Inhibition of ZEB1 leads to inversion of metastatic characteristics and restoration of paclitaxel sensitivity of chronic chemoresistant ovarian carcinoma cells.
ZEB1, a member of the zinc-finger E-box binding homeobox family, is considered to play a crucial role in cancer progression and metastasis. In the current study, we investigated the role of ZEB1 in metastasis and chronic chemoresistance of epithelial ovarian carcinoma (EOC) cells. Using several EOC and acquired paclitaxel (PTX)-resistant EOC cell lines, we investigated whether silencing ZEB1 led to a reversal of the chemoresistance and metastatic potential in vitro and in vivo. Subsequently, the expression of ZEB1 in EOC tissues and its association with the oncologic outcome were investigated. According to the immunohistochemical staining of EOC tissues, as the positivity of ZEB1 expression was increased, the overall survival of EOC patients became poorer (P = 0.0022 for trend). Additionally, cell migration and invasion were significantly decreased by ZEB1 silencing in both PTX-sensitive and PTX- resistant cells. Although PTX-sensitivity was not changed by silencing ZEB1 in parental EOC cells, the depletion of ZEB1 made the PTX-resistant EOC cells more sensitive to PTX treatment. In an animal model, mice injected with ZEB1-silencing PTX-resistant cells survived for longer than the control cell-injected mice. Although the intravenous injection of PTX did not affect the tumor weight of shCtrl cells, the tumor weight of shZEB1 cells was significantly reduced by PTX treatment. The current data indicate the possible involvement of ZEB1 in the metastasis and paclitaxel resistance of EOC, and suggest that targeting this molecule may reverse the malignant potential and improve the oncologic outcome for EOC patients.


Ticks and Borrelia in urban and peri-urban green space habitats in a city in southern England.
Ticks are becoming increasingly recognised as important vectors of pathogens in urban and peri-urban areas, including green space used for recreational activities. In the UK, the risk posed by ticks in such areas is largely unknown. In order to begin to assess the risk of ticks in urban/peri-urban areas in southern England, questing ticks were collected from five different habitat types (grassland, hedge, park, woodland and woodland edge) in a city during the spring, summer and autumn of 2013/2014 and screened for Borrelia burgdorferi sensu lato. In addition, seasonal differences in B. burgdorferi s.l. prevalence were also investigated at a single site during 2015. Ixodes ricinus presence and activity were significantly higher in woodland edge habitat and during spring surveys. DNA of Borrelia burgdorferi s.l. was detected in 18.1% of nymphs collected across the 25 sites during 2013 and 2014 and two nymphs also tested positive for the newly emerging tick-borne pathogen B. miyamotoi. Borrelia burgdorferi s.l. prevalence at a single site surveyed in 2015 were found to be significantly higher during spring and summer than in autumn, with B. garinii and B. valaisiana most commonly detected. These data indicate that a range of habitats within an urban area in southern England support ticks and that urban Borrelia transmission cycles may exist in some of the urban green spaces included in this study. Sites surveyed were frequently used by humans for recreational activities, providing opportunity for exposure to Borrelia infected ticks in an urban/peri-urban space that might not be typically associated with tick-borne disease transmission.


Reliable high risk HPV DNA testing by polymerase chain reaction: an intermethod and intramethod comparison.
The development of a reproducible, sensitive, and standardised human papillomavirus (HPV) polymerase chain reaction (PCR) test is required to implement HPV testing in cervical cancer screening programmes and for triaging women with mild to moderate dysplasia. To determine the intermethod agreement between different GP5+/6+ and MY09/11 PCR based protocols for the detection and typing of high risk (HR) HPV DNA in cervical smears and to assess the intramethod reproducibility of the GP5+/6+ PCR enzyme immunoassay (EIA) for HR-HPV detection. For the intermethod comparison, crude aliquots of 20 well characterised cervical smears comprising five HPV negative samples, and six and nine samples containing single and multiple HPV infections, respectively, were coded and sent from reference laboratory (A) to three other laboratories. One of these (laboratory B) used the GP5+/6+ PCR-EIA and was provided with standard protocols. Another laboratory (C) used GP5+/6+ PCR combined with sequence analysis and type specific PCR, whereas two laboratories (D and E) used MY09/11 PCR followed by restriction fragment length polymorphism (RFLP) analysis for the detection and typing of HR-HPV. The intramethod agreement of GP5+/6+ PCR-EIA was analysed in a subsequent study with four other laboratories (F to I) on crude aliquots of 50 well characterised cervical smears, consisting of 32 HR-HPV positive and 18 HPV negative samples. Standardised protocols, primers, and probes were also provided by the reference laboratory for HR-HPV detection. In the intermethod comparison, pairwise agreement of the different laboratories with reference laboratory A for the detection of HR-HPV varied between 75% and 100% (kappa values: 0.5 to 1). Typing data revealed a broader range in pairwise agreement rates between 32% and 100%. The highest agreement was found between laboratories A and B using standardised protocols and validated reagents. In the intramethod evaluation, pairwise comparison of the laboratories F to I with reference laboratory A revealed excellent agreement rates from 92% to 100% (kappa values: 0.88 to 1.0) with an overall sensitivity of 97.5% (195/200) and specificity of 99.5% (199/200). The detection of HR-HPV as a group is highly reproducible with GP5+/6+ PCR-EIA provided that standardised protocols and validated reagents are used.


Effects of oxygen withdrawal on catecholamine release in patients on home oxygen therapy.
1. Long-term oxygen therapy in appropriate patients prolongs survival and corrects neuropsychological function. Some tests of mental function paradoxically improve during short periods of oxygen withdrawal in patients on long-term oxygen therapy, although the mechanism of this response is unknown. 2. To evaluate the effects of transient hypoxaemia on plasma adrenaline and noradrenaline levels, we studied eight oxygen-dependent patients who underwent either a 4 h period of oxygen withdrawal or their routine therapy, in a randomized, blinded fashion, on 2 separate days. 3. Plasma noradrenaline did not differ at baseline between study days. During normoxic conditions, plasma noradrenaline levels did not increase significantly with time. By contrast, under hypoxic conditions, plasma levels of noradrenaline rose significantly from 0 to 4 h (P less than 0.05). The magnitude of the noradrenaline response was correlated with baseline noradrenaline such that subjects with the highest resting levels had the largest increase during hypoxia (r = 0.95, P less than 0.001). 4. Plasma adrenaline did not differ at baseline between study days and there were no significant effects of hypoxia on plasma adrenaline levels. 5. We conclude that the sympathetic nervous system, but not the adrenal medulla, is stimulated in chronically oxygen-dependent subjects made acutely hypoxaemic. The magnitude of this stimulation appears to be related to the state of sympathetic nervous system activity at baseline. Improvement in some tests of mental function during transient periods of oxygen withdrawal may be due to non-specific arousal caused by a catecholamine surge.


Tunable plasmonic resonances in Si-Au slanted columnar heterostructure thin films.
We report on fabrication of spatially-coherent columnar plasmonic nanostructure superlattice-type thin films with high porosity and strong optical anisotropy using glancing angle deposition. Subsequent and repeated depositions of silicon and gold lead to nanometer-dimension subcolumns with controlled lengths. We perform generalized spectroscopic ellipsometry measurements and finite element method computations to elucidate the strongly anisotropic optical properties of the highly-porous Si-Au slanted columnar heterostructures. The occurrence of a strongly localized plasmonic mode with displacement pattern reminiscent of a dark quadrupole mode is observed in the vicinity of the gold subcolumns. We demonstrate tuning of this quadrupole-like mode frequency within the near-infrared spectral range by varying the geometry of Si-Au slanted columnar heterostructures. In addition, coupled-plasmon-like and inter-band transition-like modes occur in the visible and ultra-violet spectral regions, respectively. We elucidate an example for the potential use of Si-Au slanted columnar heterostructures as a highly porous plasmonic sensor with optical read out sensitivity to few parts-per-million solvent levels in water.


Applying new genetic technologies: assessment and ethical considerations.
Discovery of genes associated with clinical disorders increases the ability of clinicians to more accurately assess risk for their clients to develop or to be carriers of certain health problems. Estimating these risks has become more precise with the addition of genetic testing. The process of client assessment and considerations associated with genetic testing for cystic fibrosis and one form of colon cancer (familial adenomatous polyposis) are presented in a case study format. Ethical considerations in the use of genetic testing include protection of privacy, protection from coercion, and assuring client understanding of implications of test results. Practitioner responsibilities also include educating clients regarding benefits and limitations of testing, collaborating with genetic counseling resources, and monitoring the client for potential adverse outcomes of testing.


Biogeographic analysis of the woody plants of the Southern Appalachians: Implications for the origins of a regional flora.
We investigated the origins of 252 Southern Appalachian woody species representing 158 clades to analyze larger patterns of biogeographic connectivity around the northern hemisphere. We tested biogeographic hypotheses regarding the timing of species disjunctions to eastern Asia and among areas of North America. We delimited species into biogeographically informative clades, compiled sister-area data, and generated graphic representations of area connections across clades. We calculated taxon diversity within clades and plotted divergence times. Of the total taxon diversity, 45% were distributed among 25 North American endemic clades. Sister taxa within eastern North America and eastern Asia were proportionally equal in frequency, accounting for over 50% of the sister-area connections. At increasing phylogenetic depth, connections to the Old World dominated. Divergence times for 65 clades with intercontinental disjunctions were continuous, whereas 11 intracontinental disjunctions to western North America and nine to eastern Mexico were temporally congruent. Over one third of the clades have likely undergone speciation within the region of eastern North America. The biogeographic pattern for the region is asymmetric, consisting of mostly mixed-aged, low-diversity clades connecting to the Old World, and a minority of New World clades. Divergence time data suggest that climate change in the Late Miocene to Early Pliocene generated disjunct patterns within North America. Continuous splitting times during the last 45 million years support the hypothesis that widespread distributions formed repeatedly during favorable periods, with serial cooling trends producing pseudocongruent area disjunctions between eastern North America and eastern Asia.


Attitudes of Infertile Couples, Fertility Clinic Staff and Researchers toward Personhood of The Human Embryo in Iran.
After the introduction of assisted reproductive techniques, human embryos were officially introduced into laboratories and now thousands of them are cryopreserved in such settings. Embryonic stem cells and the future application of such cells in the treatment of disease opened the door to further research on human embryos. These developments raise many ethical issues, some of which have religious aspects. The main question is: what is the embryo? Should we consider it a human being? Thus, the purpose of this study was to investigate attitudes towards the personhood of the embryo. In this cross sectional study, 203 infertile patients (n=406), 54 clinic staff and 49 embryo researchers, selected using convenience sampling at the Royan Institute, completed a questionnaire on personhood of human embryo. The questionnaire had been developed following qualitative research and had satisfied face and content validity tests. At the pre-implantation stage the majority of participants in all three groups considered the human embryo as "not a human being". Also, at the post-implantation stage of development, the majority of infertile couples and clinic staff considered the embryo as "not a human being" but, half the researchers (51%) considered the embryo in this stage as a "potential human". Half of the infertile couples considered the human fetus before ensoulment time (19th week of pregnancy according to the Shiite Islamic scholars) as "not-human being", while more than half of researchers (55.1%) considered it as a "potential human". Ensoulment time is a major and important border for personhood. Most infertile couples and clinic staff consider the human embryo as "not a human being" but majority of all study participants considered the human fetus to be a complete human after ensoulment time.


A semi-aquatic Arctic mammalian carnivore from the Miocene epoch and origin of Pinnipedia.
Modern pinnipeds (seals, sea lions and the walrus) are semi-aquatic, generally marine carnivores the limbs of which have been modified into flippers. Recent phylogenetic studies using morphological and molecular evidence support pinniped monophyly, and suggest a sister relationship with ursoids (for example bears) or musteloids (the clade that includes skunks, badgers, weasels and otters). Although the position of pinnipeds within modern carnivores appears moderately well resolved, fossil evidence of the morphological steps leading from a terrestrial ancestor to the modern marine forms has been weak or contentious. The earliest well-represented fossil pinniped is Enaliarctos, a marine form with flippers, which had appeared on the northwestern shores of North America by the early Miocene epoch. Here we report the discovery of a nearly complete skeleton of a new semi-aquatic carnivore from an early Miocene lake deposit in Nunavut, Canada, that represents a morphological link in early pinniped evolution. The new taxon retains a long tail and the proportions of its fore- and hindlimbs are more similar to those of modern terrestrial carnivores than to modern pinnipeds. Morphological traits indicative of semi-aquatic adaptation include a forelimb with a prominent deltopectoral ridge on the humerus, a posterodorsally expanded scapula, a pelvis with relatively short ilium, a shortened femur and flattened phalanges, suggestive of webbing. The new fossil shows evidence of pinniped affinities and similarities to the early Oligocene Amphicticeps from Asia and the late Oligocene and Miocene Potamotherium from Europe. The discovery suggests that the evolution of pinnipeds included a freshwater transitional phase, and may support the hypothesis that the Arctic was an early centre of pinniped evolution.


Cognitive Stimulation in an Intensive Care Unit: A Qualitative Evaluation of Barriers to and Facilitators of Implementation.
Delirium in the intensive care unit is associated with poor patient outcomes. Recent studies support nonpharmacological therapy, including cognitive stimulation, to address delirium. Understanding barriers to cognitive stimulation implemented by nurses during clinical care is essential to translating evidence into practice. To use qualitative methods through a structured quality improvement project to understand nurses' perceived barriers to implementing a cognitive stimulation intervention in a medical intensive care unit. Data were collected through semistructured interviews with nurses in a medical intensive care unit. Data were categorized into themes by using thematic analysis and the Consolidated Framework for Implementation Research. During cognitive stimulation, nurses reviewed with patients a workbook of evidence-based tasks (focused on math, alertness, motor skills, visual perception, memory, problem-solving, and language). The 23 nurses identified 62 barriers to and 26 facilitators of cognitive stimulation. These data were summarized into 12 barrier and 9 facilitator themes corresponding to the following Consolidated Framework for Implementation Research domains: Intervention Characteristics, Outer Setting, Inner Setting, and Characteristics of Individuals. Nurses also identified several facilitators within the Process domain. Patient-specific variables, including sedation, were the most frequently reported barriers. Other barriers included cognitive stimulation not being prioritized, nursing staff-related issues, documentation burden, and a lack of understanding of, or appreciation for, the evidence supporting cognitive stimulation. Implementation of cognitive stimulation requires a multidisciplinary approach to address perceived barriers arising from the organization, context, and individuals associated with the intervention, as well as the intervention itself.


Vertebrobasilar dolichoectasia as a risk factor for cerebral microbleeds.
Both vertebrobasilar dolichoectasia (VBD) and cerebral microbleeds (CMBs) are related with the risk of intracerebral hemorrhage. We aimed to examine the relationship between the VBD and CMB in ischaemic stroke patients. A consecutive series of 182 patients hospitalized because of ischaemic stroke or transient ischaemic attack (TIA), and who underwent gradient echo brain magnetic resonance imaging were retrospectively recruited from a prospective stroke registry. CMB locations were categorized into anterior and posterior circulation. Ectasia was defined as basilar artery (BA) diameter > 4.5 mm, and dolichosis, as either BA bifurcation above the suprasellar cistern or lateral to the margin of the clivus or dorsum sellae. Whether VBD is associated with CMB anywhere in the brain or in anterior or posterior circulation territories was analysed using binary and multinomial logistic regression models. Twenty-four subjects (13.2%) had VBD and 48 (26.4%) had CMBs. CMBs were more frequently observed in patients with VBD than without (66.7% vs. 20.3%, P < 0.001). VBD was significantly associated with CMBs in any location (crude odds ratio, 7.88; 95% confidence interval, 3.10-20.02), in the posterior circulation territory only (9.63; 2.60-34.94), and in both territories (9.25; 3.40-26.29), but not in the anterior circulation only (1.14; 0.009-11.20). These associations remained unchanged after adjusting for age, gender, hypertension, leukoaraiosis and stroke subtype. VBD in patients with ischaemic stroke or TIA is independently associated with CMBs, especially in the posterior circulation territory.


Review of ultrasound image guidance in external beam radiotherapy part II: intra-fraction motion management and novel applications.
Imaging has become an essential tool in modern radiotherapy (RT), being used to plan dose delivery prior to treatment and verify target position before and during treatment. Ultrasound (US) imaging is cost-effective in providing excellent contrast at high resolution for depicting soft tissue targets apart from those shielded by the lungs or cranium. As a result, it is increasingly used in RT setup verification for the measurement of inter-fraction motion, the subject of Part I of this review (Fontanarosa et al 2015 Phys. Med. Biol. 60 R77-114). The combination of rapid imaging and zero ionising radiation dose makes US highly suitable for estimating intra-fraction motion. The current paper (Part II of the review) covers this topic. The basic technology for US motion estimation, and its current clinical application to the prostate, is described here, along with recent developments in robust motion-estimation algorithms, and three dimensional (3D) imaging. Together, these are likely to drive an increase in the number of future clinical studies and the range of cancer sites in which US motion management is applied. Also reviewed are selections of existing and proposed novel applications of US imaging to RT. These are driven by exciting developments in structural, functional and molecular US imaging and analytical techniques such as backscatter tissue analysis, elastography, photoacoustography, contrast-specific imaging, dynamic contrast analysis, microvascular and super-resolution imaging, and targeted microbubbles. Such techniques show promise for predicting and measuring the outcome of RT, quantifying normal tissue toxicity, improving tumour definition and defining a biological target volume that describes radiation sensitive regions of the tumour. US offers easy, low cost and efficient integration of these techniques into the RT workflow. US contrast technology also has potential to be used actively to assist RT by manipulating the tumour cell environment and by improving the delivery of radiosensitising agents. Finally, US imaging offers various ways to measure dose in 3D. If technical problems can be overcome, these hold potential for wide-dissemination of cost-effective pre-treatment dose verification and in vivo dose monitoring methods. It is concluded that US imaging could eventually contribute to all aspects of the RT workflow.


The Aspergillus fumigatus cell wall is organized in domains that are remodelled during polarity establishment.
Aspergillus fumigatus is a life-threatening and increasingly frequent pathogen of the immunocompromised. Like other filamentous fungi A. fumigatus grows in a highly polar manner, adding new cell wall to the apical region of hyphae. mAbs were raised against isolated A. fumigatus cell walls. Fifteen antibodies bound reproducibly to isolated cell walls in ELISAs and to the walls of intact cells in immunofluorescence experiments. Surprisingly, individual mAbs showed distinct patterns of localization. Six antibodies labelled exclusively conidial or basal regions, seven labelled apical regions and a single antibody labelled both basal and apical regions of hyphae. Ten antibodies did not label the walls adjacent to septa. In double labelling experiments with representative mAbs there was little or no overlap between epitopes recognized. These labelling patterns suggest that the wall is made up of basal and apical domains that differ in composition or organization and that the wall region flanking septa differs from other regions of the lateral wall. In time-course experiments of early A. fumigatus growth, mAb16C4 failed to label isotropically expanding cells and labelled emerging germ tubes and branches. The same mAb failed to label the Aspergillus nidulans swoC mutant, which is defective in polarity establishment. However, mAb16C4 did label the A. nidulans swoA mutant, which completes polarity establishment, but is defective in polarity maintenance. Thus, mAb16C4 appears to recognize a cell wall change that occurs during polarity establishment. In immunogold labelling and transmission electron microscopy (TEM) experiments, conidia, basal regions and apical regions of thin-sectioned cells labelled with mAb16C4. That only apical regions labelled in intact cells (immunofluorescence) while conidial, basal and apical regions labelled in thin-sectioned cells (TEM) suggests that the 16C4 epitope is present along the whole hypha, but is masked everywhere except the tip until polarity establishment. That is to say, some remodelling of the wall during polarity establishment exposes the 16C4 epitope. The 16C4 epitope was partially purified from A. fumigatus total protein by passage through hydrophobic interaction and anion-exchange columns. The resulting single ELISA-positive fraction showed relatively few bands by SDS-PAGE and silver staining and a strong band by Western blotting with the16C4 mAb. Sequencing of the fraction yielded a predicted peptide with a 6-amino acid exact match to a region of the Cat1 protein previously identified as an immunodominant A. fumigatus catalase that localizes to the cell wall and is secreted to the medium. Experiments are under way to determine if mAb16C4 recognizes Cat1 or another protein that co-purifies with Cat1.


Hamartomas, papillomas and adenocarcinomas of the sinonasal tract and nasopharynx.
Lesions of the sinonasal tract are uncommon, with most of the specimens seen by surgical pathologists consisting primarily of fragments of inflamed sinonasal mucosa or inflammatory polyps from patients with chronic rhinosinusitis, and the occasional squamous cell carcinoma. Other lesions such as hamartomas, various types of Schneiderian papillomas and adenocarcinomas are seen only rarely by most histopathologists; therefore a biopsy or surgical resection specimen from a patient with one of these processes may represent a diagnostic challenge. The aim of this review is to present the pathological features of a group of infrequent epithelial surface and glandular lesions of the sinonasal tract which includes respiratory epithelial adenomatoid hamartoma, glandular (seromucinous) hamartoma, exophytic papilloma, inverted papilloma, cylindrical cell (oncocytic) papilloma, low-grade sinonasal adenocarcinoma and intestinal-type sinonasal adenocarcinoma.


Quantitative diffusion and swelling kinetic measurements using large-angle interferometric refractometry.
The uptake and release of sorbates into films and coatings is typically accompanied by changes of the films' refractive index and thickness. We provide a comprehensive model to calculate the concentration of the sorbate from the average refractive index and the film thickness, and validate the model experimentally. The mass fraction of the analyte partitioned into a film is described quantitatively by the Lorentz-Lorenz equation and the Clausius-Mosotti equation. To validate the model, the uptake kinetics of water and other solvents into SU-8 films (d = 40-45 μm) were explored. Large-angle interferometric refractometry measurements can be used to characterize films that are between 15 μm to 150 μm thick and, Fourier analysis, is used to determine independently the thickness, the average refractive index and the refractive index at the film-substrate interface at one-second time intervals. From these values the mass fraction of water in SU-8 was calculated. The kinetics were best described by two independent uptake processes having different rates. Each process followed one-dimensional Fickian diffusion kinetics with diffusion coefficients for water into SU-8 photoresist film of 5.67 × 10(-9) cm(2) s(-1) and 61.2 × 10(-9) cm(2) s(-1).


Comparison of dental licensure, specialization and continuing education in five countries.
Dental practice and education are becoming more globalized. Greater practitioner and patient mobility, the free flow of information, increasingly global standards of care and new legal and economic frameworks (such as European Union [EU] legislation) are forcing a review of dental licensure, specialization and continuing education systems. The objective of this study was to compare these systems in Canada, France, Germany, the UK and the US. Representatives from the five countries completed a 29-item questionnaire, and the information was collated and summarized qualitatively. Statutory bodies are responsible for licensing and re-licensing in all countries. In the two North American countries, this responsibility rests with individual states, and in Europe, with the countries themselves, mainly governed by the legal framework of the EU. In some countries, re-licensure requires completion of continuing education credits. Approaches to dental specialization tend to differ widely with regard to definition of specialities, course and duration of training, training facilities, and accreditation of training programmes. In most countries, continuing education is provided by a number of different entities, such as universities, dental associations, companies, institutes and private individuals. Accreditation and recognition of continuing education is primarily process-driven, not outcome-orientated. Working towards a global infrastructure for dental licensing, specialization and continuing education depends on a thorough understanding of the international commonalities and differences identified in this article.


The use of human CD68 transcriptional regulatory sequences to direct high-level expression of class A scavenger receptor in macrophages in vitro and in vivo.
Macrophages (Mphi) play a key role in innate and acquired immunity. The study of Mphi biology has been hampered by the absence of suitable gene regulatory sequences for the overexpression of heterologous genes in Mphi. The human CD68 gene encodes a glycoprotein that is expressed in monocytes and Mphi, and therefore represents an attractive candidate gene for the generation of a Mphi-specific gene-targeting vector. A transgene expression cassette that combines 2.9 kb of CD68 5' flanking sequence with the 83-bp first intron (IVS-1) of the CD68 gene, directed high-level, long-lasting expression of class A human scavenger receptor (hSR-A) isoforms in the murine Mphi cell line, RAW-264. By using this CD68 expression cassette to generate Mphi cell lines that overexpress a soluble secreted form of the extracellular portion of type I human SR-A, we were able to purify significant quantities of this protein and show its ability to inhibit SR-A-mediated endocytosis. Analysis of two independent lines of transgenic mice that expressed type III human SR-A under the control of the CD68 gene sequences revealed transgene mRNA expression in elicited Mphi populations and in mouse tissues in a pattern that was consistent with Mphi-specific gene targeting. These data show that CD68 transcriptional regulatory sequences can be used to direct high-level transgene expression in Mphi in vitro and in vivo.


The feasibility and acceptability of a chaplain-led intervention for caregivers of seriously ill patients: A Caregiver Outlook pilot study.
When caring for a loved one with a life-limiting illness, a caregiver's own physical, emotional, and spiritual suffering can be profound. While many interventions focus on physical and emotional well-being, few caregiver interventions address existential and spiritual needs and the meaning that caregivers ascribe to their role. To evaluate the feasibility and acceptability of the process and content of Caregiver Outlook, we employed a manualized chaplain-led intervention to improve well-being by exploring role-related meaning among caregivers of patients with a life-limiting illness. We conducted a single-arm pre-post pilot evaluation among caregivers of patients with advanced cancer or amyotrophic lateral sclerosis (ALS). Caregivers completed three chaplain-led intervention sessions focusing on (1) a relationship review, (2) forgiveness, and (3) legacy. Outcomes administered at baseline and at 1 and 2 weeks after the intervention included quality of life, anxiety, depression, spiritual well-being, religious coping, caregiver burden, and grief. The sample (N = 31) included a range of socioeconomic status groups, and the average age was approximately 60 years. A third of them worked full-time. Some 74% of our participants cared for a spouse or partner, and the other quarter of the sample cared for a parent (13%), child (10%), or other close family member (3%). At baseline, participants did not demonstrate clinical threshold levels of anxiety, depression, or other indicators of distress. Outcomes were stable over time. The qualitative results showed the ways in which Caregiver Outlook was assistive: stepping back from day-to-day tasks, the opportunity to process emotions, reflecting on support received, provoking thoughts and emotions between sessions, discussing role changes, stimulating communication with others, and the anonymity of a phone conversation. Both religious and nonreligious participants were pleased with administration of the chaplain intervention. The acceptability and feasibility of Caregiver Outlook were demonstrated among caregivers of patients with an advanced illness. Our pilot findings suggest minor modifications to study participant screening, interventionist guidance, and the study measures.


Cyclopamine and related steroidal alkaloid teratogens: their occurrence, structural relationship, and biologic effects.
A spontaneous congenital deformity is produced in lambs whose dams consume Veratrum californicum on the 14th day of gestation. The deformity is generally expressed as cyclopia, cebocephaly, anophthalmia, or microphthalmia. This teratogenic effect is produced by certain steroidal alkaloid teratogens from the plant - most notably the compound cyclopamine. Cyclopamine is a C-nor-D-homo steroid with fused furanopiperidine rings E and F at right angles to the plane of the steroid because of spiro attachment at C-17 of the steroid. Among veratrum alkaloids, only those with an intact furan ring E were teratogenic in sheep, whereas those in which the peperidine ring is not rigidly positioned at right angles to the steroid were not. Many ruminants and laboratory animals are susceptible to the teratogen. It has wide species and tissue specificity and appears to have a direct effect on the embryo, not as a consequence of metabolic alteration of its structure nor as an indirect effect through a maternal influence. Other plant sources, notably potatoes, tomatoes, and eggplant contain related spirosolane steroidal alkaloids. Among naturally occurring spirosolanes, solasodine is teratogenic in hamsters, but neither tomatidine not diosgenin, the non-nitrogen containing analog of solasodine, is teratogenic. Results of these and other studies suggest that a basic nitrogen positioned alpha with respect to the steroidal plane and at appropriate distance beyond the D ring confers the teratogenicity on the molecule. Potato sprouts with high alkaloid content are teratogenic in hamsters, but tubers and peels are not.


Relatives in end-of-life care--part 1: a systematic review of the literature the five last years, January 1999-February 2004.
To review systematically research conducted during the past five years focusing on the relatives' situation and needs in end-of-life care. That relatives make a large contribution in the care of the dying is well-known. In this situation, relatives often have to solve many new practical problems in the care as well as dealing with the sorrow of both themselves and the dying person. In recent years, palliative care has been developed in many countries and many new studies have been carried out. A systematic search of the literature was performed in the CINAHL and Medline databases. Of the 94 papers analysed, there were 59 qualitative and 35 quantitative studies with differing designs. The studies were carried out in 11 countries and were published in 34 different journals. The results were categorized in two main themes with several subthemes: (1) being a close relative--the situation: (i) exposed position--new responsibility, (ii) balance between burden and capacity and (iii) positive values; (2) being a close relative--needs: (i) good patient care, (ii) being present, (iii) knowing and communicating and (iv) support from and trusting relationship with the professional. The relative's feelings of security and trust in the professional were found to be of great importance. More than twice as many studies had a descriptive/explorative design, which is of importance in the assessment of evidence. However, different studies complement one another and in summary, it can be said that analytic evidence is unequivocal: good patient care, communication, information and the attitude of the professional are of decisive importance regarding relatives' situation. These results are also in accord with earlier review studies. Staff members have a great deal of responsibility for assuring that the patient feels as good as possible, facilitating relatives' involvement based on the family's wishes and limiting the stress and difficulties experienced by the family. The results showed that the relative's satisfaction could depend on the attitude of the professional as well as on good communication, good listening and good information. This can also be viewed as a prerequisite for the professional to get to know the family and to provide 'care in the light'.


Interfacial Reactions in the Li/Si diffusion couples: Origin of Anisotropic Lithiation of Crystalline Si in Li-Si batteries.
As opposed to the common understanding that diffusion into a cubic-structured single crystal is independent of its crystalline orientation, the diffusion of Li to crystalline Si (c-Si) is anisotropic, which acts as the major cause for the fracture of Si anodes in Li-ion batteries. Here, by conducting comprehensive/multi-scale simulation studies based on molecular dynamics and density functional theory, we elucidate how and why Li diffusion in c-Si is anisotropic. We found that Li ions diffuse to c-Si by following a particular atomic-scale space corresponding to the lowest value of the valence orbital in c-Si, causing Li ions to take a tortuous diffusion pathway. The degree of the tortuosity of the pathway differs depending on the crystallographic orientation of Si, and it acts as the major cause for anisotropic lithiation. We also develop a structural parameter that can quantitatively evaluate the orientation dependency of the lithiation of c-Si.


Peter Plus Syndrome: A Neurosurgeon's Perspective.
Peter plus syndrome (PPS) is a rare, hereditary (autosomal recessive) disorder characterized by a mutation in the beta-1,3-galactosyltransferase-like gene (chromosome 13q12), which causes impaired glycosylation of several structural and functional proteins throughout the body. Clinical signs and symptoms of PPS are highly variable and include structural malformations affecting multiple organ systems including central nervous system. We aim to discuss a neurosurgeon's perspective to PPS in this report. A 2-year-old boy presented with congenital dysmorphic facies, bilateral central corneal opacities, delayed developmental milestones, short-stature (75cm), rhizomelia with brachydactyly, and history of surgery for anal atresia on the second day of life. Screening craniospinal magnetic resonance imaging revealed mild ventriculomegaly, cavum septum pellucidum, cavum velum interpositum, vermian hypoplasia, and normal spine. Cytogenetic analysis showed a mutation in the beta-1,3-galactosyltransferase-like gene on chromosome 13. Clinical picture in our patient suggested the diagnosis of PPS. Parents often seek ophthalmological consultation due to visual impairment predominantly, and this syndrome largely remains unknown among neurosurgeons. Nonetheless, babies with PPS may present with neurological symptoms such as seizures, spastic diplegia, tinnitus, or hearing loss as well as a life-threatening neurosurgical emergency arising due to raised intracranial pressure. Therefore, the role of neurosurgeon becomes crucial in managing these cases.


The healing of suction blisters in pig skin.
The healing of intact suction blisters in pig skin was studied using fluorescein-labelled lectins as well as conventional histological techniques. After blistering, initially overt separation was observed at the dermo-epidermal junction, but the separated epidermis appeared to re-attach within 9 h. Massive infiltration of the dermis and the epidermis by inflammatory cells, including eosinophils, was observed. By day 4 focal detachment of the epidermis occurred spontaneously, and towards day 9 the appearance of the blistered areas had almost returned to normal, apart from isolated patches of thin epidermis devoid of rete ridges. It is proposed that the sloughing the of the epidermis on day 4 is related to the presence of inflammatory cells and that the restoration of normal dermo-epidermal relations is dependent on the basement membrane zone remaining intact. The secondary blistering seen in day 4 specimens and the inflammatory cell involvement are in many ways similar to the blistering processes observed in certain human cutaneous disorders, such as dermatitis herpetiformis and bullous pemphigoid, and therefore suction blisters in pig skin might provide a suitable animal model for these diseases.


Influence of mindfulness practice on cortisol and sleep in long-term and short-term meditators.
There is growing scientific interest in assessing the biological correlates of non-pharmacological interventions such as mindfulness. Examinations of the beneficial effects of mindfulness on hypothalamus-pituitary-adrenocortical system activity (HPA SA) and sleep are sparse. The aim of the present study was to explore the impact of long- and short-term meditation experience on HPA SA and sleep. There were 20 participants, 9 of whom had long-term experience in meditation (mean = 264 months) and 11 novices. Novices underwent an 8-week course in Mindfulness-Based Stress Reduction (MBSR), and cortisol samples were taken in the lab at the beginning and end of the course. To assess the cortisol awakening response, 4 morning cortisol samples were collected. Sleep and mindfulness were assessed by self-rating questionnaires. Among participants with long-term meditation experience, morning cortisol decreased with length of experience. For novices, after an 8-week introductory MBSR course, morning cortisol levels had decreased, while both sleep and self-attribution of mindfulness significantly improved. Cortisol levels did not, however, change between the beginning and end of individual MBSR sessions. The pattern of results lends support to the view that MBSR/meditation has a favorable influence both on biomarkers of stress regulation, such as cortisol secretion, and on sleep.


Guinea worm in southern Ghana: its epidemiology and impact on agricultural productivity.
In southern Ghana guinea worm disease was found to occur almost exclusively in villages dependent upon pond water during the dry season. The recent occurrence of guinea worm for the first time in many villages in the survey area suggests that the disease is spreading. The risk of increasing disease in the Accra plains is serious, because almost half of the 159 villages surveyed use pond water, and residents frequently travel to endemic areas. In this study adult male farmers were at greatest risk of becoming infected. The average work loss in untreated adults was more than 5 weeks. Because guinea worm disease is seasonal, conciding with peak agricultural activities, and few alternative labor sources are available for the incapacitated farmer, a marked reduction in agricultural output occurs. Additional research is needed to guide health education programs, to evaluate the effectiveness of chemical control of cyclops in ponds, and to develop low-cost improved rural water supplies.


A cationic vaccine adjuvant based on a saturated quaternary ammonium lipid have different in vivo distribution kinetics and display a distinct CD4 T cell-inducing capacity compared to its unsaturated analog.
Adjuvants are often composed of different constituents that can be divided into two groups based on their primary activity: the delivery system which carries and presents the vaccine antigen to antigen-presenting cells, and the immunostimulator that activates and modulates the ensuing immune response. Herein, we have investigated the importance of the delivery system and in particular its physical characteristics by comparing the delivery properties of two lipids which differ only in the degree of saturation of the acyl chains, rendering the liposomes either rigid (DDA, dimethyldioctadecylammonium) or highly fluid (DODA, dimethyldioleoylammonium) at physiological temperature. We show that these delivery systems are remarkably different in their ability to prime a Th1-directed immune response with the rigid DDA-based liposomes inducing a response more than 100 times higher compared to that obtained with the fluid DODA-based liposomes. Upon injection with a vaccine antigen, DDA-based liposomes form a vaccine depot that results in a continuous attraction of antigen-presenting cells that engulf a high amount of adjuvant and are subsequently efficiently activated as measured by an elevated expression of the co-stimulatory molecules CD40 and CD86. In contrast, the fluid DODA-based liposomes are more rapidly removed from the site of injection resulting in a lower up-regulation of co-stimulatory CD40 and CD86 molecules on adjuvant-positive antigen-presenting cells. Additionally, the vaccine antigen is readily dissociated from the DODA-based liposomes leading to a population of antigen-presenting cells that are antigen-positive but adjuvant-negative and consequently are not activated. These studies demonstrate the importance of studying in vivo characteristics of the vaccine components and furthermore show that physicochemical properties of the delivery system have a major impact on the vaccine-induced immune response.


Influence of wavefront dynamics on transmembrane potential characteristics during atrial fibrillation.
Although computerized mapping studies have demonstrated the presence of multiple wavelets during atrial fibrillation (AF) and that action potential amplitude and duration in AF vary significantly from beat to beat, no study has correlated the single cell action potential changes with the patterns of activation during AF. We studied wavefront dynamics and single cell transmembrane potential (TMP) characteristics in 12 isolated perfused canine right atria. The endocardial surface was mapped using 477 bipolar electrodes while TMP was recorded with a standard glass microelectrode from an epicardial cell. AF was induced in the presence of acetylcholine. Successful simultaneous TMP recordings and activation maps were made during six episodes of AF and for a total of 141 activations. Large variations of TMP amplitude and duration were observed frequently; 34% of them have a low amplitude (<50% of the amplitude recorded during pacing). Low-amplitude potentials were recorded when the impaled cell was (1) in an area of random reentry (67%, n = 36); (2) within 3.2 mm of the core of organized functional reentry (22%, n = 12); (3) in the middle of two merging wavefronts (9%, n = 5); and (4) at the point of spontaneous wavebreak (2%, n = 1). Large variations of TMP are observed frequently during in vitro AF. Low-amplitude TMPs are associated with specific patterns of AF activation wavefronts.


The genetic diversification of the HIV type 1 gag p17 gene in patients infected from a common source.
An evolutionary analysis was undertaken of HIV-1 gag p17 sequences taken from a small cohort of hemophilia B patients infected from a common batch of clotting factor concentrate. The sequence population found at seroconversion was highly homogeneous, suggesting that the infecting batch also contained little sequence variation. Genetic diversification was found in follow-up sequences taken approximately 3 years later and was generally found to be complex. Greater rates of synonymous to nonsynonymous substitution were observed, especially when comparing distantly related isolates, and the rate of synonymous substitution was used to estimate times of divergence for a number of isolates of HIV-1 including the origin of the subtypes A to H. The p17 region is therefore proposed as a useful marker for future epidemiological studies.


Transcriptional remodeling during metacyclogenesis in Trypanosoma cruzi I.
Metacyclogenesis is one of the most important processes in the life cycle of Trypanosoma cruzi. In this stage, noninfective epimastigotes become infective metacyclic trypomastigotes. However, the transcriptomic changes that occur during this transformation remain uncertain. Illumina RNA-sequencing of epimastigotes and metacyclic trypomastigotes belonging to T. cruzi DTU I was undertaken. Sequencing reads were aligned and mapped against the reference genome, differentially expressed genes between the two life cycle stages were identified, and metabolic pathways were reconstructed. Gene expression differed significantly between epimastigotes and metacyclic trypomastigotes. The cellular pathways that were mostly downregulated during metacyclogenesis involved glucose energy metabolism (glycolysis, pyruvate metabolism, the Krebs cycle, and oxidative phosphorylation), amino acid metabolism, and DNA replication. By contrast, the processes where an increase in gene expression was observed included those related to autophagy (particularly Atg7 and Atg8 transcripts), corroborating its importance during metacyclogenesis, endocytosis, by an increase in the expression of the AP-2 complex subunit alpha, protein processing in the endoplasmic reticulum and meiosis. Study findings indicate that in T. cruzi metacyclic trypomastigotes, metabolic processes are decreased, and expression of genes involved in specific cell cycle processes is increased to facilitate transformation to this infective stage.


The Cameroon mobile phone SMS (CAMPS) trial: a protocol for a randomized controlled trial of mobile phone text messaging versus usual care for improving adherence to highly active anti-retroviral therapy.
This trial aims at testing the efficacy of weekly reminder and motivational text messages, compared to usual care in improving adherence to Highly Active Antiretroviral Treatment in patients attending a clinic in Yaoundé, Cameroon. This is a single-centered randomized controlled single-blinded trial. A central computer generated randomization list will be generated using random block sizes. Allocation will be determined by sequentially numbered sealed opaque envelopes. 198 participants will either receive the mobile phone text message or usual care. Our hypothesis is that weekly motivational text messages can improve adherence to Highly Active Antiretroviral Treatment and other clinical outcomes in the control group by acting as a reminder, a cue to action and opening communication channels. Data will be collected at baseline, three months and six months. A blinded program secretary will send out text messages and record delivery.Our primary outcomes are adherence measured by the visual analogue scale, self report, and pharmacy refill data. Our secondary outcomes are clinical: weight, body mass index, opportunistic infections, all cause mortality and retention; biological: Cluster Designation 4 count and viral load; and quality of life. Analysis will be by intention-to-treat. Covariates and subgroups will be taken into account. This trial investigates the potential of SMS motivational reminders to improve adherence to Highly Active Antiretroviral Treatment in Cameroon. The intervention targets non-adherence due to forgetfulness and other forms of non-adherence. Pan-African Clinical Trials Registry PACTR201011000261458 http://clinicaltrials.gov/NCT01247181.


Heterologous expression and purification of Arabidopsis thaliana VIM1 protein: in vitro evidence for its inability to recognize hydroxymethylcytosine, a rare base in Arabidopsis DNA.
The discovery of 5-hydroxymethyl-cytosine (5hmC) in mammalian cells prompted us to look for this base in the DNA of Arabidopsis thaliana (thale cress), and to ask how well the Arabidopsis Variant in Methylation 1 (VIM1) protein, an essential factor in maintaining 5-cytosine methylation (5mC) homeostasis and epigenetic silencing in this plant, recognizes this novel base. We found that the DNA of Arabidopsis' leaves and flowers contain low levels of 5hmC. We also cloned and expressed in Escherichia coli full-length VIM1 protein, the archetypal member of the five Arabidopsis VIM gene family. Using in vitro binding assays, we observed that full-length VIM1 binds preferentially to hemi-methylated DNA with a single modified 5mCpG site; this result is consistent with its known role in preserving DNA methylation in vivo following DNA replication. However, when 5hmC replaces one or both cytosine residues at a palindromic CpG site, VIM1 binds with approximately ≥10-fold lower affinity. These results suggest that 5hmC may contribute to VIM-mediated passive loss of cytosine methylation in vivo during Arabidopsis DNA replication.


Factors influencing TB treatment interruption and treatment outcomes among patients in Kiambu County, 2016-2019.
Tuberculosis (TB) is the leading cause of mortality as a single infectious agent globally with increasing numbers of case notification in developing countries. This study seeks to investigate the clinical and socio-demographic factors of time to TB treatment interruption among Tuberculosis patients in Kiambu County, 2016-2019. We retrospectively analyzed data for all treatment outcomes patients obtained from TB tracing form linked with the Tuberculosis Information Basic Unit (TIBU) of patients in Kiambu County health facilities using time to treatment interruption as the main outcome. Categorical variables were presented using frequency and percentages. Kaplan-Meir curve was used to analyze probabilities of time to treatment interruptions between intensive and continuation phases. Log-rank test statistics was used to compare the equality of the curves. Cox proportion model was used to determine determinants of treatment interruption. A total of 292 participants were included in this study. Males were 68%, with majority (35%) of the participants were aged 24-35 years; 5.8% were aged 0-14 years and 5.1% aged above 55 years. The overall treatment success rate was 66.8% (cured, 34.6%; completed 32.2%), 60.3% were on intensive phase of treatment. Lack of knowledge and relocation were the major reasons of treatment interruptions. Patients on intensive phase were 1.58 times likely to interrupt treatment compared to those on continuation phase (aHR: 1.581; 95%CI: 1.232-2.031). There is need to develop TB interventions that target men and middle aged population in order to reduce treatment interruption and increase the treatment success rates in the County and Country.


Magnesia-stabilised zirconia solid electrolyte assisted electrochemical investigation of iron ions in a SiO2-CaO-MgO-Al2O3 molten slag at 1723 K.
Production of metallic iron through molten oxide electrolysis using inert electrodes is an alternative route for fast ironmaking without CO2 emissions. The fact that many inorganic oxides melt at ultrahigh temperatures (>1500 K) challenges conventional electro-analytical techniques used in aqueous, organic and molten salt electrolytes. However, in order to design a feasible and effective electrolytic process, it is necessary to best understand the electrochemical properties of iron ions in molten oxide electrolytes. In this work, a magnesia-stabilised zirconia (MSZ) tube with a closed end was used to construct an integrated three-electrode cell with a "MSZ|Pt|O2 (air)" assembly functioning as the solid electrolyte, the reference electrode and also the counter electrode. Electrochemical reduction of iron ions was systematically investigated on an iridium (Ir) wire working electrode in a SiO2-CaO-MgO-Al2O3 molten slag at 1723 K by cyclic voltammetry (CV), square wave voltammetry (SWV), chronopotentiometry (CP) and potentiostatic electrolysis (PE). The results show that the electroreduction of the Fe2+ ion to Fe on the Ir electrode in the molten slag follows a single two-electron transfer step, and the rate of the process is diffusion controlled. The peak current on the obtained CVs is proportional to the concentration of the Fe2+ ion in the molten slag and the square root of scan rate. The diffusion coefficient of Fe2+ ions in the molten slag containing 5 wt% FeO at 1723 K was derived to be (3.43 ± 0.06) × 10-6 cm2 s-1 from CP analysis. However, a couple of subsequent processes, i.e. alloy formation on the Ir electrode surface and interdiffusion, were found to affect the kinetics of iron deposition. An ECC mechanism is proposed to account for the CV observations. The findings from this work confirm that zirconia-based solid electrolytes can play an important role in electrochemical fundamental research in high temperature molten slag electrolytes.


Dynamic disulfide metathesis induced by ultrasound.
The reversible metathesis of disulfide bonds is generally induced by a combination of a reducing agent and base or by irradiation with ultraviolet light. Here we report that ultrasound irradiation is suitable for generating clean equilibrium mixtures of disulfides within one hour or one day, depending on the sonication source. Preliminary mechanistic investigations suggest that the solvent plays an active role in producing initiator radicals.


Temporal and spatio-temporal attention to tactile stimuli in extinction patients.
The temporal deployment of attention to tactile stimuli delivered to the same or to a symmetrical position of the body was assessed in 6 Right-Brain Damaged (RBD) patients with left tactile extinction and 6 healthy controls. Two different tasks called Temporal (T) and Spatio-Temporal (ST) extinction were used. In the T task single or double electro tactile stimuli were delivered to the same point to the left or, in separate blocks, to the right index finger. Double stimuli were separated by different Stimulus Onset Asynchronies (SOAs). In the ST task, stimuli could be single (left or right) or double (left and right). Double stimuli were delivered to the index finger of both hands simultaneously or sequentially. In both tasks subjects were asked to report the number of the stimuli they perceived. In the ST task, subjects were also requested to report the stimuli location. Results show that in both tasks RBD patients' detection of left sided stimuli was significantly lower than of right sided stimuli detection, mainly at shortest SOAs. Moreover, detection of left sided stimuli was higher when two stimuli were delivered in sequence and in symmetrical body areas and in different sides of the space than when stimuli were delivered in sequence in the same body area. Results suggest that the interaction between spatial and temporal variables enhances the ability of tactile extinction patients to detect left sided stimuli.


Design and development of biomimetic quadruped robot for behavior studies of rats and mice.
This paper presents the design and development of a novel biomimetic quadruped robot for behavior studies of rats and mice. Many studies have been performed using these animals for the purpose of understanding human mind in psychology, pharmacology and brain science. In these fields, several experiments on social interactions have been performed using rats as basic studies of mental disorders or social learning. However, some researchers mention that the experiments on social interactions using animals are poorly-reproducible. Therefore, we consider that reproducibility of these experiments can be improved by using a robotic agent that interacts with an animal subject. Thus, we developed a small quadruped robot WR-2 (Waseda Rat No. 2) that behaves like a real rat. Proportion and DOF arrangement of WR-2 are designed based on those of a mature rat. This robot has four 3-DOF legs, a 2-DOF waist and a 1-DOF neck. A microcontroller and a wireless communication module are implemented on it. A battery is also implemented. Thus, it can walk, rear by limbs and groom its body.


Cavo-atrial thrombectomy combined with left hemi-hepatectomy for vascular invasion from hepatocellular carcinoma on diseased liver under hypothermic cardio-circulatory arrest.
Vascular invasion of supra-hepatic veins (SHV) is a major complication of primary liver tumours. The tumorous thrombus, when extended to the vena cava and right atrium, may produce occlusion of the tricuspid valve or pulmonary embolism with sudden cardiac death. The presence of macroscopic vascular infiltration represents an advanced stage of the tumour contraindicating liver transplantation, thus liver resection with thrombectomy is the only therapeutic option in this setting despite the concerns of postoperative liver failure and the dismal results at distance. A 45-year-old male with chronic active hepatitis/cirrhosis was referred to our department for a tumour in the left hemi-liver with infiltration of the left-middle hepatic veins and a tumour thrombus extension to the right atrium. We reported a successful cavo-atrial thrombectomy, along with left hemi-hepatectomy, under hypothermic cardio-circulatory arrest (HCA). To our knowledge, this technique has been used only once for primary liver cancer on chronic liver disease, this being the second case reported in literature. We conclude that this technique should be considered for atrial thrombi removal in patients affected by liver tumours in the presence of a healthy liver or of a well compensated liver cirrhosis in order to prolong the patient's life span.


Machine learning partners in criminal networks.
Recent research has shown that criminal networks have complex organizational structures, but whether this can be used to predict static and dynamic properties of criminal networks remains little explored. Here, by combining graph representation learning and machine learning methods, we show that structural properties of political corruption, police intelligence, and money laundering networks can be used to recover missing criminal partnerships, distinguish among different types of criminal and legal associations, as well as predict the total amount of money exchanged among criminal agents, all with outstanding accuracy. We also show that our approach can anticipate future criminal associations during the dynamic growth of corruption networks with significant accuracy. Thus, similar to evidence found at crime scenes, we conclude that structural patterns of criminal networks carry crucial information about illegal activities, which allows machine learning methods to predict missing information and even anticipate future criminal behavior.


Reirradiation with IMRT for recurrent head and neck cancer: A single-institutional report on disease control, survival, and toxicity.
To study and explores the feasibility and efficacy of re-irradiation (Re-RT) for locally recurrent head and neck cancer (HNC) and second primary (SP) malignancies. The most common form of treatment failure after radiotherapy (RT) for HNC is loco-regional recurrence (LRR), and around 20-50% of patients develop LRR. Re-irradiation (Re-RT) has been the primary standard of care in the last decade for unresectable locally recurrent/SP HNC. It was a retrospective analysis in which we reviewed the medical records of 51 consecutive patients who had received Re-RT to the head and neck region at our institute between 2006 and 2015. Forty-eight patients were included for assessment of acute and late toxicities, response evaluation at 3 months post Re-RT, and analyses of locoregional control (LRC) and overall survival (OS). The median LRC was 11.2 months, and at 2 and 5 years the LRC rates were 41% and 21.2%, respectively. A multivariate analysis revealed two factors: initial surgical resection performed prior to Re-RT, and achievement of CR at 3 months after completion of Re-RT to be significantly associated with a better median LRC. The median OS was 28.2 months, and at 1, 2, and 5 years, OS were 71.1%, 55.9% and 18%, respectively. A multivariate analysis revealed initial surgical resection performed prior to Re-RT, and achievement of CR at 3 months post completion of Re-RT being only two factors significantly associated with a better median OS. Acute toxicity reports showed that no patients developed grade 5 toxicity, and 2 patients developed grade 4 acute toxicities. Re-RT for the treatment of recurrent/SP head and neck tumors is feasible and effective, with acceptable toxicity. However, appropriate patient selection criteria are highly important in determining survival and treatment outcomes.


Na+/H+ exchanger isoform 1-induced osteopontin expression facilitates cardiac hypertrophy through p90 ribosomal S6 kinase.
Cardiovascular diseases are the leading cause of death worldwide. One in three cases of heart failure is due to dilated cardiomyopathy. The Na+/H+ exchanger isoform 1 (NHE1), a multifunctional protein and the key pH regulator in the heart, has been demonstrated to be increased in this condition. We have previously demonstrated that elevated NHE1 activity induced cardiac hypertrophy in vivo. Furthermore, the overexpression of active NHE1 elicited modulation of gene expression in cardiomyocytes including an upregulation of myocardial osteopontin (OPN) expression. To determine the role of OPN in inducing NHE1-mediated cardiomyocyte hypertrophy, double transgenic mice expressing active NHE1 and OPN knockout were generated and assessed by echocardiography and the cardiac phenotype. Our studies showed that hearts expressing active NHE1 exhibited cardiac remodeling indicated by increased systolic and diastolic left ventricular internal diameter and increased ventricular volume. Moreover, these hearts demonstrated impaired function with decreased fractional shortening and ejection fraction. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) mRNA was upregulated, and there was an increase in heart cell cross-sectional area confirming the cardiac hypertrophic effect. Moreover, NHE1 transgenic mice also showed increased collagen deposition, upregulation of CD44 and phosphorylation of p90 ribosomal s6 kinase (RSK), effects that were regressed in OPN knockout mice. In conclusion, we developed an interesting comparative model of active NHE1 transgenic mouse lines which express a dilated hypertrophic phenotype expressing CD44 and phosphorylated RSK, effects which were regressed in absence of OPN.


Structural and biochemical basis for the UVB-induced alterations in epidermal barrier function.
Ultraviolet light (UVR) induces a myriad of cutaneous changes, including delayed disruption of the permeability barrier with higher doses. To investigate the basis for the UVB-induced barrier alteration, we assessed the epidermal lamellar body secretory system at various time points before and after barrier disruption with a single high dose of UVB (7.5 MED) to murine epidermis. Morphological data were correlated with changes in epidermal proliferation and lipid synthesis, indicative of lamellar body generation. Twenty-four hours following UVB, the stratum corneum (SC) is normal, but a layer of abnormal, vacuolated, and lamellar body (LB)-deficient cells is present, immediately beneath the stratum granulosum (SG)/SC interface. Immediately subjacent to this band of damaged cells, normal keratinocytes that contain intact LBs are present. By 72 h, concomitant with the appearance of a barrier abnormality, extensively damaged cells persist at the SC/SG interface, and abnormal lamellar membrane structures appear in the lower SC. Upper stratum spinosum (SS) and lower SG cells appear normal, with increased numbers of LBs. A barrier abnormality is still present at 96 h, in association with membrane abnormalities in the lower SC interstices, but up to four normal appearing, subjacent SG cell layers are present. By 120 h, accelerated LB formation and precocious LB extrusion occur throughout the thickened SG; normal lamellar membranes are present in the lower SC; and barrier recovery is almost complete. Whereas, epidermal synthesis of the major barrier lipid species (i.e., cholesterol, fatty acids, and ceramides, including acylceramides) is reduced or unchanged at 24 and 48 h, it increases significantly 72 h after exposure to UVB. Therefore, the delayed disruption of the permeability barrier following acute UVB exposure results from the arrival of a band of lamellar body-incompetent (i.e., damaged) cells at the SG/SC interface. The subsequent, rapid recovery of the barrier, in turn, results from compensatory hyperplasia of subjacent, undamaged SS/SG cells, generating increased numbers and contents of LB. These results underscore the critical role of the stratum compactum in mediating barrier function, and suggest that beneficial therapeutic effects of UV exposure may be due to enhanced lipid production and barrier regeneration.


Single versus multiple cervical dilation by osmotic dilator before induction of labor for second-trimester abortion.
In this study, we aimed to investigate whether there was a significant prognostic difference between single and multiple cervical dilations when inducing second-trimester abortion. We conducted a retrospective review of 238 pregnant women who underwent termination of pregnancy at 12-21 weeks of gestation at Osaka University Hospital in Osaka, Japan, between January 2010 and May 2018. Termination of pregnancy was performed by vaginal administration of 1 mg gemeprost every 3 h for up to five doses per day after uterine cervical dilation using lamicel. The women were categorized into two groups: 191 women had a delivery time of <24 h, whereas 47 had delivery times >24 h. Contrasting the groups, there were significant differences with regard to numbers of primiparas (88 [46.1%] and 32 [68.1%], respectively) and lamicel exchanges ± SD (1.9 ± 0.67 for <24 h and 2.4 ± 0.87 for >24 h, respectively). Additionally, we compared the prognosis of primiparas that received just a single lamicel with that of primiparas that had ≥2 exchanged, but no significant differences were noted in the number of patients with a delivery time of >24 h and the number of used gemeprost. Primipara is a risk factor for delayed delivery time of induced abortion. However, increasing the number of exchanged lamicel did not significantly reduce the delivery time; therefore, it should be performed as minimally as possible.


Low-Intensity Shockwave Therapy Improves Hemodynamic Parameters in Patients With Vasculogenic Erectile Dysfunction: A Triplex Ultrasonography-Based Sham-Controlled Trial.
Although several reports have documented the subjective improvement of erectile function after low-intensity extracorporeal shockwave therapy (LI-ESWT) in patients with vasculogenic erectile dysfunction (ED), objective assessment data of penile hemodynamics are lacking. To assess penile hemodynamics before and 3 months after LI-ESWT in a group of patients with documented vasculogenic ED. This was a double-blinded, randomized, sham-controlled trial. Forty-six patients with ED were randomized; 30 underwent LI-ESWT and 16 had a sham procedure in double-blinded fashion. All patients underwent penile triplex ultrasonography by the same investigator immediately before and 3 months after treatment. Patient demographics, International Index of Erectile Function erectile function domain (IIEF-ED) score, and minimal clinically important difference were assessed at baseline and 1, 3, 6, 9, and 12 months after treatment. Changes in peak systolic velocity and resistance index as measured by triplex ultrasonography at baseline and 3 months after treatment were the main outcomes of the study. Secondary outcomes were changes in the IIEF-EF score from baseline to 1, 3, 6, 9, and 12 months after treatment and the percentage of patients reaching a minimal clinically important difference during the same period for the two groups. IIEF-EF minimal clinically important differences for the active vs sham group were observed for 56.7% vs 12.5% (P = .005) at 1 month, 56.7% vs 12.5% (P = .003) at 3 months, 63.3% vs 18.8% (P = .006) at 6 months, 66.7% vs 31.3% (P = .022) at 9 months, and 75% vs 25% (P = .008) at 12 months. Mean peak systolic velocity increased by 4.5 and 0.6 cm/s in the LI-ESWT and sham groups, respectively (P < .001). Such results offer objective and subjective documentation of the value of this novel treatment modality for men with vasculogenic ED. Strengths include the prospective, randomized, sham-controlled type of study and the assessment of penile hemodynamics. Limitations include the small sample and strict inclusion criteria that do not reflect everyday clinical practice. The present study confirms the beneficial effect of LI-ESWT on penile hemodynamics and the beneficial effect of this treatment up to 12 months. Kalyvianakis D, Hatzichristou D. Low-Intensity Shockwave Therapy Improves Hemodynamic Parameters in Patients With Vasculogenic Erectile Dysfunction: A Triplex Ultrasonography-Based Sham-Controlled Trial. J Sex Med 2017;14:891-897.


Effect of the normalized prescription isodose line on the magnitude of Monte Carlo vs. pencil beam target dose differences for lung stereotactic body radiotherapy.
In lung stereotactic body radiotherapy (SBRT) cases, the pencil beam (PB) dose calculation algorithm is known to overestimate target dose as compared to the more accurate Monte Carlo (MC) algorithm. We investigated whether changing the normalized prescription isodose line affected the magnitude of MC vs. PB target dose differences. Forty-eight patient plans and twenty virtual-tumor phantom plans were studied. For patient plans, four alternative plans prescribed to 60%, 70%, 80%, and 90% isodose lines were each created for 12 patients who previously received lung SBRT treatments. Using 6 MV dynamic conformal arcs, the plans were individually optimized to achieve similar dose coverage and conformity for all plans of the same patient, albeit at the different prescription levels. These plans, having used a PB algorithm, were all recalculated with MC to compare the target dose differences. The relative MC vs. PB target dose variations were investigated by comparing PTV D95, Dmean, and D5 loss at the four prescription levels. The MC-to-PB ratio of the plan heterogeneity index (HI) was also evaluated and compared among different isodose levels. To definitively demonstrate the cause of the isodose line dependence, a simulated phantom study was conducted using simple, spherical virtual tumors planned with uniform block margins. The tumor size and beam energy were also altered in the phantom study to investigate the interplay between these confounding factors and the isodose line effect. The magnitude of the target dose overestimation by PB was greater for higher prescription isodose levels. The MC vs. PB reduction in the target dose coverage indices, D95 and V100 of PTV, were found to monotonically increase with increasing isodose lines from 60% to 90%, resulting in more pronounced target dose coverage deficiency at higher isodose prescription levels. No isodose level-dependent trend was observed for the dose errors in the target mean or high dose indices, Dmean or D5. The phantom study demonstrated that the observed isodose level dependence was caused by different beam margins used for the different isodose levels: a higher prescription line required a larger beam margin, leading to more low-density lung tissues in the field and, therefore, larger dose errors at the target periphery (when calculated with PB). The phantom study also found that the observed isodose level dependence was greater for smaller targets and for higher beam energies. We hereby characterized the effect of normalized prescription isodose line on magnitude of PTV dose coverage as calculated by MC vs. PB. When comparing reported MC dose deficiency values for different patients, the selection of prescription isodose line should be considered in addition to other factors known to affect differences in calculated doses between various algorithms.


Block copolymers: controlling nanostructure to generate functional materials - synthesis, characterization, and engineering.
In this perspective, we survey recent advances in the synthesis and characterization of block copolymers, discuss several key materials opportunities enabled by block copolymers, and highlight some of the challenges that currently limit further realization of block copolymers in promising nanoscale applications. One significant challenge, especially as the complexity and functionality of designer macromolecules increases, is the requirement of multiple complementary techniques to fully characterize the resultant polymers and nanoscale materials. Thus, we highlight select characterization and theoretical methods and discuss how future advances can improve understanding of block copolymer systems. In particular, we consider the application of theoretical/simulation methods to the rationalization, and prediction, of observed experimental self-assembly phenomena. Finally, we explore several next steps for the field and emphasize some general areas of emerging research that could unlock additional opportunities for nanostructure-forming block copolymers in functional materials.


Metabolic engineering of fungal strains for conversion of D-galacturonate to meso-galactarate.
D-galacturonic acid can be obtained by hydrolyzing pectin, which is an abundant and low value raw material. By means of metabolic engineering, we constructed fungal strains for the conversion of D-galacturonate to meso-galactarate (mucate). Galactarate has applications in food, cosmetics, and pharmaceuticals and as a platform chemical. In fungi D-galacturonate is catabolized through a reductive pathway with a D-galacturonate reductase as the first enzyme. Deleting the corresponding gene in the fungi Hypocrea jecorina and Aspergillus niger resulted in strains unable to grow on D-galacturonate. The genes of the pathway for D-galacturonate catabolism were upregulated in the presence of D-galacturonate in A. niger, even when the gene for D-galacturonate reductase was deleted, indicating that D-galacturonate itself is an inducer for the pathway. A bacterial gene coding for a D-galacturonate dehydrogenase catalyzing the NAD-dependent oxidation of D-galacturonate to galactarate was introduced to both strains with disrupted D-galacturonate catabolism. Both strains converted D-galacturonate to galactarate. The resulting H. jecorina strain produced galactarate at high yield. The A. niger strain regained the ability to grow on d-galacturonate when the D-galacturonate dehydrogenase was introduced, suggesting that it has a pathway for galactarate catabolism.


VIGOR, an annotation program for small viral genomes.
the decrease in cost for sequencing and improvement in technologies has made it easier and more common for the re-sequencing of large genomes as well as parallel sequencing of small genomes. It is possible to completely sequence a small genome within days and this increases the number of publicly available genomes. Among the types of genomes being rapidly sequenced are those of microbial and viral genomes responsible for infectious diseases. However, accurate gene prediction is a challenge that persists for decoding a newly sequenced genome. Therefore, accurate and efficient gene prediction programs are highly desired for rapid and cost effective surveillance of RNA viruses through full genome sequencing. we have developed VIGOR (Viral Genome ORF Reader), a web application tool for gene prediction in influenza virus, rotavirus, rhinovirus and coronavirus subtypes. VIGOR detects protein coding regions based on sequence similarity searches and can accurately detect genome specific features such as frame shifts, overlapping genes, embedded genes, and can predict mature peptides within the context of a single polypeptide open reading frame. Genotyping capability for influenza and rotavirus is built into the program. We compared VIGOR to previously described gene prediction programs, ZCURVE_V, GeneMarkS and FLAN. The specificity and sensitivity of VIGOR are greater than 99% for the RNA viral genomes tested. VIGOR is a user friendly web-based genome annotation program for five different viral agents, influenza, rotavirus, rhinovirus, coronavirus and SARS coronavirus. This is the first gene prediction program for rotavirus and rhinovirus for public access. VIGOR is able to accurately predict protein coding genes for the above five viral types and has the capability to assign function to the predicted open reading frames and genotype influenza virus. The prediction software was designed for performing high throughput annotation and closure validation in a post-sequencing production pipeline.


Targeted nuclear factor-kappaB suppression enhances gemcitabine response in human pancreatic tumor cell line murine xenografts.
Pancreatic ductal adenocarcinoma (PDAC) is an almost uniformly fatal malignancy characterized by resistance to chemotherapy. Currently, gemcitabine is the agent used most commonly but demonstrates only a partial response. The transcription factor nuclear factor-kappaB (NF-κB), known to be involved in the inflammatory response, is constitutively activated in PDAC and further activated by gemcitabine. Our aim was to examine the effects of targeted NF-κB suppression on gemcitabine resistance using an in vivo tumor growth model. To suppress the NF-κB pathway, the mutant IκBα super-repressor protein was stably expressed in PaCa-2 human PDAC cells. Athymic mice were injected subcutaneously with IκBα-super-repressor (SR) or vector-expressing PaCa-2 cells and randomized to receive phosphate-buffered saline (PBS) or 100 mg/kg gemcitabine(gem) for 4 weeks. The mean increase in tumor volume was 47 mm(3) (89%) and 196 mm(3) (326%) in gem/SR and gem/vector groups, respectively (P = .03). The PBS-treated groups demonstrated greater tumor growth, ∼340 mm(3) (850%) increase, in both PBS/vector and PBS/SR groups. Intratumoral NF-κB activity was decreased in gem/SR compared with the gem/vector group (P = .04). Decreased Ki-67 positivity was noted in gem/SR (49%) versus gem/vector tumors (73%) (P = .04), with no difference in apoptosis (apoptag, P = .3) or angiogenesis (CD31+, P = .9). Stable IκBα-SR expression in vivo potentiated the antitumor effects of gemcitabine, resulting in decreased tumor growth in association with decreased cell proliferation. Molecular suppression of the NF-κB pathway decreases successfully gemcitabine resistance in a relatively chemoresistant PDAC line. Thus, NF-κB-targeted agents may complement gemcitabine-based therapies and decrease chemoresistance in patients with PDAC.


Markers for early detection of cancer: statistical guidelines for nested case-control studies.
Recently many long-term prospective studies have involved serial collection and storage of blood or tissue specimens. This has spurred nested case-control studies that involve testing some specimens for various markers that might predict cancer. Until now there has been little guidance in statistical design and analysis of these studies. To develop statistical guidelines, we considered the purpose, the types of biases, and the opportunities for extracting additional information. The following guidelines: (1) For the clearest interpretation, statistics should be based on false and true positive rates - not odds ratios or relative risks (2) To avoid overdiagnosis bias, cases should be diagnosed as a result of symptoms rather than on screening. (3) To minimize selection bias, the spectrum of control conditions should be the same in study and target screening populations. (4) To extract additional information, criteria for a positive test should be based on combinations of individual markers and changes in marker levels over time. (5) To avoid overfitting, the criteria for a positive marker combination developed in a training sample should be evaluated in a random test sample from the same study and, if possible, a validation sample from another study. (6) To identify biomarkers with true and false positive rates similar to mammography, the training, test, and validation samples should each include at least 110 randomly selected subjects without cancer and 70 subjects with cancer. These guidelines ensure good practice in the design and analysis of nested case-control studies of early detection biomarkers.


Effectiveness of switching from antipsychotic polypharmacy to monotherapy.
This randomized trial addressed the risks and benefits of staying on antipsychotic polypharmacy or switching to monotherapy. Adult outpatients with schizophrenia taking two antipsychotics (127 participants across 19 sites) were randomly assigned to stay on polypharmacy or switch to monotherapy by discontinuing one antipsychotic. The trial lasted 6 months, with a 6-month naturalistic follow-up. Kaplan-Meier and Cox regression analyses examined time to discontinuation of assigned antipsychotic treatment, and random regression models examined additional outcomes over time. Patients assigned to switch to monotherapy had shorter times to all-cause treatment discontinuation than those assigned to stay on polypharmacy. By month 6, 86% (N=48) of those assigned to stay on polypharmacy were still taking both medications, whereas 69% (N=40) of those assigned to switch to monotherapy were still taking the same medication. Most monotherapy discontinuations entailed returning to the original polypharmacy. The two groups did not differ with respect to psychiatric symptoms or hospitalizations. On average, the monotherapy group lost weight, whereas the polypharmacy group gained weight. Discontinuing one of two antipsychotics was followed by treatment discontinuation more often and more quickly than when both antipsychotics were continued. However, two-thirds of participants successfully switched, the groups did not differ with respect to symptom control, and switching to monotherapy resulted in weight loss. These results support the reasonableness of prescribing guidelines encouraging trials of antipsychotic monotherapy for individuals receiving antipsychotic polypharmacy, with the caveat that patients should be free to return to polypharmacy if an adequate trial on antipsychotic monotherapy proves unsatisfactory.


An analysis of the mechanical disadvantage of myocardial infarction in the canine left ventricle.
An isotropic, initially spherical, membrane model of the infarcted ventricle satisfactorily predicts ventricular function in the infarcted heart when compared to clinical information and available ventricular models of higher complexity. Computations based on finite element solutions of this membrane model yield end-diastolic and end-systolic pressure-volume curves, from which ventricular function curves are calculated, for infarcts of varying size and material properties. These computations indicate a progressive degradation of cardiac performance with increasing infarct sizes such that normal cardiac outputs can be maintained with Frank-Starling compensation and increased heart rate for acute infarcts no larger than 41% of the ventricular surface. The relationship between infarct stiffness and cardiac function is found to be complex and dependent on both infarct size and end-diastolic pressure, although moderately stiff subacute infarcts are associated with better function than extensible acute infarcts. Also, calculations of extensions and stresses suggest considerable disruption of the border zone contraction pattern, as well as elevated border zone systolic stresses.


[EST-SSR identification of Lonicera japonica Thunb].
Simple and effective methods are needed for the identification of Chinese medicinal material species and their variety. Lonicera japonica Thunb. is one of Chinese herbal medicines widely demanded. A total of 3 705 EST-SSRs of L. japonica and 2 818 EST-SSRs of L. japonica var. chinensis Thunb. were identified from EST database in our lab. In average, there was one EST-SSR per 4.05 kb in L. japonica ESTs and per 7.49 kb in L. japonica var. chinensis ESTs, separately. The identified SSRs in L. japonica were consisted of 51.98% dinucleotide and 34.61% trinucleotide repeats, while SSRs in L. japonica var. chinensis had 57.45% dinucleotide and 30.09% trinucleotide. The results reviewed that the classes AG/TC and GAG/TCT were predominant in the dinucleotide motifs and the trinucleotide motifs, respectively. Total 87 EST-SSRs were identified of significant difference between L. japonica and L. japonica var. chinensis. PCR products were obtained from 52 L. japonica samples in 13 out of 15 SSR markers tested. The polymorphism in L. japonica, L. japonica var. chinensis and other honeysuckles could be distinguished by three markers (jp.ssr4, jp.ssr64 and jp.ssr65) tested.


Optimization of circadian responses with shorter and shorter millisecond flashes.
Recent work suggests that the circadian pacemaker responds optimally to millisecond flashes of light, not continuous light exposure as has been historically believed. It is unclear whether these responses are influenced by the physical characteristics of the pulsing. In the present study, Drosophila (n = 2199) were stimulated with 8, 16 or 120 ms flashes. For each duration, the energy content of the exposure was systematically varied by changing the pulse irradiance and the number of stimuli delivered over a fixed 15 min administration window (64 protocols surveyed in all). Results showed that per microjoule invested, 8 ms flashes were more effective at resetting the circadian activity rhythm than 16- and 120 ms flashes (i.e. left shift of the dose-response curve, as well as a higher estimated maximal response). These data suggest that the circadian pacemaker's photosensitivity declines within milliseconds of light contact. Further introduction of light beyond a floor of (at least) 8 ms leads to diminishing returns on phase-shifting.


Epidemiology of community-acquired pneumonia in Edmonton, Alberta: an emergency department-based study.
Patients aged 17 years and older who presented to seven emergency departments in Edmonton, Alberta over a two-year period with community-acquired pneumonia (n=8144) were studied. The admission rates were 271/100,00 and 296/100,000 persons for year 1 and year 2 of the study, respectively. The admission rate increased with increasing age, peaking at 4639/100,000/year for those 90 years of age and older. In contrast, the percentage of patients who were admitted to an intensive care unit was highest for those in the younger age groups between 17 and 59 years of age. From 59 years of age and older, there was a progressive decline in the percentage of patients admitted to an intensive care unit, with approximately 1% of those in the 90 years and older age group admitted. A pronounced seasonal effect on the number of patients presenting to emergency department was also noted. During the winter months, there was up to a 50% increase in the number of cases compared with the summer months.


Toxicological effect of joint cadmium selenium quantum dots and copper ion exposure on zebrafish.
Quantum dots (QDs) have strong adsorption capacity; therefore, their potential toxicity to aquatic organisms from the facilitated transport of other trace toxic pollutants when they coexist has received increasing interest. However, the impact of cadmium selenium (CdSe) QDs and copper ion (Cu(2+)) joint exposure on zebrafish (Danio rerio) embryo and larvae remains almost unknown. Therefore, the present study was performed to determine the developmental toxicities to zebrafish exposed to combined pollution with CdSe QDs (500 µg/L) and Cu(2+) (0, 0.1, 1, 10, and 100 µg/L CuC1(2)) compared with single exposure. Our findings for the first time revealed that: (1) QDs facilitated the accumulation of Cu(2+) in zebrafish; (2) QDs caused higher mortality, lower hatch rate, and more malformations of the exposed zebrafish; (3) junction, bifurcation, crossing, particles, and aggregation of the exposed FLI-1 transgenic zebrafish larvae can be observed; (4) embryo cell apoptosis appeared in the head and tail region; and (5) synergistic effects played an important role during joint exposure. These observations provide a basic understanding of CdSe QDs and Cu(2+) joint toxicity to aquatic organisms and suggest the need for additional research to identify the toxicological mechanism.


MicroRNA expression signature in human abdominal aortic aneurysms.
Abdominal aortic aneurysm (AAA) is a dilatation of the aorta affecting most frequently elderly men. Histologically AAAs are characterized by inflammation, vascular smooth muscle cell apoptosis, and extracellular matrix degradation. The mechanisms of AAA formation, progression, and rupture are currently poorly understood. A previous mRNA expression study revealed a large number of differentially expressed genes between AAA and non-aneurysmal control aortas. MicroRNAs (miRNAs), small non-coding RNAs that are post-transcriptional regulators of gene expression, could provide a mechanism for the differential expression of genes in AAA. To determine differences in miRNA levels between AAA (n = 5) and control (n = 5) infrarenal aortic tissues, a microarray study was carried out. Results were adjusted using Benjamini-Hochberg correction (adjusted p < 0.05). Real-time quantitative RT-PCR (qRT-PCR) assays with an independent set of 36 AAA and seven control tissues were used for validation. Potential gene targets were retrieved from miRNA target prediction databases Pictar, TargetScan, and MiRTarget2. Networks from the target gene set were generated and examined using the network analysis programs, CytoScape® and Ingenuity Pathway Core Analysis®. A microarray study identified eight miRNAs with significantly different expression levels between AAA and controls (adjusted p < 0.05). Real-time qRT-PCR assays validated the findings for five of the eight miRNAs. A total of 222 predicted miRNA target genes known to be differentially expressed in AAA based on a prior mRNA microarray study were identified. Bioinformatic analyses revealed that several target genes are involved in apoptosis and activation of T cells. Our genome-wide approach revealed several differentially expressed miRNAs in human AAA tissue suggesting that miRNAs play a role in AAA pathogenesis.


Weed Diversity Affects Soybean and Maize Yield in a Long Term Experiment in Michigan, USA.
Managing production environments in ways that promote weed community diversity may enhance both crop production and the development of a more sustainable agriculture. This study analyzed data of productivity of maize (corn) and soybean in plots in the Main Cropping System Experiment (MCSE) at the W. K. Kellogg Biological Station Long-Term Ecological Research (KBS-LTER) in Michigan, USA, from 1996 to 2011. We used models derived from population ecology to explore how weed diversity, temperature, and precipitation interact with crop yields. Using three types of models that considered internal and external (climate and weeds) factors, with additive or non-linear variants, we found that changes in weed diversity were associated with changes in rates of crop yield increase over time for both maize and soybeans. The intrinsic capacity for soybean yield increase in response to the environment was greater under more diverse weed communities. Soybean production risks were greatest in the least weed diverse systems, in which each weed species lost was associated with progressively greater crop yield losses. Managing for weed community diversity, while suppressing dominant, highly competitive weeds, may be a helpful strategy for supporting long term increases in soybean productivity. In maize, there was a negative and non-additive response of yields to the interaction between weed diversity and minimum air temperatures. When cold temperatures constrained potential maize productivity through limited resources, negative interactions with weed diversity became more pronounced. We suggest that: (1) maize was less competitive in cold years allowing higher weed diversity and the dominance of some weed species; or (2) that cold years resulted in increased weed richness and prevalence of competitive weeds, thus reducing crop yields. Therefore, we propose to control dominant weed species especially in the years of low yield and extreme minimum temperatures to improve maize yields. Results of our study indicate that through the proactive management of weed diversity, it may be possible to promote both high productivity of crops and environmental sustainability.


Body mass index and the prevalence, severity, and risk of coronary artery disease: an international multicentre study of 13,874 patients.
Obesity is associated with the presence of coronary artery disease (CAD) risk factors and cardiovascular events. We examined the relationship between body mass index (BMI) and the presence, extent, severity, and risk of CAD in patients referred for coronary computed tomographic angiography (CCTA). We evaluated 13,874 patients from a prospective, international, multicentre registry of individuals without known CAD undergoing CCTA. We compared risk factors, CAD findings, and risk of all-cause mortality and non-fatal myocardial infarction (MI) amongst individuals with underweight (18.5-20.0 kg/m(2)), normal (20.1-24.9 kg/m(2)), overweight (25-29.9 kg/m(2)), and obese (≥30 kg/m(2)) BMI. The mean follow-up was 2.4 ± 1.2 years with 143 deaths and 193 MIs. Among underweight, normal weight, overweight, and obese individuals, there was increasing prevalence of diabetes (7 vs.10% vs. 12 vs. 19%), hypertension (37 vs. 40% vs. 46 vs. 59%), and hyperlipidaemia (48 vs. 52% vs. 56 vs. 56%; P < 0.001 for trend). After multivariable adjustment, BMI was positively associated with the prevalence of any CAD [odds ratio (OR) 1.25 per +5 kg/m(2), 95% confidence interval (CI): 1.20-1.30, P < 0.001] and obstructive (≥50% stenosis) CAD (OR: 1.13 per +5 kg/m(2), 95% CI: 1.08-1.19, P < 0.001); a higher BMI was also associated with an increased number of segments with plaque (+0.26 segments per +5 kg/m(2), 95% CI: 0.22-0.30, P < 0.001). Larger BMI categories were associated with an increase in all-cause mortality (P = 0.004), but no difference in non-fatal MI. After multivariable adjustment, a higher BMI was independently associated with increased risk of MI (hazards ratio: 1.28 per +5 kg/m(2), 95% CI: 1.12-1.45, P < 0.001). Amongst patients with suspected CAD referred for CCTA, individuals with increased BMI have greater prevalence, extent, and severity of CAD that is not fully explained by the presence of traditional risk factors. A higher BMI is independently associated with increased risk of intermediate-term risk of myocardial infarction.