Pragmatic randomised controlled trial of a personalised intervention for carers of people requiring home oxygen therapy.
We used a pragmatic randomised controlled trial to evaluate a behavioural change strategy targeting carers of chronically hypoxaemic patients using long-term home oxygen therapy. Intervention group carers participated in personalised educational sessions focusing on motivating carers to take actions to assist patients. All patients received usual care. Effectiveness was measured through a composite event of patient survival to hospitalisation, residential care admission or death to 12 months. Secondary outcomes at baseline, 3, 6 and 12 months included carer and patient emotional and physical well-being. No difference between intervention (n = 100) and control (n = 97) patients was found for the composite outcome (hazard ratio (HR) 1.22, 95% confidence interval (CI) = 0.89, 1.68; p = 0.22). Improved fatigue, mastery, vitality and general health occurred in intervention group patients (all p values < 0.05). No benefits were seen in carer outcomes. Mortality was significantly higher in intervention patients (HR = 2.01, 95% CI = 1.00, 4.14; p = 0.05; adjusted for Australia-modified Karnofsky Performance Status), with a significant diagnosis-intervention interaction (p = 0.028) showing higher mortality in patients with COPD (HR 4.26; 95% CI = 1.60, 11.35) but not those with interstitial lung disease (HR 0.83; 95% CI = 0.28, 2.46). No difference was detected in the primary outcome, but patient mortality was higher when carers had received the intervention, especially in the most disabled patients. Trials examining behavioural change interventions in severe disease should stratify for functionality, and both risks and benefits should be independently monitored. Trial registration: Australian New Zealand Clinical Trials Registry (ACTRN12607000177459).


Enzyme-like replication de novo in a microcontroller environment.
The desire to start evolution from scratch inside a computer memory is as old as computing. Here we demonstrate how viable computer programs can be established de novo in a Precambrian environment without supplying any specific instantiation, just starting with random bit sequences. These programs are not self-replicators, but act much more like catalysts. The microcontrollers used in the end are the result of a long series of simplifications. The objective of this simplification process was to produce universal machines with a human-readable interface, allowing software and/or hardware evolution to be studied. The power of the instruction set can be modified by introducing a secondary structure-folding mechanism, which is a state machine, allowing nontrivial replication to emerge with an instruction width of only a few bits. This state-machine approach not only attenuates the problems of brittleness and encoding functionality (too few bits available for coding, and too many instructions needed); it also enables the study of hardware evolution as such. Furthermore, the instruction set is sufficiently powerful to permit external signals to be processed. This information-theoretic approach forms one vertex of a triangle alongside artificial cell research and experimental research on the creation of life. Hopefully this work helps develop an understanding of how information—in a similar sense to the account of functional information described by Hazen et al.—is created by evolution and how this information interacts with or is embedded in its physico-chemical environment.


A review of recent clinical trials of the nutritional supplement Chlorella pyrenoidosa in the treatment of fibromyalgia, hypertension, and ulcerative colitis.
It has been suggested that the consumption of natural "whole foods" rich in macronutrients has many healthful benefits for those who otherwise ingest a normal, nonvegetarian diet. One example is dietary supplements derived from Chlorella pyrenoidosa, a unicellular fresh water green alga rich in proteins, vitamins, and minerals. To find evidence of the potential of chlorella dietary supplements to relieve signs and symptoms, improve quality of life, and normalize body functions in people with chronic illnesses, specifically fibromyalgia, hypertension, and ulcerative colitis. Double-blind, placebo-controlled, randomized clinical trials. Virginia Commonwealth University's Medical College of Virginia. Fifty-five subjects with fibromyalgia, 33 with hypertension, and 9 with ulcerative colitis. Subjects consumed 10 g of pure chlorella in tablet form and 100 mL of a liquid containing an extract of chlorella each day for 2 or 3 months. For fibromyalgia patients, assessments of pain and overall quality of life. For hypertensive patients, measurements of sitting diastolic blood pressure and serum lipid levels. For patients with ulcerative colitis, determination of state of disease using the Disease Activity Index. Daily dietary supplementation with chlorella may reduce high blood pressure, lower serum cholesterol levels, accelerate wound healing, and enhance immune functions. The potential of chlorella to relieve symptoms, improve quality of life, and normalize body functions in patients with fibromyalgia, hypertension, or ulcerative colitis suggests that larger, more comprehensive clinical trials of chlorella are warranted.


High levels of inflammatory chemokines and cytokines in joint fluid and synovial tissue throughout the course of antibiotic-refractory lyme arthritis.
To investigate the possible role of chemokines and cytokines in the pathogenesis of Lyme arthritis. Using cytometric bead array and flow cytometry techniques, chemokine and cytokine levels were determined in 65 synovial fluid (SF) samples and 7 synovial tissue (ST) samples from 17 patients with antibiotic-responsive Lyme arthritis and 35 patients with antibiotic-refractory Lyme arthritis seen during the past 18 years. In the ST samples, expression of chemokine receptors was measured using immunohistochemistry. Before or during antibiotic therapy, when the majority of patients had positive polymerase chain reaction (PCR) results for Borrelia burgdorferi DNA, SF from patients with antibiotic-refractory arthritis contained exceptionally high levels of Th1 chemoattractants and cytokines, particularly CXCL9 and interferon-gamma (IFNgamma). Compared with the patients whose arthritis was responsive to antibiotic treatment, those with antibiotic-refractory arthritis had significantly higher levels of CXCL9 and CXCL10 (both P<or=0.001) and CCL3, CCL4, CXCL8, IFNgamma, tumor necrosis factor alpha, interleukin-1beta (IL-1beta), and IL-6 (all P<or=0.01). During the post-antibiotic period, when the results of PCR for B burgdorferi DNA in SF and ST were uniformly negative, patients with antibiotic-refractory arthritis continued to exhibit high SF and ST levels of these chemokines and cytokines. In addition, synovial samples showed marked expression of the receptors for T cell or macrophage chemokines, CXCR3 and CCR5. Patients with antibiotic-refractory Lyme arthritis have high synovial fluid levels of proinflammatory chemokines and cytokines, especially CXCL9 and IFNgamma, throughout the illness. Thus, even when antibiotic treatment reduces or completely clears the infection in these patients, the inflammatory response in synovium persists.


Improving Physical Activity Levels in Prevocational Students by Student Participation: Protocol for a Cluster Randomized Controlled Trial.
A consistent finding in the literature is the decline in physical activity during adolescence, resulting in activity levels below the recommended guidelines. Therefore, promotion of physical activity is recommended specifically for prevocational students. This protocol paper describes the background and design of a physical activity promotion intervention study in which prevocational students are invited to participate in the design and implementation of an intervention mix. The intervention is expected to prevent a decline in physical activity in the target group. The effectiveness of the intervention was evaluated in a two-group cluster randomized controlled trial with assessments at baseline and 2-year follow-up. A simple randomization was applied, allocating 11 schools to the intervention group and 11 schools to the control group, which followed the regular school curriculum. The research population consisted of 3003 prevocational students, aged 13-15 years. The primary outcome measures were self-reported physical activity levels (screen time, active commuting, and physical activity). As a secondary outcome, direct assessment of physical fitness (leg strength, arm strength, hip flexibility, hand speed, abdominal muscle strength, BMI, and body composition) was included. An intervention-control group comparison was presented for the baseline results. The 2-year interventions began by mapping the assets of the prevocational adolescents of each intervention school using motivational interviewing in the structured interview matrix and the photovoice method. In addition, during focus group sessions, students, school employees, and researchers cocreated and implemented an intervention plan that optimally met the students' assets and opportunities in the school context. The degree of student participation was evaluated through interviews and questionnaires. Data collection of the SALVO (stimulating an active lifestyle in prevocational students) study began in October 2015 and was completed in December 2017. Data analyses will be completed in 2021. Baseline comparisons between the intervention and control groups were not significant for age (P=.12), screen time behavior (P=.53), nonschool active commuting (P=.26), total time spent on sports activities (P=.32), total physical activities (P=.11), hip flexibility (P=.22), maximum handgrip (P=.47), BMI (P=.44), and sum of skinfolds (P=.29). Significant differences between the intervention and control groups were found in ethnicity, gender, active commuting to school (P=.03), standing broad jump (P=.02), bent arm hang (P=.01), 10× 5-m sprint (P=.01), plate tapping (P=.01), sit-ups (P=.01), and 20-m shuttle run (P=.01). The SALVO study assesses the effects of a participatory intervention on physical activity and fitness levels in prevocational students. The results of this study may lead to a new understanding of the effectiveness of school-based physical activity interventions when students are invited to participate and cocreate an intervention. This process would provide structured health promotion for future public health. ISRCTN Registry ISRCTN35992636; http://www.isrctn.com/ISRCTN35992636. DERR1-10.2196/28273.


Reinforcement expectations explain the relationship between depressive history and smoking status in college students.
Little is understood about biobehavioral mechanisms that mediate the comorbidity between cigarette smoking and depression. We hypothesized that expectancies about nicotine's reinforcing effects are associated with vulnerability to depression, and may partially explain the relationship between history of depression and smoking. Young adult smokers and never smokers (N=175, mean age=19.9 years, S.D.=3.2) were assessed for history of depression and expectations about the negative (e.g., dispels bad moods) and positive (e.g., increases pleasure) reinforcing effects of smoking. Results are inconsistent with the premise that negative reinforcement expectancies mediate the comorbidity between depression and nicotine dependence. Instead, findings suggest that young adults with a prior history of major depression hold exaggerated expectations about nicotine's positive effects, which could enhance their likelihood of initiating smoking.


Predicting occupational performance: handwriting versus keyboarding.
To determine whether there is a correlation between handwriting and keyboarding speed and accuracy, and whether handwriting and keyboarding share common underlying components. Sixty-three typically developing 5th-grade students attended a series of 15 keyboarding lessons for a total of 5 hours. Prior to the lessons, cognitive, sensory, and motor skills related to handwriting were evaluated. Prior to and following the lessons keyboarding and handwriting accuracy and speed were also tested. Correlations were employed to examine relationships between handwriting and keyboarding skills and multiple regression analyses were used to examine the contribution of performance components to handwriting and keyboarding performance. Following keyboarding instruction, a significant correlation was found between handwriting and keyboarding speed, but not in accuracy of these tasks. Similarly, some of the specific tests measuring tactile and oculo-motor functions were found to be related to both handwriting and keyboarding speed, yet accuracy of these tasks did not share common underlying components. It appears that handwriting and keyboarding accuracy may entail different skills, suggesting that keyboarding may be a potential alternative writing tool for students with handwriting difficulties. It also appears that when students write slowly, handwriting speed should be considered prior to recommending keyboarding for these students. Additional research is required to further support these findings.


An MBA: the utility and effect on physicians' careers.
Higher economic, legislative, legal, and administrative constraints in health-care services in the United States have led to an increase in physician dissatisfaction and a decrease in physician morale. In this study, we attempted to understand the motivation for a physician to enroll in a business school, and to discover the utility of the Master of Business Administration degree and how it changed the career path for the practicing clinician. We conducted a retrospective study in which a twenty-seven-question survey was distributed by the United States Postal Service and by e-mail to 161 physician graduates of three East Coast business schools. The results were evaluated, and a statistical analysis was performed. Eighty-seven physicians (54%) responded. Eight surveys were discarded because of incomplete data or stray marks, leaving seventy-nine surveys. The average age of the respondents was 41.4 years. The major motivations for going back to school included learning the business aspects of the health-care system (fifty-three respondents; 67%) and obtaining a more interesting job (forty-one respondents; 52%). The time that the respondents allocated for health-care-related activities before and after obtaining the degree was 58.3% and 31.8%, respectively, for patient care (p < 0.001); 8.5% and 3.68% for teaching (p < 0.001); 4.57% and 1.46% for basic-science research (p = 0.11); 4.23% and 4.55% for clinical research (p = 0.90); and 11.8% and 33.5% for administrative responsibilities (p < 0.001). The physicians stated that the most pertinent skills they had acquired were those related to evaluating systems operations and implementing improvements (thirty-nine respondents; 49%), learning how to be an effective leader (thirty-five; 44%), comprehending financial principles (thirty-three; 42%), working within a team (twenty-seven; 34%), and negotiating effectively (twenty-five; 32%). Sixty-four physicians (81%) believed that their business degree had been very useful or essential in the advancement of their careers. Many physicians decide to acquire a Master of Business Administration degree to understand the business of medicine. After they complete the degree program, their practice patterns substantially change, which is reflected particularly by an increase in time spent on administrative responsibilities. In order for physicians to overcome the multifaceted challenges of the evolving health-care system, it is essential to continue educating a proportion of physicians in both medicine and business.


Modeling patients' acceptance of provider-delivered e-health.
Health care providers are beginning to deliver a range of Internet-based services to patients; however, it is not clear which of these e-health services patients need or desire. The authors propose that patients' acceptance of provider-delivered e-health can be modeled in advance of application development by measuring the effects of several key antecedents to e-health use and applying models of acceptance developed in the information technology (IT) field. This study tested three theoretical models of IT acceptance among patients who had recently registered for access to provider-delivered e-health. An online questionnaire administered items measuring perceptual constructs from the IT acceptance models (intrinsic motivation, perceived ease of use, perceived usefulness/extrinsic motivation, and behavioral intention to use e-health) and five hypothesized antecedents (satisfaction with medical care, health care knowledge, Internet dependence, information-seeking preference, and health care need). Responses were collected and stored in a central database. All tested IT acceptance models performed well in predicting patients' behavioral intention to use e-health. Antecedent factors of satisfaction with provider, information-seeking preference, and Internet dependence uniquely predicted constructs in the models. Information technology acceptance models provide a means to understand which aspects of e-health are valued by patients and how this may affect future use. In addition, antecedents to the models can be used to predict e-health acceptance in advance of system development.


Osteogenesis imperfecta--multi-systemic and life-long disease that affects whole family.
Osteogenesis imperfecta or brittle bone disease, a heritable disorder of connective tissue, is the most common of the inherited disorders primarily affecting bone. There are approximately 400 individuals with OI in Croatia alone. It is estimated that twice that number is present, represented by individuals with mild OI in whom the diagnosis has not been made. Due to the relatively low number of patients in the general population, treating physicians have limited experience with this disease, either with children or adults. The basis of this disease in European populations is mostly the result of defects in the structure or processing of collagen type I, an important protein of the extracellular matrix of many tissues. Presently, molecular defects in 16 different genes have been discovered to result in at least one type of OI of which 14 are not COL1 mutation loci. Although fractures occurring with no injury or minor injury are the hallmark of OI, other non-mineralized tissues can be affected as well and the pathological changes can be present in skin, tendons, eyes, teeth and blood vessels. Clinical manifestations are very heterogeneous and numerous signs and symptoms such as blue sclera, deafness, abnormal teeth development, joint hypermobility, increased risk of hernias, capillary fragility, aneurysms etc. Although there is no cure for this disease, there are specific therapies that can reduce the pain and complications associated with OI. The purpose of this review is to provide a brief overview of the molecular basis of this disease, describe clinical presentations, as well as to present orthopaedic therapeutic modalities for the patients with OI.


NALP3 inflammasome upregulation and CASP1 cleavage of the glucocorticoid receptor cause glucocorticoid resistance in leukemia cells.
Glucocorticoids are universally used in the treatment of acute lymphoblastic leukemia (ALL), and resistance to glucocorticoids in leukemia cells confers poor prognosis. To elucidate mechanisms of glucocorticoid resistance, we determined the prednisolone sensitivity of primary leukemia cells from 444 patients newly diagnosed with ALL and found significantly higher expression of CASP1 (encoding caspase 1) and its activator NLRP3 in glucocorticoid-resistant leukemia cells, resulting from significantly lower somatic methylation of the CASP1 and NLRP3 promoters. Overexpression of CASP1 resulted in cleavage of the glucocorticoid receptor, diminished the glucocorticoid-induced transcriptional response and increased glucocorticoid resistance. Knockdown or inhibition of CASP1 significantly increased glucocorticoid receptor levels and mitigated glucocorticoid resistance in CASP1-overexpressing ALL. Our findings establish a new mechanism by which the NLRP3-CASP1 inflammasome modulates cellular levels of the glucocorticoid receptor and diminishes cell sensitivity to glucocorticoids. The broad impact on the glucocorticoid transcriptional response suggests that this mechanism could also modify glucocorticoid effects in other diseases.


FungiFun: a web-based application for functional categorization of fungal genes and proteins.
FungiFun assigns functional annotations to fungal genes or proteins and performs gene set enrichment analysis. Based on three different classification methods (FunCat, GO and KEGG), FungiFun categorizes genes and proteins for several fungal species on different levels of annotation detail. It is web-based and accessible to users without any programming skills. FungiFun is the first tool offering gene set enrichment analysis including the FunCat categorization. Two biological datasets for Aspergillus fumigatus and Candida albicans were analyzed using FungiFun, providing an overview of the usage and functions of the tool. FungiFun is freely accessible at https://www.omnifung.hki-jena.de/FungiFun/.


Intraocular production of a cytokine (CINC) responsible for neutrophil infiltration in endotoxin induced uveitis.
The subcutaneous injection of bacterial endotoxin in Lewis rats produces an acute intraocular inflammation evolving over a 24 hour period. This endotoxin induced uveitis (EIU) is characterised by a biphasic protein exudation and a cellular infiltrate composed of macrophages and polymorphonuclear neutrophils (PMNs). This model was used to study the mechanism of cellular infiltration in ocular inflammation. EIU was induced by a subcutaneous injection of lipopolysaccharide (LPS) (S typhimurium) at 350 micrograms/kg. The levels of cytokine induced neutrophil chemoattractant (CINC) were measured every 2 hours in the serum and in the aqueous humour by ELISA. The intraocular inflammation was quantified by protein measurement and leucocyte counting. The kinetics of CINC production in the systemic circulation showed a rapid rise, peaking 2 hours after LPS injection, followed by a progressive decline over the next 8 hours. In the eye, the CINC levels increased above the serum levels 10 hours after EIU induction corresponding to the time of cellular infiltration. When leucocyte entry in the eye was inhibited by 56% and 64% with an antiadhesion molecule antibody, there was only a slight reduction in the aqueous humour CINC levels of 9% and 16%, respectively, indicating that CINC was produced by ocular tissue cells. The specific effect of CINC in the eye was confirmed when a direct intraocular injection of 250 ng of purified CINC was followed by significant PMN infiltration, in the absence of protein exudation. The data indicate that the production of the CINC chemotactic factor by ocular tissue participates in the inflammatory reaction in EIU.


Dye-sensitized Solar Cells: New Approaches with Organic Solid-state Hole Conductors.
Solid-state dye-sensitized solar cells (sDSCs) in which a solid organic charge-transfer medium, or hole conductor (HC), is interposed between a dye-coated mesoporous oxide electrode and a conductive counter electrode, have attracted considerable interest as viable alternatives to the more ubiquitous mediator-electrolyte DSC. Of particular importance to efficient operation are, in addition to the useful processes contributing to current generation (light harvesting, electron injection and current collection), the recombinative deleterious processes. The organic HCs are highly reactive toward electrons in the oxide or the conducting glass support, therefore necessitating the inclusion of a carefully prepared thin blocking oxide underlayer support as well as the molecular design of special dark current-suppressing dyes. Initially (mid-1990s) sDSCs with organic small molecular weight hole conductors have undergone systematic investigation. At the same time the first tests of sDSCs with conducting polymer hole conductors were published, with subsequent emphasis on the in situ generation of the HC inside the pores. For both types of devices a light-to-electricity conversion efficiency, in the 5-10% range for several dye-HC combinations, approaches that of the most efficient DSCs with non-volatile liquid electrolytes, thereby encouraging further efforts for obtaining stable, efficient and inexpensive sDSCs.


Implementation of an efficient SARS-CoV-2 specimen pooling strategy for high throughput diagnostic testing.
The rapid identification and isolation of infected individuals remains a key strategy for controlling the spread of SARS-CoV-2. Frequent testing of populations to detect infection early in asymptomatic or presymptomatic individuals can be a powerful tool for intercepting transmission, especially when the viral prevalence is low. However, RT-PCR testing-the gold standard of SARS-CoV-2 diagnosis-is expensive, making regular testing of every individual unfeasible. Sample pooling is one approach to lowering costs. By combining samples and testing them in groups the number of tests required is reduced, substantially lowering costs. Here we report on the implementation of pooling strategies using 3-d and 4-d hypercubes to test a professional sports team in South Africa. We have shown that infected samples can be reliably detected in groups of 27 and 81, with minimal loss of assay sensitivity for samples with individual Ct values of up to 32. We report on the automation of sample pooling, using a liquid-handling robot and an automated web interface to identify positive samples. We conclude that hypercube pooling allows for the reliable RT-PCR detection of SARS-CoV-2 infection, at significantly lower costs than lateral flow antigen (LFA) tests.


Reducing the risk of sensitivity and pulpal complications after the placement of crowns and fixed partial dentures.
Sensitivity after cementation of a crown with glass-ionomer cement is often attributed to an adverse effect on the pulp by the luting agent. Most permanent restorative materials in common use today do not tend to irritate the pulp; the main cause of pulpal damage is infection, the bacteria originating in the smear layer or deep in the dental tubules, inaccessible to caries-excavating procedures. A poorly fitting provisional crown may expose cut dentin to the oral fluids, and mechanical trauma caused by frictional heat during preparation may also damage the pulp. The following precautions are recommended during precementation procedures to reduce the risk of an inflammatory response in the pulp: (1) The provisional crown should be well fitting, covering cervical dentin but not impinging on the periodontal tissues. The permanent crown should be cemented as soon as possible. (2) The superficial smear layer should be removed and the dentinal surface should be treated with an antibacterial solution before the provisional crown is placed. (3) To decrease dentinal permeability under the provisional crown, the dentinal surface should be covered with a liner that can be easily removed before final cementation. (4) to ensure optimal mircomechanical bonding, the dentinal surface should be thoroughly cleaned, and the dentin should be kept moist until cementation. (5) The occlusion should be carefully checked before cementation of the crown.


Analysis of the fecal microbiota of irritable bowel syndrome patients and healthy controls with real-time PCR.
The gut microbiota may contribute to the onset and maintenance of irritable bowel syndrome (IBS). In this study, the microbiotas of patients suffering from IBS were compared with a control group devoid of gastrointestinal (GI) symptoms. Fecal microbiota of patients (n = 27) fulfilling the Rome II criteria for IBS was compared with age- and gender-matched control subjects (n = 22). Fecal samples were obtained at 3 months intervals. Total bacterial DNA was analyzed by 20 quantitative real-time PCR assays covering approximately 300 bacterial species. Extensive individual variation was observed in the GI microbiota among both the IBS- and control groups. Sorting of the IBS patients according to the symptom subtypes (diarrhea, constipation, and alternating predominant type) revealed that lower amounts of Lactobacillus spp. were present in the samples of diarrhea predominant IBS patients whereas constipation predominant IBS patients carried increased amounts of Veillonella spp. Average results from three fecal samples suggested differences in the Clostridium coccoides subgroup and Bifidobacterium catenulatum group between IBS patients (n = 21) and controls (n = 15). Of the intestinal pathogens earlier associated with IBS, no indications of Helicobacter spp. or Clostridium difficile were found whereas one case of Campylobacter jejuni was identified by sequencing. With these real-time PCR assays, quantitative alterations in the GI microbiota of IBS patients were found. Increasing microbial DNA sequence information will further allow designing of new real-time PCR assays for a more extensive analysis of intestinal microbes in IBS.


OsHKT1;5 mediates Na+ exclusion in the vasculature to protect leaf blades and reproductive tissues from salt toxicity in rice.
Salt tolerance quantitative trait loci analysis of rice has revealed that the SKC1 locus, which is involved in a higher K+ /Na+ ratio in shoots, corresponds to the OsHKT1;5 gene encoding a Na+ -selective transporter. However, physiological roles of OsHKT1;5 in rice exposed to salt stress remain elusive, and no OsHKT1;5 gene disruption mutants have been characterized to date. In this study, we dissected two independent T-DNA insertional OsHKT1;5 mutants. Measurements of ion contents in tissues and 22 Na+ tracer imaging experiments showed that loss-of-function of OsHKT1;5 in salt-stressed rice roots triggers massive Na+ accumulation in shoots. Salt stress-induced increases in the OsHKT1;5 transcript were observed in roots and basal stems, including basal nodes. Immuno-staining using an anti-OsHKT1;5 peptide antibody indicated that OsHKT1;5 is localized in cells adjacent to the xylem in roots. Additionally, direct introduction of 22 Na+ tracer to leaf sheaths also demonstrated the involvement of OsHKT1;5 in xylem Na+ unloading in leaf sheaths. Furthermore, OsHKT1;5 was indicated to be present in the plasma membrane and found to localize also in the phloem of diffuse vascular bundles in basal nodes. Together with the characteristic 22 Na+ allocation in the blade of the developing immature leaf in the mutants, these results suggest a novel function of OsHKT1;5 in mediating Na+ exclusion in the phloem to prevent Na+ transfer to young leaf blades. Our findings further demonstrate that the function of OsHKT1;5 is crucial over growth stages of rice, including the protection of the next generation seeds as well as of vital leaf blades under salt stress.


Job burnout.
Burnout is a prolonged response to chronic emotional and interpersonal stressors on the job, and is defined by the three dimensions of exhaustion, cynicism, and inefficacy. The past 25 years of research has established the complexity of the construct, and places the individual stress experience within a larger organizational context of people's relation to their work. Recently, the work on burnout has expanded internationally and has led to new conceptual models. The focus on engagement, the positive antithesis of burnout, promises to yield new perspectives on interventions to alleviate burnout. The social focus of burnout, the solid research basis concerning the syndrome, and its specific ties to the work domain make a distinct and valuable contribution to people's health and well-being.


CDKN2A mutations in Spanish cutaneous malignant melanoma families and patients with multiple melanomas and other neoplasia.
The CDKN2A gene has been implicated in cutaneous malignant melanoma (CMM) in about 40% of families with linkage to chromosome 9p21, while a small proportion of families have mutations in the CDK4 gene. In order to estimate the importance of these genes in the predisposition to CMM in Spanish families and patients we have analysed, by SSCA, a total of 56 subjects belonging to 34 CMM families, and nine patients with multiple CMM and other neoplasia. We have detected germline CDKN2A mutations in six out of the 34 families (17%). A frameshift mutation (358delG) and four missense mutations (G59V, G101W (two cases), D84Y, and R87W) were identified. Five CMM patients from different families (14%) carried the A148T variant, which is known not to affect p16 activity. No mutations were detected in the patients with multiple CMM or other neoplasms. We have not found mutations either in exon 1 beta of the CDKN2A gene or in exon 2A of CDK4. Linkage analysis of the 9p21 region showed exclusion for one of the families for CMM and for four families for CMM/dysplastic naevi. This study indicates a small role for CDKN2A in Spanish CMM families and suggests that other genes are also responsible for CMM predisposition.


Segmental oscillators in axial motor circuits of the salamander: distribution and bursting mechanisms.
The rhythmic and coordinated activation of axial muscles that underlie trunk movements during locomotion are generated by specialized networks in the spinal cord. The operation of these networks has been extensively investigated in limbless swimming vertebrates. But little is known about the architecture and functioning of the axial locomotor networks in limbed vertebrates. We investigated the rhythm-generating capacity of the axial segmental networks in the salamander (Pleurodeles waltlii). We recorded ventral root activity from hemisegments and segments that were surgically isolated from the mid-trunk cord and chemically activated with bath-applied N-methyl-d-aspartate (NMDA). We provide evidence that the rhythmogenic capacity of the axial network is distributed along the mid-trunk spinal cord without an excitability gradient. We demonstrate that the burst generation in a hemisegment depends on glutamatergic excitatory interactions. Reciprocal glycinergic inhibition between opposite hemisegments ensures left-right alternation and lowers the rhythm frequency in segments. Our results further suggest that persistent sodium current contributes to the rhythmic regenerating process both in hemisegments and segments. Burst termination in hemisegments is not achieved through the activation of apamine-sensitive Ca(2+)-activated K(+) channels and burst termination in segments relies on crossed glycinergic inhibition. Together our results indicate that the basic design of the salamander axial network is similar to most of axial networks investigated in other vertebrates, albeit with some significant differences in the cellular mechanism that underlies segmental bursting. This finding supports the view of a phylogenetic conservation of basic building blocks of the axial locomotor network among the vertebrates.


Unraveling 50-Year-Old Clues Linking Neurodegeneration and Cancer to Cycad Toxins: Are microRNAs Common Mediators?
Recognition of overlapping molecular signaling activated by a chemical trigger of cancer and neurodegeneration is new, but the path to this discovery has been long and potholed. Six conferences (1962-1972) examined the puzzling neurotoxic and carcinogenic properties of a then-novel toxin [cycasin: methylazoxymethanol (MAM)-β-d-glucoside] in cycad plants used traditionally for food and medicine on Guam where a complex neurodegenerative disease plagued the indigenous population. Affected families showed combinations of amyotrophic lateral sclerosis (ALS), parkinsonism (P), and/or a dementia (D) akin to Alzheimer's disease (AD). Modernization saw declining disease rates on Guam and remarkable changes in clinical phenotype (ALS was replaced by P-D and then by D) and in two genetically distinct ALS-PDC-affected populations (Kii-Japan, West Papua-Indonesia) that used cycad seed medicinally. MAM forms DNA lesions - repaired by O(6)-methylguanine methyltransferase (MGMT) - that perturb mouse brain development and induce malignant tumors in peripheral organs. The brains of young adult MGMT-deficient mice given a single dose of MAM show DNA lesion-linked changes in cell-signaling pathways associated with miRNA-1, which is implicated in colon, liver, and prostate cancers, and in neurological disease, notably AD. MAM is metabolized to formaldehyde, a human carcinogen. Formaldehyde-responsive miRNAs predicted to modulate MAM-associated genes in the brains of MGMT-deficient mice include miR-17-5p and miR-18d, which regulate genes involved in tumor suppression, DNA repair, amyloid deposition, and neurotransmission. These findings marry cycad-associated ALS-PDC with colon, liver, and prostate cancer; they also add to evidence linking changes in microRNA status both to ALS, AD, and parkinsonism, and to cancer initiation and progression.


Dimethyl fumarate activates the prostaglandin EP2 receptor and stimulates cAMP signaling in human peripheral blood mononuclear cells.
Dimethyl fumarate (DMF) was recently approved by the FDA for the treatment of relapsing remitting MS. The pathology of MS is a result of both immune dysregulation and oxidative stress induced damage, and DMF is believed to have therapeutic effects on both of these processes. However, the mechanisms of action of DMF are not fully understood. To determine if DMF is able to activate signaling cascades that affect immune dysregulation, we treated human peripheral blood mononuclear cells with DMF. We discovered that DMF stimulates cyclic adenosine monophosphate (cAMP) production after 1 min treatment in vitro. cAMP is a small molecule second messenger that has been shown to modulate immune response. Using pharmacological inhibitors, we determined that adenylyl cyclase mediates DMF induced cAMP production; DMF activated the prostaglandin EP2 receptor to produce cAMP. This response was not due to increased endogenous production of prostaglandin E2 (PGE2), but was enhanced by addition of exogenous PGE2. Furthermore, we determined that the bioactive metabolite of DMF, monomethyl fumarate (MMF), also stimulates cAMP production. These novel findings suggest that DMF may provide protection against MS by inhibiting immune cell function via the cAMP signaling pathway.


Insecticide sensitivity of native chloride and sodium channels in a mosquito cell line.
The aim of this study was to investigate the utility of cultured Anopheles gambiae Sua1B cells for insecticide screening applications without genetic engineering or other treatments. Sua1B cells were exposed to the known insecticidal compounds lindane and DIDS, which inhibited cell growth at micromolar concentrations. In patch clamp studies, DIDS produced partial inhibition (69%) of chloride current amplitudes, and an IC50 of 5.1μM was determined for Sua1B cells. A sub-set of chloride currents showed no response to DIDS; however, inhibition (64%) of these currents was achieved using a low chloride saline solution, confirming their identity as chloride channels. In contrast, lindane increased chloride current amplitude (EC50=116nM), which was reversed when cells were bathed in calcium-free extracellular solution. Voltage-sensitive chloride channels were also inhibited by the presence of fenvalerate, a type 2 pyrethroid, but not significantly blocked by type 1 allethrin, an effect not previously shown in insects. Although no evidence of fast inward currents typical of sodium channels was observed, studies with fenvalerate in combination with veratridine, a sodium channel activator, revealed complete inhibition of cell growth that was best fit by a two-site binding model. The high potency effect was completely inhibited in the presence of tetrodotoxin, a specific sodium channel blocker, suggesting the presence of some type of sodium channel. Thus, Sua1B cells express native insect ion channels with potential utility for insecticide screening.


Complex object wave direct extraction method in off-axis digital holography.
Off-axis digital holography generally uses a 2D-FFT based spatial filtering method to extract the complex object wave from an off-axis hologram. In this paper, we describe a novel single exposure complex object wave extraction method which can provide a faster solution than the FFT based spatial filtering approach while maintaining the reconstructed phase image quality. And also, we show that the proposed direct filtering scheme can provide more robust filtering capability to the off-axis spatial carrier frequency variation than the spatial filtering method.


Effect of regression of enlarged neck lymph nodes on radiation doses received by parotid glands during intensity-modulated radiotherapy for head and neck cancer.
The regression of enlarged neck lymph nodes during intensity-modulated radiotherapy (IMRT) may increase actual radiation doses to the parotid glands of patients with head-and-neck cancer. We investigated the changes in the lymph nodes volume during IMRT and the effect of these changes to the parotid gland doses. Ten head and neck cancer patients with enlarged neck lymph nodes were enrolled in this study. Computed tomography (CT) imaging was repeated to evaluate the change in lymph nodes volume after initial 45 Gy, and the second part of IMRT (21 Gy) was then replanned to reflect the change of nodal tumor volume. The dosimetric benefit of parotid sparing with replanning was compared with that of no replanning. The enlarged neck lymph nodes in all patients pushed the parotid glands outward in pretreatment CT images. After 45 Gy of IMRT, nodal regression caused the parotid glands to shift inward into the high-dose area. When compared with those without replanning, we found modification of IMRT plan after 45 Gy significantly reduced radiation dose to parotid glands (mean reduction of 2.95 +/- 1.10 Gy to the left and 3.23 +/- 1.37 Gy to the right, respectively; P < 0.001). Excessive parotid gland doses secondary to the regression of enlarged neck nodes could be mitigated by replanning after 45 Gy. However, recontouring of large lymph nodes that regress during therapy has a risk of under-dosing extracapsular extension of lymph node metastases. Therefore, recontouring should be done with extreme caution.


Characterization of the M918T sodium channel gene mutation associated with strong resistance to pyrethroid insecticides in the peach-potato aphid, Myzus persicae (Sulzer).
Recent advances in the characterisation of insect sodium channel gene sequences have identified a small number of point mutations within the channel protein that are implicated in conferring target-site resistance to pyrethroid insecticides (so-called knockdown resistance or kdr). The L1014F (leucine-to-phenylalanine) mutation located in the centre of segment 6 of the domain II region (IIS6) of the sodium channel (the so-called kdr trait) has been detected in the peach-potato aphid, Myzus persicae (Sulzer), and is considered to be the primary cause of pyrethroid resistance in this species. Here we report on the characterisation of a second mutation, M918T (methione-to-threonine), within the nearby IIS4-S5 intracellular linker (the so-called super-kdr trait) in a field clone also possessing L1014F, with both mutations present in heterozygous form. The resistance phenotype of M. persicae clones possessing various combinations of L1014F and M918T to a wide range of pyrethroids (both Type I and II) was assessed in leaf-dip bioassays and to lambda-cyhalothrin applied at up to ten times the recommended field rate as foliar sprays to aphids feeding on whole plants. Bioassay results demonstrated that presence of both mutations was associated with extreme resistance to all the pyrethroids tested relative to aphids lacking the mutations. Furthermore, this resistance well exceeded that shown by aphids that were homozygous for L1014F but lacking M918T. However, pre-treatment with piperonyl butoxide in the leaf-dip bioassays failed to suppress pyrethroid resistance in aphids carrying one or both of the mutations. The relevance of these findings for monitoring and managing pyrethroid resistance in M. persicae populations in the field is discussed.


Dynamic tomography with a priori information.
We present "dynamic tomography" algorithms that allow for the high-resolution, time-resolved imaging of dynamic (i.e., continuously time evolving) complex systems at existing x-ray micro-CT facilities. The behavior of complex systems is constrained by the underlying physics. By exploiting a priori knowledge of the geometry of the physical process being studied to allow the use of sophisticated iterative reconstruction techniques that incorporate constraints, we improve on current frame rates by at least an order of magnitude. This allows time-resolved imaging of previously intractable processes, such as two-phase fluid flow. We present reconstructions from experimental data collected at the Australian National University x-ray micro-CT facility.


Effect of different substituents on the water-solubility and stability properties of 1 : 2 [60]fullerene derivative·gamma-cyclodextrin complexes.
We have demonstrated that C60 derivatives bearing a pyrrolidine moiety as well as a variety of other substituents can form 1 : 2 complexes with γ-cyclodextrin (γ-CDx) using a mechanochemical high-speed vibration milling apparatus. When the influence of the steric hindrance of the substituents on the formation of the complexes was negligible, the water-solubilities of the complexes were shown experimentally to be completely dependent on the hydrophobic properties of the substituent. Furthermore, the stabilities of the γ-CDx-complexes of several different C60 derivatives were found to be similar to or slightly higher than that of the C60·γ-CDx complex, with the solubilities of the complexes showing no correlation to the stabilities. Based on the results of a series of theoretical investigations, we have shown that the stabilities of the γ-CDx-complexes can be affected not only by steric effects but also by the polarities of the substituent groups, which exist in the vicinity of the upper rim of γ-CDx, because the water bound to the polar group can assist in the stabilisation of the complexes.


Modern approaches to accelerate discovery of new antischistosomal drugs.
The almost exclusive use of only praziquantel for the treatment of schistosomiasis has raised concerns about the possible emergence of drug-resistant schistosomes. Consequently, there is an urgent need for new antischistosomal drugs. The identification of leads and the generation of high quality data are crucial steps in the early stages of schistosome drug discovery projects. Herein, the authors focus on the current developments in antischistosomal lead discovery, specifically referring to the use of automated in vitro target-based and whole-organism screens and virtual screening of chemical databases. They highlight the strengths and pitfalls of each of the above-mentioned approaches, and suggest possible roadmaps towards the integration of several strategies, which may contribute for optimizing research outputs and led to more successful and cost-effective drug discovery endeavors. Increasing partnerships and access to funding for drug discovery have strengthened the battle against schistosomiasis in recent years. However, the authors believe this battle also includes innovative strategies to overcome scientific challenges. In this context, significant advances of in vitro screening as well as computer-aided drug discovery have contributed to increase the success rate and reduce the costs of drug discovery campaigns. Although some of these approaches were already used in current antischistosomal lead discovery pipelines, the integration of these strategies in a solid workflow should allow the production of new treatments for schistosomiasis in the near future.


Spatio-temporal patterns of gun violence in Syracuse, New York 2009-2015.
Gun violence in the United States of America is a large public health problem that disproportionately affects urban areas. The epidemiology of gun violence reflects various aspects of an infectious disease including spatial and temporal clustering. We examined the spatial and temporal trends of gun violence in Syracuse, New York, a city of 145,000. We used a spatial scan statistic to reveal spatio-temporal clusters of gunshots investigated and corroborated by Syracuse City Police Department for the years 2009-2015. We also examined predictors of areas with increased gun violence using a multi-level zero-inflated Poisson regression with data from the 2010 census. Two space-time clusters of gun violence were revealed in the city. Higher rates of segregation, poverty and the summer months were all associated with increased risk of gun violence. Previous gunshots in the area were associated with a 26.8% increase in the risk of gun violence. Gun violence in Syracuse, NY is both spatially and temporally stable, with some neighborhoods of the city greatly afflicted.


Socioeconomic differentials in cancer among men.
The relationship between cancer and socioeconomic position is examined for men using data from three sources--the Whitehall Study of London civil servants, the OPCS Longitudinal Study and the Registrar General's Decennial Supplement. Mortality from, or registration for, malignant neoplasms was higher overall in lower socioeconomic groups. There was considerable variation in the strength, and to a lesser extent direction, of the association of specific cancer sites and socioeconomic position within each of the studies. However, between the studies the relationships between socioeconomic position and the particular cancers were very similar. The similarity in results, taken in conjunction with the differences in design and methods of the three studies, makes it very unlikely that these consistent associations are due to artefacts. The heterogeneity in relationships between specific cancer sites and socioeconomic position suggests that no single factor--such as differences in general susceptibility or differences in smoking behaviour--can account for these associations. However socioeconomic differentials displayed by a particular malignancy do offer clues to its aetiology, and provide an indication of the scope that exists for reducing the burden of cancer within a population.


Evaluation of a pulsed-xenon ultraviolet room disinfection device for impact on contamination levels of methicillin-resistant Staphylococcus aureus.
Healthcare-acquired infections with methicillin-resistant Staphylococcus aureus (MRSA) are a significant cause of increased mortality, morbidity and additional health care costs in United States. Surface decontamination technologies that utilize pulsed xenon ultraviolet light (PPX-UV) may be effective at reducing microbial burden. The purpose of this study was to compare standard manual room-cleaning to PPX-UV disinfection technology for MRSA and bacterial heterotrophic plate counts (HPC) on high-touch surfaces in patient rooms. Rooms vacated by patients that had a MRSA-positive polymerase chain reaction or culture during the current hospitalization and at least a 2-day stay were studied. 20 rooms were then treated according to one of two protocols: standard manual cleaning or PPX-UV. This study evaluated the reduction of MRSA and HPC taken from five high-touch surfaces in rooms vacated by MRSA-positive patients, as a function of cleaning by standard manual methods vs a PPX-UV area disinfection device. Colony counts in 20 rooms (10 per arm) prior to cleaning varied by cleaning protocol: for HPC, manual (mean = 255, median = 278, q1-q3 132-304) vs PPX-UV (mean = 449, median = 365, q1-q3 332-530), and for MRSA, manual (mean = 127; median = 28.5; q1-q3 8-143) vs PPX-UV (mean = 108; median = 123; q1-q3 14-183). PPX-UV was superior to manual cleaning for MRSA (adjusted incident rate ratio [IRR] = 7; 95% CI <1-41) and for HPC (IRR = 13; 95% CI 4-48). PPX-UV technology appears to be superior to manual cleaning alone for MRSA and HPC. Incorporating 15 minutes of PPX-UV exposure time to current hospital room cleaning practice can improve the overall cleanliness of patient rooms with respect to selected micro-organisms.


The construct of state-level suspicion: a model and research agenda for automated and information technology (IT) contexts.
The objective was to review and integrate available research about the construct of state-level suspicion as it appears in social science literatures and apply the resulting findings to information technology (IT) contexts. Although the human factors literature is replete with articles about trust (and distrust) in automation, there is little on the related, but distinct, construct of "suspicion" (in either automated or IT contexts). The construct of suspicion--its precise definition, theoretical correlates, and role in such applications--deserves further study. Literatures that consider suspicion are reviewed and integrated. Literatures include communication, psychology, human factors, management, marketing, information technology, and brain/neurology. We first develop a generic model of state-level suspicion. Research propositions are then derived within IT contexts. Fundamental components of suspicion include (a) uncertainty, (b) increased cognitive processing (e.g., generation of alternative explanations for perceived discrepancies), and (c) perceptions of (mal)intent. State suspicion is defined as the simultaneous occurrence of these three components. Our analysis also suggests that trust inhibits suspicion, whereas distrust can be a catalyst of state-level suspicion. Based on a three-stage model of state-level suspicion, associated research propositions and questions are developed. These propositions and questions are intended to help guide future work on the measurement of suspicion (self-report and neurological), as well as the role of the construct of suspicion in models of decision making and detection of deception. The study of suspicion, including its correlates, antecedents, and consequences, is important. We hope that the social sciences will benefit from our integrated definition and model of state suspicion. The research propositions regarding suspicion in IT contexts should motivate substantial research in human factors and related fields.


Within-person across-neuropsychological test variability and incident dementia.
Neuropsychological tests are used to predict and diagnose dementia. However, to our knowledge, no studies to date have examined whether within-person across-neuropsychological test variability predicts dementia. To examine whether within-person across-neuropsychological test variability predicts future dementia. The Einstein Aging Study (EAS) is a population-based longitudinal study of aging and dementia located in Bronx County, New York. We used Cox proportional hazards models using age as the time scale to estimate hazard ratios (HRs) for performance on individual neuropsychological tests (Free and Cued Selective Reminding Test, Digit Symbol Substitution subtest of the Wechsler Adult Intelligence Scale Revised, and the Vocabulary subtest of the Wechsler Adult Intelligence Scale Revised) and for within-person across-neuropsychological test variability as predictors of incident dementia. Analyses were stratified by sex, and controlled for education and medical illness. A total of 1797 participants (age > or = 70 years) enrolled in the EAS between October 1993 and December 2007. Participants seen for the baseline visit only (n = 750), prevalent dementia cases (n = 72), and those with missing follow-up information (n = 78) were excluded. A total of 897 individuals were included in this investigation. Participants had follow-up visits every 12 to 18 months. Incident dementia. Sixty-one cases of incident dementia were identified during follow-up (mean [SD], 3.3 [2.4] years), of which 26 were in the highest quartile of within-person across-neuropsychological test variability. Adjusting for sex, education, and medical illness, variability was associated with incident dementia (HR for 1-point difference in variability, 3.93 [95% confidence interval {CI}, 2.04-7.56]). The association persisted even after adjusting for level of performance on individual neuropsychological tests (HR for 1-point difference in variability, 2.10 [95% CI, 1.04-4.23]). Comparing Cox models using neuropsychological tests with and without within-person across-neuropsychological test variability showed that the former improved the prediction of dementia. Sensitivity in a model predicting dementia at 1 year also improved when neuropsychological test variability was included. In this population, within-person across-neuropsychological test variability was associated with development of incident dementia independent of neuropsychological test performance. This finding needs to be confirmed in future studies.


High-throughput sorting of the highest producing cell via a transiently protein-anchored system.
Developing a high-throughput method for the effecient selection of the highest producing cell is very important for the production of recombinant protein drugs. Here, we developed a novel transiently protein-anchored system coupled with fluorescence activated cell sorting (FACS) for the efficient selection of the highest producing cell. A furin cleavage peptide (RAKR) was used to join a human anti-epithelial growth factor antibody (αEGFR Ab) and the extracellular-transmembrane-cytosolic domains of the mouse B7-1 antigen (B7). The furin inhibitor can transiently switch secreted αEGFR Ab into a membrane-anchored form. After cell sorting, the level of membrane αEGFR Ab-RAKR-B7 is proportional to the amount of secreted αEGFR Ab in the medium. We further selected 23 αEGFR Ab expressing cells and demonstrated a high correlation (R2 = 0.9165) between the secretion level and surface expression levels of αEGFR Ab. These results suggested that the novel transiently protein-anchored system can easily and efficiently select the highest producing cells, reducing the cost for the production of biopharmaceuticals.


Tbx genes and limb identity in chick embryo development.
Tbx-2, Tbx-3, Tbx-4 and Tbx-5 chick genes have been isolated and, like the mouse homologues, are expressed in the limb regions. Tbx-2 and Tbx-3 are expressed in anterior and posterior domains in wings and legs, as well as throughout the flank. Of particular interest, however, are Tbx-5, which is expressed in wing and flank but not leg, and Tbx-4, which is expressed very strongly in leg but not wing. Grafts of leg tissue to wing and wing tissue to leg give rise to toe-like or wing-like digits in wing and leg respectively. Expression of Tbx-4 is stable when leg tissue is grafted to wing, and Tbx-5 expression is stable when wing tissue is grafted to leg. Induction of either extra wings or legs from the flank by applying FGF-2 in different positions alters the expression of Tbx-4 and Tbx-5 in such a way that suggests that the amount of Tbx-4 that is expressed in the limb determines the type that will form. The ectopic limb always displays a limb-like Tbx-3 expression. Thus Tbx-4 and Tbx-5 are strong candidates for encoding 'wingness' and 'legness'.


The relationships between science and sport: application in triathlon.
The relationships between sport sciences and sports are complex and changeable, and it is not clear how they reciprocally influence each other. By looking at the relationship between sport sciences and the "new" (~30-year-old) sport of triathlon, together with changes in scientific fields or topics that have occurred between 1984 and 2006 (278 publications), one observes that the change in the sport itself (eg, distance of the events, wetsuit, and drafting) can influence the specific focus of investigation. The sport-scientific fraternity has successfully used triathlon as a model of prolonged strenuous competition to investigate acute physiological adaptations and trauma, as support for better understanding cross-training effects, and, more recently, as a competitive sport with specific demands and physiological features. This commentary discusses the evolution of the scientific study of triathlon and how the development of the sport has affected the nature of scientific investigation directly related to triathlon and endurance sport in general.


A coarse-to-fine subpixel registration method to recover local perspective deformation in the application of image super-resolution.
In this paper, a coarse-to-fine framework is proposed to register accurately the local regions of interest (ROIs) of images with independent perspective motions by estimating their deformation parameters. A coarse registration approach based on control points (CPs) is presented to obtain the initial perspective parameters. This approach exploits two constraints to solve the problem with a very limited number of CPs. One is named the point-point-line topology constraint, and the other is named the color and intensity distribution of segment constraint. Both of the constraints describe the consistency between the reference and sensed images. To obtain a finer registration, we have converted the perspective deformation into affine deformations in local image patches so that affine refinements can be used readily. Then, the local affine parameters that have been refined are utilized to recover precise perspective parameters of a ROI. Moreover, the location and dimension selections of local image patches are discussed by mathematical demonstrations to avoid the aperture effect. Experiments on simulated data and real-world sequences demonstrate the accuracy and the robustness of the proposed method. The experimental results of image super-resolution are also provided, which show a possible practical application of our method.


Are depressive symptoms associated with cancer screening and cancer stage at diagnosis among postmenopausal women? The Women's Health Initiative observational cohort.
Women with depressive symptoms may use preventive services less frequently and experience poorer health outcomes. We investigated the association of depressive symptoms with breast and colorectal cancer screening rates and stage of cancer among a cohort of postmenopausal women. In The Women's Health Initiative Observational Study, 93,676 women were followed on average for 7.6 years. Depressive symptoms were measured at baseline and at 3 years using the 6-item scale from the Center for Epidemiological Studies Depression scale (CES-D). We calculated a cancer screening rate expressed as a proportion of the years that women were current with recommended cancer screening over the number of follow-up visits in the study. Breast and colorectal cancers were staged based on Surveillance, Epidemiology and End Results (SEER) classification. At baseline, 15.8% (12,621) women were positive for depressive symptoms, and 6.9% (4,777) were positive at both baseline screening and at 3 years. The overall average screening rate was 71% for breast cancer and 53% for colorectal cancer. The breast cancer screening rate was 1.5% (CI 0.9%-2.0%) lower among women who reported depressive symptoms at baseline than among those who did not. Depressive symptoms were not a predictor for colorectal cancer screening. Stage of breast and colorectal cancer was not found to be associated with depressive symptoms after adjusting for covariates. Among a healthy and self-motivated cohort of women, self-reported depressive symptoms were associated with lower rates of screening mammography but not with colorectal cancer screening.


Clinical usefulness of testing for a heparin-dependent platelet-aggregating factor in patients with suspected heparin-associated thrombocytopenia.
It is important to confirm the diagnosis of heparin-associated thrombocytopenia, because discontinuation of heparin requires the institution of other antithrombotic therapy. Reports describing a heparin-dependent platelet-aggregating factor in the serum of patients with heparin-associated thrombocytopenia suggest the potential for a specific diagnostic test. No study has evaluated the diagnostic usefulness of testing for this factor, and we tested for a heparin-dependent platelet-aggregating factor in sera from (1) 14 patients with heparin-associated thrombocytopenia, (2) 14 nonthrombocytopenic controls given heparin, (3) 16 patients with consumptive thrombocytopenic disorders not associated with heparin, and (4) 13 healthy laboratory personnel. Coded serum samples plus varying concentrations of heparin (final concentration 0.01, 0.1, 1.0, and 5 U/ml) plus platelets from healthy individuals were incubated together, and aggregation was measured. Positive results (greater than 20% aggregation) occurred in (1) five of 14 patients with heparin-associated thrombocytopenia, (2) 0 of 16 consumptive thrombocytopenic controls not given heparin therapy, (3) one of 14 nonthrombocytopenic controls given heparin, and (4) one of 13 healthy controls, giving a sensitivity of 36% and specificities of 100%, 93%, and 92%, respectively. No unique clinical or laboratory feature distinguished those patients with heparin-associated thrombocytopenia with positive aggregation results from those patients with heparin-associated thrombocytopenia with negative results. Fourteen of the 16 patients (86%) with heparin-associated thrombocytopenia had elevated levels of platelet-associated IgG; however, the test was also positive in 67% of the 16 patients with other consumptive (and probably immune) thrombocytopenic disorders not associated with heparin administration.(ABSTRACT TRUNCATED AT 250 WORDS)


[Effects of delayed cord clamping on hemoglobin and ferritin levels in infants at three months of age].
This study assessed the effect of delayed (1 minute after delivery) clamping of the umbilical cord on hemoglobin and ferritin levels in infants at three months of age. Mothers and their infants born through vaginal delivery, at term, and without congenital anomalies (325 pairs) were recruited at a hospital in São Paulo, Brazil, in 2006 (164 in the delayed clamping subgroup and 161 in the early clamping subgroup). Maternal hemoglobin at delivery, umbilical cord hemoglobin, and ferritin were recorded. At three months follow-up, venous blood samples were drawn from 224 (69%) infants for hemoglobin and ferritin measurement. Socioeconomic, maternal reproductive, anthropometric, and infant feeding variables were studied. Multiple linear regression models were used to analyze the data. The effect of delayed clamping at birth, measured at three months, was only significant for ferritin (p = 0.040), and the concentration was higher (23.29ng/mL) in this subgroup as compared to the early clamping subgroup. Delayed umbilical cord clamping can serve as a strategy to improve infant iron status and prevent iron deficiency.


Energy intake at breakfast and weight change: prospective study of 6,764 middle-aged men and women.
To investigate the association between percentage of total daily energy intake consumed at breakfast and weight change in middle-aged men and women, the authors analyzed data from a prospective population-based cohort study from Norfolk, United Kingdom. Participants were 6,764 men and women aged 40-75 years at baseline (1993-1997). Participants completed a 7-day food diary at baseline, and objective measurements of height and weight were carried out at baseline and follow-up (1998-2000). Mean baseline body mass index (weight (kg)/height (m)(2)) was lowest among persons in the highest quintile of percentage of daily energy consumed at breakfast (mean values were 26.0 in the highest quintile and 26.3 in the lowest quintile), despite higher daily total energy intake in this group. Although all participants gained weight, increased percentage of daily energy consumed at breakfast was associated with relatively lower weight gain (adjusted beta coefficient = -0.021, 95% confidence interval: -0.035, -0.007; p = 0.004). The association between percentage of daily energy intake consumed at breakfast and weight gain was independent of age, sex, smoking, total energy intake, macronutrient intake, social class, and physical activity. Redistribution of daily energy intake, so that more energy is consumed at breakfast and less energy is consumed later in the day, may help to reduce weight gain in middle-aged adults.


Marine debris in bottom trawl catches and their effects on the selectivity grids in the north eastern Mediterranean.
In this study composition of marine debris and their blocking potential on the selectivity grid systems deployed on demersal trawls were investigated in the north eastern Mediterranean. For this, a total of 132 hauls were examined in two fishing season between 20 September 2010 and 19 February 2012. Results showed that plastic items were the most abundant debris (73% in terms of weight) and they were followed by metals (10%). Because of plastics and packing debris, it is highly probable that grids may have been blocked in 85% of trawl hauls. The bathymetric and geographical variability in the quantity of debris were evaluated, and concluded that particularly in some areas where direction of currents and bottom topography favor deposition, such devices may easily be rendered ineffective by the plastics and packing debris in particular. To solve this problem, several solution proposals are submitted.


Haemodiafiltration, haemofiltration and haemodialysis for end-stage kidney disease.
Convective dialysis modalities (haemofiltration (HF), haemodiafiltration (HDF), and acetate-free biofiltration (AFB)) removed excess body fluid across the dialysis membrane with positive pressure and accumulated middle- and larger-size accumulated solutes more efficiently than haemodialysis (HD). This increased larger solute removal combined with use of ultra-pure dialysis fluid in convective dialysis is hypothesised to reduce the frequency and severity of symptoms during dialysis as well as improve clinical outcomes. Convective dialysis therapies (HDF and HF) are associated with lower mortality compared to diffusive therapy (HD) in observational studies. This is an update of a review first published in 2006. To compare convective (HF, HDF, or AFB) with diffusive (HD) dialysis modalities on clinical outcomes (mortality, major cardiovascular events, hospitalisation and treatment-related adverse events) in men and women with end-stage kidney disease (ESKD). We searched the Cochrane Renal Group's Specialised Register (to 18 February 2015) through contact with a Trials' Search Co-ordinator using search terms relevant to this review. We included randomised controlled trials comparing convective therapy (HF, HDF, AFB) with another convective therapy or diffusive therapy (HD) for treatment of ESKD. Two independent authors identified studies, extracted data and assessed study risk of bias. We summarised treatment effects using the random effects model. We reported results as a risk ratio (RR) for dichotomous outcomes and mean difference (MD) for continuous data together with 95% confidence intervals (CI). We assessed for heterogeneity using the Chi(2) test and explored the amount of variation in treatment estimates beyond that expected by chance using the I(2) statistic. Twenty studies comprising 667 participants were included in the 2006 review. In that review, there was insufficient evidence of treatment effects on major clinical outcomes to draw clinically meaningful conclusions. Searching to February 2015 identified 40 eligible studies comprising 3483 participants overall. In total, 35 studies (4039 participants) compared HF, HDF or AFB with HD, three studies (54 participants) compared AFB with HDF, and three studies (129 participants) compared HDF with HF.Risks of bias in all studies were generally high resulting in low confidence in estimated treatment effects. Convective dialysis had no significant effect on all-cause mortality (11 studies, 3396 participants: RR 0.87, 95% CI 0.72 to 1.05; I(2) = 34%), but significantly reduced cardiovascular mortality (6 studies, 2889 participants: RR 0.75, 95% CI 0.61 to 0.92; I(2) = 0%). One study reported no significant effect on rates of nonfatal cardiovascular events (714 participants: RR 1.14, 95% CI 0.86 to 1.50) and two studies showed no significant difference in hospitalisation (2 studies, 1688 participants: RR 1.23, 95% CI 0.93 to 1.63; I(2) = 0%). One study reported rates of hypotension during dialysis were significantly reduced with convective therapy (906 participants: RR 0.72, 95% CI 0.66 to 0.80). Adverse events were not systematically evaluated in most studies and data for health-related quality of life were sparse. Convective therapies significantly reduced predialysis levels of B2 microglobulin (12 studies, 1813 participants: MD -5.55 mg/dL, 95% CI -9.11 to -1.98; I(2) = 94%) and increased dialysis dose (Kt/V urea) (14 studies, 2022 participants: MD 0.07, 95% CI -0.00 to 0.14; I(2) = 90%) compared to diffusive therapy, but results across studies were very heterogeneous. Sensitivity analyses limited to studies comparing HDF with HD showed very similar results. Directly comparative data for differing types of convective dialysis were insufficient to draw conclusions.Studies had important risks of bias leading to low confidence in the summary estimates and were generally limited to patients who had adequate dialysis vascular access. Convective dialysis may reduce cardiovascular but not all-cause mortality and effects on nonfatal cardiovascular events and hospitalisation are inconclusive. However, any treatment benefits of convective dialysis on all patient outcomes including cardiovascular death are unreliable due to limitations in study methods and reporting. Future studies which assess treatment effects of convection dose on patient outcomes including mortality and cardiovascular events would be informative.


Investigation of downstream signals of the soybean autoregulation of nodulation receptor kinase GmNARK.
The Glycine max nodule autoregulation receptor kinase (GmNARK) plays a central role in the systemic signal transduction pathway controlling nodulation in soybean. We used transcriptional profiling to identify potential downstream signals of this receptor kinase. These studies revealed that GmNARK-mediated signaling controls the expression of genes involved in the jasmonic acid (JA) pathway. Genes encoding the key enzymes controlling JA biosynthesis as well as JA-response genes were regulated systemically but not locally by root inoculation with Bradyrhizobium japonicum. This systemic regulation was abolished in Gmnark mutant plants, indicating that their expression was specifically controlled by signaling events associated with this receptor kinase. Foliar application of a JA biosynthesis inhibitor significantly reduced nodulation specifically in supernodulating mutant plants. These results indicate that the receptor-mediated regulation of JA signaling plays an important role in the AON signal transduction pathway. A second class of genes was identified that were controlled by GmNARK in a rhizobia-independent manner. These candidates provide insight on additional, nonsymbiotic signaling pathways that are likely regulated by GmNARK, such as those involved in root growth and defense. The discovery of downstream components of the GmNARK receptor kinase advances our understanding of the systemic control of nodule development and its association with other signaling networks.


Predictors of oncological outcomes in T1G3 patients treated with BCG who undergo radical cystectomy.
To evaluate the oncological impact of postponing radical cystectomy (RC) to allow further conservative therapies prior to progression in a large multicentre retrospective cohort of T1-HG/G3 patients initially treated with BCG. According to the time of RC, the population was divided into 3 groups: patients who did not progress to muscle-invasive disease, patients who progressed before radical cystectomy and patients who experienced progression at the time of radical cystectomy. Clinical and pathological outcomes were compared across the three groups. Of 2451 patients, 509 (20.8%) underwent RC. Patients with tumors > 3 cm or with CIS had earlier cystectomies (HR = 1.79, p = 0.001 and HR = 1.53, p = 0.02, respectively). Patients with tumors > 3 cm, multiple tumors or CIS had earlier T3/T4 or N + cystectomies. In patients who progressed, the timing of cystectomy did not affect the risk of T3/T4 or N + disease at RC. Patients with T3/T4 or N + disease at RC had a shorter disease-specific survival (HR = 4.38, p < 0.001), as did patients with CIS at cystectomy (HR = 2.39, p < 0.001). Patients who progressed prior to cystectomy had a shorter disease-specific survival than patients for whom progression was only detected at cystectomy (HR = 0.58, p = 0.024) CONCLUSIONS: Patients treated with RC before experiencing progression to muscle-invasive disease harbor better oncological and survival outcomes compared to those who progressed before RC and to those upstaged at surgery. Tumor size and concomitant CIS at diagnosis are the main predictors of surgical treatment while tumor size, CIS and tumor multiplicity are associated with extravesical disease at surgery.


Merkel cell polyomavirus-specific CD8⁺ and CD4⁺ T-cell responses identified in Merkel cell carcinomas and blood.
Merkel cell polyomavirus (MCPyV) is prevalent in the general population, integrates into most Merkel cell carcinomas (MCC), and encodes oncoproteins required for MCC tumor growth. We sought to characterize T-cell responses directed against viral proteins that drive this cancer as a step toward immunotherapy. Intracellular cytokine cytometry, IFN-γ enzyme-linked immunospot (ELISPOT) assay, and a novel HLA-A*2402-restricted MCPyV tetramer were used to identify and characterize T-cell responses against MCPyV oncoproteins in tumors and blood of MCC patients and control subjects. We isolated virus-reactive CD8 or CD4 T cells from MCPyV-positive MCC tumors (2 of 6) but not from virus-negative tumors (0 of 4). MCPyV-specific T-cell responses were also detected in the blood of MCC patients (14 of 27) and control subjects (5 of 13). These T cells recognized a broad range of peptides derived from capsid proteins (2 epitopes) and oncoproteins (24 epitopes). HLA-A*2402-restricted MCPyV oncoprotein processing and presentation by mammalian cells led to CD8-mediated cytotoxicity. Virus-specific CD8 T cells were markedly enriched among tumor infiltrating lymphocytes as compared with blood, implying intact T-cell trafficking into the tumor. Although tetramer-positive CD8 T cells were detected in the blood of 2 of 5 HLA-matched MCC patients, these cells failed to produce IFN-γ when challenged ex vivo with peptide. Our findings suggest that MCC tumors often develop despite the presence of T cells specific for MCPyV T-Ag oncoproteins. The identified epitopes may be candidates for peptide-specific vaccines and tumor- or virus-specific adoptive immunotherapies to overcome immune evasion mechanisms in MCC patients.


Health utility bias: a systematic review and meta-analytic evaluation.
A common assertion is that rating scale (RS) values are lower than both standard gamble (SG) and time tradeoff (TTO) values. However, differences among these methods may be due to method specific bias. Although SG and TTOs suffer systematic bias, RS responses are known to depend on the range and frequency of other health states being evaluated. Over many diverse studies this effect is predicted to diminish. Thus, a systematic review and data synthesis of RS-TTO and RS-SG difference scores may better reveal persistent dissimilarities. The purpose of this study was to establish through systematic review and meta-analysis the net effect of biases that endure over many studies of utilities. A total of 2206 RS and TTO and 1318 RS and SG respondents in 27 studies of utilities participated. MEDLINE was searched for data from 1976 to 2004, complemented by a hand search of full-length articles and conference abstracts for 9 journals known to publish utility studies, as well as review of results and additional recommendations by 5 outside experts in the field. Two investigators abstracted the articles. We contacted the investigators of the original if required information was not available. No significant effect for RS and TTO difference scores was observed: effect size (95% confidence interval [CI]) = 0.04 (-0.02, 0.09). In contrast, RS scores were significantly lower than SG scores: effect size (95% CI ) =-0.23 (-0.28, -0.19). Correcting SG scores for 3 known biases (loss aversion, framing, and probability weighting) eliminated differences between RS and SG scores: effect size (95% CI ) = 0.01 (-0.03, 0.05). Systematic bias in the RS method may exist but be heretofore unknown. Bias correction formulas were applied to mean not individual utilities. The results of this study do not support the common view that RS values are lower than TTO values, may suggest that TTO biases largely cancel, and support the validity of formulas for correcting SG bias.


Carcinogenic organic content of particulate matter at urban locations with different pollution sources.
Polycyclic aromatic hydrocarbons (PAHs) are compounds known for their adverse effects on human health. Many of them are proven carcinogens, especially those with 5 and 6 aromatic rings, which under normal tropospheric conditions are found in the particle-phase. Benzo(a)pyrene (BaP) is often measured as their general representative. Sarajevo, the capital of Bosnia and Herzegovina, is among the European cities with the poorest air quality. However, in Sarajevo PAHs are neither routinely measured within the air quality monitoring network nor have been a subject of extended, continuous field studies during the most polluted cold periods of the year. The capital of Croatia, Zagreb, is located approximately 300 km air distance north-west from Sarajevo. PAH mass concentrations in Zagreb have been measured continuously since 1994 within air quality monitoring networks. During winter 2017/2018, the SAFICA project (Sarajevo Canton Winter Field Campaign 2018) was carried out in order to characterize the chemical composition of organic and inorganic aerosol in the Sarajevo Canton. This paper presents the results of PAH measurements in the cities of Sarajevo and Zagreb at one urban location per city. Daily (24 h), continuous samples of PM10 (particulate matter with aerodynamic diameters ≤10 μm) were collected during heating season, from December 27, 2017 to February 27, 2018. Mass concentrations of eleven particle-phase PAHs in Sarajevo and Zagreb from filter samples collected during the same period were compared. The average BaP ambient mass concentrations in Sarajevo and Zagreb were 6.93 ng m-3 and 3.11 ng m-3, respectively. The contribution of BaP to the total PAH mass concentration was similar at both locations (11%). However, much higher contributions of particle-phase fluoranthene and pyrene were found in Sarajevo. Contributions of individual PAH, diagnostic ratios and factor analysis indicate that combustion of gasoline and diesel from vehicle traffic are a potential source of PAHs at both locations, as well as combustion of other liquid fossil fuels (petroleum and fuel oil). Wood burning was occasionally indicated as a PAH emission source in Zagreb, while in Sarajevo the contribution of PAHs from wood and coal combustion was more evident. Calculated value for total carcinogenic potency (TCP) of PAHs, which was estimated using toxic equivalence factors from the literature, in PM10 samples collected in Sarajevo was more than twice higher than in Zagreb (10.6 ng m-3 and 4.7 ng m-3, respectively). BaP had the highest contribution to the TCP at both locations (69 and 67%).


Comorbidity Correlates of Death Among New Veterans of Iraq and Afghanistan Deployment.
Veterans of the wars in Iraq and Afghanistan who receive care in the Veterans Health Administration (VA) have high disease burden. Distinct comorbidity patterns have been shown to be differentially associated with adverse outcomes, including death. This study determined correlates of 5-year mortality. VA demographic, military, homelessness, and clinical measures informed this retrospective analysis. Previously constructed comorbidity classifications over 3 years of care were entered into a Cox proportional hazards model of death. There were 164,933 veterans in the cohort, including African Americans (16%), Hispanics (11%), and whites (65%). Most were in their 20s at baseline (60%); 12% were women; 4% had attempted suicide; 4% had been homeless. Having clustered disorders of pain, posttraumatic stress disorder, and traumatic brain injury was associated with death [hazard ratio (HR)=2.0]. Mental disorders including substance abuse were similarly associated (HR=2.1). Prior suicide attempt (HR=2.2) or drug overdose (HR=3.0) considerably increased risk of death over 5 years. As congressional actions such as Veterans Choice Act offer more avenues to seek care outside of VA, coordination of care, and suicide prevention outreach for recent veterans may require innovative approaches to preserve life.


External quality assessment of multi-analyte chromatographic methods in oral fluid.
A proficiency testing scheme was set up for the DRUID (Driving under the influence of Drugs, Alcohol and Medicines) research project, funded by the European Commission, in which oral fluid is analysed by eleven laboratories. A common collection and analysis methodology is used: Statsure Saliva Sampler is used for collection and LC-MS/MS or GC-MS confirmation analysis of 22 substances is performed on all samples. Despite internal validation and quality control samples, external quality assessment is still necessary to further increase comparability of results. Four rounds of proficiency testing (PT) were organized between March 2008 and September 2009. Qualitative results were evaluated using sensitivity and specificity. Quantitative results were evaluated using z-scores and the standard deviation of Horwitz. Specificity was above 99% in each round, sensitivity per analyte varied between 81.7 and 100%, and 20 out of 22 analytes had a sensitivity above 90%. The percentage of satisfactory z-scores increased from 79.4% to 89.2%. This trend was seen for all drug classes, except zopiclone. Results were discussed with participating laboratories and problems were addressed. Because of these corrective actions, DRUID laboratories have a lower variation in results than previously published PT schemes in oral fluid.


Cytotoxic effect of extract from Dunaliella salina against SH-SY5Y neuroblastoma cells.
Cytotoxic effects of essential oils extracted from Dunaliella salina on SH-SY5Y human neuroblastoma cells were investigated in this study. GC-MS analysis was used for determination of the composition of essential oils found in Dunaliella salina extract. All experimented concentrations of Dunaliella salina extract on SH-SY5Y human neuroblastoma cells were significantly more cytotoxic than the tested concentrations of the extract on ECV304 human endothelial cells used as a control. Fifthy compounds were detected in GC-MS analysis of the extract, and five major compounds were predominantly found as follows: octadecanoic acid, methyl ester (27.43%); hexadecanoic acid, methyl ester (Cas) methyl palmitate (24.82%); 9,12,15-octadecatrienoic acid, ethyl ester, (Z,Z,Z)- (7.39%); octadecanoic acid (5.03%), pentadecanoic acid (3.60%). The cytotoxic activity of Dunaliella salina extract on SH-SY5Y human neuroblastoma cells might be due to high concentrations of octadecanoic acid and hexadecanoic acid. Furthermore, results indicate that the extract demonstrates some proliferative effect on ECV304 cells in a dose-dependent manner between 0.25 and 5 μg/ml. These results suggest that Dunaliella salina may have anticancer potential against human neuroblastoma cells.


Building a robotic link between muscle dynamics and hydrodynamics.
This study used a novel feedback approach to control a robotic foot using force and length signals transmitted from an isolated Xenopus laevis frog muscle. The foot's environment (inertial versus hydrodynamic), gearing (outlever/inlever) and size were changed to alter the muscle's load. Upon nerve stimulation (250 Hz, 80 ms train duration), variation in loading generated a range of muscle stress (19.8±5.3 to 66.0±22.5 kPa), work (1.89±0.67 to 6.87±2.96 J kg(-1) muscle) and power (12.4±7.5 to 64.8±28.3 W kg(-1) muscle; mean ± s.d., N=6 frogs). Inertial versus hydrodynamic loading dramatically shifted contractile dynamics. With the foot in water, the muscle generated ∼30% higher force, yet shortened slower, producing lower power than inertial loading. Power increased in air from 22.6±5.8 to 63.6±27.2 W kg(-1) muscle in response to doubling the gear ratio, but did not increase in water. Surprisingly, altering foot size diminished muscle performance in water, causing power to drop significantly from 41.6±11.1 to 25.1±8.0 W kg(-1) muscle as foot area was doubled. Thus, morphological modifications influenced muscle dynamics independently of neural control; however, changes in loading environment and gearing affected contractile output more strongly than changes in foot size. Confirming recent theory, these findings demonstrate how muscle contractile output can be modulated solely by altering the mechanical environment.


Strain differences in behavioral inhibition in a Go/No-go task demonstrated using 15 inbred mouse strains.
High levels of impulsivity have been associated with a number of substance abuse disorders including alcohol abuse. Research has not yet revealed whether these high levels predate the development of alcohol abuse. The current study examined impulsivity in 15 inbred strains of mice (A/HeJ, AKR/J, BALB/cJ, C3H/HeJ, C57BL/6J, C57L/J, C58/J, CBA/J, DBA/1J, DBA/2J, NZB/B1NJ, PL/J, SJL/J, SWR/J, and 129P3/J) using a Go/No-go task, which was designed to measure a subject's ability to inhibit a behavior. Numerous aspects of response to ethanol and other drugs of abuse have been examined in these strains. There were significant strain differences in the number of responses made during the No-go signal (false alarms) and the extent to which strains responded differentially during the Go and No-go signals (d'). The rate of responding prior to the cue did not differ among strains, although there was a statistically significant correlation between false alarms and precue responding that was not related to basal activity level. Interstrain correlations suggested that false alarms and rate of responding were associated with strain differences in ethanol-related traits from the published literature. The results of this study do support a link between innate level of impulsivity and response to ethanol and are consistent with a genetic basis for some measures of behavioral inhibition.


Therapeutic approaches for Duchenne muscular dystrophy.
Duchenne muscular dystrophy (DMD) is a monogenic muscle-wasting disorder and a priority candidate for molecular and cellular therapeutics. Although rare, it is the most common inherited myopathy affecting children and so has been the focus of intense research activity. It is caused by mutations that disrupt production of the dystrophin protein, and a plethora of drug development approaches are under way that aim to restore dystrophin function, including exon skipping, stop codon readthrough, gene replacement, cell therapy and gene editing. These efforts have led to the clinical approval of four exon skipping antisense oligonucleotides, one stop codon readthrough drug and one gene therapy product, with other approvals likely soon. Here, we discuss the latest therapeutic strategies that are under development and being deployed to treat DMD. Lessons from these drug development programmes are likely to have a major impact on the DMD field, but also on molecular and cellular medicine more generally. Thus, DMD is a pioneer disease at the forefront of future drug discovery efforts, with these experimental treatments paving the way for therapies using similar mechanisms of action being developed for other genetic diseases.


Ecosystem Management to Achieve Ecological Sustainability: The Case of South Florida
The ecosystems of South Florida are unique in the world. The defining features of the natural Everglades (large spatial scale, temporal patterns of water storage and sheetflow, and low nutrient levels) historically allowed a mosaic of habitats with characteristic animals. Massive hydrological alterations have halved the Everglades, and ecological sustainability requires fundamental changes in management.The US Man and the Biosphere Human-Dominated Systems Directorate is conducting a case study of South Florida using ecosystem management as a framework for exploring options for mutually dependent sustainability of society and the environment. A new methodology was developed to specify sustainability goals, characterize human factors affecting the ecosystem, and conduct scenario/consequence analyses to examine ecological and societal implications. South Florida has sufficient water for urban, agricultural, and ecological needs, but most water drains to the sea through the system of canals; thus, the issue is not competition for resources but storage and management of water. The goal is to reestablish the natural system for water quantity, timing, and distribution over a sufficient area to restore the essence of the Everglades.The societal sustainability in the Everglades Agricultural Area (EAA) is at risk because of soil degradation, vulnerability of sugar price supports, policies affecting Cuban sugar imports, and political/economic forces aligned against sugar production. One scenario suggested using the EAA for water storage while under private sugar production, thereby linking sustainability of the ecological system with societal sustainability. Further analyses are needed, but the US MAB project suggests achieving ecological sustainability consistent with societal sustainability may be feasible.


Framework PEACE: an organizational model for examining physical exercise across the cancer experience.
The primary purpose of this article is to provide a framework for organizing research on physical exercise and cancer control. A secondary purpose is to use this framework to provide an overview of the extant literature and to offer directions forr future research. The proposed framework, entitled Physical Exercise Across the Cancer Experience (PEACE), divides the cancer experience into 6 time periods: 2 prediagnosis (i.e., prescreening and screening/diagnosis) and 4 postdiagnosis (i.e., pretreatment, treatment, posttreatment, and resumption). Based on these time periods, 8 general cancer control outcomes are highlighted. Two cancer control outcomes occur prediagnosis (i.e., prevention and detection), and 6 occur postdiagnosis (i.e., buffering, coping, rehabilitation, health promotion, palliation, and survival). An overview of the physical exercise literature indicates that only I time period (i.e., prescreening) and cancer control outcome (i.e., prevention) has received significant research attention. Some time periods (i.e., treatment and resumption) and cancer control outcomes (i.e., coping and health promotion) have received modest research attention, whereas other time periods (i.e., screening/diagnosis, pretreatment, and posttreatment) and cancer control outcomes (i.e., detection, buffering, rehabilitation, palliation, and survival) have received only minimal attention. It is hoped that Framework PEACE will stimulate a more comprehensive and in-depth inquiry into the role of physical exercise in cancer control.


A new surgical technique of uterine auto-transplantation in cynomolgus monkey: preliminary report about two cases.
Uterine transplantation experiments have been performed in various animal species for future clinical applications of uterine transplantation for permanent uterine factor infertility in humans. The aim of this study was to confirm the feasibility of uterine auto-transplantation in cynomolgus monkeys by developing new surgical techniques. Two female cynomolgus monkeys underwent surgery under general anesthesia. The uterus with vascular grafts and the vaginal wall was removed, and back-table preparation was performed using heparinized saline. The uterus with vascular grafts and the vaginal wall was anastomosed with the vaginal stump and blood vessels in the pelvis, respectively. The auto-transplant uterine function was evaluated by confirming engraftment of the uterus by laparotomy, endometrial proliferation by transabdominal ultrasonography and periodical menstruation. The first animal died due to acute renal failure 2 days after the operation. Second-look laparotomy in the second animal at 40 days after the operation indicated there was no congestion in the uterus, and the uterus showed the typical red color of a normal uterus. Thereafter, endometrial proliferation was observed by transabdominal ultrasonography and periodical menstruation was confirmed, indicating re-established uterine function. This is the preliminary report of uterine auto-transplantation in cynomolgus monkeys. This study demonstrates the feasibility of uterine auto-transplantation by using new surgical technique in cynomolgus monkeys. Accumulation of basic experimental data in non-human primates is required prior to performing the procedure in humans.