Mechanistic species distribution modelling as a link between physiology and conservation.
Climate change conservation planning relies heavily on correlative species distribution models that estimate future areas of occupancy based on environmental conditions encountered in present-day ranges. The approach benefits from rapid assessment of vulnerability over a large number of organisms, but can have poor predictive power when transposed to novel environments and reveals little in the way of causal mechanisms that define changes in species distribution or abundance. Having conservation planning rely largely on this single approach also increases the risk of policy failure. Mechanistic models that are parameterized with physiological information are expected to be more robust when extrapolating distributions to future environmental conditions and can identify physiological processes that set range boundaries. Implementation of mechanistic species distribution models requires knowledge of how environmental change influences physiological performance, and because this information is currently restricted to a comparatively small number of well-studied organisms, use of mechanistic modelling in the context of climate change conservation is limited. In this review, we propose that the need to develop mechanistic models that incorporate physiological data presents an opportunity for physiologists to contribute more directly to climate change conservation and advance the field of conservation physiology. We begin by describing the prevalence of species distribution modelling in climate change conservation, highlighting the benefits and drawbacks of both mechanistic and correlative approaches. Next, we emphasize the need to expand mechanistic models and discuss potential metrics of physiological performance suitable for integration into mechanistic models. We conclude by summarizing other factors, such as the need to consider demography, limiting broader application of mechanistic models in climate change conservation. Ideally, modellers, physiologists and conservation practitioners would work collaboratively to build models, interpret results and consider conservation management options, and articulating this need here may help to stimulate collaboration.


Computerized curve fitting in the analysis of hydrogen gas clearance curves.
Hydrogen gas clearance curves obtained from the rat gastric corpus were digitized into a computer and then analyzed by three methods: 1) linear regression of log-transformed data, 2) direct curve fitting with a modified Gauss-Newton nonlinear regression algorithm, and 3) Zierler's height-over-area algorithm. For linear regression of log-transformed data, if the initial base-line estimate was inaccurate or normal amounts of experimental noise were present, the log-transformed data was skewed, leading to deviation of the regression line and incorrect estimation of blood flow. By utilization of the direct-fit routine, the initial estimate of the parameters or experimental noise had little influence on the blood flow determination because of iterative improvement of the parameters. In a study of isoproterenol-stimulated gastric blood flow, Zierler's algorithm underestimated the blood flow estimate. We conclude that analysis of hydrogen gas clearance curves by linear regression of log-transformed data or by Zierler's algorithm may potentially introduce errors in blood flow estimates that may be avoided by analysis with a direct-fitting, nonlinear regression algorithm.


The health disparities industry: is it an ethical conundrum?
Reducing health disparities is the purported mission of a huge network of professionals representing many specialties and organizations offering a variety of products and services. Given its elaborate infrastructure and specialized set of activities, we identity the network as the health disparities industry. In this article, we question the ethics of this industry. Specifically, we ask whether the public mission is trumped by questionable industry leadership, ethics, and quality assurances. Drawing on general principles of ethics and differentiating ethical concerns from ethical problems, we conclude that the collective behaviors within the industry may represent an ethical conundrum. The article concludes with a call for the cross-examination of the industry practices.


Patterns of nodal staging during breast conservation surgery in the medicare patient: will the ACOSOG Z0011 trial change the pattern of care?
ACOSOG Z0011 spares axillary dissection (AD) in breast conservation surgery (BCS) patients with T1/T2 tumors and 1-2 positive nodes. Current patterns of care and the impact of Z0011 on AD versus additional surgery rates for Medicare patients undergoing BCS are unknown. SEER data linked to Medicare claims for 1999-2005 were reviewed for women with invasive nonmetastatic breast cancer who underwent nodal staging on the same day as BCS. There were 3,280 women with T1/T2 tumors and positive nodes who underwent same-day nodal staging; 2,532 (77.2 %) of these women had 1-2 positive nodes. Assuming 25.7 % have extracapsular extension, 651 women would require AD. However, 1,881 women, or 57.4 % of those with T1/T2 tumors and positive nodes, would be spared AD. Meanwhile, among the 748 women having ≥ 3 positive nodes, 579 underwent same-day AD, but under Z0011, would now wait for permanent section. A total of 160 of these women underwent re-excision or completion mastectomy at a later date anyway, when delayed AD could be performed. The remaining 419 women with ≥ 3 positive nodes would require an additional surgery date for the sole purpose of completion AD. The Z0011 paradigm would consequently necessitate an additional surgery date for 1,070 (651 + 419) women, or 32.6 % of those with T1/T2 tumors and positive nodes. The Z0011 paradigm appears to increase the number of Medicare patients undergoing BCS who require an additional surgery date but decrease the number requiring AD to a greater extent. Future changes in the use of AD or axillary irradiation may yet modify that impact substantially.


Construction of a SNP-Based High-Density Genetic Map Using Genotyping by Sequencing (GBS) and QTL Analysis of Nut Traits in Chinese Chestnut (Castanea mollissima Blume).
Chinese chestnut is a wildly distributed nut species with importantly economic value. The nut size and ripening period are mainly desired breeding objectives in Chinese chestnut. However, high-density linkage maps and quantitative trait loci (QTL) analyses related to nut traits are less than satisfactory, which hinders progress in the breeding of Chinese chestnut. Here, a single nucleotide polymorphism (SNP)-based high-density linkage map was constructed through genotyping-by-sequencing (GBS) of an F1 cross between the two widely grown Chinese chestnut cultivars 'Yanshanzaofeng' and 'Guanting No. 10'. The genetic linkage map consists of 2,620 SNP markers with a total length of 1078.06 cM in 12 linkage groups (LGs) and an average marker distance of 0.41 cM. 17 QTLs were identified for five nut traits, specifically single-nut weight (SNW), nut width (NW), nut thickness (NT), nut height (NH), and ripening period (RP), based on phenotypic data from two successive years. Of the 17 QTLs, two major QTLs, i.e., qNT-I-1 and qRP-B-1 related to the NT and RP traits, respectively, were exploited. Moreover, the data revealed one pleiotropic QTL at 23.97 cM on LG I, which might simultaneously control SNW, NT, and NW. This study provides useful benchmark information concerning high-density genetic mapping and QTLs identification related to nut size and ripening period, and will accelerate genetic improvements for nuts in the marker-assisted selection (MAS) breeding of Chinese chestnut.


Experimental arthritis in CC chemokine receptor 2-null mice closely mimics severe human rheumatoid arthritis.
The prevailing paradigm is that in human rheumatoid arthritis (RA), the accumulation of monocytes and T cells in the joint, mediated in part by such CC chemokine receptors (CCRs) as CCR2 and CCR5, respectively, plays a central role in disease pathogenesis. To further validate this paradigm, we conducted proof-of-principle studies and tested the hypothesis that gene inactivation of Ccr2 or Ccr5 will ameliorate experimental RA. Contrary to our expectations, we found that in two well-established murine models of experimental RA, CCR2 expression in the hematopoietic cell compartment served as a negative regulator of autoantibody production as well as arthritic disease onset, severity, and resolution. In contrast, the RA phenotype in Ccr5-null mice was similar to that of WT mice. Remarkably, the collagen-induced arthritis phenotype of Ccr2-/- mice mimicked closely that of severe human RA, including production of rheumatoid factor, enhanced T cell production, and monocyte/macrophage accumulation in the joints. Our findings demonstrate an essential protective role of CCR2 expression in RA, indicate the existence of alternative receptors responsible for monocyte/macrophage accumulation to inflamed joints, and emphasize the need to clarify carefully the complex effects of the chemokine system in RA before they can be considered as therapeutic targets.


Induced and sustained hypernatremia for the prevention and treatment of cerebral edema following brain injury.
Cerebral edema develops in response to and as a result of a variety of neurologic insults such as ischemic stroke, traumatic brain injury, and tumor. It deforms brain tissue, resulting in localized mass effect and increase in intracranial pressure (ICP) that are associated with a high rate of morbidity and mortality. When administered in bolus form, hyperosmolar agents such as mannitol and hypertonic saline have been shown to reduce total brain water content and decrease ICP, and are currently the mainstays of pharmacological treatment. However, surprisingly, little is known about the increasingly common clinical practice of inducing a state of sustained hypernatremia. Herein, we review the available studies employing sustained hyperosmolar therapy to induce hypernatremia for the prevention and/or treatment of cerebral edema. Insufficient evidence exists to recommend pharmacologic induction of hypernatremia as a treatment for cerebral edema. The strategy of vigilant avoidance of hyponatremia is currently a safer, potentially more efficacious paradigm.


Nationwide antibiotic resistance mapping of Helicobacter pylori in Korea: A prospective multicenter study.
The eradication rates for Helicobacter pylori have decreased in Korea although the prevalence of this bacterium has also decreased. Antibiotic resistance is likely to be a crucial factor in H. pylori eradication success, and we therefore mapped these resistance patterns nationwide in Korea. Five hundred and ninety adult subjects were prospectively enrolled from 2017 to 2018 from 15 centers across six geographic areas of Korea. A total of 580 biopsy tissues had been sampled from these patients during an upper endoscopy and were frozen at -80°C and delivered to a central laboratory. The agar dilution method was used to determine the minimum inhibitory concentration of amoxicillin, clarithromycin, metronidazole, tetracycline, ciprofloxacin, and levofloxacin for each H. pylori isolate. The culture success rate was 60.2% (349/580). Resistance rates against clarithromycin, metronidazole, amoxicillin, tetracycline, levofloxacin, and ciprofloxacin were 17.8%, 29.5%, 9.5%, 0%, 37.0%, and 37.0%, respectively. The geographic distribution of metronidazole and quinolone resistance was highly variable. Some subjects had multiple H. pylori strains in the antrum and body of the stomach and showed a heterogeneous resistance profile between these anatomic areas. The H. pylori multidrug resistance (MDR) rate was 25.2% (88/349) among amoxicillin, clarithromycin, metronidazole, tetracycline, and quinolone and 11.2% (39/349) among four of these major antibiotics except for quinolone. The Seoul and Chungcheong areas showed a relatively lower MDR rate. The antibiotic resistance of H. pylori differs by drug and geographic area in Korea. Detailed nationwide antibiotic resistance mapping is needed to develop an effective H. pylori eradication strategy.


High-quality autostereoscopic display with spatial and sequential hybrid control.
A novel design of an autostereoscopic display system with full resolution, low crosstalk, and weak Moiré pattern is presented. The system involves the usage of an LED backlight array and a liquid crystal display (LCD) panel, in conjunction with a Fresnel lens array, to form a 3D optical image system. The finer temporal synchronization is made possible with a dynamic synchronized backlight, so that the scanning of the LCD is in phase with the backlight array. The systematic optimization presents a full HD, or even an ultra HD, display for a single left or right channel. The achieved minimum systematic crosstalk is 2.64%, a sufficiently low value reported so far with an autostereoscopic system.


Determining both surface position and orientation in structured-light-based sensing.
Position and orientation profiles are two principal descriptions of shape in space. We describe how a structured light system, coupled with the illumination of a pseudorandom pattern and a suitable choice of feature points, can allow not only the position but also the orientation of individual surface elements to be determined independently. Unlike traditional designs which use the centroids of the illuminated pattern elements as the feature points, the proposed design uses the grid points between the pattern elements instead. The grid points have the essences that their positions in the image data are inert to the effect of perspective distortion, their individual extractions are not directly dependent on one another, and the grid points possess strong symmetry that can be exploited for their precise localization in the image data. Most importantly, the grid lines of the illuminated pattern that form the grid points can aid in determining surface normals. In this paper, we describe how each of the grid points can be labeled with a unique color code, what symmetry they possess and how the symmetry can be exploited for their precise localization at subpixel accuracy in the image data, and how 3D orientation in addition to 3D position can be determined at each of them. Both the position and orientation profiles can be determined with only a single pattern illumination and a single image capture.


Development and conceptual validation of a questionnaire to help contraceptive choice: CHLOE (Contraception: HeLping for wOmen's choicE).
The aim of this research was to develop a questionnaire to facilitate choice of the most appropriate contraceptive method for individual women. A literature review was conducted to identify key aspects influencing contraceptive choice and inform development of a questionnaire for online completion. Questionnaire development was overseen by a steering committee consisting of eight gynaecologists from across Europe. The initial draft underwent conceptual validation through cognitive debriefing interviews with six native English-speaking women. A qualitative content analysis was conducted to accurately identify potential issues and areas for questionnaire improvement. A revised version of the questionnaire then underwent face-to-face and online evaluation by 115 international gynaecologists/obstetricians with expertise in contraception, prior to development of a final version. The final conceptually validated Contraception: HeLping for wOmen's choicE (CHLOE) questionnaire takes ≤10 min to complete and includes three sections to elicit general information about the individual, the health conditions that might influence contraceptive choice, and the woman's needs and preferences that might influence contraceptive choice. The questionnaire captures the core aspects of personalisation, efficacy and safety, identified as key attributes influencing contraceptive choice, and consists of 24 closed-ended questions for online completion prior to a health care provider (HCP) consultation. The HCP receives a summary of the responses. The CHLOE questionnaire has been developed to help women choose the contraception that best suits their needs and situation while optimising the HCP's time.


Measuring retinal nerve fiber layer birefringence, retardation, and thickness using wide-field, high-speed polarization sensitive spectral domain OCT.
We presented a novel polarization sensitive optical coherence tomography (PS-OCT) system for measuring retinal nerve fiber layer (RNFL) birefringence, retardation, and thickness, and report on the repeatability of acquiring these quantities. A new PS-OCT system, measuring at 840 nm, was developed that supports scan angles of up to 40° × 40° with an A-scan rate of 70 kHz. To test the performance and reproducibility, we measured 10 eyes of 5 healthy human volunteers five times each. All volunteers were imaged further with scanning laser polarimetry (SLP). The obtained RNFL birefringence, retardation, and thickness maps were averaged, and standard deviation maps were calculated. For quantitative comparison between the new PS-OCT and SLP, a circumpapillary evaluation within 2 annular segments (superior and inferior to the optic disc) was performed. High quality RNFL birefringence, retardation, and thickness maps were obtained. Within the superior and inferior segments, the mean retardation for individual eyes ranged from 20° to 28.9° and 17.2° to 28.2°, respectively. The quadrant precision over the 5 consecutive measurements for each subject, calculated for the average retardation obtained within the superior and inferior quadrants ranged from 0.16° to 0.69°. The mean birefringence ranged from 0.106°/μm to 0.141°/μm superior and 0.101°/μm to 0.135°/μm inferior, with a quadrant precision of 0.001°/μm to 0.007°/μm. The mean RNFL thickness varied from 114 to 150 μm superior, and 111 to 140.9 μm inferior (quadrant precision ranged from 3.6 to 11.9 μm). The new PS-OCT system showed high image quality and reproducibility, and, therefore, might be a valuable tool for glaucoma diagnosis.


Polyphasic approach and typification of selected Phormidium strains (Cyanobacteria).
Cyanobacteria (phylum Cyanophyta/Cyanobacteria, class Cyanophyceae) are among the most widespread organisms and are able to adapt themselves to different extreme environments. These micro-organisms have an important ecological role, given their ability to perform oxygenic photosynthesis, and are employed in different fields based on their ability to produce several bioactive compounds. Their prokaryotic nature, the presence of many cryptic species, and the coexistence of different nomenclature systems make the taxonomic identification of cyanobacteria particularly difficult. Moreover, for several species, the original reference strains (holotypes) are lacking. Increasingly, authors are using a polyphasic approach to characterize cyanobacteria, while typification is a recent trend that is being used to solve the problem of missing holotypes in other micro-organisms. Here we focus on a filamentous cyanobacterium, isolated from the Euganean Thermal District (Padova, Italy) and temporarily named strain ETS-02, using a polyphasic approach that includes morphological, ultrastructural, biochemical (pigment and fatty acid content), physiological (nitrogen fixation), and genetic (16S rRNA, 16S-23S ITS, cpcB-IGS-cpcA, rpoC1, gyrB, rbcL, nifD loci) analyses. The description of Phormidium cf. irriguum CCALA 759 as the epitype of Phormidium irriguum was also used to complete the characterization of strain ETS-02.


Attitudes of women with chronic pelvic pain to the gynaecological consultation: a qualitative study.
To describe the attitudes that women with chronic pelvic pain (CPP) attending gynaecology clinics have to their consultations and to determine the ways in which their health care can be improved. Qualitative study using semistructured individual interviews. UK gynaecology outpatient clinics in district general and teaching hospitals. Twenty-six women with CPP. Semistructured individual interviews were conducted. Data gathering and analysis followed a grounded theory approach. Women's wishes regarding their care and their actual experiences of care. Four main themes emerged. The women wanted (a) personal care, which they often did not receive; (b) to feel understood and to be taken seriously, although they often felt dismissed, which applied both to women with and without an explanation for their pain; (c) explanation as much as cure, but an adequate explanation was often not provided; and (d) to be reassured, which often they were not. Effective reassurance was complex as it included general reassurance and specific reassurance about cause and treatment. Improvements are needed in the outpatient care of women presenting with CPP. Changes should focus on providing more personal care, so that presenting problems are seen to be taken seriously, findings and management are appropriately explained, and women are more effectively reassured. Interventions need to be developed that meet these needs and tested to determine if they are feasible, acceptable, and improve outcomes.


Methylation as a crucial step in plant microRNA biogenesis.
Methylation on the base or the ribose is prevalent in eukaryotic ribosomal RNAs (rRNAs) and is thought to be crucial for ribosome biogenesis and function. Artificially introduced 2'-O-methyl groups in small interfering RNAs (siRNAs) can stabilize siRNAs in serum without affecting their activities in RNA interference in mammalian cells. Here, we show that plant microRNAs (miRNAs) have a naturally occurring methyl group on the ribose of the last nucleotide. Whereas methylation of rRNAs depends on guide RNAs, the methyltransferase protein HEN1 is sufficient to methylate miRNA/miRNA* duplexes. Our studies uncover a new and crucial step in plant miRNA biogenesis and have profound implications in the function of miRNAs.


Diode side-pumped 1.3414 microm Nd:YAP laser in Q-switched mode.
A diode side-pumped acousto-optic Q-switched Nd:YAP laser operating at 1.3414 microm has been reported. The stabilities of resonators and the influence of the temperature of cooling water on output power have been experimentally investigated. The average output powers and pulse widths with different couplers and repetition rates have also been measured and analyzed. Under the repetition rate of 5 kHz, a maximum average output power of 47.5 W was obtained with an optical-optical conversion efficiency of 8.6% and a slope efficiency of 20.2%. The peak power and the pulse width were 48.8 kW and 195 ns FWHM. The beam quality factors M(2) directed along the a and c axes were 22 and 28, respectively.


A Study Protocol for an Open-Label Feasibility Treatment Trial of Visual Snow Syndrome With Transcranial Magnetic Stimulation.
Background: Visual Snow (VS) syndrome is believed to be due to aberrant central visual processing. Positron Emission Tomography (PET) brain imaging and visual evoked potential studies provide evidence for excessive neuronal activity in the medial temporal lobe, specifically the lingual gyrus, and suggest the VS syndrome is a hyperexcitability syndrome. These data provide the basis for consideration of repetitive transcranial magnetic stimulation (rTMS) as a potential treatment for the VS syndrome. Objective: To publish the study protocol for a pilot study underway at the University of Colorado School of Medicine to investigate the use of rTMS intervention to improve symptoms and visual dysfunction associated with VS. The study aims to determine the adverse events and drop-out rate, evaluate performance of outcome measures, including a novel VS symptom scale, and describe changes in outcomes associated with treatment. Methods and Design: Up to 10 participants meeting criteria for VS syndrome, age 19-65 years, will undergo an open-label intervention consisting of 10 rTMS sessions, occurring 5 days a week over a 2-week period. Participants will complete pre-treatment and post-treatment assessments that include: the Colorado Visual Snow Scale (CVSS), the National Eye Institute Visual Functional Questionnaire-25 (VFQ-25), the General Anxiety Disorder-7 scale (GAD-7), and three psychophysical visual processing tasks. Discussion: Knowledge gained from this pilot study will inform future study planning and provide valuable lessons for future investigation of rTMS for the VS syndrome. An overview of study proceedings thus far demonstrates recruitment challenges associated with the COVID-19 pandemic, and additional challenges that are unique to the VS syndrome and to treatment schedules associated with TMS. Registration: This study has been approved by the Colorado Multiple Institutional Review Board. ClinicalTrials.gov Identifier: NCT04925232.


The effects of dopamine, ephinephrine, and esmolol on the hemodynamic energy in terms of the energy equivalent pressure.
The generation of pulsatile flow depends on the hemodynamic energy gradient rather than the pressure gradient. We hypothesized that either positive or negative inotropic agents can affect the hemodynamic energy, which can be measured using the energy equivalent pressure (EEP) and surplus hemodynamic energy (SHE). This study examined the change in hemodynamic energy induced by dopamine, epinephrine, and esmolol infusion in terms of the EEP and SHE. Dopamine (5, 10 microg/kg/min), epinephrine (0.02, 0.1 microg/kg/min) and esmolol (after bolus 1 mg/kg, 0.1, 0.3 mg/kg/min) were infused into six anesthetized dogs. The hemodynamic parameters were collected in the descending thoracic aorta. The mean arterial pressure, blood flow, EEP, and SHE increased significantly with the dopamine infusion. The mean arterial pressure and EEP decreased significantly after the esmolol infusion, while it increased after the epinephrine infusion (p < 0.05 respectively). There was a correlation between the EEP and flow on the descending aorta during the dopamine, esmolol and epinephrine infusions (p < 0.05 respectively). In conclusion, the change in hemodynamic energy induced by dopamine, esmolol, and epinephrine may be expressed in terms of the EEP and SHE. In addition, there was a strong correlation between the EEP and flow.


Identification of rice Allene Oxide Cyclase mutants and the function of jasmonate for defence against Magnaporthe oryzae.
Two photomorphogenic mutants of rice, coleoptile photomorphogenesis 2 (cpm2) and hebiba, were found to be defective in the gene encoding allene oxide cyclase (OsAOC) by map-based cloning and complementation assays. Examination of the enzymatic activity of recombinant GST-OsAOC indicated that OsAOC is a functional enzyme that is involved in the biosynthesis of jasmonic acid and related compounds. The level of jasmonate was extremely low in both mutants, in agreement with the fact that rice has only one gene encoding allene oxide cyclase. Several flower-related mutant phenotypes were observed, including morphological abnormalities of the flower and early flowering. We used these mutants to investigate the function of jasmonate in the defence response to the blast fungus Magnaporthe oryzae. Inoculation assays with fungal spores revealed that both mutants are more susceptible than wild-type to an incompatible strain of M. oryzae, in such a way that hyphal growth was enhanced in mutant tissues. The level of jasmonate isoleucine, a bioactive form of jasmonate, increased in response to blast infection. Furthermore, blast-induced accumulation of phytoalexins, especially that of the flavonoid sakuranetin, was found to be severely impaired in cpm2 and hebiba. Together, the present study demonstrates that, in rice, jasmonate mediates the defence response against blast fungus.


Development of an eHealth Program for Parents of Adolescents With Type 1 Diabetes.
Purpose The purpose of this study was to understand the experience of parenting an adolescent with type 1 diabetes (T1DM), to develop a prototype of an eHealth program for parents of adolescents with T1DM, and to evaluate the prototype content and acceptability from the perspective of parents and health care providers. Methods A multiphase method was used generating both qualitative and quantitative data at multiple time points. There were 27 parents of adolescents aged 12 to 18 years with T1DM and 16 health care providers who participated in semistructured interviews to identify parental challenges; 53 parents and 27 providers evaluated the prototype. Thematic content analysis was used to analyze interview transcripts, and descriptive statistics were used to summarize survey data. Results Challenges experienced by parents of adolescents with T1DM included understanding the developmental and hormonal changes of adolescence that affect diabetes care, feeling tension between adolescent independence and parent control, communicating without nagging or conflict, transferring diabetes care responsibility safely, dealing with feelings of stress and distress, and perceiving a lack of resources for T1DM care and insufficient personal time for self-care. In the prototype evaluation, both parents and providers found content to be relevant and provided feedback to guide the development of the full program. Conclusions Parents of adolescents with T1DM and providers expressed a need for parents to have more support in transitioning diabetes care from parent to adolescent. eHealth programs offer an ideal way to address these needs and ultimately can be linked to electronic medical records improving quality and efficiency of health care in this population.


MAPK kinase 3 is a tumor suppressor with reduced copy number in breast cancer.
Cancers are initiated as a result of changes that occur in the genome. Identification of gains and losses in the structure and expression of tumor-suppressor genes and oncogenes lies at the root of the understanding of cancer cell biology. Here, we show that the mitogen-activated protein kinase (MAPK) MKK3 suppresses the growth of breast cancer, in which it varies in copy number. A pervasive loss of MKK3 gene copy number in patients with breast cancer is associated with an impairment of MKK3 expression and protein level in malignant tissues. To assess the functional role of MKK3 in breast cancer, we showed in an animal model that MKK3 activity is required for suppression of tumor growth. Active MKK3 enhanced expression of the cyclin-dependent kinase inhibitors p21(Cip1/Waf1) and p27(Kip1), leading to increased cell-cycle arrest in G1 phase of the cell cycle. Our results reveal the functional significance of MKK3 as a tumor suppressor and improve understanding of the dynamic role of the MAPK pathway in tumor progression.


In vitro studies on space-conforming self-assembling silk hydrogels as a mesenchymal stem cell-support matrix suitable for minimally invasive brain application.
Advanced cell therapies require robust delivery materials and silk is a promising contender with a long clinical track record. Our aim was to optimise self-assembling silk hydrogels as a mesenchymal stem cell (MSC)-support matrix that would allow future minimally invasive brain application. We used sonication energy to programme the transition of silk (1-5% w/v) secondary structure from a random coil to a stable β-sheet configuration. This allowed fine tuning of self-assembling silk hydrogels to achieve space conformity in the absence of any silk hydrogel swelling and to support uniform cell distribution as well as cell viability. Embedded cells underwent significant proliferation over 14 days in vitro, with the best proliferation achieved with 2% w/v hydrogels. Embedded MSCs showed significantly better viability in vitro after injection through a 30G needle when the gels were in the pre-gelled versus post-gelled state. Silk hydrogels (4% w/v) with physical characteristics matching brain tissue were visualised in preliminary in vivo experiments to exhibit good space conformity in an ischemic cavity (intraluminal thread middle cerebral artery occlusion model) in adult male Sprague-Dawley rats (n = 3). This study informs on optimal MSC-hydrogel matrix conditions for minimally invasive application as a platform for future experiments targeting brain repair.


Circulating leptin levels are not influenced by thyroid status in hypothyroid and euthyroid women.
Leptin regulates body weight by suppressing food intake and increasing energy expenditure. Alterations in thyroid hormone levels are also associated with changes in body weight but the effect of thyroid hormone deficiency on serum leptin in humans is unclear. The aim of this study was to measure leptin levels and to investigate their associations with thyroid hormones in 22 women with severe hypothyroidism after total thyroidectomy, and in a group of 22 healthy euthyroid control female subjects matched for age and body mass index (BMI). Their plasma leptin, free thyroxine, triiodothyronine and TSH were measured. Leptin levels in subjects and controls were (pg/mL) 18761.64+/-16973.96 and 18729.19+/-18014.05, respectively, p=0.9; leptin did not correlate with free thyroxine, triiodothyroinine and TSH: r=0.1039 and p=0.6453, r=0.0113 and p=0.9602, and r=-0.0525 and p=0.8165 for leptin and FT4, leptin and FT3, and leptin and TSH, respectively in subjects; r=-0.00056 and p=0.9980, r=0.248727 and p=0.2643, and r=-0.046919 and p=0.8357 for leptin and FT4, leptin and FT3, and leptin and TSH, respectively in controls. Leptin levels did not differ between subjects and controls and they did not correlate with thyroid hormones. Leptin levels are not influenced by hypothyroidism and do not correlate with thyroid hormones in euthyroid and hypothyroid women.


Telomerase-specific oncolytic virotherapy for human cancer with the hTERT promoter.
Replication-selective tumor-specific viruses present a novel approach for treatment of neoplastic disease. Telomerase activation is considered to be a critical step in carcinogenesis and its activity correlates closely with human telomerase reverse transcriptase (hTERT) expression. We constructed an attenuated adenovirus 5 vector (Telomelysin, OBP-301), in which the hTERT promoter element drives expression of E1 genes. Telomelysin replicated efficiently and induced marked cell killing in a panel of human cancer cell lines, whereas replication as well as cytotoxicity was highly attenuated in normal human cells lacking telomerase activity. We further modified the E3 region of OBP-301 to contain green fluorescent protein (GFP) gene for monitoring viral replication (TelomeScan, OBP-401). When TelomeScan was intratumorally injected into human tumors orthotopically implanted into the rectum in mice, para-aortic lymph node metastasis could be visualized at laparotomy under a three-chip color cooled charged-coupled device camera. This article reviews recent highlights in this rapidly evolving field: cancer therapeutic and cancer diagnostic approaches using the telomerase-specific oncolytic adenoviruses.


School Contextual Features of Social Disorder and Mental Health Complaints-A Multilevel Analysis of Swedish Sixth-Grade Students.
This study addressed school-contextual features of social disorder in relation to sixth-grade students' experiences of bullying victimization and mental health complaints. It investigated, firstly, whether the school's concentrations of behavioural problems were associated with individual students' likelihood of being bullied, and secondly, whether the school's concentrations of behavioural problems and bullying victimization predicted students' emotional and psychosomatic health complaints. The data were derived from the Swedish National Survey of Mental Health among Children and Young People, carried out among sixth-grade students (approximately 12-13 years old) in Sweden in 2009. The analyses were based on information from 59,510 students distributed across 1999 schools. The statistical method used was multilevel modelling. While students' own behavioural problems were associated with an elevated risk of being bullied, attending a school with a higher concentration of students with behavioural problems also increased the likelihood of being bullied. Attending a school with higher levels of bullying victimization and behavioural problems predicted more emotional and psychosomatic complaints, even when adjusting for their individual level analogues. The findings indicate that school-level features of social disorder influence bullying victimization and mental health complaints among students.


Phylodynamic profile of HIV-1 subtype B, CRF01_AE and the recently emerging CRF51_01B among men who have sex with men (MSM) in Singapore.
HIV-1 subtype B and CRF01_AE are the predominant infecting subtypes among men who have sex with men (MSM) in Singapore. The genetic history, population dynamics and pattern of transmission networks of these genotypes remain largely unknown. We delineated the phylodynamic profiles of HIV-1 subtype B, CRF01_AE and the recently characterized CRF51_01B strains circulating among the MSM population in Singapore. A total of 105 (49.5%) newly-diagnosed treatment-naïve MSM were recruited between February 2008 and August 2009. Phylogenetic reconstructions of the protease gene (HXB2: 2239 - 2629), gp120 (HXB2: 6942 - 7577) and gp41 (HXB2: 7803 - 8276) of the env gene uncovered five monophyletic transmission networks (two each within subtype B and CRF01_AE and one within CRF51_01B lineages) of different sizes (involving 3 - 23 MSM subjects, supported by posterior probability measure of 1.0). Bayesian coalescent analysis estimated that the emergence and dissemination of multiple sub-epidemic networks occurred between 1995 and 2005, driven largely by subtype B and later followed by CRF01_AE. Exponential increase in effective population size for both subtype B and CRF01_AE occurred between 2002 to 2007 and 2005 to 2007, respectively. Genealogical estimates suggested that the novel CRF51_01B lineages were probably generated through series of recombination events involving CRF01_AE and multiple subtype B ancestors. Our study provides the first insight on the phylodynamic profiles of HIV-1 subtype B, CRF01_AE and CRF51_01B viral strains circulating among MSM in Singapore.


Knowledge, beliefs, and practices in relation to malaria transmission and vector control in Guatemala.
As part of an effort to involve community members in malaria control activities, we studied knowledge, beliefs, and practices of residents of both the Pacific coastal plain and northeastern Guatemala related to malaria transmission and Anopheles albimanus control. Most residents recognized the role of mosquitoes in malaria transmission, but few knew how mosquitoes acquired their infections or understood the risk of having an untreated person in their midst. If this were more widely known, residents might put greater pressure on infected patients to seek timely and appropriate antimalarial treatment. Seventy-three percent of families owned one or more bed nets; however, even though most informants believed that bed nets help protect against malaria, the major reason for using them was to prevent nuisance mosquito bites. It is concluded that efforts should be made to promote bed net use by seeking ways to make them more affordable and by emphasizing their effectiveness as a barrier to nuisance mosquitoes. Although residents have a very positive opinion of the National Malaria Service spray teams, it is proposed that cooperation might be improved if malaria workers would emphasize the fact that house spraying reduces the numbers of nuisance mosquitoes and other pest insects, rather than focusing solely on malaria prevention, which most informants believed was less important. This study emphasizes the importance of understanding community beliefs and practices when planning or evaluating vector control activities.


Transcutaneous Electrical Nerve Stimulation Improves Walking Performance in Patients With Intermittent Claudication.
The purpose of this study was to investigate the effects of 2 types of transcutaneous electrical nerve stimulation (TENS) on walking distance and measures of pain in patients with peripheral arterial disease (PAD) and intermittent claudication (IC). In a phase 2a study, 40 participants with PAD and IC completed a graded treadmill test on 2 separate testing occasions. Active TENS was applied to the lower limb on the first occasion; and placebo TENS, on the second. The participants were divided into 2 experimental groups. One group received high-frequency TENS; and the other, low-frequency TENS. Measures taken were initial claudication distance, functional claudication distance, and absolute claudication distance. The McGill Pain Questionnaire (MPQ) vocabulary was completed at the end of the intervention, and the MPQ-Pain Rating Index score was calculated. Four participants were excluded from the final analysis because of noncompletion of the experimental procedure. Median walking distance increased with high-frequency TENS for all measures (P < .05, Wilcoxon signed rank test, all measures). Only absolute claudication distance increased significantly with low-frequency TENS compared with placebo (median, 179-228; Ws = 39; z = 2.025; P = .043; r = 0.48). No difference was observed between reported median MPQ-Pain Rating Index scores: 21.5 with placebo TENS and 21.5 with active TENS (P = .41). Transcutaneous electrical nerve stimulation applied to the lower limb of the patients with PAD and IC was associated with increased walking distance on a treadmill but not with any reduction in pain. Transcutaneous electrical nerve stimulation may be a useful adjunctive intervention to help increase walking performance in patients with IC.


3d single-ion magnets.
One of the determining factors in whether single-molecule magnets (SMMs) may be used as the smallest component of data storage, is the size of the barrier to reversal of the magnetisation, Ueff. This physical quantity depends on the magnitude of the magnetic anisotropy of a complex and the size of its spin ground state. In recent years, there has been a growing focus on maximising the anisotropy generated for a single 3d transition metal (TM) ion, by an appropriate ligand field, as a means of achieving higher barriers. Because the magnetic properties of these compounds arise from a single ion in a ligand field, they are often referred to as single-ion magnets (SIMs). Here, the synthetic chemist has a significant role to play, both in the design of ligands to enforce propitious splitting of the 3d orbitals and in the judicious choice of TM ion. Since the publication of the first 3d-based SIM, which was based on Fe(ii), many other contributions have been made to this field, using different first row TM ions, and exploring varied coordination environments for the paramagnetic ions.


Healthy work environments, nurse-physician communication, and patients' outcomes.
Adverse events and serious errors are common in critical care. Although factors in the work environment are important predictors of adverse outcomes for patients, communication between nurses and physicians may be the most significant factor associated with excess hospital mortality in critical care settings. To examine the relationships between nurses' perceptions of their practice environment, nurse-physician communication, and selected patients' outcomes. A nonexperimental, descriptive design was used, and all nurses (N=866) working in 25 intensive care units in southeastern Michigan were surveyed. The Conditions for Work Effectiveness Questionnaire-II and the Practice Environment Scale of the Nursing Work Index were used to measure characteristics of the work environment; the ICU Nurse-Physician Questionnaire was used to measure nurse-physician communication. Nurses self-rated the frequency of ventilator-associated pneumonia, catheter-related sepsis, and medication errors in patients under their care. A total of 462 nurses (53%) responded. According to multilevel modeling, both practice environment scales accounted for 47% of the variance in nurse-physician communication scores (P=.001). Nurse-physician communication was predictive of nurse-assessed medication errors only (R2=0.11). Neither environment scale was predictive of any of the patient outcomes. Healthy work environments are important for nurse-physician communication. In intensive care units, characteristics of the work environment did not vary enough to be significantly predictive of outcomes, suggesting that even in various types of critical care units, characteristics of the work environment may be more similar than different.


Growing up in an affluent family: unique psychosocial issues for the adolescent.
Most people would agree that it is preferable to grow up in a wealthy family than in one that is impoverished. However, adolescents who live in affluent families are in danger of developing a sense of entitlement that may impede future vocational and social success. Parental presence may be minimal, with discipline and child-rearing delegated to paid caretakers. The pressure to achieve in school may overwhelm the less than gifted adolescent. Excessive parental participation in school affairs may deter the adolescent from developing a sense of independence and competency. Eating disorders are more likely to develop in affluent youth. Participation in delinquent behaviors may be due to boredom with the affluent lifestyle, and such behavior may not be punished since youth from affluent families are often shielded from proper discipline by law enforcement authorities. Because of their social standing in the community and as a consequence of their wealth, affluent youth are in unique positions to become leaders and to participate in altruistic endeavors. Health care providers taking care of adolescents in wealthy families should be aware of these issues and should discuss them with adolescents and their families.


Neurula rotation determines left-right asymmetry in ascidian tadpole larvae.
Tadpole larvae of the ascidian Halocynthia roretzi show morphological left-right asymmetry. The tail invariably bends towards the left side within the vitelline membrane. The structure of the larval brain is remarkably asymmetric. nodal, a conserved gene that shows left-sided expression, is also expressed on the left side in H. roretzi but in the epidermis unlike in vertebrates. We show that nodal signaling at the late neurula stage is required for stereotypic morphological left-right asymmetry at later stages. We uncover a novel mechanism to break embryonic symmetry, in which rotation of whole embryos provides the initial cue for left-sided expression of nodal. Two hours prior to the onset of nodal expression, the neurula embryo rotates along the anterior-posterior axis in a counterclockwise direction when seen in posterior view, and then this rotation stops when the left side of the embryo is oriented downwards. It is likely that epidermis monocilia, which appear at the neurula rotation stage, generate the driving force for the rotation. When the embryo lies on the left side, protrusion of the neural fold physically prevents it from rotating further. Experiments in which neurula rotation is perturbed by various means, including centrifugation and sandwiching between glass, indicate that contact of the left epidermis with the vitelline membrane as a consequence of neurula rotation promotes nodal expression in the left epidermis. We suggest that chemical, and not mechanical, signals from the vitelline membrane promote nodal expression. Neurula rotation is also conserved in other ascidian species.


Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial.
No specific antiviral drug has been proven effective for treatment of patients with severe coronavirus disease 2019 (COVID-19). Remdesivir (GS-5734), a nucleoside analogue prodrug, has inhibitory effects on pathogenic animal and human coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro, and inhibits Middle East respiratory syndrome coronavirus, SARS-CoV-1, and SARS-CoV-2 replication in animal models. We did a randomised, double-blind, placebo-controlled, multicentre trial at ten hospitals in Hubei, China. Eligible patients were adults (aged ≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection, with an interval from symptom onset to enrolment of 12 days or less, oxygen saturation of 94% or less on room air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen of 300 mm Hg or less, and radiologically confirmed pneumonia. Patients were randomly assigned in a 2:1 ratio to intravenous remdesivir (200 mg on day 1 followed by 100 mg on days 2-10 in single daily infusions) or the same volume of placebo infusions for 10 days. Patients were permitted concomitant use of lopinavir-ritonavir, interferons, and corticosteroids. The primary endpoint was time to clinical improvement up to day 28, defined as the time (in days) from randomisation to the point of a decline of two levels on a six-point ordinal scale of clinical status (from 1=discharged to 6=death) or discharged alive from hospital, whichever came first. Primary analysis was done in the intention-to-treat (ITT) population and safety analysis was done in all patients who started their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT04257656. Between Feb 6, 2020, and March 12, 2020, 237 patients were enrolled and randomly assigned to a treatment group (158 to remdesivir and 79 to placebo); one patient in the placebo group who withdrew after randomisation was not included in the ITT population. Remdesivir use was not associated with a difference in time to clinical improvement (hazard ratio 1·23 [95% CI 0·87-1·75]). Although not statistically significant, patients receiving remdesivir had a numerically faster time to clinical improvement than those receiving placebo among patients with symptom duration of 10 days or less (hazard ratio 1·52 [0·95-2·43]). Adverse events were reported in 102 (66%) of 155 remdesivir recipients versus 50 (64%) of 78 placebo recipients. Remdesivir was stopped early because of adverse events in 18 (12%) patients versus four (5%) patients who stopped placebo early. In this study of adult patients admitted to hospital for severe COVID-19, remdesivir was not associated with statistically significant clinical benefits. However, the numerical reduction in time to clinical improvement in those treated earlier requires confirmation in larger studies. Chinese Academy of Medical Sciences Emergency Project of COVID-19, National Key Research and Development Program of China, the Beijing Science and Technology Project.


Definitions of cardiovascular insufficiency and relation to outcomes in critically ill newborn infants.
We previously reported on the overall incidence, management, and outcomes in infants with cardiovascular insufficiency (CVI). However, there are limited data on the relationship of the specific different definitions of CVI to short-term outcomes in term and late preterm newborn infants. This study aims to evaluate how four definitions of CVI relate to short-term outcomes and death. The previously reported study was a multicenter, prospective cohort study of 647 infants ≥ 34 weeks gestation admitted to a Neonatal Research Network (NRN) newborn intensive care unit (NICU) and mechanically ventilated (MV) during their first 72 hours. The relationship of five short-term outcomes at discharge and four different definitions of CVI were further analyzed. All the four definitions were associated with greater number of days on MV and days on O2. The definition using a threshold blood pressure (BP) measurement alone was not associated with days of full feeding, days in the NICU or death. The definition based on the treatment of CVI was associated with all the outcomes including death. The definition using a threshold BP alone was not consistently associated with adverse short-term outcomes. Using only a threshold BP to determine therapy may not improve outcomes.


Multiple mechanisms of consciousness: the neural correlates of emotional awareness.
Emotional stimuli, including facial expressions, are thought to gain rapid and privileged access to processing resources in the brain. Despite this access, we are conscious of only a fraction of the myriad of emotion-related cues we face everyday. It remains unclear, therefore, what the relationship is between activity in neural regions associated with emotional representation and the phenomenological experience of emotional awareness. We used functional magnetic resonance imaging and binocular rivalry to delineate the neural correlates of awareness of conflicting emotional expressions in humans. Behaviorally, fearful faces were significantly more likely to be perceived than disgusted or neutral faces. Functionally, increased activity was observed in regions associated with facial expression processing, including the amygdala and fusiform gyrus during emotional awareness. In contrast, awareness of neutral faces and suppression of fearful faces were associated with increased activity in dorsolateral prefrontal and inferior parietal cortices. The amygdala showed increased functional connectivity with ventral visual system regions during fear awareness and increased connectivity with perigenual prefrontal cortex (pgPFC; Brodmann's area 32/10) when fear was suppressed. Despite being prioritized for awareness, emotional items were associated with reduced activity in areas considered critical for consciousness. Contributions to consciousness from bottom-up and top-down neural regions may be additive, such that increased activity in specialized regions within the extended ventral visual system may reduce demands on a frontoparietal system important for awareness. The possibility is raised that interactions between pgPFC and the amygdala, previously implicated in extinction, may also influence whether or not an emotional stimulus is accessible to consciousness.


Characterization of the C-terminal domain of a potassium channel from Streptomyces lividans (KcsA).
KcsA, a potassium channel from Streptomyces lividans, is a good model for probing the general working mechanism of potassium channels. To date, the physiological activator of KcsA is still unknown, but in vitro studies showed that it could be opened by lowering the pH of the cytoplasmic compartment to 4. The C-terminal domain (CTD, residues 112-160) was proposed to be the modulator for this pH-responsive event. Here, we support this proposal by examining the pH profiles of: (a) thermal stability of KcsA with and without its CTD and (b) aggregation properties of a recombinant fragment of CTD. We found that the presence of the CTD weakened and enhanced the stability of KcsA at acidic and basic pH values, respectively. In addition, the CTD fragment oligomerized at basic pH values with a transition profile close to that of channel opening. Our results are consistent with the CTD being a pH modulator. We propose herein a mechanism on how this domain may contribute to the pH-dependent opening of KcsA.


Metal leaching from the bridge paint waste in the presence of steel grit.
The disposal of paint waste from bridge rehabilitation is a significant issue because of the potential release of contaminants and the consequent impact to human health and the environment. In this study, leaching behavior of paint waste was evaluated for 24 bridges in New York State. Although elevated Pb (5-168,090 mg kg(-1)) and other metal concentrations were observed in the paint samples, leaching experiments that included the toxicity characteristic leaching procedure (TCLP) and the multiple extraction procedure (MEP) revealed toxicity characteristic (TC) limits were not exceeded. The relatively low concentrations observed are attributed to the use of iron-based abrasives (steel grit) in the paint removal process. In this research, trace metals are hypothesized to be sequestered through interactions with iron oxide coatings formed on the steel grit surface resulting in reduced leachable concentrations. Through sequential extraction iron oxides were observed at 11.03% by wt and X-ray diffraction (XRD) further corroborated the presence of iron oxide coatings on the steel grit surface. Sequential extraction demonstrated that less than 6.8% of Pb, Cr, and Ba were associated with the exchangeable and carbonate forms, while greater contributions were found with iron oxides. The largest fraction, however, greater than 80%, was associated with the residual phase comprised of minerals in the paint including SiO2 and TiO2.


Transmission of SARS-CoV-2 in Australian educational settings: a prospective cohort study.
School closures have occurred globally during the COVID-19 pandemic. However, empiric data on transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among children and in educational settings are scarce. In Australia, most schools have remained open during the first epidemic wave, albeit with reduced student physical attendance at the epidemic peak. We examined SARS-CoV-2 transmission among children and staff in schools and early childhood education and care (ECEC) settings in the Australian state of New South Wales (NSW). Laboratory-confirmed paediatric (aged ≤18 years) and adult COVID-19 cases who attended a school or ECEC setting while considered infectious (defined as 24 h before symptom onset based on national guidelines during the study period) in NSW from Jan 25 to April 10, 2020, were investigated for onward transmission. All identified school and ECEC settings close contacts were required to home quarantine for 14 days, and were monitored and offered SARS-CoV-2 nucleic acid testing if symptomatic. Enhanced investigations in selected educational settings included nucleic acid testing and SARS-CoV-2 antibody testing in symptomatic and asymptomatic contacts. Secondary attack rates were calculated and compared with state-wide COVID-19 rates. 15 schools and ten ECEC settings had children (n=12) or adults (n=15) attend while infectious, with 1448 contacts monitored. Of these, 633 (43·7%) of 1448 had nucleic acid testing, or antibody testing, or both, with 18 secondary cases identified (attack rate 1·2%). Five secondary cases (three children; two adults) were identified (attack rate 0·5%; 5/914) in three schools. No secondary transmission occurred in nine of ten ECEC settings among 497 contacts. However, one outbreak in an ECEC setting involved transmission to six adults and seven children (attack rate 35·1%; 13/37). Across all settings, five (28·0%) of 18 secondary infections were asymptomatic (three infants [all aged 1 year], one adolescent [age 15 years], and one adult). SARS-CoV-2 transmission rates were low in NSW educational settings during the first COVID-19 epidemic wave, consistent with mild infrequent disease in the 1·8 million child population. With effective case-contact testing and epidemic management strategies and associated small numbers of attendances while infected, children and teachers did not contribute significantly to COVID-19 transmission via attendance in educational settings. These findings could be used to inform modelling and public health policy regarding school closures during the COVID-19 pandemic. NSW Government Department of Health.


Pattern of Utilization of Cervical Cancer Screening Services among Female Sex Workers in Some Selected Brothels in Abuja, Nigeria.
The utilization of cervical cancer screening services remains low among Female Sex Workers (FSWs) in Sub-Saharan Africa, with few or no studies conducted in Nigeria. However, the prevalence of human papillomavirus in this population is reportedly high because of associated risk factors. This study examined the pattern of cervical cancer screening service utilizations among FSWs in the Abuja metropolis. This descriptive cross-sectional survey used a purposive sampling technique to select 406 respondents via a structured questionnaire including questions regarding whether they had been screened for cervical cancer, the frequency of screening and type of screening method. Data were analyzed using SPSS version 22 and presented using frequency tables and percentages. The response rate among the participants was 97.6%. The mean age of the FSWs was 32 ± 5.1 years. Regarding the pattern of screening age, the mean age at the first screening was 28 ± 4.3 years. Only 81 (20%) participants had been screened annually, and visual inspection with acetic acid was most frequently used (20.9%). Respondents preferred to undergo screening in their brothels. The awareness of screening services was high (n = 290, 71.4%); however, the utilization of cervical cancer screening services remained low, as 246 (60.6%) FSWs had never been screened. The nonutilization of screening services was related to poor accessibility and a lack of awareness and interest. Although a high level of awareness that would be expected to influence uptake, cervical cancer screening services were rather underutilized by the study respondents. Therefore, a concerted effort is needed to ensure that FSWs understand cervical cancer and its consequences. Hopefully, this effort will improve the uptake.


INternational ORthopaedic MUlticentre Study (INORMUS) in Fracture Care: Protocol for a Large Prospective Observational Study.
Despite the fact that orthopaedic trauma injuries represent a serious cause of mortality and morbidity worldwide, there are few data in low-middle income countries quantifying the burden of fractures and describing current treatment practices. To address this critical knowledge gap, a large multinational prospective observational study of 40,000 patients with musculoskeletal trauma in Africa, Asia, and Latin America is proposed. The International Orthopaedic Multicentre Study in Fracture Care (INORMUS) study seeks to determine the incidence of major complications (mortality, reoperation, and infection) within 30 days after a musculoskeletal injury and to determine patient, treatment, and system factors associated with these major complications in low-middle income countries. This study coincides with the World Health Organization's Global Road Traffic Safety Decade (2011-2020) and other international efforts to reduce the burden of injury on developing populations. Insight gained from the INORMUS study will not only inform the global burden of orthopaedic trauma but also drive the development of future randomized trials to evaluate simple solutions and practical interventions to decrease deaths and improve the quality of life for trauma patients worldwide.


Portable Analyzer for On-Site Determination of Dissolved Organic Carbon-Development and Field Testing.
Dissolved organic carbon (DOC) is a sum parameter that is frequently used in water analytics. Highly resolved and accurate DOC data are necessary, for instance, for water quality monitoring and for the evaluation of the efficiency of treatment processes. The conventional DOC determination methods consist of on-site sampling and subsequent analysis in a stationary device in a laboratory. However, especially in regions where no or only poorly equipped laboratories are available, this method bears the risk of getting erroneous results. For this reason, the objective of the present study was to set up a reliable and portable DOC analyzer for on-site analysis. The presented DOC system is equipped with an electrolysis-based decomposition cell with boron-doped diamond electrodes (BDD) that oxidizes the organic compounds to carbon dioxide. Within this study, the influence of different electrode materials and the composition of the applied electrolytes on the DOC decomposition in an undivided electrolytic cell were systematically investigated. Furthermore, some technical aspects of the portable prototype are discussed. After a detailed validation, the prototype was used in an ongoing monitoring program in Northern India. The limit of detection is 0.1 mg L-1 C with a relative standard deviation of 2.3% in a linear range up to 1000 mg L C-1. The key features of the portable DOC analyzer are: No need for ultra-pure gases, catalysts or burning technology, an analyzing time per sample below 5 min, and a reliable on-site DOC determination.


The deleterious effects of bed rest on human skeletal muscle fibers are exacerbated by hypercortisolemia and ameliorated by dietary supplementation.
Prolonged inactivity associated with bed rest in a clinical setting or spaceflight is frequently associated with hypercortisolemia and inadequate caloric intake. Here, we determined the effect of 28 days of bed rest (BR); bed rest plus hypercortisolemia (BRHC); and bed rest plus essential amino acid (AA) and carbohydrate (CHO) supplement (BRAA) on the size and function of single slow- and fast-twitch muscle fibers. Supplementing meals, the BRAA group consumed 16.5 g essential amino acids and 30 g sucrose at 1100, 1600, and 2100 h, and the BRHC subjects received 5 daily doses of 10-15 mg of oral hydrocortisone sodium succinate throughout bed rest. Bed rest induced atrophy and loss of force (mN) and power (muN.FL.s(-1)) in single fibers was exacerbated by hypercortisolemia where soleus peak force declined by 23% in the type I fiber from a prevalue of 0.78 +/- 0.02 to 0.60 +/- 0.02 mN post bed rest (compared to a 7% decline with bed rest alone) and 27% in the type II fiber (1.10 +/- 0.08 vs. 0.81 +/- 0.05 mN). In the BRHC group, peak power dropped by 19, 15, and 11% in the soleus type I, and vastus lateralis (VL) type I and II fibers, respectively. The AA/CHO supplement protected against the bed rest-induced loss of peak force in the type I soleus and peak power in the VL type II fibers. These results provide evidence that an AA/CHO supplement might serve as a successful countermeasure to help preserve muscle function during periods of relative inactivity.


Wetting and cavitation pathways on nanodecorated surfaces.
In this contribution we study the wetting and nucleation of vapor bubbles on nanodecorated surfaces via free energy molecular dynamics simulations. The results shed light on the stability of superhydrophobicity in submerged surfaces with nanoscale corrugations. The re-entrant geometry of the cavities under investigation is capable of sustaining a confined vapor phase within the surface roughness (Cassie state) both for hydrophobic and hydrophilic combinations of liquid and solid. The atomistic system is of nanometric size; on this scale thermally activated events can play an important role ultimately determining the lifetime of the Cassie state. Such a superhydrophobic state can break down by full wetting of the texture at large pressures (Cassie-Wenzel transition) or by nucleating a vapor bubble at negative pressures (cavitation). Specialized rare event techniques show that several pathways for wetting and cavitation are possible, due to the complex surface geometry. The related free energy barriers are of the order of 100kBT and vary with pressure. The atomistic results are found to be in semi-quantitative accord with macroscopic capillarity theory. However, the latter is not capable of capturing the density fluctuations, which determine the destabilization of the confined liquid phase at negative pressures (liquid spinodal).


DNA polymorphisms and haplotypes of apolipoprotein A5's attribution to the plasma triglyceride levels in Koreans.
Recent studies using human and mice reported that apolipoprotein A-V (APOA5) gene plays an important role in controlling triglyceride (TG) concentrations. The purpose of the present study was to investigate the correlation between single nucleotide polymorphisms (SNPs) and haplotypes in the APOA5 gene and TG in subjects and to search for possible associations of the APOA5 gene variants and common haplotypes with hypertriglyceridemia (HTG). We examined the case-control subjects including 100 HTG patients and 243 unrelated healthy control. The genes were screened for SNPs by direct sequencing in 48 genetically unrelated individuals. Six SNPs (-1390C>T, -1020G>A, -3A>G, V150M, G182C and 1259T>C) were genotyped in case and control populations. In this study, our results indicated a strong association between APOA5 SNP -3A>G and G182C and elevated TG levels (p<0.001). Analysis of the SNPs from APOA5 gene has identified major haplotype showing very strong association with HTG, CGGGTT (p<0.001). Likelihood ratio test (LRT) of these six SNPs revealed that haplotypes were strong independent predictors of HTG (p<0.001). Haplotype-trend logistic regression (HTR) analysis revealed a significant association between the CGGGGC (haplotype 2) and CGGGTT (haplotype 4) and HTG (OR=2.48, 95% CI=1.06-5.76 and OR=8.54, 95% CI=2.66-27.42, respectively). We confirm that the APOA5 variants are associated with triglyceride levels and the haplotype may be strong independent predictors of HTG among Koreans.


Leiomyosarcoma of inferior vena cava: a case series of four cases.
Vascular leiomyosarcomas are rare tumors, arising most frequently from inferior vena cava (IVC). They are mostly seen in sixth decade, with a female predominance. Their diagnosis is often challenging, as patients may present with non-specific complaints such as dyspnea, malaise, weight loss, abdominal pain, or back pain, preceding the diagnosis by several years. Leiomyosarcoma of the IVC most frequently occurs in the middle segment. The final diagnosis can be made by an ultrasound or computed tomography guided biopsy. Because of limited experience with this disease, optimal management of IVC leiomyosarcoma is unknown. Curative surgical resection remains the current treatment of choice for primary leiomyosarcoma of IVC. Neoadjuvant therapy may be given to downsize the tumor and increase resectability rates. Nonetheless, when complete resection is not possible, debulking combined with radiation therapy still provides good palliation. We, hereby, report four cases of this rare entity with emphasis on management.


Modulation of the Erwinia ligand-gated ion channel (ELIC) and the 5-HT3 receptor via a common vestibule site.
Pentameric ligand-gated ion channels (pLGICs) or Cys-loop receptors are involved in fast synaptic signaling in the nervous system. Allosteric modulators bind to sites that are remote from the neurotransmitter binding site, but modify coupling of ligand binding to channel opening. In this study, we developed nanobodies (single domain antibodies), which are functionally active as allosteric modulators, and solved co-crystal structures of the prokaryote (Erwinia) channel ELIC bound either to a positive or a negative allosteric modulator. The allosteric nanobody binding sites partially overlap with those of small molecule modulators, including a vestibule binding site that is not accessible in some pLGICs. Using mutagenesis, we extrapolate the functional importance of the vestibule binding site to the human 5-HT3 receptor, suggesting a common mechanism of modulation in this protein and ELIC. Thus we identify key elements of allosteric binding sites, and extend drug design possibilities in pLGICs with an accessible vestibule site.


Initial formation of IGROV1 ovarian cancer multicellular aggregates involves vitronectin.
Ovarian cancer progression is frequently associated with the development of malignant ascites. Multicellular aggregates of carcinoma cells (spheroids) found within ascites are thought to be able to promote peritoneal carcinomatosis. We have previously demonstrated the involvement of the vitronectin/alphav integrin adhesive system in the dissemination of ovarian cancer cells and continue to investigate the influence of these molecules by studying their role(s) in spheroid behavior. The aim of this study was to generate ovarian cancer multicellular aggregates and to focus on the role of vitronectin and alphav integrins in their initiation. IGROV1 cancer cells cultured in the absence of adhesive substratum formed multicellular aggregates comparable to spheroids. After 21 days, a fraction of the cells within clusters remained viable and proliferated recurrently. Within the multicellular aggregates, vitronectin and alphav integrins were co-localized at intercellular sites, suggesting their involvement in cell-cell interactions. Initial formation of IGROV1 aggregates was inhibited using anti-vitronectin and anti-alphav integrin blocking antibodies or the cyclic peptide cRGDfV. Vitronectin expression persisted during cluster disaggregation on fibronectin. These results demonstrate the ability of IGROV1 cells to generate multicellular aggregates and point to a contributory role for the vitronectin/alphav integrin system in the initial step of this process. These events could represent a prerequisite for further dissemination.


First Report of Chickpea chlorotic stunt virus Infecting Legume Crops in Tunisia.
During a survey of legume crops in the northeast and northwest regions of Tunisia in April 2010, plants showing yellowing, reddening, and stunting symptoms were observed. A total of 281 symptomatic samples were collected: 142 plants from 10 chickpea (Cicer arietinum L.) fields, 84 plants from six faba bean (Vicia faba L.) fields, and 55 plants from six pea (Pisum sativum L.) fields. All samples were tested by the tissue-blot immunoassay procedure with the following monoclonal antibodies (MAbs): a broad-spectrum legume-luteovirus MAb (5G4), Faba bean necrotic yellows virus (FBNYV; genus Nanovirus, family Nanovirudae) (3-2E9; provided by J. Vetten, BBA, Braunschweig, Germany), Beet western yellows virus (BWYV; genus Polerovirus, family Luteoviridae) (A5977; Agdia, Elkhart, IN), Bean leafroll virus (BLRV; genus Luteovirus, family Luteoviridae) (4B10), Soybean dwarf virus (SbDV; genus Luteovirus, family Luteoviridae) (ATCC PVAS-650; American Type Culture Collection ATCC, Rockville, MD,), and a mixture of three MAbs (5-2B8, -3D5, and -5B8) to a Syrian isolate of Chickpea chlorotic stunt virus (CpCSV) (1). Serological tests showed that CpCSV was detected in 121 samples (43.06%) (62 chickpea, 57 faba bean, and 2 pea), followed by FBNYV (detected in three faba bean and three pea), BWYV (detected in three chickpea and one faba bean), and BLRV (detected in one pea sample). FBNYV, BLRV, and BWYV have been previously detected in faba bean and chickpea in Tunisia (4), but to our knowledge, this is the first report of CpCSV affecting legumes in Tunisia, which was found in seven chickpea, seven faba bean, and two pea fields. CpCSV has been reported to naturally infect legume crops such as chickpea, lentil, field pea, and faba bean as well as some leguminous weeds and a few wild non-legume plants species in many countries in West Asia and North Africa and causes economic losses on chickpea in Eritrea, Ethiopia, and Syria (1-3). Serological results of CpCSV was confirmed in four (two pea, one faba bean, and one chickpea) samples by reverse transcription (RT)-PCR using CpCSV specific primers (F:5'-TAGGCGTACTGTTCAGCGGG-3' and R:5'-TCCTTTGTCCATTCGAGGTGA-3') (3), which produced an amplicon of expected size (413 bp). No amplification was observed from healthy plant extracts. Sequence analysis revealed that the four Tunisian isolates (TuV 258-201 collected from faba bean [GenBank Accession No. HQ199310], TuC 215-201 collected from chickpea [HQ199307], and TuP 163-201 [HQ199308] and TuP 166-201 collected from pea [HQ199309]) were most similar to each other with a high sequence identity (99%) and clustered with isolates of CpCSV from Syria (GenBank Accession No. EU541270), Egypt (EU541269), and Morocco (EU541267), to which they were most closely related (98%). The Tunisian isolates also showed high sequence identity (96%) in the coat protein region with Ethiopian (GenBank Accession No. EU541257) and Sudanese (EU541263) isolates. However, all isolates are distinct from BWYV, BLRV, and SbDV (less than 70% sequence identity). Since CpCSV is transmitted by aphids only, additional studies are needed to identify the host range of the virus and the efficient aphid vectors to better understand the epidemiology of this virus under Tunisian conditions References: (1) A. D. Abraham et al. Arch.Virol. 154:791; 2009. (2) N. Y. Asaad et al. J. Phytopathol. 157:756, 2009. (3) S. G. Kumari et al. Phytopathol. Mediterr. 47:42, 2008. (4) A. Najar et al. Phytopathol. Mediterr. 39:423, 2000.


Cannabinoid receptor CB1 mediates baseline and activity-induced survival of new neurons in adult hippocampal neurogenesis.
Adult neurogenesis is a particular example of brain plasticity that is partially modulated by the endocannabinoid system. Whereas the impact of synthetic cannabinoids on the neuronal progenitor cells has been described, there has been lack of information about the action of plant-derived extracts on neurogenesis. Therefore we here focused on the effects of Delta9-tetrahydrocannabinol (THC) and Cannabidiol (CBD) fed to female C57Bl/6 and Nestin-GFP-reporter mice on proliferation and maturation of neuronal progenitor cells and spatial learning performance. In addition we used cannabinoid receptor 1 (CB1) deficient mice and treatment with CB1 antagonist AM251 in Nestin-GFP-reporter mice to investigate the role of the CB1 receptor in adult neurogenesis in detail. THC and CBD differed in their effects on spatial learning and adult neurogenesis. CBD did not impair learning but increased adult neurogenesis, whereas THC reduced learning without affecting adult neurogenesis. We found the neurogenic effect of CBD to be dependent on the CB1 receptor, which is expressed over the whole dentate gyrus. Similarly, the neurogenic effect of environmental enrichment and voluntary wheel running depends on the presence of the CB1 receptor. We found that in the absence of CB1 receptors, cell proliferation was increased and neuronal differentiation reduced, which could be related to CB1 receptor mediated signaling in Doublecortin (DCX)-expressing intermediate progenitor cells. CB1 affected the stages of adult neurogenesis that involve intermediate highly proliferative progenitor cells and the survival and maturation of new neurons. The pro-neurogenic effects of CBD might explain some of the positive therapeutic features of CBD-based compounds.


Role of the TonB amino terminus in energy transduction between membranes.
Escherichia coli TonB protein is an energy transducer, coupling cytoplasmic membrane energy to active transport of vitamin B12 and iron-siderophores across the outer membrane. TonB is anchored in the cytoplasmic membrane by its hydrophobic amino terminus, with the remainder occupying the periplasmic space. In this report we establish several functions for the hydrophobic amino terminus of TonB. A G-26-->D substitution in the amino terminus prevents export of TonB, suggesting that the amino terminus contains an export signal for proper localization of TonB within the cell envelope. Substitution of the first membrane-spanning domain of the cytoplasmic membrane protein TetA for the TonB amino terminus eliminates TonB activity without altering TonB export, suggesting that the amino terminus contains sequence-specific information. Detectable TonB cross-linking to ExbB is also prevented, suggesting that the two proteins interact primarily through their transmembrane domains. In vivo cleavage of the amino terminus of TonB carrying an engineered leader peptidase cleavage site eliminates (i) TonB activity, (ii) detectable interaction with a membrane fraction having a density intermediate to those of the cytoplasmic and outer membranes, and (iii) cross-linking to ExbB. In contrast, the amino terminus is not required for cross-linking to other proteins with which TonB can form complexes, including FepA. Additionally, although the amino terminus clearly is a membrane anchor, it is not the only means by which TonB associates with the cytoplasmic membrane. TonB lacking its amino-terminal membrane anchor still remains largely associated with the cytoplasmic membrane.


Gross primary production responses to warming, elevated CO2 , and irrigation: quantifying the drivers of ecosystem physiology in a semiarid grassland.
Determining whether the terrestrial biosphere will be a source or sink of carbon (C) under a future climate of elevated CO2 (eCO2 ) and warming requires accurate quantification of gross primary production (GPP), the largest flux of C in the global C cycle. We evaluated 6 years (2007-2012) of flux-derived GPP data from the Prairie Heating and CO2 Enrichment (PHACE) experiment, situated in a grassland in Wyoming, USA. The GPP data were used to calibrate a light response model whose basic formulation has been successfully used in a variety of ecosystems. The model was extended by modeling maximum photosynthetic rate (Amax ) and light-use efficiency (Q) as functions of soil water, air temperature, vapor pressure deficit, vegetation greenness, and nitrogen at current and antecedent (past) timescales. The model fits the observed GPP well (R2 = 0.79), which was confirmed by other model performance checks that compared different variants of the model (e.g. with and without antecedent effects). Stimulation of cumulative 6-year GPP by warming (29%, P = 0.02) and eCO2 (26%, P = 0.07) was primarily driven by enhanced C uptake during spring (129%, P = 0.001) and fall (124%, P = 0.001), respectively, which was consistent across years. Antecedent air temperature (Tairant ) and vapor pressure deficit (VPDant ) effects on Amax (over the past 3-4 days and 1-3 days, respectively) were the most significant predictors of temporal variability in GPP among most treatments. The importance of VPDant suggests that atmospheric drought is important for predicting GPP under current and future climate; we highlight the need for experimental studies to identify the mechanisms underlying such antecedent effects. Finally, posterior estimates of cumulative GPP under control and eCO2 treatments were tested as a benchmark against 12 terrestrial biosphere models (TBMs). The narrow uncertainties of these data-driven GPP estimates suggest that they could be useful semi-independent data streams for validating TBMs.


Synthesis of a "super bulky" guanidinate possessing an expandable coordination pocket.
Friedel-Crafts alkylation of 4-tert-butylaniline with 2 equiv of benzhydrol affords bulky 2,6-bis(diphenylmethyl)-4-tert-butylaniline (Ar*NH2) in good yield, which can be readily synthesized on a tens of grams scale. The reaction of 6 equiv of Ar*NH2 with triphosgene generates the symmetric urea (Ar*NH)2CO, which, upon dehydration with a P2O5/Al2O3 slurry in pyridine, produces the sterically encumbered carbodiimide (Ar*N)2C as an air-stable white solid. The treatment of (Ar*N)2C with LiN═C(t)Bu2 in tetrahydrofuran cleanly gives the monomeric lithium guanidinate Li[(Ar)*ketguan], free of coordinating solvent, in 85% yield. Protonation of Li[(Ar)*ketguan] with lutidinium chloride produces the guanidine (Ar)*ketguanH (MW = 1112.60 g/mol), which is easily derivatized to give the monomeric alkali metal complexes M[(Ar)*ketguan] (M = K, Cs) in 94% and 51% yield, respectively. The solid-state molecular structures of M[(Ar)*ketguan] (M = Li, K, Cs) show formally two-coordinate alkali metal cations encapsulated within a hydrophobic coordination pocket formed by the peripheral diphenylmethyl substituents of the guanidinate. Remarkably, percent buried volume analyses (% V(Bur)) of M[(Ar)*ketguan] [M = Li (94.8% V(Bur)), K (92.1% V(Bur)), Cs (81.7% V(Bur))] reveal a coordination cavity that adjusts to individually accommodate the variously sized metal ions despite the highly encumbering nature of the ligand. This demonstrates a flexible ligand framework that is able to stabilize low-coordinate metal centers within a "super bulky" coordination environment.


Interactions between effects of adrenalectomy and diet on insulin secretion in fa/fa Zucker rats.
Our objective was to determine if a cafeteria-type diet with increased fat content would block the decrease in insulin secretion induced by adrenalectomy in obese rats. Five week old Zucker (fa/fa) rats were adrenalectomized. One week later, half of the adrenalectomized groups, and age-matched, sham-operated animals were given a diet of 16% fat and 44% carbohydrate. Control animals were maintained on standard rat chow (4.6% fat and 49% carbohydrate). After 4 weeks on the diets, in vivo measurements included caloric intake, weight gain, plasma corticosterone, triglyceride, free fatty acids, and oral glucose tolerance tests. In vitro measurements included glucose-stimulated insulin secretion, glucose phosphorylating activity, islet triglyceride content, and fatty acid oxidizing activity of cultured islets. Generally, the cafeteria diet did not block the effects of adrenalectomy on in vitro insulin secretion parameters, even though in sham-operated animals weight gain and insulin resistance was induced by the diet in vivo. Adrenalectomy and the diet exerted independent effects on glucose phosphorylation and fatty acid oxidation in islets. In conclusion, adrenalectomy decreased the elevated insulin secretion in fa/fa rats. The failure of a cafeteria diet enriched in fat to block the adrenalectomy-mediated changes in B-cell function indicates the importance of glucocorticoids and centrally-mediated effects on insulin secretion and other metabolic parameters.


Blocking of LFA-1 enhances expansion of Th17 cells induced by human CD14(+) CD16(++) nonclassical monocytes.
Among human peripheral blood (PB) monocyte (Mo) subsets, the classical CD14(++) CD16(-) (cMo) and intermediate CD14(++) CD16(+) (iMo) Mos are known to activate pathogenic Th17 responses, whereas the impact of nonclassical CD14(+) CD16(++) Mo (nMo) on T-cell activation has been largely neglected. The aim of this study was to obtain new mechanistic insights on the capacity of Mo subsets from healthy donors (HDs) to activate IL-17(+) T-cell responses in vitro, and assess whether this function was maintained or lost in states of chronic inflammation. When cocultured with autologous CD4(+) T cells in the absence of TLR-2/NOD2 agonists, PB nMos from HDs were more efficient stimulators of IL-17-producing T cells, as compared to cMo. These results could not be explained by differences in Mo lifespan and cytokine profiles. Notably, however, the blocking of LFA-1/ICAM-1 interaction resulted in a significant increase in the percentage of IL-17(+) T cells expanded in nMo/T-cell cocultures. As compared to HD, PB Mo subsets of patients with rheumatoid arthritis were hampered in their T-cell stimulatory capacity. Our new insights highlight the role of Mo subsets in modulating inflammatory T-cell responses and suggest that nMo could become a critical therapeutic target against IL-17-mediated inflammatory diseases.


Alcohol dehydrogenase and aldehyde dehydrogenase gene polymorphisms, alcohol intake and the risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition study.
Heavy alcohol drinking is a risk factor of colorectal cancer (CRC), but little is known on the effect of polymorphisms in the alcohol-metabolizing enzymes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) on the alcohol-related risk of CRC in Caucasian populations. A nested case-control study (1269 cases matched to 2107 controls by sex, age, study centre and date of blood collection) was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC) to evaluate the impact of rs1229984 (ADH1B), rs1573496 (ADH7) and rs441 (ALDH2) polymorphisms on CRC risk. Using the wild-type variant of each polymorphism as reference category, CRC risk estimates were calculated using conditional logistic regression, with adjustment for matching factors. Individuals carrying one copy of the rs1229984(A) (ADH1B) allele (fast metabolizers) showed an average daily alcohol intake of 4.3 g per day lower than subjects with two copies of the rs1229984(G) allele (slow metabolizers) (P(diff)<0.01). None of the polymorphisms was associated with risk of CRC or cancers of the colon or rectum. Heavy alcohol intake was more strongly associated with CRC risk among carriers of the rs1573496(C) allele, with odds ratio equal to 2.13 (95% confidence interval: 1.26-3.59) compared with wild-type subjects with low alcohol consumption (P(interaction)=0.07). The rs1229984(A) (ADH1B) allele was associated with a reduction in alcohol consumption. The rs1229984 (ADH1B), rs1573496 (ADH7) and rs441 (ALDH2) polymorphisms were not associated with CRC risk overall in Western-European populations. However, the relationship between alcohol and CRC risk might be modulated by the rs1573496 (ADH7) polymorphism.


Ocular gene therapy for choroideremia: clinical trials and future perspectives.
Gene therapy offers the potential for targeted replacement of single gene defects in inherited retinal degenerations. Choroideremia is an X-linked blinding retinal disease resulting from deficiency of the CHM gene product, REP1. The disease represents an ideal target for retinal gene therapy, as it is readily diagnosed in the clinic, relatively homogenous in phenotype and slow progressing, thereby providing a wide therapeutic window for intervention. Ongoing clinical trials of retinal gene therapy for choroideremia using an adeno-associated viral vector have demonstrated safety and early efficacy. We review the clinical characteristics of the disease with a view to interpreting the findings of gene therapy clinical trials and discuss future directions. Choroideremia gene therapy has so far demonstrated good safety profile and early functional visual acuity gains in a proportion of trial participants, which appear to be sustained.


Hamiltonian modelling of macro-economic urban dynamics.
The rapid urbanization makes the understanding of the evolution of urban environments of utmost importance to steer societies towards better futures. Many studies have focused on the emerging properties of cities, leading to the discovery of scaling laws mirroring the dependence of socio-economic indicators on city sizes. However, few efforts have been devoted to the modelling of the dynamical evolution of cities, as reflected through the mutual influence of socio-economic variables. Here, we fill this gap by presenting a maximum entropy generative model for cities written in terms of a few macro-economic variables, whose parameters (the effective Hamiltonian, in a statistical-physical analogy) are inferred from real data through a maximum-likelihood approach. This approach allows for establishing a few results. First, nonlinear dependencies among indicators are needed for an accurate statistical description of the complexity of empirical correlations. Second, the inferred coupling parameters turn out to be quite robust along different years. Third, the quasi time-invariance of the effective Hamiltonian allows guessing the future state of a city based on a previous state. Through the adoption of a longitudinal dataset of macro-economic variables for French towns, we assess a significant forecasting accuracy.


The Timing and Nature of Behavioural Responses Affect the Course of an Epidemic.
During an epidemic, the interplay of disease and opinion dynamics can lead to outcomes that are different from those predicted based on disease dynamics alone. Opinions and the behaviours they elicit are complex, so modelling them requires a measure of abstraction and simplification. Here, we develop a differential equation model that couples SIR-type disease dynamics with opinion dynamics. We assume a spectrum of opinions that change based on current levels of infection as well as interactions that to some extent amplify the opinions of like-minded individuals. Susceptibility to infection is based on the level of prophylaxis (disease avoidance) that an opinion engenders. In this setting, we observe how the severity of an epidemic is influenced by the distribution of opinions at disease introduction, the relative rates of opinion and disease dynamics, and the amount of opinion amplification. Some insight is gained by considering how the effective reproduction number is influenced by the combination of opinion and disease dynamics.


A role for p38(MAPK)/HSP27 pathway in smooth muscle cell migration.
Smooth muscle cells are exposed to growth factors and cytokines that contribute to pathological states including airway hyperresponsiveness, atherosclerosis, angiogenesis, smooth muscle hypertrophy, and hyperplasia. A common feature of several of these conditions is migration of smooth muscle beyond the initial boundary of the organ. Signal transduction pathways activated by extracellular signals that instigate migration are mostly undefined in smooth muscles. We measured migration of cultured tracheal myocytes in response to platelet-derived growth factor, interleukin-1beta, and transforming growth factor-beta. Cellular migration was blocked by SB203580, an inhibitor of p38(MAPK). Time course experiments demonstrated increased phosphorylation of p38(MAPK). Activation of p38(MAPK) resulted in the phosphorylation of HSP27 (heat shock protein 27), which may modulate F-actin polymerization. Inhibition of p38(MAPK) activity inhibited phosphorylation of HSP27. Adenovirus-mediated expression of activated mutant MAPK kinase 6b(E), an upstream activator for p38(MAPK), increased cell migration, whereas overexpression of p38alpha MAPK dominant negative mutant and an HSP27 phosphorylation mutant blocked cell migration completely. The results indicate that activation of the p38(MAPK) pathway by growth factors and proinflammatory cytokines regulates smooth muscle cell migration and may contribute to pathological states involving smooth muscle dysfunction.


Chondrosarcoma of the arytenoid cartilage.
Chondrosarcoma is the most frequently encountered nonepithelial tumor of the larynx. Still, laryngeal chondrosarcoma is a rare disease, accounting for less than 1% of all laryngeal neoplasms; only about 600 cases have been reported in the world literature. The two most common sites of origin are the cricoid cartilage (69% of cases) and the thyroid cartilage (9%); arytenoid cartilage origin has been seen in less than 3% of cases. The diagnosis of laryngeal chondrosarcoma is easy to miss because of its infrequent occurrence, its indolent pattern of growth, and the difficulty in differentiating it histopathologically from chondroma. However, suspicion of arytenoid chondrosarcoma may be raised by a finding of its characteristic appearance as a smooth, hard, mucosa-covered supraglottic mass that is fairly recognizable on indirect laryngoscopy. We report a new case of chondrosarcoma of the arytenoid cartilage in a 47-year-old man, and we discuss the clinical features, diagnosis, and management of this uncommon tumor.


Value of preoperative ultrasonography in the surgical management of initial and reoperative papillary thyroid cancer.
Cervical recurrences, predominantly in lymph nodes, occur in 14% to 30% of patients with papillary thyroid cancer (PTC). Postoperative surveillance for recurrent PTC increasingly includes thyrotropin-stimulated thyroglobulin and high-resolution ultrasonography (US). This combination commonly can detect recurrent disease as small as 5 mm. Preoperative US will increase detection and assessment of the extent of lymph node metastasis (LNM) in patients with PTC. Retrospective cohort study. Tertiary care academic center. From January 1, 1999, to December 31, 2004, a total of 770 patients were seen, 551 (381 female and 170 male; median age, 47 years; age range, 9-89 years) who underwent initial surgical management and 219 (154 female and 65 male; median age, 44 years; age range, 5-90 years) who underwent cervical reoperation for PTC. The US images were obtained preoperatively for 486 initial and 216 reoperative patients. Therapeutic radioactive iodine was administered to 151 (68.9%) of the reoperative patients before the subsequent operation (median dose, 5.6 x 10(9) Bq; range, 7.4 x 10(8)-3.7 x 10(10) Bq). Ultrasonography identified nonpalpable lateral jugular LNMs in 70 (14.4%) of the patients undergoing initial exploration. Similarly, in reoperative patients, nonpalpable lateral LNMs were detected via US in 106 (64.2%), and 61 (28.2%) had LNMs detected in the central neck. Even when nodes were palpable preoperatively (37 [6.7%] of the initial and 56 [25.6%] of the reoperative patients), US assessment of the extent of LNM involvement altered the operation in 15 (40.5%) of the initial and 24 (42.9%) of the reoperative patients. The sensitivity, specificity, and positive predictive value for US were 83.5%, 97.7%, and 88.8% in initial patients, and 90.4%, 78.9%, and 93.9% in reoperative patients. Overall, preoperative US detected nonpalpable LNMs in 231 (32.9%) of the 702 patients with PTC who underwent US, thereby altering the operative procedure performed. In addition, even in patients with palpable LNs, US helped to guide the extent of lymphadenectomy.


The hierarchical factor model of ADHD: invariant across age and national groupings?
To examine the factor structure of attention-deficit/hyperactivity disorder (ADHD) in a clinical sample of 1,373 children and adolescents with ADHD and their 1,772 unselected siblings recruited from different countries across a large age range. Hierarchical and correlated factor analytic models were compared separately in the ADHD and sibling samples, across three different instruments and across parent and teacher informants. Specific consideration was given to factorial invariance analyses across different ages and different countries in the ADHD sample. A sample of children and adolescents between 5 and 17 years of age with ADHD and their unselected siblings was assessed. Participants were recruited from seven European countries and Israel. ADHD symptom data came from a clinical interview with parents Parental Account of Childhood Symptoms and questionnaires from parents and teachers (Conners Parent and Teacher). A hierarchical general factor model with two specific factors best represented the structure of ADHD in both the ADHD and unselected sibling groups, and across informants and instruments. The model was robust and invariant with regard to age differences in the ADHD sample. The model was not strongly invariant across different national groups in the ADHD sample, likely reflecting severity differences across the different centers and not any substantial difference in the clinical presentation of ADHD. The results replicate previous studies of a model with a unitary ADHD component and separable specific traits of inattention and hyperactivity/impulsivity. The unique contribution of this study was finding support for this model across a large developmental and multinational/multicultural sample and its invariance across ages.