment of state-level physical activity and screen-time policy changes early childhood education (ECE) centers and child physical activity.
Early childhood education (ECE) centers are an important place for preschool-aged children to obtain physical activity (PA). A U.S. state government (Louisiana) recently updated requirements for licensed centers' PA and screen-time policies, which allowed for assessment of 1) ECE center practices, environment, staff behaviors, and policies changes on child-level PA and 2) state level changes on the ECE center. ECE centers were assessed at the beginning of state licensing changes and 1-year later. The ECE centers were assessed via the Environmental Policy Assessment and Observation (EPAO) tool. The EPAO Sedentary Opportunities score, which primarily assesses television viewing time, was revised to reflect viewing non-television devices (e.g. tablets). Child-level PA was measured using accelerometry. For Aim 1, mixed models assessed ECE center changes and child PA with adjustment for demographic characteristics (fixed effects), baseline EPAO score (random effects), and clustering for center. For Aim 2, paired t-tests assessed ECE center environment differences between baseline and follow-up. Nine ECE centers participated and 49 preschoolers provided complete measures at both time points. For Aim 1, increases in the EPAO revised-Sedentary Opportunities score (as in less non-television screen-time) resulted in increased child PA (p = 0.02). For Aim 2, ECE centers improved their EPAO Active Opportunities and Staff Behaviors score (p = 0.04 and p = 0.02 respectively). ECE centers improved their environment after 1-year, resulting in additional child PA. Changes in ECE centers environment, possibly through policy, can positively influence children's PA.


Origin and diversification of the Greater Cape flora: ancient species repository, hot-bed of recent radiation, or both?
Like island-endemic taxa, whose origins are expected to postdate the appearance of the islands on which they occur, biome-endemic taxa should be younger than the biomes to which they are endemic. Accordingly, the ages of biome-endemic lineages may offer insights into biome history. In this study, we used the ages of multiple lineages to explore the origin and diversification of two southern African biomes whose remarkable floristic richness and endemism has identified them as global biodiversity hotspots (succulent karoo and fynbos). We used parsimony optimization to identify succulent karoo- and fynbos-endemic lineages across 17 groups of plants, for which dated phylogenies had been inferred using a relaxed Bayesian (BEAST) approach. All succulent karoo-endemic lineages were less than 17.5 My old, the majority being younger than 10 My. This is largely consistent with suggestions that this biome is the product of recent radiation, probably triggered by climatic deterioration since the late Miocene. In contrast, fynbos-endemic lineages showed a broader age distribution, with some lineages originating in the Oligocene, but most being more recent. Also, in groups having both succulent karoo- and fynbos-endemic lineages, there was a tendency for the latter to be older. These patterns reflect the greater antiquity of fynbos, but also indicate considerable recent speciation, probably through a combination of climatically-induced refugium fragmentation and adaptive radiation.


The role of recipient derived interleukin-17A in a murine orthotopic lung transplant model of restrictive chronic lung allograft dysfunction.
The single most important cause of late mortality after lung transplantation is chronic lung allograft dysfunction (CLAD). However, the pathological development of CLAD was not as simple as previously presumed and subclassification phenotypes, bronchiolitis obliterans syndrome (BOS) and restrictive CLAD (rCLAD), have been introduced. We want to re-investigate how CLAD manifests in the murine orthotopic lung transplant model and investigate the role of interleukin 17A (IL-17A) within this model. Orthotopic LTx was performed in CB57BL/6, IL-17 WT and IL-17 KO mice. In a first experiment, CB57BL/6 mice receiving an isograft (CB57BL/6) or allograft (BALB/C) were compared. In a second experiment IL-17 WT and IL-17 KO mice (both CB57BL/6 background) received an allograft (BALB/C). Mice received daily immunosuppression with steroids and cyclosporine and were sacrificed 10weeks after transplantation for histopathological analysis by an experienced lung pathologist. After murine orthotopic lung transplantation, the allograft histopathologically presented features of human rCLAD (i.e. overt inflammation, pleural/parenchymal fibrosis and obliterative bronchiolitis). In the IL-17A KO group, less inflammation in the bronchovascular axis (p=0.03) was observed and a non-significant trend towards less bronchovascular fibrosis, pleural/septal inflammation and fibrosis, and parenchymal inflammation and fibrosis when compared to WT mice. The major mismatch orthotopic lung transplant model resembles features of human rCLAD. IL-17A mediated immunity is involved in the inflammatory component, but had little influence on the degree of fibrosis. Further mechanistic and therapeutic studies in this mouse model are needed to fully understand the mechanisms in rCLAD.


Selenium Stimulates Cadmium Detoxification in Caenorhabditis elegans through Thiols-Mediated Nanoparticles Formation and Secretion.
Antagonism between heavy metal and selenium (Se) could significantly affect their biotoxicity, but little is known about the mechanisms underlying such microbial-mediated antagonistic processes as well as the formed products. In this work, we examined the cadmium (Cd)-Se interactions and their fates in Caenorhabditis elegans through in vivo and in vitro analysis and elucidated the machinery of Se-stimulated Cd detoxification. Although the Se introduction induced up to 3-fold higher bioaccumulation of Cd in C. elegans than the Cd-only group, the nematode viability remained at a similar level to the Cd-only group. The relatively lower level of reactive oxygen species in the Se & Cd group confirms a significantly enhanced Cd detoxification by Se. The Cd-Se interaction, mediated by multiple thiols, including glutathione and phytochelatin, resulted in the formation of less toxic cadmium selenide (CdSe)/cadmium sulfide (CdS) nanoparticles. The CdSe/CdS nanoparticles were mainly distributed in the pharynx and intestine of the nematodes, and continuously excreted from the body, which also benefitted the C. elegans survival. Our findings shed new light on the microbial-mediated Cd-Se interactions and may facilitate an improved understanding and control of Cd biotoxicity in complicated coexposure environments.


Silent myocardial ischemia in prediabetics in relation to insulin resistance.
Myocardial perfusion imaging (MPI) is a powerful diagnostic and prognostic tool for evaluating coronary artery disease (CAD). Several studies have shown Type 2 diabetics are at increased risk for having CAD. In addition, insulin resistance is generally considered to be of major importance in the pathophysiology of Type 2 diabetes mellitus. However, the area of screening prediabetics for CAD remains unclear. Given that glucose intolerance and insulin resistance precede the development of overt diabetes, these factors would be associated with CAD. This study was designed to evaluate the state of myocardial perfusion in prediabetic adults detected by single photon emission computed tomography (SPECT) in relation to insulin resistance. A descriptive study was performed. Out of 113 consecutive prediabetic adults, 32 had insulin resistance (Group A) and 81 had insulin sensitivity (Group B). All were subjected to full medical history and clinical examination including blood pressure, waist circumference, and body mass index. Biochemical studies including lipids profile, fasting blood glucose, and homeostasis model assessments (HOMA) test. Exercise treadmill technetium (99mTC) sestamibi SPECT scintigraphy were done for assessment of myocardial perfusion assessed by summed difference score as well as occurrence of transient left ventricular dilatation. Significant increase in summed difference score as well as transient left ventricular dilatation was observed in Group A than Group B. It is correlated with insulin resistance, and the correlation appears to be independent of glucose tolerance status and obesity. Similar correlations were observed with age, triglycerides, and waist circumference. Prediabetics have myocardial perfusion defects which represent a pattern of cardiovascular risk. These are predominantly observed in prediabetics with increased HOMA IR and visceral obesity independent of glucose levels.