Risks and Benefits of Nalmefene in the Treatment of Adult Alcohol Dependence: A Systematic Literature Review and Meta-Analysis of Published and Unpublished Double-Blind Randomized Controlled Trials.
Nalmefene is a recent option in alcohol dependence treatment. Its approval was controversial. We conducted a systematic review and meta-analysis of the aggregated data (registered as PROSPERO 2014:CRD42014014853) to compare the harm/benefit of nalmefene versus placebo or active comparator in this indication. Three reviewers searched for published and unpublished studies in Medline, the Cochrane Library, Embase, ClinicalTrials.gov, Current Controlled Trials, and bibliographies and by mailing pharmaceutical companies, the European Medicines Agency (EMA), and the US Food and Drug Administration. Double-blind randomized clinical trials evaluating nalmefene to treat adult alcohol dependence, irrespective of the comparator, were included if they reported (1) health outcomes (mortality, accidents/injuries, quality of life, somatic complications), (2) alcohol consumption outcomes, (3) biological outcomes, or (4) treatment safety outcomes, at 6 mo and/or 1 y. Three authors independently screened the titles and abstracts of the trials identified. Relevant trials were evaluated in full text. The reviewers independently assessed the included trials for methodological quality using the Cochrane Collaboration tool for assessing risk of bias. On the basis of the I2 index or the Cochrane's Q test, fixed or random effect models were used to estimate risk ratios (RRs), mean differences (MDs), or standardized mean differences (SMDs) with 95% CIs. In sensitivity analyses, outcomes for participants who were lost to follow-up were included using baseline observation carried forward (BOCF); for binary measures, patients lost to follow-up were considered equal to failures (i.e., non-assessed patients were recorded as not having responded in both groups). Five randomized controlled trials (RCTs) versus placebo, with a total of 2,567 randomized participants, were included in the main analysis. None of these studies was performed in the specific population defined by the EMA approval of nalmefene, i.e., adults with alcohol dependence who consume more than 60 g of alcohol per day (for men) or more than 40 g per day (for women). No RCT compared nalmefene with another medication. Mortality at 6 mo (RR = 0.39, 95% CI [0.08; 2.01]) and 1 y (RR = 0.98, 95% CI [0.04; 23.95]) and quality of life at 6 mo (SF-36 physical component summary score: MD = 0.85, 95% CI [-0.32; 2.01]; SF-36 mental component summary score: MD = 1.01, 95% CI [-1.33; 3.34]) were not different across groups. Other health outcomes were not reported. Differences were encountered for alcohol consumption outcomes such as monthly number of heavy drinking days at 6 mo (MD = -1.65, 95% CI [-2.41; -0.89]) and at 1 y (MD = -1.60, 95% CI [-2.85; -0.35]) and total alcohol consumption at 6 mo (SMD = -0.20, 95% CI [-0.30; -0.10]). An attrition bias could not be excluded, with more withdrawals for nalmefene than for placebo, including more withdrawals for safety reasons at both 6 mo (RR = 3.65, 95% CI [2.02; 6.63]) and 1 y (RR = 7.01, 95% CI [1.72; 28.63]). Sensitivity analyses showed no differences for alcohol consumption outcomes between nalmefene and placebo, but the weight of these results should not be overestimated, as the BOCF approach to managing withdrawals was used. The value of nalmefene for treatment of alcohol addiction is not established. At best, nalmefene has limited efficacy in reducing alcohol consumption.


Reduction in the exchange of coastal dissolved organic matter and microgels by inputs of extra riverine organic matter.
Rivers drive large amounts of terrestrial and riverine organic matter into oceans. These organic materials may alter the self-assembly of marine dissolved organic matter (DOM) polymers into microgels and can even affect the behavior of existing natural microgels. We used Suwannee River humic acid, fulvic acid, and natural organic matter as a model of riverine organic matter (ROM) to investigate the impacts of ROM input on DOM polymer and microgel conversion. Our results indicated that the release of extra ROM, even at low concentrations (0.1-10 mg L-1), into the marine organic matter pool decreased the size of self-assembled DOM polymers (from 4-5 μm to < 1 μm) and dispersed the existing natural microgels into smaller particles (from 4-5 μm to 2-3 μm). The particle size of the microgel phase was also less sensitive than that of the DOM polymers to external changes (addition of ROM). This size reduction in DOM aggregation and existing microgels may be closely tied to the surface chemistry of the organic matter, such as negative surface charge stabilization and Ca2+ cross-linking bridges. These findings reveal that ROM inputs may therefore impede the self-assembly of DOM polymers into particulate organic matter and reduce the sedimentation flux of organic carbon and other elements from surface water to the deep ocean, thereby disturbing the biological pump, the downward transportation of nutrients, and the marine organic carbon cycle.


Preparation and Catalytic Study on a Novel Amino-functionalized Silica-coated Cobalt Oxide Nanocomposite for the Synthesis of Some Indazoles.
In this research an efficient synthesis of a novel nanocomposite including SiO2@(3-aminopropyl)triethoxysilane-coated cobalt oxide (Co3O4) nanocomposite has been reported by three step method. The structure and magnetic characterization of Co3O4@SiO2@NH2 have been done by using various spectroscopic analyses which include FT-IR, X-ray powder diffraction, scanning electron microscopy, transmission electron microscopy, energy dispersive X-ray spectroscopy and vibrating sample magnetometry. Amino-functionalized SiO2 coated Co3O4 nanocomposite exhibited superparamagnetic behavior and strong magnetization at room temperature. The average crystallite sizes of the Co3O4 are 23.7 nm. The obtained magnetic nanocomposite showed excellent catalytic activity as a new heterogeneous magnetic catalyst for the synthesis of some indazole derivatives under mild reaction conditions along with high level of reusability.


Plasma Epstein-Barr Virus Load as an Early Biomarker and Prognostic Factor of Human Immunodeficiency Virus-related Lymphomas.
Epstein-Barr virus (EBV) has been implicated in lymphomagenesis and can be found infecting tumor cells and in plasma at lymphoma diagnosis, especially in human immunodeficiency virus (HIV)-infected patients. Our aim was to evaluate the usefulness of plasma EBV load as biomarker and prognostic factor in HIV-positive patients with lymphomas. EBV loads were measured by polymerase chain reaction in plasma samples of 81 HIV-positive patients' lymphomas at different moments: within 1 year before lymphoma diagnosis, at diagnosis, and at complete response (CR). Control samples included HIV-negative patients with lymphomas and HIV-positive patients without neoplasia or opportunistic infections. HIV-positive patients with lymphomas had more frequently-detectable EBV load at lymphoma diagnosis (53%) than either HIV-negative patients with the same lymphoma type (16%; P < .001) or HIV-positive individuals without neoplasia or opportunistic infection (1.2%; P < .001). HIV-positive lymphoma patients with detectable EBV load in plasma at lymphoma diagnosis had statistically significant decrease of EBV load at CR. High EBV load (>5000 copies/mL) at lymphoma diagnosis was an independent negative prognostic factor for overall survival and progression-free survival in HIV-positive patients with lymphomas. Detectable plasma EBV loads identified HIV-positive subjects that would eventually develop lymphoma (area under the curve, 82%; 95% CI: 0.67-0.96). Plasma EBV load can be used as a biomarker and as a prognostic factor in HIV-positive patients with lymphomas. The presence of the EBV load in the plasma of an HIV-positive patient can be an early predictor of lymphoma development.


Signatures of Majorana fermions in hybrid superconductor-semiconductor nanowire devices.
Majorana fermions are particles identical to their own antiparticles. They have been theoretically predicted to exist in topological superconductors. Here, we report electrical measurements on indium antimonide nanowires contacted with one normal (gold) and one superconducting (niobium titanium nitride) electrode. Gate voltages vary electron density and define a tunnel barrier between normal and superconducting contacts. In the presence of magnetic fields on the order of 100 millitesla, we observe bound, midgap states at zero bias voltage. These bound states remain fixed to zero bias, even when magnetic fields and gate voltages are changed over considerable ranges. Our observations support the hypothesis of Majorana fermions in nanowires coupled to superconductors.


Pavlovian conditioning analysis of morphine tolerance.
It has been demonstrated that many conditional responses to a variety of drugs are opposite in direction to the unconditional effects of the drug, and the conditioning analysis of morphine tolerance emphasizes the fact that subjects with a history of morphine administration display morphine-compensatory conditional responses when confronted with the usual administration procedure but without the drug. Thus, when the drug is presented in the context of the usual administration cues, these conditional morphine-compensatory responses would be expected to attenuate the drug-induced unconditional responses, thereby decreasing the observed response to the drug. Research has been summarized which supports this compensatory conditioning model of tolerance by demonstrating that the display of tolerance is specific to the environment in which the drug has been previously administered. Further evidence supporting this theory of tolerance has been provided by studies establishing that extinction, partial reinforcement, and latent inhibition--non-pharmacological manipulations known to be effective in generally affecting the display of conditional responses--similarly affect the display of morphine tolerance. Additional research has suggested many parallels between learning and morphine tolerance: Both processes exhibit great retention, both are disrupted by electroconvulsive shock and frontal cortical stimulation, both are retarded by inhibitors of protein synthesis, and both are facilitated by antagonists of these metabolic inhibitors.


Total internal reflection microscopy: inspection of surfaces of high bulk scatter materials.
The technique of total internal reflection microscopy (TIRM) introduced by P. Temple for inspection of the surface structure of transparent substrates is extended here for use with materials exhibiting high bulk scatter. A strong dependence of scratch illumination on the angle between scratches and the S polarization direction is observed and explained via a simple model.


Economic impact of dengue fever/dengue hemorrhagic fever in Thailand at the family and population levels.
Dengue fever and dengue hemorrhagic fever constitute a substantial health burden on the population in Thailand. In this study, the impact of symptomatic dengue virus infection on the families of patients hospitalized at the Kamphaeng Phet Provincial Hospital with laboratory-confirmed dengue in 2001 was assessed, and the disability-adjusted life years (DALYs) lost for fatal and non-fatal cases of dengue were calculated using population level data for Thailand. When we accounted for the direct cost of hospitalization, indirect costs due to loss of productivity, and the average number of persons infected per family, we observed a financial loss of approximately US$61 per family, which is more than the average monthly income in Thailand. The DALYs were calculated using select results from a family level survey, and resulted in an estimated 427 DALYs/million population in 2001. This figure is of the same order of magnitude as the impact of several diseases currently given priority in southeast Asia, such as the tropical cluster (trypanosomiasis, Chagas disease, schistosomiasis, leishmaniasis, lymphatic filariasis, and onchocerciasis), malaria, meningitis, and hepatitis. These results indicate that dengue prevention, control, and research should be considered equally important as that of diseases currently given priority.


Matrix-embedded cells control osteoclast formation.
Osteoclasts resorb the mineralized matrices formed by chondrocytes or osteoblasts. The cytokine receptor activator of nuclear factor-κB ligand (RANKL) is essential for osteoclast formation and thought to be supplied by osteoblasts or their precursors, thereby linking bone formation to resorption. However, RANKL is expressed by a variety of cell types, and it is unclear which of them are essential sources for osteoclast formation. Here we have used a mouse strain in which RANKL can be conditionally deleted and a series of Cre-deleter strains to demonstrate that hypertrophic chondrocytes and osteocytes, both of which are embedded in matrix, are essential sources of the RANKL that controls mineralized cartilage resorption and bone remodeling, respectively. Moreover, osteocyte RANKL is responsible for the bone loss associated with unloading. Contrary to the current paradigm, RANKL produced by osteoblasts or their progenitors does not contribute to adult bone remodeling. These results suggest that the rate-limiting step of matrix resorption is controlled by cells embedded within the matrix itself.


Synthetic affinity ligands as a novel tool to improve protein stability.
Cutinase from Fusarium solani pisi is the model-system for a new approach to assess and enhance protein stability based on the use of synthetic triazine-scaffolded affinity ligands as a novel protein-stabilizing tool. The active site of cutinase is excluded from the main surface regions postulated to be involved in early protein's thermal unfolding events. Hence, these regions are suitable targets for binding complementary affinity ligands with a potential stabilizing effect. A random solid-phase combinatorial library of triazine-bisubstituted molecules was screened for binding cutinase by a rapid fluorescence-based method and affinity chromatography. The best binding substituents were combined with those previously selected by screening a rationally designed library. A second-generation solid-phase biased library was designed and synthesized, following a semi-rational methodology. A dual screening of this library enabled the selection of ligands binding cutinase with higher affinity while retaining its functionality. These compounds were utilized for thermostability assessment with adsorbed cutinase at 60 degrees C and pH 8.0. When bound to different types of ligands, the enzyme showed markedly distinct activity retention profiles, with some synthetic affinity ligands displaying a stabilizing effect on cutinase and others a clearly destabilizing effect, when compared with the free enzyme.


A General Strategy for the Semisynthesis of Ratiometric Fluorescent Sensor Proteins with Increased Dynamic Range.
We demonstrate how a combination of self-labeling protein tags and unnatural amino acid technology permits the semisynthesis of ratiometric fluorescent sensor proteins with unprecedented dynamic range in vitro and on live cells. To generate such a sensor, a binding protein is labeled with a fluorescent competitor of the analyte using SNAP-tag in conjugation with a second fluorophore that is positioned in vicinity of the binding site of the binding protein using unnatural amino acid technology. Binding of the analyte by the sensor displaces the tethered fluorescent competitor from the binding protein and disrupts fluorescence resonance energy transfer between the two fluorophores. Using this design principle, we generate a ratiometric fluorescent sensor protein for methotrexate that exhibits large dynamic ranges both in vitro (ratio changes up to 32) and on cell surfaces (ratio change of 13). The performance of these semisynthetic sensor proteins makes them attractive for applications in basic research and diagnostics.


Appreciating the 'person' in long-term care.
Internationally, approaches to the long-term care of older people are changing. New models are being developed that aim to de-institutionalise care settings, maximise opportunities for older people to participate in decision-making and move from a predominant medical model of care to one that is community orientated. The aim of this study is to highlight similarities and differences between the different models that exist and explore the implications of these for the role of the registered nurse in long-term care. We chose three models for review as these represent a range of views of person centredness, each having distinct roots and focus. The models chosen were as follows: (i) culture change, (ii) person-centred practice and (iii) relationship-centred care. The review highlights two key issues - (i) the distinctiveness of different models and frameworks and (ii) different interpretations of 'person'. Firstly, we identify a disconnection between espoused differences between models and frameworks and the reality of these differences. The evidence also identifies how some models and frameworks adopt a more inclusive conceptualisation of person and personhood and do not define personhood in relation to role (resident, nurse and family member). There is merit in the development of models and frameworks that try to make explicit the different dimensions of person centredness in long-term care. However, the focus on the development of these, without sufficient attention being paid to evidence of best practices grounded in the concept of personhood, person-centred care is in danger of losing its original humanistic emphasis. Further, models and frameworks need to take account of the personhood of all persons. Registered nurses need to have an understanding of the concept of personhood to make sense of the various person-centred practice frameworks that exist. Without this understanding, there is a danger that the essence of personhood may be lost in the zeal to implement particular models and frameworks.


Using the ACGME Milestones for Resident Self-Evaluation and Faculty Engagement.
Since July 2014 General Surgery residency programs have been required to use the Accreditation Council for Graduate Medical Education milestones twice annually to assess the progress of their trainees. We felt this change was a great opportunity to use this new evaluation tool for resident self-assessment and to furthermore engage the faculty in the educational efforts of the program. We piloted the milestones with postgraduate year (PGY) II and IV residents during the 2013/2014 academic year to get faculty and residents acquainted with the instrument. In July 2014, we implemented the same protocol for all residents. Residents meet with their advisers quarterly. Two of these meetings are used for milestones assessment. The residents perform an independent self-evaluation and the adviser grades them independently. They discuss the evaluations focusing mainly on areas of greatest disagreement. The faculty member then presents the resident to the clinical competency committee (CCC) and the committee decides on the final scores and submits them to the Accreditation Council for Graduate Medical Education website. We stored all records anonymously in a MySQL database. We used Anova with Tukey post hoc analysis to evaluate differences between groups. We used intraclass correlation coefficients and Krippendorff's α to assess interrater reliability. We analyzed evaluations for 44 residents. We created scale scores across all Likert items for each evaluation. We compared score differences by PGY level and raters (self, adviser, and CCC). We found highly significant increases of scores between most PGY levels (p < 0.05). There were no significant score differences per PGY level between the raters. The interrater reliability for the total score and 6 competency domains was very high (ICC: 0.87-0.98 and α: 0.84-0.97). Even though this milestone evaluation process added additional work for residents and faculty we had very good participation (93.9% by residents and 92.9% by faculty) and feedback was generally positive. Even though implementation of the milestones has added additional work for general surgery residency programs, it has also opened opportunities to furthermore engage the residents in reflection and self-evaluation and to create additional venues for faculty to get involved with the educational process within the residency program. Using the adviser as the initial rater seems to correlate closely with the final CCC assessment. Self-evaluation by the resident is a requirement by the RRC and the milestones seem to be a good instrument to use for this purpose. Our early assessment suggests the milestones provide a useful instrument to track trainee progression through their residency.


Particle sizing by inversion of the optical transform pattern.
An inversion method is presented for recovering size information from the optical transform pattern for spherical particles. Comparisons are made with the Shifrin inversion method for two different types of particle-size distribution. For a monodispersed size distribution optical transform experiments reveal that the new method shows better capabilities in recovering information about the size and number of scatterers. Using a noise-free continuous distribution in a computer simulation, we found that the two methods are equally capable of recovering the form of the original distribution function. Then shot noise is simulated in the transform pattern, and it is shown that the new inversion method is less susceptible to error.


Effectiveness of general practice based, practice nurse led telephone coaching on glycaemic control of type 2 diabetes: the Patient Engagement and Coaching for Health (PEACH) pragmatic cluster randomised controlled trial.
To evaluate the effectiveness of goal focused telephone coaching by practice nurses in improving glycaemic control in patients with type 2 diabetes in Australia. Prospective, cluster randomised controlled trial, with general practices as the unit of randomisation. General practices in Victoria, Australia. 59 of 69 general practices that agreed to participate recruited sufficient patients and were randomised. Of 829 patients with type 2 diabetes (glycated haemoglobin (HbA1c) >7.5% in the past 12 months) who were assessed for eligibility, 473 (236 from 30 intervention practices and 237 from 29 control practices) agreed to participate. Practice nurses from intervention practices received two days of training in a telephone coaching programme, which aimed to deliver eight telephone and one face to face coaching episodes per patient. The primary end point was mean absolute change in HbA1c between baseline and 18 months in the intervention group compared with the control group. The intervention and control patients were similar at baseline. None of the practices dropped out over the study period; however, patient attrition rates were 5% in each group (11/236 and 11/237 in the intervention and control group, respectively). The median number of coaching sessions received by the 236 intervention patients was 3 (interquartile range 1-5), of which 25% (58/236) did not receive any coaching sessions. At 18 months' follow-up the effect on glycaemic control did not differ significantly (mean difference 0.02, 95% confidence interval -0.20 to 0.24, P=0.84) between the intervention and control groups, adjusted for HbA1c measured at baseline and the clustering. Other biochemical and clinical outcomes were similar in both groups. A practice nurse led telephone coaching intervention implemented in the real world primary care setting produced comparable outcomes to usual primary care in Australia. The addition of a goal focused coaching role onto the ongoing generalist role of a practice nurse without prescribing rights was found to be ineffective. Current Controlled Trials ISRCTN50662837.


BTN3A molecules considerably improve Vγ9Vδ2T cells-based immunotherapy in acute myeloid leukemia.
Given their recognized ability to kill acute myeloid leukemia (AML) blasts both in vitro and in vivo, Vγ9Vδ2 T cells are of growing interest in the design of new strategies of immunotherapy. We show that the Butyrophilin3A (BTN3A, CD277) subfamily is a critical determinant of Vγ9Vδ2 TCR-mediated recognition of human primary AML blasts ex vivo. Moreover, anti-BTN3A 20.1 agonist monoclonal antibodies (mAbs) can trigger BTN3A on AML blasts leading to further enhanced Vγ9Vδ2 T cell-mediated killing, but this mAb had no enhancing effect upon NK cell-mediated killing. We show that monocytic differentiation of primary AML blasts accounts for their AminoBisphosphonate (N-BP)-mediated sensitization to Vγ9Vδ2 T cells. In addition, anti-BTN3A 20.1 mAbs could specifically sensitize resistant blasts to Vγ9Vδ2 T cells lysis and overcome the poor effect of N-BP treatment on those blasts. We confirmed the enhancement of Vγ9Vδ2 T cells activity by anti-BTN3A 20.1 mAb using a human AML xenotransplantation mouse model. We showed that anti-BTN3A 20.1 mAb combined with Vγ9Vδ2 T cells immunotherapy could increase animal survival and decrease the leukemic burden in blood and bone marrow. These findings could be of great interest in the design of new immunotherapeutic strategies for treating AML.


Mechanisms of calcium release and sequestration in eggs of Chaetopterus pergamentaceus.
Increases in the intracellular free calcium concentration are of great importance to the initiation of development in deuterostomes. Their involvement has not yet been clearly defined in protostomes. We used endogenous ligands (IP3, cADPR, ryanodine and NAADP) and pharmacological agents (thapsigargin [Tg], thimerosal, caffeine and heparin) to study smooth endoplasmic reticulum Ca2+ pump and release mechanisms in eggs of an annelid, Chaetopterus. Oocyte homogenates effectively sequestered Ca2+ and released it in response to IP3 in a concentration-dependent manner. Repeated additions of IP3 were unable to cause further release. Heparin inhibited Ca2+ release in response to IP3. The homogenates also released Ca2+ in response to thimerosal, and this release was sensitive to heparin. Two antibodies to IP3 receptors recognized an appropriate band in Chaetopterus egg lysates. These results indicate that the oocytes possess type-1 IP3-gated Ca2+ channels. Neither calcium itself, nor strontium, cADPR, ryanodine, caffeine nor NAADP released appreciable Ca2+. At low concentrations, Tg caused a slow release of Ca2+; at higher concentrations, it elicited a rapid release. Release of Ca2+ by Tg activated development. Since one theory of fertilization invokes the introduction of a Ca2+ releasing soluble protein into the egg upon sperm-egg fusion, we also tested whether soluble extracts of Chaetopterus sperm could stimulate Ca2+ release in Chaetopterus egg homogenates. There was no Ca2+ release when the sperm extract was added to the homogenate; however, homogenates exposed to sperm extract became refractory to IP3. Thus, Ca2+ release at fertilization in these oocytes occurs through IP3-gated channels.


Clinical interpretation of outcome measures generated from a lumbar computerized adaptive test.
A computerized adaptive test (CAT) provides a way of efficiently estimating functional status in people with specific impairments. The purpose of this study was to describe meaningful interpretations of functional status (FS) estimated using a lumbar CAT developed using items from the Back Pain Functional Scale (BPFS) and selected physical functioning items. Design and Setting This was a prospective longitudinal cohort study of 17,439 patients with lumbar spine impairments in 377 outpatient rehabilitation clinics in 30 states. Outcome Measures Patient self-reports of functional status were assessed using a lumbar CAT (0-100 scale). Outcome data were interpreted using 4 methods. First, the standard error of the estimate was used to construct a 95% confidence interval for each CAT estimated score. Second, percentile ranks of FS scores were presented. Third, 2 threshold approaches were used to define individual patient-level change: minimal detectable change (MDC) and clinically important change. Fourth, a functional staging model, the Back Pain Function Classification System (BPFCS), was developed and applied. On average, precision of a single score was estimated by FS score+/-4. Based on score distribution, 25th, 50th and 75th percentile ranks corresponded to intake FS scores of 44, 51, and 59, and discharge FS scores of 54, 62, and 74, respectively. An MDC(95) value of 8 or more represented statistically reliable change. Receiver operating characteristic analyses supported that changes in FS scores of 5 or more represented minimal clinically important improvement. The BPFCS appeared clinically logical and provided insight for clinical interpretation of patient progress. The BPFCS should be assessed for validity using prospective designs. Results may improve clinical interpretation of CAT-generated outcome measures and assist clinicians using patient-reported outcomes during physical therapist practice.


A complicated case of atypical hemolytic uremic syndrome with frequent relapses under eculizumab.
Atypical hemolytic uremic syndrome (aHUS) is a form of thrombotic microangiopathy characterized by uncontrolled activation of the alternative complement pathway with consecutive generation of the terminal complement complex. Mortality is increased, particularly in the first year of the disease. Therapeutic options include plasma therapy and terminal complement blockade using the anti-C5 monoclonal antibody eculizumab. Eculizumab prevents activation of the terminal sequence of the complement cascade and formation of the potentially lytic terminal complement complex (C5b-9). We report a 3-year-old boy with aHUS due to a novel heterozygous truncating complement Factor H mutation in combination with other changes known to be associated with an increased risk for aHUS. Despite eculizumab treatment and maximal suppression of the classical and alternative complement pathways, C3d and sC5b-9 remained consistently elevated and the patient showed repeated relapses. Not every patient with aHUS and uncontrolled complement activation shows optimal therapeutic response to eculizumab with the recommended or even increased dosing regimen. Reliable outcome measures to determine the efficacy of treatment have to be defined.


Topoisomerase II- and condensin-dependent breakage of MEC1ATR-sensitive fragile sites occurs independently of spindle tension, anaphase, or cytokinesis.
Fragile sites are loci of recurrent chromosome breakage in the genome. They are found in organisms ranging from bacteria to humans and are implicated in genome instability, evolution, and cancer. In budding yeast, inactivation of Mec1, a homolog of mammalian ATR, leads to chromosome breakage at fragile sites referred to as replication slow zones (RSZs). RSZs are proposed to be homologous to mammalian common fragile sites (CFSs) whose stability is regulated by ATR. Perturbation during S phase, leading to elevated levels of stalled replication forks, is necessary but not sufficient for chromosome breakage at RSZs or CFSs. To address the nature of additional event(s) required for the break formation, we examined involvement of the currently known or implicated mechanisms of endogenous chromosome breakage, including errors in replication fork restart, premature mitotic chromosome condensation, spindle tension, anaphase, and cytokinesis. Results revealed that chromosome breakage at RSZs is independent of the RAD52 epistasis group genes and of TOP3, SGS1, SRS2, MMS4, or MUS81, indicating that homologous recombination and other recombination-related processes associated with replication fork restart are unlikely to be involved. We also found spindle force, anaphase, or cytokinesis to be dispensable. RSZ breakage, however, required genes encoding condensin subunits (YCG1, YSC4) and topoisomerase II (TOP2). We propose that chromosome break formation at RSZs following Mec1 inactivation, a model for mammalian fragile site breakage, is mediated by internal chromosomal stress generated during mitotic chromosome condensation.


Mutation induced modulation of hydrogen bonding to P700 studied using FTIR difference spectroscopy.
Site-directed mutagenesis in combination with Fourier transform infrared difference spectroscopy has been used to study how hydrogen bonding modulates the electronic and physical organization of P700, the primary electron donor in photosystem I. Wild-type PS I particles from Chlamydomonas reinhardtii and a mutant in which ThrA739 is changed to alanine [TA(A739) mutant] were studied. ThrA739 is thought to provide a hydrogen bond to the chlorophyll-a' molecule of P700 (the two chlorophylls of P700 (P700(+)) will be called P(A) and P(B) (P(A)(+) and P(B)(+))). The mutation considerably alters the (P700(+)-P700) FTIR difference spectra. However, we were able to describe all of the mutation induced changes in the difference spectra in terms of difference band assignments that were proposed recently (Hastings, G., Ramesh, V. M., Wang, R., Sivakumar, V. and Webber, A. (2001) Biochemistry 40, 12943-12949). Upon comparison of mutant and wild type (P700(+)-P700) FTIR difference spectra, it is shown that (1) the 13(3) ester carbonyl modes of P(A) and P(B) are unaltered upon mutation of ThrA739 to alanine. (2) The 13(3) ester carbonyl modes of P(A)(+)/P(B)(+) upshift/downshift upon mutation. These oppositely directed shifts indicate that the mutation modifies the charge distribution over the pigments in the P700(+) state, with charge on P(B) being relocated onto P(A). We also show that the 13(1) keto carbonyl mode of P(B)/P(B)(+) is unaltered/downshifted upon mutation, as is expected for the above-described mutation induced charge redistribution in P700(+). Although the 13(3) ester carbonyl modes of the chlorophylls of P700 in the ground state are unaltered upon mutation, the 13(1) keto carbonyl mode of P(A) upshifts upon mutation, as does the 13(1) keto carbonyl mode of P(A)(+). For P700 in the ground state, bands that we associate with HisA676/HisB656 upshift/downshift upon mutation. For the P700(+) state, bands that we associate with HisA676/HisB656 also upshift/downshift upon mutation. These observations are also consistent with the notion that the mutation leads to the charge on P(B)(+) being relocated onto P(A)(+). In addition, we suggest that a hydrogen bond to the 13(1) keto carbonyl of P(A) is still present in the TA(A739) mutant, probably mediated through an introduced water molecule.


Complete Genome Sequence of an N-Acyl Homoserine Lactone Producer, Breoghania sp. Strain L-A4, Isolated from Rhizosphere of Phragmites australis in a Coastal Wetland.
The Breoghania sp. strain L-A4 was isolated from the rhizosphere of Phragmites australis in the Qinhaungdao coastal wetland in China. Here, we present the complete genome sequence of strain L-A4, which consists of a chromosome of 5,029,620 bp with a G+C content of 64.53% and 4,964 coding DNA sequences. This strain was the first detected to produce N-acyl homoserine lactone (AHL) signals in a member of this genus.


Effectiveness of laparoscopic computer simulator versus usage of box trainer for endoscopic surgery training of novices.
Teaching of laparoscopic skills is a challenge in surgical training programs. Because of the highly technical nature and the steep learning curve, students and residents must learn laparoscopic skills before performing them in the operating room. To improve efficiency of learning and patient safety, research in simulation is essential. Two types of simulators currently in use include virtual reality and box trainers. Our study examined which simulator technique was most effective in teaching novice trainees laparoscopic techniques. This is a prospective, randomized, blinded, controlled trial that enrolled fourth-year medical students and surgical interns to participate in a supervised 6-month laparoscopic training program with either computer simulators or box trainers. Subjects were randomized and trained on appropriate laparoscopic camera skills, instrument handling, object positioning, dissection, ligation, suturing, and knot tying. Students within one group were not allowed to practice, learn or train on the opposing trainers. At time points 0, 2, and 6 months all subjects completed a series of laparoscopic exercises in a live porcine model, which were captured on DVD and scored by blinded expert investigators. Scores improved overall from the pretest to subsequent tests after training with no difference between the virtual reality and box simulator groups. In the medical students specifically, there was overall improvement, and improvement in the needle-transfer and knot-tying skills specifically, with no difference between the box simulator and virtual reality groups. For the interns, both groups showed significant overall improvement with no difference between the virtual reality and box simulator groups or on individual skills. We conclude that laparoscopic simulator training improves surgical skills in novice trainees. We found both the box trainers and the virtual reality simulators are equally effective means of teaching laparoscopic skills to novice learners.


Prenatal ethanol exposure delays the onset of spermatogenesis in the rat.
During late prenatal and early postnatal life, the reproductive system in males undergoes an extensive series of physiological and morphological changes. Prenatal ethanol (EtOH) exposure has marked effects on the development of the reproductive system, with long-term effects on function in adulthood. The present study tested the hypothesis that prenatal EtOH exposure will delay the onset of spermatogenesis. Development of the seminiferous tubules and the onset of spermatogenesis were examined utilizing a rat model of fetal alcohol spectrum disorder (FASD). Male offspring from ad libitum-fed control (C), pair-fed (PF), and EtOH-fed (prenatal alcohol exposure [PAE]) dams were terminated on postnatal (PN) days 5, 15, 18, 20, 25, 35, 45, and 55, to investigate morphological changes through morphometric analysis of the testes from early neonatal life through young adulthood. PAE males had lower relative (adjusted for body weight) testis weights compared with PF and/or C males from PN15 through puberty (PN45). In addition, fewer gonocytes (primordial germ cells) were located on the basal lamina on PN5, while more of those touching the basal lamina were dividing in PAE compared with PF and C males, suggesting delayed cell division and migration processes. As well, the percentage of tubules with open lumena was lower in PAE compared with PF and C males on PN18 and 20, and PAE males had fewer primary spermatocytes per tubule on PN18 and round spermatids per tubule on PN25 compared with C males. Finally, the percentage of tubules at stages VII and VIII, when mature spermatids move to the apex of the epithelium and are released, was lower in PAE compared with PF and/or C males in young adulthood (PN55). Maternal EtOH consumption appears to delay both reproductive development and the onset of spermatogenesis in male offspring, with effects persisting at least until young adulthood.


Maternal prenatal smoking and hearing loss among adolescents.
Although smoking and secondhand smoke exposure are associated with sensorineural hearing loss (SNHL) in children and adults, the possible association between prenatal smoke exposure and hearing loss has not been investigated despite the fact that more than 12% of US children experience such prenatal exposure each year. To investigate whether exposure to prenatal tobacco smoke is independently associated with SNHL in adolescents. Cross-sectional data were examined for 964 adolescents aged 12 to 15 years from the National Health and Nutrition Examination Survey 2005-2006. Participants underwent standardized audiometric testing, and serum cotinine levels and self-reports were used to identify adolescents exposed to secondhand smoke or active smokers. Prenatal exposure was defined as an affirmative parental response to, "Did [Sample Person's Name] biological mother smoke at any time while she was pregnant with [him/her]?" Sensorineural hearing loss was defined as an average pure-tone hearing level more than 15 dB for 0.5, 1, and 2 kHz (low frequency) and 3, 4, 6, and 8 kHz (high frequency). Parental responses affirmed prenatal smoke exposure in 16.2% of 964 adolescents. Prenatal smoke exposure was associated with elevated pure-tone hearing thresholds at 2 and 6 kHz (P < .05), a higher rate of unilateral low-frequency SNHL (17.6% vs 7.1%; P < .05) in bivariate analyses, and a 2.6-fold increased odds of having unilateral low-frequency SNHL in multivariate analyses (95% CI, 1.1-6.4) after controlling for multiple hearing-related covariates. Prenatal smoke exposure is independently associated with higher pure-tone hearing thresholds and an almost 3-fold increase in the odds of unilateral low-frequency hearing loss among adolescents. These novel findings suggest that in utero exposure to tobacco smoke may be injurious to the auditory system.


Motor effect of neurokinins on the rat duodenum: evidence for the involvement of substance K and substance P receptors.
The motor effects of kassinin (KAS), substance P (SP) or neurokinin A (NKA) on rat duodenum have been investigated in vivo (urethane anesthesia) or in vitro. Intravenous neurokinins produced a phasic contraction of the duodenum that was unaffected by atropine, hexamethonium or tetrodotoxin. KAS, NKA and SP were almost equieffective in producing this phasic contraction. In addition KAS and NKA (but not SP) induced a tonic contraction with a superimposed series of rhythmic contractions. SP did not produce tonic or rhythmic contractions even in doses producing maximal effects on blood pressure. The KAS-induced tonic and rhythmic contractions were unaffected by atropine or hexamethonium and potentiated markedly by tetrodotoxin. Similar findings were obtained after topical application of neurokinins on the outer surface of the duodenum in vivo or recording the mechanical response of the longitudinal muscle in vitro. The phasic component of the KAS- or SP-induced contraction was reduced selectively, both in vivo and in vitro by [D-Pro2,D-Trp7,9]SP, an SP antagonist. It is concluded that two types of receptors mediate the motor effects of neurokinins in the rat duodenum, one of which is of the SP-P type and is mainly involved in producing the phasic contraction. The other receptor is of the SP-K type and mediates mainly the tonic contraction.


Perfusion-related stimuli for compensatory lung growth following pneumonectomy.
Following pneumonectomy (PNX), two separate mechanical forces act on the remaining lung: parenchymal stress caused by lung expansion, and microvascular distension and shear caused by increased perfusion. We previously showed that parenchymal stress and strain explain approximately one-half of overall compensation; the remainder was presumptively attributed to perfusion-related factors. In this study, we directly tested the hypothesis that perturbation of regional pulmonary perfusion modulates post-PNX lung growth. Adult canines underwent banding of the pulmonary artery (PAB) to the left caudal (LCa) lobe, which caused a reduction in basal perfusion to LCa lobe without preventing the subsequent increase in its perfusion following right PNX while simultaneously exaggerating the post-PNX increase in perfusion to the unbanded lobes, thereby creating differential perfusion changes between banded and unbanded lobes. Control animals underwent sham pulmonary artery banding followed by right PNX. Pulmonary function, regional pulmonary perfusion, and high-resolution computed tomography of the chest were analyzed pre-PNX and 3-mo post-PNX. Terminally, the remaining lobes were fixed for detailed morphometric analysis. Results were compared with corresponding lobes in two control (Sham banding and normal unoperated) groups. PAB impaired the indices of post-PNX extravascular alveolar tissue growth by up to 50% in all remaining lobes. PAB enhanced the expected post-PNX increase in alveolar capillary formation, measured by the prevalence of double-capillary profiles, in both unbanded and banded lobes. We conclude that perfusion distribution provides major stimuli for post-PNX compensatory lung growth independent of the stimuli provided by lung expansion and parenchymal stress and strain.


Cytoplasmic pH measurement and homeostasis in bacteria and archaea.
Of all the molecular determinants for growth, the hydronium and hydroxide ions are found naturally in the widest concentration range, from acid mine drainage below pH 0 to soda lakes above pH 13. Most bacteria and archaea have mechanisms that maintain their internal, cytoplasmic pH within a narrower range than the pH outside the cell, termed "pH homeostasis." Some mechanisms of pH homeostasis are specific to particular species or groups of microorganisms while some common principles apply across the pH spectrum. The measurement of internal pH of microbes presents challenges, which are addressed by a range of techniques under varying growth conditions. This review compares and contrasts cytoplasmic pH homeostasis in acidophilic, neutralophilic, and alkaliphilic bacteria and archaea under conditions of growth, non-growth survival, and biofilms. We present diverse mechanisms of pH homeostasis including cell buffering, adaptations of membrane structure, active ion transport, and metabolic consumption of acids and bases.


Concomitant use of direct-acting antivirals and chemotherapy in hepatitis C virus-infected patients with cancer.
Antiviral therapy improves hepatic outcomes in hepatitis C virus (HCV)-infected cancer patients. However, such patients are not treated simultaneously with antivirals and chemotherapy, owing to overlapping toxicities with previous standard of care treatment of pegylated interferon and ribavirin. To examine the safety and clinically-significant drug-drug interactions observed in patients who received simultaneous treatment with direct-acting antivirals (DAAs) and chemotherapy. Safety was determined by the presence of adverse events which were graded according to the division of AIDS Table (version 2.0). Adverse events were monitored throughout antiviral treatment and up to 3 months after its completion. Drug-drug interactions were assessed using current online databases. Sustained virological response (SVR) was defined as absence of serum HCV RNA 12 weeks after end of DAA treatment. Cirrhosis was diagnosed via imaging, biopsy or with the use of non-invasive fibrosis markers. Twenty-one patients received concomitant treatment with DAAs and chemotherapy between January 2013 and September 2016. Concomitant treatment was started either for virological (14; 67%) or oncologic (7; 33%) reasons. DAAs used were sofosbuvir, ledipasvir, simeprevir, daclatasvir ± ribavirin. The adverse events observed were mainly constitutional (12; 57%), hematological and gastrointestinal (7; 33% each). Physicians changed the DAA regimens in two patients (10%) in anticipation of drug-drug interactions with daclatasvir and dexamethasone. The overall SVR rate was 95% (20/21). Hepatitis C virus-targeted antiviral therapy can be used concomitantly with selected anti-neoplastic agents under close monitoring for drug-drug interactions. This therapeutic intervention may prevent delay in the administration of chemotherapy in HCV-infected cancer patients.


Zinc-based fixative improves preservation of genomic DNA and proteins in histoprocessing of human tissues.
Advantageous preservation of histology and detailed cellular morphology has rendered neutral buffered formalin (NBF) the most widely used fixative in clinical pathology. Despite excellent morphology for routine diagnostics, a major drawback of NBF fixation is its detrimental effect on DNA and RNA quality. In addition to complicating analysis of genes and transcripts in complex tissues, NBF denatures proteins and thereby hampers immunohistochemical visualization of certain antigens. In the present study, we evaluated a zinc-based fixative (ZBF) regarding its effects on tissue morphology, quality of genomic DNA, and preservation of protein immunoreactivity in a broad spectrum of tissues. Four different modes of fixation were analyzed: ZBF-paraffin embedding, NBF-paraffin embedding, ZBF-fixation prior to snap-freezing, and immediate snap-freezing. Laser-assisted microdissection, allowing retrieval of a defined number of cells for PCR, was used to study DNA quality. Genomic DNA was analyzed using primers for beta2-microglobulin and the transferrin receptor. Immunohistochemistry was performed using nine antibodies. Tissue microarray blocks were used for analysis of morphology and immunoreactivity. Only slight impairment of morphologic qualities was found after ZBF-paraffin embedding, whereas ZBF prior to freezing resulted in a more crisp morphology compared with routine cryosections. A significantly higher DNA yield was observed in samples isolated from ZBF-paraffin-embedded tissues compared with NBF-paraffin-embedded tissues. Both yield and quality of DNA was comparable in frozen tissues irrespective to prior ZBF fixation. Immunoreactivity in paraffin-embedded tissue was superior in ZBF-fixated tissue compared with NBF-fixated for a majority of tested antibodies. Furthermore, for seven out of nine antibodies, antigen retrieval pretreatment proved unnecessary in ZBF-fixated tissue. Thus, despite a slight impairment of morphology, ZBF preserves protein structures well. We conclude that ZBF is superior to NBF for analysis of DNA and protein expression. Fixation of tissues in ZBF may also be an alternative strategy to freeze storage of tissue specimens, eg, in future bio-banks.


Vitamin D and the nutritional environment in functions of intestinal stem cells: Implications for tumorigenesis and prevention.
Sporadic colon cancer accounts for ∼80% of CRC, with high incidence in western societies strongly linked to dietary patterns. The only mouse model for sporadic CRC results from feeding mice a purified rodent western-style diet (NWD1), establishing mouse intake of several common nutrients that mimic for each its level consumed in western populations at higher risk for colon cancer (higher fat, lower vitamin D3, calcium, methyl donors and fiber). This causes sporadic colon and small intestinal tumors at an incidence and frequency similar to that of humans. NWD1 perturbs intestinal cell maturation and Wnt signaling throughout villi and colonic crypts before tumors are detected. Surprisingly, feeding NWD1 decreases mouse Lgr5hi intestinal stem cell contribution to homeostasis and tumorigenesis, associated with extensive Lgr5hi cell transcriptional reprogramming, with nutrient levels interactive in these effects. There is a key impact of the lower vitamin D3 in NWD1 and its signaling through the Vdr. The DNA mismatch repair pathway is elevated in Lgr5hi cells by lower vitamin D3 and/or calcium in NWD1, reducing accumulation of relevant somatic mutations detected by single cell exome sequencing. There are also alterations in metabolic pathways, including down-regulation of oxidative phosphorylation. In compensation for compromise of Lgr5hi cells, NWD1 also reprograms cells derived from the Bmi1+ population, defined as those cells marked in Bmi1creERT2, Rosa26tom mice following tamoxifen injection, and at least a portion of these cells then function and persist as stem-like cells in mucosal homeostasis and tumorigenesis. The data establish a key role of the nutrient environment, and vitamin D signaling, in defining contribution of at least two different stem cell populations to mucosal homeostasis and tumorigenesis. This raises significant questions regarding impact of variable human diets on which and how multiple potential intestinal stem cell populations function in the human and give rise to tumors. Moreover, genetic and epigenetic changes in long-lived stem cells have important implications for understanding the effects of vitamin D and other nutrients on intestinal homeostasis and on intervention strategies for altering probability of tumor development.


Relationship of admissions variables and college of osteopathic medicine variables to performance on COMLEX-USA level 3.
New accreditation standards require that all US colleges of osteopathic medicine (COMs) publically report the first-time pass rates of graduates on the Comprehensive Osteopathic Medical Licensing Examination-USA (COMLEX-USA) Level 3. Little is known about the extent to which admissions variables or COM performance measures relate to Level 3 performance. To examine the relationship of admissions variables and COM performance to scores on Level 3 and to assess whether a relationship existed between Level 3 scores and sex, curriculum track, year of graduation, and residency specialty in the first postgraduate year. Data were analyzed from 4 graduating classes (2008-2011) of the West Virginia School of Osteopathic Medicine in Lewisburg. Relationships were examined between first-attempt scores on COMLEX-USA Level 3 and Medical College Admission Test (MCAT) scores; undergraduate grade point averages (GPAs); GPAs in COM year 1, year 2, and clinical rotation years (years 3 and 4); and first-attempt scores on COMLEX-USA Level 1, Level 2-Cognitive Evaluation, and Level 2-Performance Evaluation. Of the 556 graduates during this 4-year period, COMLEX-USA Level 3 scores were available for 552 graduates (99.3%). No statistically significant differences were found in Level 3 scores based on sex, curriculum track, graduating class, or residency specialty. The strongest relationship between Level 3 scores and any admissions variable was with total MCAT score, which accounted for 4.2% of the variation in Level 3 scores. The strongest relationship between Level 3 scores and COM year performance measures was with year 2 GPA, which accounted for 35.4% of the variation in Level 3 scores. Level 1 scores accounted for 38.5% of the variation in Level 3 scores, and Level 2-Cognitive Evaluation scores accounted for the greatest percentage of variation (45.7%). The correlation of Level 3 scores with passing the Level 2-Performance Evaluation on the first attempt was not statistically significant. A weak relationship was found between admissions variables and performance on COMLEX-USA Level 3, suggesting that graduates with lower MCAT scores and undergraduate GPAs may have overcome their early disadvantage. Strong relationships were found between Level 3 scores and year 2 GPAs, as well as scores on COMLEX-USA Level 1 and Level 2-Cognitive Evaluation.


Use of data from registered clinical trials to identify gaps in health research and development.
To explore what can be learnt about the current composition of the "global landscape" of health research and development (R&D) from data on the World Health Organization's International Clinical Trials Registry Platform (ICTRP). A random 5% sample of the records of clinical trials that were registered as interventional and actively recruiting was taken from the ICTRP database. Overall, 2381 records of trials were investigated. Analysis of these records indicated that, for every million disability-adjusted life years (DALYs) caused by communicable, maternal, perinatal and nutritional conditions, by noncommunicable diseases, or by injuries, the ICTRP database contained an estimated 7.4, 52.4 and 6.0 trials in which these causes of burden of disease were being investigated, respectively. For every million DALYs in high-income, upper-middle-income, lower-middle-income and low-income countries, an estimated 292.7, 13.4, 3.0 and 0.8 registered trials, respectively, were recruiting in such countries. The ICTRP constitutes a valuable resource for assessing the global distribution of clinical trials and for informing policy development for health R&D. Populations in lower-income countries receive much less attention, in terms of clinical trial research, than populations in higher-income countries.


Multidimensional scaling for evolutionary algorithms--visualization of the path through search space and solution space using Sammon mapping.
Multidimensional scaling as a technique for the presentation of high-dimensional data with standard visualization techniques is presented. The technique used is often known as Sammon mapping. We explain the mathematical foundations of multidimensional scaling and its robust calculation. We also demonstrate the use of this technique in the area of evolutionary algorithms. First, we present the visualization of the path through the search space of the best individuals during an optimization run. We then apply multidimensional scaling to the comparison of multiple runs regarding the variables of individuals and multi-criteria objective values (path through the solution space).


Review of current research in the prevention of nerve damage in leprosy.
Nerve damage and the consequences of nerve damage set leprosy apart from other diseases. The irreversible motor and sensory impairments caused by leprosy lead to increasing secondary impairments long after the disease process has been arrested. Interventions that prevent, reverse or limit the impairments resulting from leprosy are, therefore, of the highest priority. Self-care has been demonstrated to be an effective means of preventing secondary tissue damage, and its implementation must now be encouraged within the framework of basic health care. Currently, a comprehensive effort has been made to address all dimensions of impairment of nerve function and its consequences, from prevention of both primary and secondary impairments to interventions in long-term nerve damage. The BANDS prospective study of a cohort of 2664 previously untreated leprosy patients in Bangladesh has provided both a valuable baseline and insight into the epidemiology of nerve damage in leprosy. This work has defined the numbers of patients who present with acute nerve damage, the numbers who are not treated, and the importance of the MB classification, and has described the simple clinical prediction rule. This study also provided the basis for the development of the three TRIPOD randomized clinical trials in Nepal and Bangladesh. Follow-up of the BANDS cohort, which is continuing, will yield more data on the natural history of nerve damage. The encouraging results from the TRIPOD trials of low-dose prophylactic steroids will be followed up, to see whether the effect is sustained over time. The TRIPOD trials are to be completed, a trial of three steroid regimens in reversal reaction is to be completed, and a number of specific research topics within the ILEP programme, INFIR, are to be developed.


Selection of the appropriate method for the assessment of insulin resistance.
Insulin resistance is one of the major aggravating factors for metabolic syndrome. There are many methods available for estimation of insulin resistance which range from complex techniques down to simple indices. For all methods of assessing insulin resistance it is essential that their validity and reliability is established before using them as investigations. The reference techniques of hyperinsulinaemic euglycaemic clamp and its alternative the frequently sampled intravenous glucose tolerance test are the most reliable methods available for estimating insulin resistance. However, many simple methods, from which indices can be derived, have been assessed and validated e.g. homeostasis model assessment (HOMA), quantitative insulin sensitivity check index (QUICKI). Given the increasing number of simple indices of IR it may be difficult for clinicians and researchers to select the most appropriate index for their studies. This review therefore provides guidelines and advices which must be considered before proceeding with a study.


Phenological synchrony affects interaction strength of an exotic weevil with Platte thistle, a native host plant.
Phenological synchrony of a consumer population with its resource populations is expected to affect interaction intensity. We quantified phenological variation and synchrony of populations of an invasive Eurasian flower head weevil, Rhinocyllus conicus, that consumes florets, ovules, and seeds of developing flower heads of a native North American thistle, Cirsium canescens, in Sand Hills prairie in Nebraska, USA. Variation in timing of adult activity among weevil populations was larger than variation in timing of flower head development among C. canescens populations, and it drove the observed variation in the phenological synchrony between weevil and host plant populations. Furthermore, the degree of phenological synchrony between populations was significant in explaining variation in weevil egg load on the newly acquired host plant. Because population growth of C. canescens is limited by predispersal seed losses to floral herbivores, variation in the synchrony of herbivore and plant flowering will affect the density of the plant population. These results provide strong quantitative support for the hypothesis that the synchrony of insect activity with plant resources can determine the magnitude of impact of floral herbivores on their host plant populations.


ANALYSIS OF MULTIPLE SCLEROSIS LESIONS VIA SPATIALLY VARYING COEFFICIENTS.
Magnetic resonance imaging (MRI) plays a vital role in the scientific investigation and clinical management of multiple sclerosis. Analyses of binary multiple sclerosis lesion maps are typically "mass univariate" and conducted with standard linear models that are ill suited to the binary nature of the data and ignore the spatial dependence between nearby voxels (volume elements). Smoothing the lesion maps does not entirely eliminate the non-Gaussian nature of the data and requires an arbitrary choice of the smoothing parameter. Here we present a Bayesian spatial model to accurately model binary lesion maps and to determine if there is spatial dependence between lesion location and subject specific covariates such as MS subtype, age, gender, disease duration and disease severity measures. We apply our model to binary lesion maps derived from T2-weighted MRI images from 250 multiple sclerosis patients classified into five clinical subtypes, and demonstrate unique modeling and predictive capabilities over existing methods.


Initial Clinical Experience With a New Automated Antitachycardia Pacing Algorithm: Feasibility and Safety in an Ambulatory Patient Cohort.
Antitachycardia pacing (ATP) in implantable cardioverter-defibrillators (ICD) decreases patient shock burden but has recognized limitations. A new automated ATP (AATP) based on electrophysiological first principles was designed. The study objective was to assess the feasibility and safety of AATP in ambulatory ICD patients. Enrolled patients had dual chamber or cardiac resynchronization therapy ICDs, history of ≥1 ICD-treated ventricular tachycardias (VT)/ventricular fibrillation episode, or a recorded, sustained monomorphic VT. Detection was set to ventricular fibrillation number of intervals to detect=24/32, VT number of intervals to detect≥16, and a fast VT zone of 240 to 320 ms. AATP prescribed the components and delivery of successive ATP sequences in real time, using the same settings for all patients. ICD datalogs were uploaded every ≈3 months, at unscheduled visits, exit, and death. Episodes and adverse events were adjudicated by separate committees. Results were adjusted (generalized estimating equations) for multiple episodes. AATP was downloaded into the ICDs of 144 patients (121 men), aged 67.4±11.9 years, left ventricular ejection fraction 33.1±13.6% (n=137), and treated 1626 episodes in 49 patients during 14.5±5.1 months of follow-up. Datalogs permitted adjudication of 702 episodes, including 669 sustained monomorphic VT, 20 polymorphic VT, 10 supraventricular tachycardia, and 3 malsensing episodes. AATP terminated 39 of 69 (59% adjusted) sustained monomorphic VT in the fast VT zone, 509 of 590 (85% adjusted) in the VT zone, and 6 of 10 in the ventricular fibrillation zone. No supraventricular tachycardias converted to VT or ventricular fibrillation. No anomalous AATP behavior was observed. The new AATP algorithm safely generated ATP sequences and controlled therapy progression in all zones without need for individualized programing.


Identification of an HIV-1 BG Intersubtype Recombinant Form (CRF73_BG), Partially Related to CRF14_BG, Which Is Circulating in Portugal and Spain.
HIV-1 exhibits a characteristically high genetic diversity, with the M group, responsible for the pandemic, being classified into nine subtypes, 72 circulating recombinant forms (CRFs) and numerous unique recombinant forms (URFs). Here we characterize the near full-length genome sequence of an HIV-1 BG intersubtype recombinant virus (X3208) collected in Galicia (Northwest Spain) which exhibits a mosaic structure coincident with that of a previously characterized BG recombinant virus (9601_01), collected in Germany and epidemiologically linked to Portugal, and different from currently defined CRFs. Similar recombination patterns were found in partial genome sequences from three other BG recombinant viruses, one newly derived, from a virus collected in Spain, and two retrieved from databases, collected in France and Portugal, respectively. Breakpoint coincidence and clustering in phylogenetic trees of these epidemiologically-unlinked viruses allow to define a new HIV-1 CRF (CRF73_BG). CRF73_BG shares one breakpoint in the envelope with CRF14_BG, which circulates in Portugal and Spain, and groups with it in a subtype B envelope fragment, but the greatest part of its genome does not appear to derive from CRF14_BG, although both CRFs share as parental strain the subtype G variant circulating in the Iberian Peninsula. Phylogenetic clustering of partial pol and env segments from viruses collected in Portugal and Spain with X3208 and 9691_01 indicates that CRF73_BG is circulating in both countries, with proportions of around 2-3% Portuguese database HIV-1 isolates clustering with CRF73_BG. The fact that an HIV-1 recombinant virus characterized ten years ago as a URF has been shown to represent a CRF suggests that the number of HIV-1 CRFs may be much greater than currently known.


Acute cannabis consumption and motor vehicle collision risk: systematic review of observational studies and meta-analysis.
To determine whether the acute consumption of cannabis (cannabinoids) by drivers increases the risk of a motor vehicle collision. Systematic review of observational studies, with meta-analysis. We did electronic searches in 19 databases, unrestricted by year or language of publication. We also did manual searches of reference lists, conducted a search for unpublished studies, and reviewed the personal libraries of the research team. Review methods We included observational epidemiology studies of motor vehicle collisions with an appropriate control group, and selected studies that measured recent cannabis use in drivers by toxicological analysis of whole blood or self report. We excluded experimental or simulator studies. Two independent reviewers assessed risk of bias in each selected study, with consensus, using the Newcastle-Ottawa scale. Risk estimates were combined using random effects models. We selected nine studies in the review and meta-analysis. Driving under the influence of cannabis was associated with a significantly increased risk of motor vehicle collisions compared with unimpaired driving (odds ratio 1.92 (95% confidence interval 1.35 to 2.73); P=0.0003); we noted heterogeneity among the individual study effects (I(2)=81). Collision risk estimates were higher in case-control studies (2.79 (1.23 to 6.33); P=0.01) and studies of fatal collisions (2.10 (1.31 to 3.36); P=0.002) than in culpability studies (1.65 (1.11 to 2.46); P=0.07) and studies of non-fatal collisions (1.74 (0.88 to 3.46); P=0.11). Acute cannabis consumption is associated with an increased risk of a motor vehicle crash, especially for fatal collisions. This information could be used as the basis for campaigns against drug impaired driving, developing regional or national policies to control acute drug use while driving, and raising public awareness.


The ABC transporter ABCG36 is required for cadmium tolerance in rice.
Cadmium (Cd) is a highly toxic heavy metal in nature, which causes severe damage to plant growth. The molecular mechanisms for Cd detoxification are poorly understood. Here, we report that a G-type ATP-binding cassette transporter, OsABCG36, is involved in Cd tolerance in rice. OsABCG36 was expressed in both roots and shoots at a low level, but expression in the roots rather than the shoots was greatly up-regulated by a short exposure to Cd. A spatial expression analysis showed that Cd-induced expression of OsABCG36 was found in both the root tip and the mature root region. Transient expression of OsABCG36 in rice protoplast cells showed that it was localized to the plasma membrane. Immunostaining showed that OsABCG36 was localized in all root cells except the epidermal cells. Knockout of OsABCG36 resulted in increased Cd accumulation in root cell sap and enhanced Cd sensitivity, but did not affect tolerance to other metals including Al, Zn, Cu, and Pb. The concentration of Cd in the shoots was similar between the knockout lines and wild-type rice. Heterologous expression of OsABCG36 in yeast showed an efflux activity for Cd, but not for Zn. Taken together, our results indicate that OsABCG36 is not involved in Cd accumulation in the shoots, but is required for Cd tolerance by exporting Cd or Cd conjugates from the root cells in rice.


Mineral intake and lung cancer risk in the NIH-American Association of Retired Persons Diet and Health study.
Using data from a case-control study, we previously reported that low dietary intakes of magnesium (Mg), iron (Fe), zinc (Zn), copper (Cu), but not selenium (Se) and calcium (Ca), were associated with increased lung cancer risk. Due to dietary recall bias in case-control studies, our objective was to assess whether these findings hold in a prospective cohort study. We analyzed data from the NIH-American Association of Retired Persons Diet and Health study of 482,875 subjects (288,257 men and 194,618 women) who were cancer-free and completed a food frequency questionnaire at enrollment between 1995 and 2003. Cox proportional hazards models were computed to estimate the relative risk adjusted for potential confounders. During a mean follow-up of 7 years, 7,052 lung cancer cases were identified. For all subjects, we observed no significant associations between total (diet + supplement) Ca, Mg, Fe, Cu, Se, and Zn intakes and lung cancer risk. Total Ca intake was protective (P trend < 0.05) for current smokers and subjects with adenocarcinomas. Total Mg intake increased risk (P trend < 0.05) in men and current smokers. Total Fe intake was inversely associated with risk in women (P trend < 0.01). For dietary minerals, Mg increased risk (P trend < 0.05) in all subjects, among men and current smokers. Increased dietary Ca intake reduced risk in women (P trend = 0.05). Dietary Fe decreased risk in all subjects and among women (P trend < 0.05). Mineral intake from supplements did not affect lung cancer risk. Dietary minerals are risk factors for lung cancer. Dietary mineral consumption may influence lung cancer risk, but the associations differ by type of mineral and population subgroups.


Accumulation, release, and solubility of arsenic, molybdenum, and vanadium in wetland sediments.
This study was undertaken to determine the fate of As, Mo, and V (trace elements, TEs) in the sediments of a constructed wetland in use for the remediation of potentially toxic trace element-contaminated agricultural drainwater. After three years of wetland operation, sediment cores were collected to determine changes in TE concentrations as a function of depth and the effects of varying water column depth. All TE concentrations were highest in the top 2 to 4 cm and decreased with depth. Molybdenum accumulated in the wetland sediments, up to levels of 32.5 +/- 4.6, 30.2 +/- 8.9, and 59.3 +/- 26.1 mg kg(-1) in the top 1 cm of sediment at water depths of 15, 30, and 60 cm, respectively. In the top 2 cm of sediment, As accumulated (28.2 +/- 3.0 mg kg(-1)) only at the 60-cm water depth. Below 2 cm, as much as 10 mg kg(-1) of As was lost from the sediment at all water depths. In most cases, V concentrations decreased in the sediment. In this wetland system, the lowest redox potentials were found near the sediment surface and increased with depth. Thus, in general As, Mo, and V concentrations in the sediment were highest under more reducing conditions and lowest under more oxidizing conditions. Most of the accumulated Mo (73%) became water soluble on drying of samples. This has important implications for systems undergoing changes in redox status; for instance, if these wetland sediments are dried, potentially large amounts of Mo may be solubilized.


Hemodynamics in coronary arteries with overlapping stents.
Coronary artery stenosis is commonly treated by stent placement via percutaneous intervention, at times requiring multiple stents that may overlap. Stent overlap is associated with increased risk of adverse clinical outcome. While changes in local blood flow are suspected to play a role therein, hemodynamics in arteries with overlapping stents remain poorly understood. In this study we analyzed six cases of partially overlapping stents, placed ex vivo in porcine left coronary arteries and compared them to five cases with two non-overlapping stents. The stented vessel geometries were obtained by micro-computed tomography of corrosion casts. Flow and shear stress distribution were calculated using computational fluid dynamics. We observed a significant increase in the relative area exposed to low wall shear stress (WSS<0.5 Pa) in the overlapping stent segments compared both to areas without overlap in the same samples, as well as to non-overlapping stents. We further observed that the configuration of the overlapping stent struts relative to each other influenced the size of the low WSS area: positioning of the struts in the same axial location led to larger areas of low WSS compared to alternating struts. Our results indicate that the overlap geometry is by itself sufficient to cause unfavorable flow conditions that may worsen clinical outcome. While stent overlap cannot always be avoided, improved deployment strategies or stent designs could reduce the low WSS burden.


Musashi1 regulates breast tumor cell proliferation and is a prognostic indicator of poor survival.
Musashi1 (Msi1) is a conserved RNA-binding protein that regulates the Notch and Wnt pathways, and serves as a stem cell marker in the breast and other tissues. It is unknown how Msi1 relates to other breast cancer markers, whether it denotes tumor initiating cells (TICs), and how it affects gene expression and tumor cell survival in breast cancer cells. Msi1 expression was analyzed in 20 breast cancer cell lines and in 140 primary breast tumors by western blotting and immunohistochemistry, respectively. Lentivirus RNA interference was used to reduce Msi1 expression in breast cancer cell lines MCF-7 and T47D grown as spheroid cultures and to assess stem cell gene expression and the growth of these cell lines as xenografts. In normal human breast tissue, Msi1 was expressed in 10.6% of myoepithelum and 1.2% of ductal epithelium in the terminal ductal lobular unit (TDLU), whereas, less than 0.05% of ductal epithelium and myoepithelium in large ducts outside the TDLU expressed Msi1. Msi1 was expressed in 55% of the breast cancer cell lines and correlated with ErbB2 expression in 50% of the cell lines. Msi1 was expressed in 68% of primary tumors and in 100% of lymph node metastases, and correlated with 5 year survival. Msi1 was enriched in CD133+ MCF-7 and T47D cells and in spheroid cultures of these cells, and Msi1 'knockdown' (KD) with a lentivirus-expressed shRNA decreased the number and size of spheroid colonies. Msi1 KD reduced Notch1, c-Myc, ErbB2 and pERK1/2 expression, and increased p21CIP1 expression, which is consistent with known Msi1 target mRNAs. Msi1 KD also reduced the expression of the somatic and embryonic stem cell markers, CD133, Bmi1, Sox2, Nanog and Oct4. Xenografts of MCF-7 and T47D Msi1 KD cells resulted in a marked reduction of tumor growth, reduced Msi1 and Notch1 expression and increased p21CIP1 expression. Msi1 is a negative prognostic indicator of breast cancer patient survival, and is indicative of tumor cells with stem cell-like characteristics. Msi1 KD reduces tumor cell survival and tumor xenograft growth, suggesting that it may represent a novel target for drug discovery.


Medicinal Plants used during Antenatal Care by Pregnant Women in Eastern Uganda.
Plants are commonly used during the antenatal stage in pregnancy to manage different ailments in Africa. In Uganda, both medicinal and food plants are used to handle common pregnancy related conditions. An ethnobotanical survey was conducted in Iganga district, eastern Uganda. Seven traditional birth attendants (TBA) and 46 mothers were interviewed. Data was collected using structured questionnaires and household interviews. The TBAs were identified using snowball sampling. A total of 33 plant species, belonging to 23 families were documented. Out of these, the pregnant mothers used 45.5 % as both food and medicine. The most frequently used plant life form was herbs (58.8%). The leaves are the most commonly used plant parts (59%). Most of the plants (58.8%) were semi cultivated and were being domesticated in crop fields and home gardens. Most of the plants were used to manage anaemia and for child development and good health among the pregnant women. The pregnant women and TBAs in Namungalwe sub County have diverse knowledge on medicinal and nutri-medicinal plants in the management of common pregnancy related diseases, which can be used to supplement modern antenatal services, inspite of the ban of the activities of TBA. Further research on the bioavailability of nutrients, efficacy and safety of the medicinal plants used by pregnant women should be done.


Duration of unemployment and depression: a cross-sectional survey in Lithuania.
In spite of a growing economy, unemployment is still a severe socio-economic problem in Lithuania. Nonetheless, no studies have been performed about the associations between unemployment and mental health in Lithuania. The aim of this study was to evaluate the associations between unemployment duration and depression in Lithuania. The data was collected in a cross-sectional study in 2005. There were 429 filled-in questionnaires received (53.6% response rate) from unemployed persons registered with the Kaunas Labour Market Office. The severity of depression symptoms was evaluated using the Beck Depression Inventory (BDI). Logistic regression was used to estimate the risk factors for occurrence of depression. Sex, age, place of residence, marital status, education, income and practiced religion were the independent variables. Long-term unemployment was defined as lasting a duration of 12 months or more. The findings showed that long-term unemployed persons had more episodes of a depressive mood in the past 12 months in comparison with the group of the short-term unemployed. In addition, the BDI score mean was higher among the long-term unemployed compared with the short-term unemployed (10.1 +/- 8.8 and 14.2 +/- 9.5 respectively, p < 0.001). It was estimated that the duration of unemployment and BDI score had a positive correlation (r = 0.1968, p < 0.001). Among the short-term unemployed, the risk of depression increased significantly when the person was female, had an older age and had experienced more episodes of unemployment. Among the long-term unemployed, an older age was the risk factor for development of depression. However, higher education and income were the factors that significantly decreased the risk of developing depression for-short term as well as for long-term unemployed. The results indicated that depression is a severe problem in the unemployed population. Depression is more elevated among the long-term unemployed. This leads to arguing for common efforts in providing needed social support and health care to reduce the effects of unemployment on mental health.


Biofouling-resilient nanoporous gold electrodes for DNA sensing.
Electrochemical nucleic acid sensors are promising tools for point-of-care diagnostic platforms with their facile integration with electronics and scalability. However, nucleic acid detection in complex biological fluids is challenging as biomolecules nonspecifically adsorb on the electrode surface and adversely affect the sensor performance by obscuring the transport of analytes and redox species to the electrode. We report that nanoporous gold (np-Au) electrodes, prepared by a microfabrication-compatible self-assembly process and functionalized with DNA probes, enabled detection of target DNA molecules (10-200 nM) in physiologically relevant complex media (bovine serum albumin and fetal bovine serum). In contrast, the sensor performance was compromised for planar gold electrodes in the same conditions. Hybridization efficiency decreased by 10% for np-Au with coarser pores revealing a pore-size dependence of sensor performance in biofouling conditions. This nanostructure-dependent functionality in complex media suggests that the pores with the optimal size and geometry act as sieves for blocking the biomolecules from inhibiting the surfaces within the porous volume while allowing the transport of nucleic acid analytes and redox molecules.


Effect of the multimodal acting antidepressant vortioxetine on rat hippocampal plasticity and recognition memory.
Depression is frequently associated with cognitive disturbances. Vortioxetine is a multimodal acting antidepressant that functions as a 5-HT3 and 5-HT7 and 5-HT1D receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and inhibitor of the 5-HT transporter. Given its pharmacological profile, the present study was undertaken to determine whether vortioxetine could modulate several preclinical parameters known to be involved in cognitive processing. In the dorsal hippocampus of anaesthetized rats, the high-frequency stimulation of the Schaffer collaterals provoked a stable long-term potentiation (LTP) of ~25%. Interestingly, vortioxetine (10mg/kg, i.p.) counteracted the suppressant effect of elevated platform stress on hippocampal LTP induction. In the novel object recognition test, vortioxetine (10mg/kg, i.p.) increased the time spent exploring the novel object during the retention test and this pro-cognitive effect was prevented by the partial 5-HT3 receptor agonist SR57227 (1mg/kg, i.p.). Finally, compared to fluoxetine, sustained administration of vortioxetine (5mg/kg/day, s.c.) induced a rapid increase of cell proliferation in the hippocampal dentate gyrus. In summary, vortioxetine prevented the effect of stress on hippocampal LTP, increased rapidly hippocampal cell proliferation and enhanced short-term episodic memory, via, at least in part, its 5-HT3 receptor antagonism. Taken together, these preclinical data suggest that the antidepressant vortioxetine may have a beneficial effect on human cognitive processes.


Crystallographic analyses of NADH peroxidase Cys42Ala and Cys42Ser mutants: active site structures, mechanistic implications, and an unusual environment of Arg 303.
NADH peroxidase from Enterococcus faecalis is a tetrameric flavoenzyme of 201,400 Da which employs Cys 42 as a redox-active center cycling between sulfhydryl (Cys-SH) and sulfenic acid (Cys-SOH) states along the catalytic pathway. The role of the active site cysteine 42 in NADH peroxidase has been elucidated using biochemical and crystallographic techniques. Here we describe the crystal structures of two active site cysteine mutants, Cys42Ala and Cys42Ser, which were determined to 2.0 A resolution and refined to crystallographic R values of 17.6 and 18.3%, respectively. The overall chain fold and the quaternary structure of the two mutants appear to be very similar to wild-type enzyme. Therefore, the substantially lower activity of the mutants is due to the absence of the Cys-SOH redox center. One of the oxygen atoms of the nonnative cysteine sulfonic acid in the wild-type structure is replaced by a water molecule in both mutant structures. Two other residues near the active site are His 10 and Arg 303. A detailed analysis of the environment of these residues in the mutant and wild-type peroxidase structures indicates that the imidazole ring of His 10 is uncharged. The interactions made by the guanidinium group of Arg 303 involve not only His 10 but also the carboxylate of Glu 14 and Tyr 60. Interestingly, the Nn1H function of Arg 303 is oriented perpendicular to the plane of the phenyl ring of Tyr 60 with a Nn1 to phenyl ring center distance of 3.8 A, suggesting a favorable electrostatic interaction between Arg 303 and Tyr 60.(ABSTRACT TRUNCATED AT 250 WORDS)


Optical anisotropy and light extraction efficiency of MBE grown GaN nanowires epilayers.
The use of nanowires as active medium seems very promising for the development of high brightness LEDs. With a lower effective refractive index than bulk, semiconductor nanowire layers may lead to a high light extraction efficiency. We hereafter discuss the anisotropic properties of dense arrays of molecular beam epitaxy (MBE) grown gallium nitride (GaN) nanowires and the consequences on the optical design of nanowire based LEDs. In particular we show numerically that light extraction efficiency as high as 72% can be expected for GaN nanowires layer grown on a low cost Si substrate.


Intensive thermodynamic parameters in nonequilibrium systems.
Considering a broad class of steady-state nonequilibrium systems for which some additive quantities are conserved by the dynamics, we introduce from a statistical approach intensive thermodynamic parameters (ITPs) conjugated to the conserved quantities. This definition does not require any detailed balance relation to be fulfilled. Rather, the system must satisfy a general additivity property, which holds in most of the models usually considered in the literature, including those described by a matrix product ansatz with finite matrices. The main property of these ITPs is to take equal values in two subsystems, making them a powerful tool to describe nonequilibrium phase coexistence, as illustrated on different models. We finally discuss the issue of the equalization of ITPs when two different systems are put into contact. This issue is closely related to the possibility of measuring the ITPs using a small auxiliary system, in the same way as temperature is measured with a thermometer, and points at one of the major difficulties of nonequilibrium statistical mechanics. In addition, an efficient alternative determination, based on the measure of fluctuations, is also proposed and illustrated.


First Report of Stagonosporiopsis cucurbitacearum Causing Fruit Rot of Luffa cylindrica in Brazil.
Luffa cylindrica (Cucurbitaceae) is an Asian vine widely known as the source of loofah (4). In Brazil (local name bucha), it is cultivated by small scale producers as a cash crop. In January 2012, samples of fruits were collected in three areas in the municipality of Cipotânea, state of Minas Gerais (Brazil) bearing rot symptoms. These had large necrotic areas with a grayish epidermis and slightly sunken tissue. Internally, the fibrous parts were necrosed, darkened, and unmarketable. Isolations by surface sterilization of necrotic tissue with 10% bleach and plating onto potato dextrose agar yielded colonies with consistent morphology. A representative culture was deposited in the culture collection of the Universidade Federal de Viçosa (UFV) as COAD1119. Inoculations of seven healthy-appearing L. cylindrica fruits were performed with culture disks obtained from 4-day-old cultures grown on PDA, which were placed onto two points on the epidermis of each of seven fruits. Each point was either intact or previously injured with a sterile needle. Controls consisted of two fruits treated equally but with tap water agar disks in place of fungal inoculum. Fruits were then placed on trays with water-soaked cotton and the trays were wrapped in plastic bags and left over a bench at room temperature for 2 days. The plastic bags were then removed. After 5 days, necrosis was evident and fungal fruit bodies appeared at points with injury. No symptoms appeared on controls. Isolation from diseased tissue yielded colonies identical to those of the inoculated fungus. A dried sample was deposited in the local herbarium at UFV (VIC 32053). Slides were mounted in lactophenol and observed. The fungus had subepidermal perithecia, globose to subglobose, from 75.5 to 134 μm diam.; asci bitunicate, cylindrical, 8-spored; pseudoparaphyses filiform; ascospores fusoid to ellipsoidal, from 26 to 45 μm long and 8 to 11.5 μm wide, one septate, and hyaline. This morphology is consistent with Stagonosporopsis cucurbitacearum (syn. Didymella bryoniae) (3), a broad spectrum pathogen of cucurbits. Genomic DNA was extracted from the isolate growing in pure culture and ITS and LSU sequences were generated and deposited in GenBank under the accession numbers KC582022 and KC582021, respectively. Sequences were compared in BLASTn with other entries in GenBank, and the closest match for each region were S. cucurbitacearum strain CAP14C and D. bryoniae strain CBS 133.96 (JQ936326 and GU456335) with 100% of nucleotide homology for ITS and 100% of nucleotide homology for LSU. Cercospora citrullina and C. cucurbitae have been reported in Brazil on L. cylindrica and mistakenly indicated as synonyms of D. bryoniae (2). To our knowledge, this is the first valid report of S. cucurbitacearum causing fruit rot of loofah in Brazil and the first time pathogenicity to this host has been demonstrated. Losses due to the disease on the crop were reported to be high by growers and management to be difficult since there are no fungicides registered for this crop in Brazil. References: (1) M. M. Aveskamp et al. Stud. Mycol 65:1, 2010. (2) M. A. S. Mendes and A. F. Urben. Fungos em Plantas no Brasil. Brasília, Brazil: EMBRAPA-SPI. Retrieved from http://pragawall.cenargen.embrapa.br/aiqweb/michtml/micbanco01a.asp , 2012. (3) E. Puithalingam and P. Holliday. CMI Descriptions of Pathogenic Fungi and Bacteria 332:1, 1972. (4) J. W. Purseglove. Tropical Crops - Dicotyledons. Longman Group, London, 1968.


The impact of September 11 on dreaming.
This study focuses on a set of dreams related to the September 11, 2001 terrorist attacks and their aftermath, using content analysis and cognitive psychology to explore the interweaving of external public catastrophe and internal psychological processes. The study tests several recent claims in contemporary dream research, including the central image theory of Hartmann [Hartmann, E., & Basile, R. (2003). Dream imagery becomes more intense after 9/11/01. Dreaming, 13(2), 61-66; Hartmann, E., & Brezler, T. (2008). A systematic change in dreams after 9/11/01. Sleep, 31(2), 213-218], the media exposure factor postulated by Propper [Propper, R. E., Stickgold, R., Keeley, R., & Christman, S. D. (2007). Is television traumatic? Dreams, stress, and media exposure in the aftermath of September 11, 2001. Psychological Science, 18(4), 334-340], the continuity hypothesis of Domhoff [Domhoff, W. G. (1996). Finding meaning in dreams: A quantitative approach. New York: Plenum], the cognitive and metacognitive approach of Kahan [Kahan, T. L. (2001). Consciousness in dreaming: A metacognitive approach. In K. Bulkeley (Ed.), Dreams: A reader on the religious, cultural, and psychological dimensions of dreaming (pp. 333-360). New York: Palgrave], and the threat simulation theory of Revonsuo [Revonsuo, A. (2000). The reinterpretation of dreams: An evolutionary hypothesis of the function of dreaming. Behavioral and Brain Sciences, 23(6), 877-901]. Our findings suggest the terrorist attacks had a tangible impact on the content of many people's dreams, but did not fundamentally alter the cognitive processing features of their dreaming. The 9/11 attacks affected what they dreamed about, but not the way they dreamed.


Migraine headache disability and health-related quality-of-life: a population-based case-control study from England.
The aims of this study were: (i) to compare health-related quality of life (HRQoL) as measured by the Medical Outcomes Study Short Form 36-Item Health Survey (SF-36) in a population sample of migraine headache sufferers and controls without migraine; (ii) to assess the relationship of HRQoL and work-related disability attributed to headache in a population sample. The study was conducted in two phases. First, a population-based, telephone interview survey of 5769 residents of greater London, England was conducted to identify individuals with migraine headache (cases) and controls without migraine. In the second stage, in-person interviews were conducted in a matched sample of 200 migraine cases and 200 controls selected from survey respondents. At the beginning of the in-person interview, participants were asked to complete the SF-36. In addition, a work-related disability score based on the telephone interview was defined as the number of lost work days or days when usual activity was reduced by 50% or more over the previous year. The disability score was trichotomized as mild (n = 98), moderate (n = 49), and severe disability (n = 49). Compared with controls, individuals with migraine headache scored significantly lower in eight of the nine domains of the SF-36 as well as in the overall Physical Component Summary (PCS) score and Mental Component Summary (MCS) score. Further, among migraine sufferers, each of the disability groups scored significantly lower in seven of the nine domains and in the summary scales. Scores showed greater reductions in HRQoL for the moderate and severe disability groups vs. the mild disability group in five of nine scales and in the Total Physical Summary score. We conclude that, in a population-based sample of migraine headache sufferers, individuals with migraine headache have lower HRQoL scores compared with controls. Moreover, among individuals with migraine headache, work-related disability is associated with lower HRQoL scores. Specifically, individuals classified with moderate to severe work-related disability had lower HRQoL scores than those classified with low disability.


Portal vein chemotherapy for colorectal cancer: a meta-analysis of 4000 patients in 10 studies. Liver Infusion Meta-analysis Group.
Systemic delivery of cytotoxic drugs yields relatively low doses in the liver, a major site of recurrence for colorectal cancer. Giving chemotherapy by means of continuous portal vein infusion (PVI) into the liver during the immediate postoperative period may improve therapeutic efficacy. We undertook a meta-analysis to assess the effects on recurrence and survival of administering fluorouracil (5-FU)-based chemotherapy by PVI after colorectal cancer surgery. Data on mortality and recurrence were sought for all patients enrolled in randomized trials initiated before 1987 in which a few days (range, 5-7 days) of continuous postoperative PVI of cytotoxic drugs was compared with no further treatment. Data from 10 trials (a promising initial study and nine hypothesis-testing trials) involving about 4000 patients were available for analysis. The main cytotoxic drug in each trial was 5-FU (given with heparin); however, mitomycin C was co-administered in two of the trials. Four trials included an additional control group of patients treated with continuous noncytotoxic PVI of either heparin or urokinase alone; one trial included a second control group of patients treated with continuous systemic infusion of 5-FU. Reported P values are two-sided. Among the 3499 patients randomly assigned to receive either cytotoxic PVI or no further treatment, 1557 deaths are known to have occurred. Survival with and without PVI appeared to be the same for the first 2 years; thereafter, it diverged significantly, with the absolute survival difference (i.e., improvement) associated with PVI at 5 years being 4.7 % (standard deviation [SD] = 1.2 %) (P = .006). When just the nine hypothesis-testing trials were considered, the absolute survival difference was 3.6% (SD = 1.2%) (P = .04). If, ignoring any potential for bias in stage assignment, attention was restricted to patients with Dukes' stage A, B, or C disease (88.3% of the total), the absolute effect on 5-year survival for all 10 trials increased to 6.0% (SD = 1.8%) (P = .001); this estimate remained statistically significant when the initial study was excluded (absolute survival difference = 4.8%; SD = 1.8%; P = .01). In contrast to the highly significant reduction in liver metastases seen in the initial study (79% reduction; SD = 15%; P = .00000007), the reduction found in the nine hypothesis-testing trials was not significant (14% reduction; SD = 10%; P = .2). In the trials with additional control groups, survival appeared to be better with cytotoxic PVI than with noncytotoxic PVI or with systemic cytotoxic drug infusion. PVI of 5-FU (with or without other cytotoxic drugs) for about 1 week after surgery in patients with colorectal cancer may produce an absolute improvement in 5-year survival of a few percent. Although encouraging, this finding is not statistically secure, and additional evidence from randomized trials involving several thousand more patients is needed.