Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303).
The combination of gemcitabine plus bevacizumab produced a 21% response rate and a median survival of 8.8 months in a multicenter phase II trial in patients with metastatic pancreatic cancer. These encouraging data led Cancer and Leukemia Group B (CALGB) to conduct a double-blind, placebo-controlled, randomized phase III trial of gemcitabine/bevacizumab versus gemcitabine/placebo in advanced pancreatic cancer patients. Eligible patients had no prior therapy for advanced disease, Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2, no tumor invasion of adjacent organs, and no increased bleeding risk. The primary end point was overall survival. Patients were stratified by performance status, extent of disease, and prior radiotherapy. Patients received gemcitabine at 1,000 mg/m(2) over 30 minutes on days 1, 8, and 15 every 28 days and bevacizumab at 10 mg/kg or placebo on days 1 and 15 every 28 days. Between June 2004 and April 2006, 602 patients were enrolled onto the study and 535 were treated. Median overall survival was 5.8 months for gemcitabine/bevacizumab and 5.9 months for gemcitabine/placebo (P = .95). Median progression-free survival was 3.8 and 2.9 months, respectively (P = .07). Overall response rates were 13% and 10%, respectively. Patients with a performance status of 0, 1, and 2 survived a median of 7.9, 4.8, and 2.4 months, respectively. The only statistically significant differences in grades 3 and 4 toxicity occurred for hypertension (10% v 3%; P < .001) and proteinuria (5% v 1%; P = .002); venous thrombosis grade > or = 3 was equivalent in both arms (14% and 15%, respectively). The addition of bevacizumab to gemcitabine does not improve survival in advanced pancreatic cancer patients.


Subliminal Priming-State of the Art and Future Perspectives.
The influence of subliminal priming (behavior outside of awareness) in humans is an interesting phenomenon and its understanding is crucial as it can impact behavior, choices, and actions. Given this, research about the impact of priming continues to be an area of investigative interest, and this paper provides a technical overview of research design strengths and issues in subliminal priming research. Efficient experiments and protocols, as well as associated electroencephalographic and eye movement data analyses, are discussed in detail. We highlight the strengths and weaknesses of different priming experiments that have measured affective (emotional) and cognitive responses. Finally, very recent approaches and findings are described to summarize and emphasize state-of-the-art methods and potential future directions in research marketing and other commercial applications.


Mental health services use among adults with or without mental disorders: Do development stages matter?
Mental health services (MHS) use is a complex behaviour that does not only concern individuals with current mental disorder. To date, few studies have examined age-related contextualisation of MHS use. Reasons for seeking help may vary according to development stages in adulthood. This study aimed to determine which predisposing, enabling and need factors, using Andersen's model, were associated with MHS use according to adult development stages among individuals with or without current psychiatric diagnosis. Three age groups were examined: 18- to 29-year-olds (n = 775), 30- to 49-year-olds (n = 1,560) and 50- to 64-year-olds (n = 960). Data were obtained from the Montreal Longitudinal Catchment Area Study. Bivariate and multivariate logistic regression analyses were conducted for each age group separately to determine which predisposing, enabling and need factors were associated with MHS use in the past 12 months. For 18- to 29-year-olds, one enabling factor (Internet search) and two need factors (presence of major depressive disorder and number of stressful events) were positively associated with MHS use. For 30- to 49-year-olds, one predisposing factor (family history of mental disorder), four enabling factors (not currently working or in school, perceiving neighbourhood disorder, social cohesion and Internet searching) and one need factor (major depressive disorder) correlated with help seeking. For 50- to 64-year-olds, two predisposing factors (family history of mental disorder and higher self-perceived stigma), two enabling factors (low satisfaction in personal relationship and Internet searching) and one need factor (alcohol dependence) were associated with MHS use. Factors associated with MHS use differ according to adult development stages. Programmes and policies should be based on age-related contextualisation to increase MHS use.


Long-term outcomes from dose-escalated image-guided intensity-modulated radiotherapy with androgen deprivation: encouraging results for intermediate- and high-risk prostate cancer.
Dose-escalated (DE) radiotherapy in the setting of localized prostate cancer has been shown to improve biochemical disease-free survival (bDFS) in several studies. In the same group of patients, androgen deprivation therapy (ADT) has been shown to confer a survival benefit when combined with radiotherapy doses of up to 70 Gy; however, there is currently little long-term data on patients who have received high-dose intensity-modulated radiotherapy (IMRT) with ADT. We report the long-term outcomes in a large cohort of patients treated with the combination of DE image-guided IMRT (IG-IMRT) and ADT. Patients with localized prostate cancer were identified from a centralized database across an integrated cancer center. All patients received DE IG-IMRT, combined with ADT, and had a minimum follow up of 12 months post-radiotherapy. All relapse and toxicity data were collected prospectively. Actuarial bDFS, metastasis-free survival, prostate cancer-specific survival, and multivariate analyses were calculated using the SPSS v20.0 statistical package. Seven hundred and eighty-two eligible patients were identified with a median follow up of 46 months. Overall, 4.3% of patients relapsed, 2.0% developed distant metastases, and 0.6% died from metastatic prostate cancer. At 5-years, bDFS was 88%, metastasis-free survival was 95%, and prostate cancer-specific survival was 98%. Five-year grade 2 genitourinary and gastrointestinal toxicity was 2.1% and 3.4%, respectively. No grade 3 or 4 late toxicities were reported. Pretreatment prostate specific antigen (P=0.001) and Gleason score (P=0.03) were significant in predicting biochemical failure on multivariate analysis. There is a high probability of tumor control with DE IG-IMRT combined with androgen deprivation, and this is a technique with a low probability of significant late toxicity. Our long term results corroborate the safety and efficacy of treating with IG-IMRT to high doses and compares favorably with published series for the treatment of prostate cancer.


Sulf1A and HGF regulate satellite-cell growth.
The role of Sulf1A, sulfation and hepatocyte growth factor (HGF) in satellite-cell growth was examined in an in vitro model of dissociated whole skeletal muscle fibres. Pax7-positive quiescent satellite cells express little or no Sulf1A but show rapid re-expression in regenerating myoblasts and myotubes, similar to embryonic muscle and in vitro satellite cells preceding asynchronous MyoD activation. Once activated, Sulf1A and MyoD re-expression persists up to 72 hours in most satellite cells under normal culture conditions and following moderate changes in sulfation, whereas Sulf1A neutralisation by antibodies not only enhances satellite-cell proliferation but also downregulates MyoD and Pax7 expression in a large proportion of the satellite cells. The HGF exposure also induces similar but even more pronounced changes characterised by variable sulfation levels and rapid downregulation of MyoD and Pax7 without myogenin activation in a sub-set of cells. This Pax7-MyoD-myogenin-negative sub-population expresses Sulf1A and Myf5. The transfer of all such satellite-cell progenies onto gelatin-coated-substratum re-activates MyoD and Pax7 gene expression in all cells, thus detecting a distinct sub-population of satellite cells. We conclude that HGF and fine-tuned sulfation levels are major contributory factors controlling satellite-cell growth by regulating the relative activities of actively proliferating and differentiating cells.


Variations in the NRAMP1 gene and susceptibility to tuberculosis in West Africans.
Genetic factors may affect the susceptibility to tuberculosis, but no specific genes governing susceptibility have been identified. In mice, natural resistance to infection with some mycobacteria is influenced by the gene for natural-resistance-associated macrophage protein 1 (Nramp1), but the role of the human homologue of this gene, NRAMP1, in tuberculosis is unknown. We typed polymorphisms in NRAMP1 in a case-control study of tuberculosis in the Gambia, West Africa. Sequence-specific oligonucleotide hybridization and microsatellite analysis were used to type NRAMP1 polymorphisms in 410 adults (mean age, 34.7 years) with smear-positive pulmonary tuberculosis and 417 ethnically matched, healthy controls. Patients with human immunodeficiency virus infection were excluded. Four NRAMP1 polymorphisms were each significantly associated with tuberculosis. Subjects who were heterozygous for two NRAMP1 polymorphisms in intron 4 and the 3' untranslated region of the gene were particularly overrepresented among those with tuberculosis, as compared with those with the most common NRAMP1 genotype (odds ratio, 4.07; 95 percent confidence interval, 1.86 to 9.12; chi-square= 14.58; P<0.001). Genetic variation in NRAMP1 affects susceptibility to tuberculosis in West Africans.


A clinical prediction rule for the diagnosis of coronary artery disease: validation, updating, and extension.
The aim was to validate, update, and extend the Diamond-Forrester model for estimating the probability of obstructive coronary artery disease (CAD) in a contemporary cohort. Prospectively collected data from 14 hospitals on patients with chest pain without a history of CAD and referred for conventional coronary angiography (CCA) were used. Primary outcome was obstructive CAD, defined as ≥ 50% stenosis in one or more vessels on CCA. The validity of the Diamond-Forrester model was assessed using calibration plots, calibration-in-the-large, and recalibration in logistic regression. The model was subsequently updated and extended by revising the predictive value of age, sex, and type of chest pain. Diagnostic performance was assessed by calculating the area under the receiver operating characteristic curve (c-statistic) and reclassification was determined. We included 2260 patients, of whom 1319 had obstructive CAD on CCA. Validation demonstrated an overestimation of the CAD probability, especially in women. The updated and extended models demonstrated a c-statistic of 0.79 (95% CI 0.77-0.81) and 0.82 (95% CI 0.80-0.84), respectively. Sixteen per cent of men and 64% of women were correctly reclassified. The predicted probability of obstructive CAD ranged from 10% for 50-year-old females with non-specific chest pain to 91% for 80-year-old males with typical chest pain. Predictions varied across hospitals due to differences in disease prevalence. Our results suggest that the Diamond-Forrester model overestimates the probability of CAD especially in women. We updated the predictive effects of age, sex, type of chest pain, and hospital setting which improved model performance and we extended it to include patients of 70 years and older.


Effects of 'elemental' diets on absorptive and enzymic activities and on 5-fluorouracil toxicity in rat small intestine.
1. Water absorption and cytoplasmic dipeptidase activities were determined in isolated rat small intestine after animals had fed on various 'elemental' diets or a standard rat diet and after a single injection of 5-fluorouracil. 2. Vivonex diets were associated with a decrease in dry weight of the small intestine and an increase in glucose and water absorption in vitro. 3. The nature of the dietary nitrogen profoundly affects the activities of intestinal peptidases. 4. Water absorption was severly depressed 3 days after 5-fluorouracil administration: the extent of depression was independent of the diet. Thus, any ameliorative effects of 'elemental' diets on 5-fluorouracil toxicity are unlikely to be mediated by direct protection of intestinal absorption.


Functional and stability orientation synthesis of materials and structures in aprotic Li-O2 batteries.
The lithium-O2 battery is one of most promising energy storage and conversion devices due to its ultrahigh theoretical energy density and hence has broad application potential in electrical vehicles and stationary power systems. However, the present Li-O2 battery suffers from a series of challenges for its practical application, such as its low capacity and rate capability, poor round-trip efficiency and short cycle life. These challenges mainly arise from the sluggish and unsustainable discharge and charge reactions at lithium and oxygen electrodes, which determine the performance and durability of a battery. In this review, we first provide insights on the present understanding of the discharge/charge mechanism of such a battery and follow up with establishing a correlation between the specific materials/structures of the battery modules and their functionality/stability within the recent progress in electrodes, electrolytes and redox mediators. Considerable emphasis is paid to the importance of functional orientation design and the synthesis of materials/structures towards accelerating and sustaining the electrode reactions of Li-O2 batteries. Moreover, the future directions and perspectives of rationally constructed material and surface/interface structures, as well as their optimal combinations are proposed for enhancement of the electrode reaction rate and sustainability, and consequently for a better performance and durability of such batteries.


Drought Stress Causes Specific Changes to the Spliceosome and Stress Granule Components.
The spliceosome processes RNAs from a pre-RNA state to a mature mRNA thereby influencing RNA availability for translation, localization, and turnover. It consists of complex structures containing RNA-binding proteins (RBPs) essential for post-transcriptional gene expression control. Here we investigate the dynamic modifications of spliceosomal RBPs under stress and in particular drought stress. We do so by mRNA interactome capture in Arabidopsis thaliana using label free quantitation. This approach identified 44 proteins associated with the spliceosome and further 32 proteins associated with stress granules. We noted a high enrichment in the motifs RDRR and RSRSRS that are characteristic of RNA interacting proteins. Identification of splicing factors reflect direct and/or indirect stress induced splicing events that have a direct effect on transcriptome and proteome changes under stress. Furthermore, detection of stress granule components is consistent with transcriptional arrest. Identification of drought induced stress granule components is critical in determining common abiotic stress-induced foci that can have biotechnological applications. This study may therefore open ways to modify plant stress responses at a systems level through the modification of key spliceosome components.


Atrial natriuretic factor during development and reversal of one-kidney, one clip hypertension.
Atrial natriuretic factor (ANF) was studied in rat plasma and atria 1, 2, 4, 6, and 8 weeks after constriction of the left renal artery and removal of the contralateral kidney. Plasma ANF was elevated at all periods of investigation. A positive correlation was observed between plasma ANF and blood pressure (r = 0.56, p less than 0.001). The total atrial ANF content (microgram/atrium) in one-kidney, one clip (1K1C) rats was lower during Weeks 1 and 2, but only in the left atrium. Lower ANF concentrations (microgram/mg protein) were also evident in the left atrium at Weeks 1, 2, and 8, and in the right atrium at Week 8. A negative correlation between ANF in plasma and in the left atrium was discerned (r = 0.43, p less than 0.01). Blood pressure (184 +/- 4 vs 114 +/- 4 mm Hg), body weight, and plasma ANF were also examined in 1K1C rats and their normotensive controls before and after unclipping. Blood pressure was normalized 6 hours after unclipping. Plasma ANF declined in 1K1C rats within 6 hours after clip removal, but it was still higher than in the controls. Plasma ANF was similar in both groups on Days 9 and 13 after unclipping. There were no differences in atrial ANF between hypertensive and normotensive animals 13 days after unclipping. The high levels of plasma ANF observed in 1K1C rats probably are secondary to increased intra-atrial pressure caused by the dual mechanism of expanded plasma volume and high blood pressure.


Pure red cell aplasia caused by Parvovirus B19 infection in solid organ transplant recipients: a case report and review of literature.
Human Parvovirus B19 (PV B19) is one of the several recently described 'emerging viruses' and has been identified as the etiological agent of 'fifth disease' in childhood. Human PV B19, which is the etiological agent of transient erythroblastopenia in hemolytic anemia, is also a recognized rare cause of red cell aplasia in immunocompromised patients, including transplant recipients. To date, 26 cases of PV B19-induced red cell aplasia have been reported in solid organ transplant recipients. Twelve patients had cyclosporine-based immunosuppression and 14 had tacrolimus-based immunosuppression. Sixteen of these patients required treatment with commercial intravenous immunoglobulin alone, 1 required treatment with intravenous immunoglobulin and plasmapheresis, 4 required intravenous immunoglobulin and erythropoietin, 1 required treatment with intravenous immunoglobulin and conversion of tacrolimus to cyclosporine, 1 had improvement in hematocrit with erythropoietin alone and in 3 patients the disease was self-limiting. Herein, we report a case of pure red cell aplasia caused by acute PV B19 infection in a renal transplant recipient in whom the immunosuppressive regimen included prednisone, mycophenolate mofetil and tacrolimus and the red cell aplasia resolved with discontinuation of mycophenolate mofetil.


Fermented milk containing Bifidobacterium lactis DN-173 010 improves gastrointestinal well-being and digestive symptoms in women reporting minor digestive symptoms: a randomised, double-blind, parallel, controlled study.
The ability of probiotics to improve bowel habits or transit time has been shown in healthy populations. Additional data are required to support the use of specific probiotics to improve gastrointestinal (GI) well-being. The present study was designed to investigate the effect of consuming fermented milk (FM) on GI well-being, digestive symptoms and health-related quality of life (HRQoL) amongst women without diagnosed GI disorders. In this double-blind, controlled, parallel-design study, subjects were randomised to ingest daily either 2 x 125 g FM containing Bifidobacterium lactis DN-173 010 and yoghurt strains or a control non-fermented dairy product for 4 weeks followed by a 4-week wash-out period. GI well-being and digestive symptoms were assessed weekly. HRQoL was measured every 4 weeks. Data were analysed using analysis of covariance and logistic regression, correcting for baseline values on the full analysis set population of 197 women (aged 18-60 years). The percentage of women reporting an improvement in their GI well-being was significantly (P < 0.01) higher in the FM group v. the control group (OR 1.69; 95 % CI 1.17, 2.45). A significantly (P < 0.05) more pronounced decrease in the composite score of digestive symptoms was observed in the FM group when comparing with the control group (least squares mean - 0.57; 95 % CI - 1.12, - 0.02). Among HRQoL dimensions, the digestive comfort score was significantly (P < 0.05) improved in the FM group compared with the control group. The present study showed that the daily consumption of a specific FM is able to improve GI well-being and digestive symptoms in adult women without GI disorders.


Decision aids that support decisions about prenatal testing for Down syndrome: an environmental scan.
Prenatal screening tests for Down syndrome (DS) are routine in many developed countries and new tests are rapidly becoming available. Decisions about prenatal screening are increasingly complex with each successive test, and pregnant women need information about risks and benefits as well as clarity about their values. Decision aids (DAs) can help healthcare providers support women in this decision. Using an environmental scan, we aimed to identify publicly available DAs focusing on prenatal screening/diagnosis for Down syndrome that provide effective support for decision making. Data sources searched were the Decision Aids Library Inventory (DALI) of the Ottawa Patient Decision Aids Research Group at the Ottawa Health Research Institute; Google searches on the internet; professional organizations, academic institutions and other experts in the field; and references in existing systematic reviews on DAs. Eligible DAs targeted pregnant women, focused on prenatal screening and/or diagnosis, applied to tests for fetal abnormalities or aneuploidies, and were in French, English, Spanish or Portuguese. Pairs of reviewers independently identified eligible DAs and extracted characteristics including the presence of practical decision support tools and features to aid comprehension. They then performed quality assessment using the 16 minimum standards established by the International Patient Decision Aids Standards (IPDASi v4.0). Of 543 potentially eligible DAs (512 in DALI, 27 from experts, and four on the internet), 23 were eligible and 20 were available for data extraction. DAs were developed from 1996 to 2013 in six countries (UK, USA, Canada, Australia, Sweden, and France). Five DAs were for prenatal screening, three for prenatal diagnosis and 12 for both). Eight contained values clarification methods (personal worksheets). The 20 DAs scored a median of 10/16 (range 6-15) on the 16 IPDAS minimum standards. None of the 20 included DAs met all 16 IPDAS minimum standards, and few included practical decision support tools or aids to comprehension. Our results indicate there is a need for DAs that effectively support decision making regarding prenatal testing for Down syndrome, especially in light of the recently available non-invasive prenatal screening tests.


Coordinated leading- and lagging-strand synthesis at the Escherichia coli DNA replication fork. IV. Reconstitution of an asymmetric, dimeric DNA polymerase III holoenzyme.
Individually purified subunits have been used to reconstitute the action of the Escherichia coli DNA polymerase III holoenzyme (Pol III HE) at a replication fork formed in the presence of the primosome, the single-stranded DNA binding protein, and a tailed form II DNA template. Complete activity, indistinguishable from that of the intact DNA Pol III HE, could be reproduced with a combination of the DNA polymerase III core (Pol III core), the gamma.delta complex, and the beta subunit. Experiments where the Pol III core in reaction mixtures containing active replication forks was diluted suggested that the lagging-strand Pol III core remained associated continuously with the replication fork through multiple cycles of Okazaki fragment synthesis. Since the lagging-strand Pol III core must dissociate from the 3' end of the completed Okazaki fragment, this suggests that its association with the fork is via protein-protein interactions, lending credence to the idea that it forms a dimeric complex with the leading-strand Pol III core. An asymmetry in the action of the subunits was revealed under conditions (high ionic strength) that were presumably destabilizing to the integrity of the replication fork. Under these conditions, tau acted to stimulate DNA synthesis only when the primase was present (i.e. when lagging-strand DNA synthesis was ongoing). This stimulation was reflected by an inhibition of the formation of small Okazaki fragments, suggesting that, within the context of the model developed to account for the temporal order of steps during a cycle of Okazaki fragment synthesis, the presence of tau accelerated the transit of the lagging-strand Pol III core from the 3' end of the completed Okazaki fragment to the 3' end of the new primer.


Association Between Portable Music Player Use and Hearing Loss Among Children of School Age in the Netherlands.
Portable music player use may have harmful effects on hearing. The magnitude and effect of frequent music exposure, especially at younger ages, on hearing are unclear. To examine the prevalence of noise-induced hearing loss in a 9- to 11-year-old population and associations with portable music player use and sociodemographic factors. A cross-sectional study within an ongoing, prospective, birth cohort study within Rotterdam, the Netherlands was conducted. Between ages 9 and 11 years, 5355 children underwent their first audiometric evaluation. Children were excluded if they had missing or failed tympanometry results. The study was conducted from April 16, 2012, to October 25, 2015. Portable music player (PMP) use and sociodemographic factors assessed via parental questionnaires. Hearing acuity measured by pure-tone audiometry at 0.5 to 8 kHz. Possible noise-induced hearing loss was contingent on a high-frequency notch and/or high-frequency hearing loss in the audiogram, or reported hearing-related symptoms. The final sample included 3116 participants who were a mean (interquartile range) age of 9.7 (9.6-9.9) years and equally distributed between boys (1550 [49.7%]) and girls (1566 [50.3%]). Of these, 1244 (39.9%) reported no PMP use, 577 (18.5%) reported use 1 or 2 days per week, 254 (8.2%) reported use 3 or more days per week, and for 1041 (33.4%), PMP use was not reported. Audiometric notches and high-frequency hearing loss were present in 443 (14.2%) of all children; 140 (4.5%) fulfilled the criteria of a notch, 238 (7.6%) of high-frequency hearing loss, and 65 (2.1%) of both. Of the cohort, 52 (1.7%) showed bilateral impairment. Hearing-related symptoms were reported for 232 (11.3%) of the respondents, and 831 (40.0%) of the respondents used portable music players. Portable music player use was associated with high-frequency hearing loss (odds ratio [OR], 2.88; 95% CI, 1.36-6.980 for 1 or 2 days per week and OR, 2.74; 95% CI, 1.22-6.96 for ≥3 days per week), but listening time and duration were not. There was no association of music exposure with high-frequency notches. In this study, 14.2% of school-aged children showed audiometric notches or high-frequency hearing loss. This hearing impairment is already present prior to exposure to known noise hazards, such as club and concert attendance, and may have lifelong consequences. Repeated measurements are needed to confirm the association of portable music player use with hearing impairment in children.


A graph-based genetic algorithm and generative model/Monte Carlo tree search for the exploration of chemical space.
This paper presents a comparison of a graph-based genetic algorithm (GB-GA) and machine learning (ML) results for the optimization of log P values with a constraint for synthetic accessibility and shows that the GA is as good as or better than the ML approaches for this particular property. The molecules found by the GB-GA bear little resemblance to the molecules used to construct the initial mating pool, indicating that the GB-GA approach can traverse a relatively large distance in chemical space using relatively few (50) generations. The paper also introduces a new non-ML graph-based generative model (GB-GM) that can be parameterized using very small data sets and combined with a Monte Carlo tree search (MCTS) algorithm. The results are comparable to previously published results (Sci. Technol. Adv. Mater., 2017, 18, 972-976) using a recurrent neural network (RNN) generative model, and the GB-GM-based method is several orders of magnitude faster. The MCTS results seem more dependent on the composition of the training set than the GA approach for this particular property. Our results suggest that the performance of new ML-based generative models should be compared to that of more traditional, and often simpler, approaches such a GA.


Echinocandin pharmacodynamics: review and clinical implications.
Echinocandins have made a significant impact in the treatment of select invasive fungal infections, most notably invasive candidiasis and aspergillosis. However, treatment outcomes for such infections are still less than optimal, prompting an examination of dosing and administration techniques in an attempt to exploit known pharmacodynamic properties and improve outcomes. Echinocandins generally exhibit concentration-dependent, fungicidal activity against Candida spp. and fungistatic activity against Aspergillus spp. However, increasing drug concentrations of echinocandins above the organism's MIC may result in a paradoxical increase in fungal growth as demonstrated in some in vitro and in vivo models (known most commonly as the 'Eagle effect'). Therefore, the potential impact of dose escalations on improving the clinical efficacy of echinocandins based on in vitro and animal models are uncertain and are still being evaluated. In addition, such strategies have to consider the potential for increased treatment-related toxicities and costs. To date, published clinical studies (both superiority and non-inferiority) demonstrating the potential for dose-related improvements in treatment outcomes have been limited to mucocutaneous and oesophageal candidiasis. Further research is needed to determine if a role exists for optimizing echinocandin pharmacodynamics in various clinical settings.


Randomized controlled trial of daily total end range time (TERT) for Capener splinting of the stiff proximal interphalangeal joint.
Capener splinting is a common treatment for extension deficit of the proximal interphalangeal (PIP) joint. This study compared the effect of daily splint total end range time (TERT) of 6-12 hr versus 12-16 hr. Twenty-two participants with extension deficits of the PIP joint were randomly allocated to a daily TERT of 6-12 hr or 12-16 hr. Progress after 8 wk of splinting was evaluated. No significant difference was found in change in extension range of motion (ROM) between groups (active ROM, F[4, 17] = 2.19, p = .13; passive ROM, F[4, 17] = 0.95, p = .46; torque ROM, F[4, 17] = 1.49, p = .26). Considerable crossover between groups resulted in a similar average daily TERT (9.5 hr for the 6-12 hr group vs. 11.5 hr for the 12-16 hr group). Further research with a larger sample is needed to determine whether longer daily TERT is beneficial. Our results suggest, however, that most patients find it difficult to wear splints >12 hr/day.


Genetic analysis of the Replication Protein A large subunit family in Arabidopsis reveals unique and overlapping roles in DNA repair, meiosis and DNA replication.
Replication Protein A (RPA) is a heterotrimeric protein complex that binds single-stranded DNA. In plants, multiple genes encode the three RPA subunits (RPA1, RPA2 and RPA3), including five RPA1-like genes in Arabidopsis. Phylogenetic analysis suggests two distinct groups composed of RPA1A, RPA1C, RPA1E (ACE group) and RPA1B, RPA1D (BD group). ACE-group members are transcriptionally induced by ionizing radiation, while BD-group members show higher basal transcription and are not induced by ionizing radiation. Analysis of rpa1 T-DNA insertion mutants demonstrates that although each mutant line is likely null, all mutant lines are viable and display normal vegetative growth. The rpa1c and rpa1e single mutants however display hypersensitivity to ionizing radiation, and combination of rpa1c and rpa1e results in additive hypersensitivity to a variety of DNA damaging agents. Combination of the partially sterile rpa1a with rpa1c results in complete sterility, incomplete synapsis and meiotic chromosome fragmentation, suggesting an early role for RPA1C in promoting homologous recombination. Combination of either rpa1c and/or rpa1e with atr revealed additive hypersensitivity phenotypes consistent with each functioning in unique repair pathways. In contrast, rpa1b rpa1d double mutant plants display slow growth and developmental defects under non-damaging conditions. We show these defects in the rpa1b rpa1d mutant are likely the result of defective DNA replication leading to reduction in cell division.


PSEN1 polymorphisms alter the rate of cognitive decline in sporadic Alzheimer's disease patients.
Mutations in amyloid precursor protein (APP) and presenilin (PSEN) genes are known to cause familial early-onset Alzheimer's disease (AD), which account for around 5% of AD cases. Genetic associations for the remaining "sporadic" cases, other than the risks associated with the apolipoprotein (APOE) epsilon4 allele are currently not fully established. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) in PSEN1 are associated with a modified risk for sporadic AD or a modified disease phenotype. Eight tag SNPs were identified using linkage disequilibrium (LD) data from the International HapMap project providing coverage of the entire PSEN1 gene. These SNPs were investigated for AD susceptibility in a case-control haplotype association study (N=714) and for genotype-specific effects on cognitive performance in AD patients (N=169) using non-linear mixed effects modelling. Replication of a mild associated-risk of an intronic PSEN1 polymorphism with AD was achieved (P=0.03). No other single SNPs or haplotypes were associated with AD risk. However, 3 SNPs were associated with an altered rate of cognitive decline underlining their role as genetic modifiers of disease.


Thyroxine-binding globulin: investigation of microheterogeneity.
Preparations of T4-binding globulin (TBG) from human serum was performed using only two affinity chromatography steps. Purity of the protein was demonstrated by a single band in overloaded disc and sodium dodecyl sulfate electrophoresis, equimolar binding to T4, and linearity in sedimentation velocity run. The molecular weight was calculated to be 60,000 +/- 3,000 daltons (n = 3), the sedimentation coefficient was 3.95S, and the Stokes' radius was 37 A. The amino acid composition was found to be in good agreement with the calculations of other authors. By isoelectric focussing (IEF), pure TBG showed four main bands at pH 4.25, 4.35, 4.45, and 4.55 together with several fainter bands. The N-acetylneuraminic acid (NANA) content of the four TBG bands isolated by preparative IEF was found to decrease from 10.2 mol NANA/mol TBG in the band at pH 4.25 to 4.8 mol NANA/mol TBG in the band at pH 4.55. No significant difference in the affinity constants of the TBG bands to T4 was found. The affinity constants for TBG ranged from 3.1 x 10(9) to 7.2 x 10(9) M-1. Sequential kinetic desialylation of pure TBG resulted in a progressive tendency toward one major band at pH 6.0. In native sera, microheterogeneity of TBG was detected after IEF on polyacrylamide gel plates by immunofixation. The typical TBG patterns shown by pure TBG were also found in normal subjects. Characteristic deviations from this pattern were found in the sera of females during estrogen therapy or pregnancy, where there was a gradual increase in density of the band at pH 4.25 and the appearance of an additional band at pH 4.15. In sera from patients with liver disease and elevated TBG levels, there was a fading of the acidic bands, whereas the more alkaline band at pH 4.55 was intensified. It is therefore proposed that microheterogeneity of TBG is caused by differences in NANA content and that variations of TBG patterns in native sera may reflect altered TBG synthesis or degradation. A genetically related microheterogeneity of TBG could not be demonstrated after examination of 800 sera, including 2 families with quantitative TBG deficiency.


Cannabinoids in late-onset Alzheimer's disease.
Given the lack of effective treatments for late-onset Alzheimer's disease (LOAD) and the substantial burden on patients, families, health care systems, and economies, finding an effective therapy is one of the highest medical priorities. The past few years have seen a growing interest in the medicinal uses of cannabinoids, the bioactive components of the cannabis plant, including the treatment of LOAD and other physical conditions that are common in older people. Several in vitro and in vivo studies have demonstrated that cannabinoids can reduce oxidative stress, neuroinflammation, and the formation of amyloid plaques and neurofibrillary tangles, the key hallmarks of LOAD. In addition, in population-based studies, cannabinoids reduced dementia-related symptoms (e.g., behavioral disturbances). The current article provides an overview of the potential of cannabinoids in the treatment of LOAD and related neuropsychiatric symptoms in older people. We also discuss the efficacy, safety, and pharmacokinetics of cannabinoid-based drugs in older people with dementia.


Evidence for epigenetic abnormalities of the androgen receptor gene in foreskin from children with hypospadias.
Hypospadias is a malformation of the penis due to an incomplete development of the male urethra, the exact etiology of which in the majority of cases remains unknown. The objective of the study was to assess whether defects of the androgen receptor (AR) gene (CAG repeats and methylation pattern) and DNA methyltransferases (DNMT) family are present in hypospadic patients. CAG repeats length, methylation status, and expression of the AR gene were analyzed. The DNMT family was studied at the protein level and the DNMT3A sequenced. The study was performed at a pediatric endocrinology referral clinic. Twenty boys with isolated glandular hypospadias and 20 age-matched control children undergoing a surgical procedure for circumcision were studied. CAG repeats length and AR methylation pattern in PBLs and foreskin tissue, DNMT expression and sequencing in patients and controls, and in vitro studies in cultured fibroblasts were measured. AR gene methylation in foreskin tissues from patients with hypospadias was higher than in normal children. AR expression in foreskin tissue of hypospadic patients was lower than in controls, whereas the DNMT3A protein level was significantly higher in patients than controls. In cultured fibroblasts, both dihydrotestosterone and testosterone significantly reduced AR gene methylation and DNMT3A expression in a dose-dependent fashion and increased AR expression. The AR gene in target tissues from patients with hypospadias is more methylated than in control children, resulting in a decreased expression of the AR. The mechanism underlying the modulation of the AR gene expression seems to be mediated by DNMT3A. This epigenetic alteration of the AR gene might be involved in the pathogenesis of hypospadias.


Failure to rescue and disparities in emergency general surgery.
Racial and socioeconomic disparities are well documented in emergency general surgery (EGS) and have been highlighted as a national priority for surgical research. The aim of this study was to identify whether disparities in the EGS setting are more likely to be caused by major adverse events (MAEs) (e.g., venous thromboembolism) or failure to respond appropriately to such events. A retrospective cohort study was undertaken using administrative data. EGS cases were defined using International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic codes recommended by the American Association for the Surgery of Trauma. The data source was the National Inpatient Sample 2012-2013, which captured a 20%-stratified sample of discharges from all hospitals participating in the Healthcare Cost and Utilization Project. The outcomes were MAEs, in-hospital mortality, and failure to rescue (FTR). There were 1,345,199 individual patient records available within the National Inpatient Sample. There were 201,574 admissions (15.0%) complicated by an MAE, and 12,006 of these (6.0%) resulted in death. The FTR rate was therefore 6.0%. Uninsured patients had significantly higher odds of MAEs (adjusted odds ratio, 1.16; 95% confidence interval, 1.13-1.19), mortality (1.28, 1.16-1.41), and FTR (1.20, 1.06-1.36) than those with private insurance. Although black patients had significantly higher odds of MAEs (adjusted odds ratio, 1.14; 95% confidence interval, 1.13-1.16), they had lower mortality (0.95, 0.90-0.99) and FTR (0.86, 0.80-0.91) than white patients. Uninsured EGS patients are at increased risk of MAEs but also the failure of health care providers to respond effectively when such events occur. This suggests that MAEs and FTR are both potential targets for mitigating socioeconomic disparities in the setting of EGS.


The effects of human population structure on large genetic association studies.
Large-scale association studies hold substantial promise for unraveling the genetic basis of common human diseases. A well-known problem with such studies is the presence of undetected population structure, which can lead to both false positive results and failures to detect genuine associations. Here we examine approximately 15,000 genome-wide single-nucleotide polymorphisms typed in three population groups to assess the consequences of population structure on the coming generation of association studies. The consequences of population structure on association outcomes increase markedly with sample size. For the size of study needed to detect typical genetic effects in common diseases, even the modest levels of population structure within population groups cannot safely be ignored. We also examine one method for correcting for population structure (Genomic Control). Although it often performs well, it may not correct for structure if too few loci are used and may overcorrect in other settings, leading to substantial loss of power. The results of our analysis can guide the design of large-scale association studies.


Argon ion beam hemostasis with albumin after liver resection.
Bleeding is common after liver resection and establishing hemostasis with sutures or argon beam coagulation can be difficult. In our laboratory, concentrated albumin applied to the liver surface before argon beam coagulation improves sealing of the resected surface of the liver, including closure of blood vessels and ducts not generally seen with standard argon beam coagulation. Domestic swine underwent heparinization, then laparotomy and wedge resection of the left medial segment of the liver, using finger fracture technique. Blood vessels and ducts 5 mm or greater were ligated. For achieving hemostasis, the animals were randomized to either a control group using argon beam coagulation alone (n = 15) or an albumin group using argon beam coagulation with concentrated 38% albumin (n = 13). After initial hemostasis, the resected liver surfaces were packed for 3 minutes. Repeated applications of argon beam coagulation with or without albumin were performed as needed, followed by 3 minutes of repacking, until complete hemostasis was achieved. Liver functions and blood counts were examined 4 days postoperatively. The albumin group was less likely to require repeat applications of argon beam coagulation than control animals (mean 0.5 versus 1.5 times, P = 0.006). The total time of argon beam coagulation was significantly shorter in the albumin group (mean 90 versus 154 seconds, P = 0.001). Adding albumin to the liver surface substantially increases the durability of the repaired surface and reduces the time needed to achieve stable hemostasis when compared with standard argon beam coagulation. Further investigations using this technique are warranted.


The value of (18)F-fluorodeoxyglucose positron emission tomography/computed tomography for staging of primary extranodal head and neck lymphomas.
Using a retrospective approach, the aim of this study was to confirm the previously described value of fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG-PET/CT) in patients with primary extranodal lymphoma of the head and neck region. Additionally, the clinical significance of the semiquantitative analysis of the standardized uptake value (SUV), its predictive role in the follow-up setting, and its value in detection of synchronous primaries were studied. Retrospective chart review. Twenty-six patients with a primary extranodal head and neck lymphoma (22 diffuse large B-cell lymphoma, one Hodgkin's lymphoma, three malignant T-cell lymphomas) were included. We retrospectively evaluated the clinical outcomes according to the maximum standardized uptake values of the primary lesion (SUV(max)) and whether a positron emission tomography/computed tomography (PET/CT) was performed or not in the follow-up studies. The median SUV(max) was chosen as the cutoff value. The patients were then grouped as those with either low or high SUV(max), respective to the cutoff value. Event-free survival and cumulative survival were endpoints of interest. Nineteen patients (73%) were above the age of 60 years; the median age was 70 years (range, 28-87 years). Most primary sites were in the Waldeyer's ring (15 patients, 60%), whereas in four patients (27%) only the palatine tonsil was affected. The SUV(max) ranged from 5.8 to 33.9. In one patient, relevant fluorodeoxyglucose (FDG) uptake within the intestine revealed a cecal adenocarcinoma as a secondary primary. Twenty of the 25 clinically followed patients (80%) achieved complete remission after treatment. Patients with high SUV(max) showed favorable survival (log-rank test, P = .044). A tendency for longer survival within the group with follow-up PET/CT studies could be noted but with no significant statistical difference (P = .349). (18)F-FDG-PET/CT imaging is a potent primary staging tool. It also has application as an instrument for evaluation of follow-up and response to therapy in patients suffering from primary extranodal lymphoma and for detection of secondary malignancies. Furthermore, (18)F-FDG uptake by the primary lesion may be related to better survival.


Impact of red blood cell transfusion on clinical outcomes in patients with acute myocardial infarction.
Divergent views remain regarding the safety of treating anemia with red blood cell (RBC) transfusion in patients with acute coronary syndrome (ACS). We used a prospective database to study effect of RBC transfusion in patients with acute myocardial infarction (MI; n = 2,358). Cox regression models were used to determine the association between RBC transfusion and 6-month outcomes, incorporating transfusion as a time-dependent variable. The models adjusted for baseline variables, propensity for transfusion, and nadir hemoglobin previous to the transfusion. One hundred ninety-two patients (8.1%) received RBC transfusion. Six-month mortality rates were higher in patients receiving transfusion (28.1% vs 11.7%, p <0.0001). The adjusted hazard ratio (HR) for mortality was 1.9 in transfused patients (95% confidence interval [CI] 1.3 to 2.9). Interaction between RBC transfusion and nadir hemoglobin with respect to mortality (p = 0.004) was significant. Stratified analyses showed a protective effect of transfusion in patients with nadir hemoglobin < or=8 g/dL (adjusted HR 0.13, 95% CI 0.03 to 0.65, p = 0.013). By contrast, transfusion was associated with increased mortality in patients with nadir hemoglobin >8 g/dL (adjusted HR 2.2, 95% CI 1.5 to 3.3; p <0.0001). Similar results were obtained for the composite end point of death/MI/heart failure (p for interaction = 0.04). In conclusion, RBC transfusion in patients with acute MI and hemoglobin < or =8 g/dL may be appropriate. The increased mortality observed in transfused patients with nadir hemoglobin above 8 g/dL underscores the clinical difficulty of balancing risks and benefits of RBC transfusion in the setting of ACS.


Anticancer and immunomodulatory activity of egg proteins and peptides: a review.
Eggs are widely recognized as a highly nutritious food source that offer specific health benefits for humans. Eggs contain all of the proteins, lipids, vitamins, minerals, and growth factors necessary for embryonic development. In particular, egg white and yolk proteins are considered functional food substances because they possess biological activities such as antimicrobial, antioxidant, metal-chelating, antihypertensive, anticancer, and immunomodulatory activities. Peptides produced via processes such as enzymatic hydrolysis, fermentation by microorganisms, and some chemical and physical treatments of egg proteins have been shown to enhance the functional properties and solubility of these peptides. Peptide activity is strongly related to amino acid sequence, composition, and length. At present, cancer remains among the leading causes of mortality worldwide, and therefore research aimed at developing new treatments for cancer immunotherapy is of great interest. The present review focuses primarily on the anticancer and immunomodulatory activities of egg proteins and their peptides and provides some insight into their underlying mechanisms of action. A number of egg proteins and peptides have been reported to induce apoptosis in cancer cells, protect against DNA damage, decrease the invasion ability of cancer cells, and exhibit cytotoxic and antimutagenic activity in various cancer cell lines. Furthermore, egg proteins and peptides can stimulate or suppress pro- or anti-inflammatory cytokines, as well as affect the production of inflammatory mediators in a variety of cell lines. In addition, the composition of eggs and the processes of egg proteins and peptides production will be discussed.


Strategic rule breaking: Time wasting to win soccer games.
Rules regulate behavior, but in competitive contexts they also create incentives for rule-breaking because enforcement is imperfect. Sports is a prime example of this, and one that lends itself well to investigation because strategic rule-breaking is often measurable. Professional soccer is a highly competitive team sport with economic rewards for winning given to teams and players. It has a set of rules to ensure fair play, but the enforcement is incomplete, and hence can lead to strategic behavior. Using newly available data, we examine strategic time-wasting, a behavior that help teams win games, or tie games against superior opponents, but is contrary to the objective of game play as entertainment for the spectators. We demonstrate that strategic time-wasting is widespread and is done through delayed restart of the game after goalie capture of the ball, goal kick, throw-in, free kick, corner kick, and substitution. The strategic time-wasting has substantial magnitude, and models of the value per minute predict time-wasting well. Because this time-wasting is a result of incentives created by not stopping the game clock, we predict that a change to rules with stopped game clock when the play is stopped would make game play more time efficient.


Lived experiences of nurse educators on teaching in a large class at a nursing college in Gauteng.
The gradual increase in the number of learners admitted into a nursing college in Gauteng resulted in an increase in class size without a proportional increase in the number of nurse educators. To explore and describe the experiences of nurse educators teaching in large classes at a nursing college in Gauteng in order to present recommendations to facilitate teaching and learning. A qualitative, exploratory, descriptive, and phenomenological research design which is contextual in nature was used. A total of 20 nurse educators were selected through purposive sampling, and in-depth phenomenological semi-structured individual interviews were conducted between January and February 2013. Data were analysed together with the field notes, using Tesch's open coding protocol of qualitative data analysis. Lincoln and Guba's four principles were used to ensure trustworthiness. The themes that emerged from this study were that nurse educators experienced difficulty in recognising learners as individuals in a large class, using innovative pedagogical strategies, and managing a large class. These findings had a negative impact on meaningful teaching and learning as they interfered with an enabling learning environment. Nurse educators should be empowered with facilitative skills in order to effectively manage a large class and hence to achieve teaching and learning abilities. There is a need for nurse educators to finding alternative ways to overcome challenges associated with teaching in large classes and prepare learners to render individualised, caring and holistic nursing care to each unique patient in the healthcare setting.


c-ret regulates cholinergic properties in mouse sympathetic neurons: evidence from mutant mice.
The search for signalling systems regulating development of noradrenergic and cholinergic sympathetic neurons is a classical problem of developmental neuroscience. While an essential role of bone morphogenetic proteins for induction of noradrenergic properties is firmly established, factors involved in the development of cholinergic traits in vivo are still enigmatic. Previous studies have shown that the c-ret receptor and cholinergic properties are coexpressed in chick sympathetic neurons. Using in situ hybridization we show now that a loss-of-function mutation of the c-ret receptor in mice dramatically reduces numbers of cells positive for choline acetyltransferase (ChAT) and the vesicular acetylcholine transporter (VAChT) in stellate ganglia of homozygous newborn animals. The number of neurons positive for tyrosine hydroxylase (TH) mRNA, the rate-limiting enzyme of noradrenaline synthesis, is reduced to a smaller degree and expression levels are not detectably altered. Already at embryonic day 16 (E16), ChAT and VAChT-positive cells are affected by the c-ret mutation. At E14, however, ChAT and VAChT mRNAs are detectable at low levels and no difference is observed between wildtype and mutant mice. Our data suggest that c-ret signalling is necessary for the maturation of cholinergic sympathetic neurons but dispensable for de novo induction of ChAT and VAChT expression.


Aerosol particle microphotography and glare-spot absorption spectroscopy.
The relative intensities of glare spots in the image of an electrodynamically trapped aerosol droplet are measured experimentally with an aerosol particle microscope and calculated theoretically. The theoretical calculations are in good agreement with these experiments and indicate that the intensities of these spots are extremely sensitive to the imaginary part of the refractive index. Experimentally, we obtain the molecular absorption spectrum of an impurity within a droplet by recording the spectrum of an individual glare spot produced by broadband illumination.


Photoresponsive polyesters by incorporation of alkoxyphenacyl or coumarin chromophores along the backbone.
The synthesis and photochemical characterization of two classes of photoresponsive polyesters are described. These polyesters contain either alkoxyphenacyl or coumarin chromophores embedded along the polymer chain. The alkoxyphenacyl polyesters undergo efficient photoinduced chain scission upon irradiation at 300 nm in solution or as a nanoparticle suspension. At 254 nm the coumarin polyesters undergo polymer chain scission. Irradiation of the coumarin polyesters in solution at 350 nm results in both chain crosslinking and chain scission behavior, while irradiation of the coumarin polyesters as nanoparticles results in chain crosslinking. The properties of the alkoxyphenacyl and coumarin polyesters are influenced by the choice of diacid as seen from their thermal behavior. The use of glutamic acid enabled surface or bulk functionalization of the photoresponsive polymers. In addition, controlled release of Nile Red from coumarin polyester nanoparticles is demonstrated by modulation of the wavelength and intensity of irradiation.


Interepisode Sleep Bruxism Intervals and Myofascial Face Pain.
Sleep bruxism (SB) is considered as a possible etiological factor for temporomandibular disorder (TMD) pain. However, polysomnographic (PSG) studies, which are current "gold standard" diagnostic approach to SB, failed to prove an association between SB and TMD. A possible explanation could be that PSG studies have considered only limited characteristics of SB activity: the number of SB events per hour and, sometimes, the total duration of SB per night. According to the sports sciences literature, lack of adequate rest time between muscle activities leads to muscle overloading and pain. Therefore, the aim of this study was to determine whether the intervals between bruxism events differ between patients with and without TMD pain. Two groups of female volunteers were recruited: myofascial TMD pain group (n=124) and non-TMD control group (n=46). From these groups, we selected 86 (69%) case participants and 37 (80%) controls who had at least two SB episodes per night based on PSG recordings. A linear mixed model was used to compare case and control groups over the repeated observations of interepisode intervals. The duration of interepisode intervals was statistically similar in the case (mean [standard deviation {SD}] 1137.7 [1975.8] seconds)] and control (mean [SD] 1192.0 [1972.0] seconds) groups. There were also a similar number of SB episodes per hour and a total duration of SB episodes in both groups. The current data fail to support the idea that TMD pain can be explained by increasing number of SB episodes per hour of sleep or decreasing the time between SB events.


Comparative effectiveness of the BNT162b2 and ChAdOx1 vaccines against Covid-19 in people over 50.
Although pivotal trials with varying populations and study methods suggest higher efficacy for mRNA than adenoviral Covid-19 vaccines, not many studies have directly compared vaccine effectiveness in the population. Here, we conduct a head-to-head comparison of BNT162b2 versus ChAdOx1 against Covid-19. We analyse 235,181 UK Biobank participants aged 50 years or older and vaccinated with one or two doses of BNT162b2 or ChAdOx1. People are followed from the vaccination date until 18/10/2021. Inverse probability weighting is used to minimise confounding and the Cox models to derive hazard ratio. We find that, compared with one dose of ChAdOx1, vaccination with BNT162b2 is associated with a 28% (95% CI, 12-42) decreased risk of SARS-CoV-2 infection. Also, two doses of BNT162b2 vs ChAdOx1 confers 30% (95% CI, 25-35) and 29% (95% CI, 10-45) lower risks of both infection and hospitalisation during the study period when the Delta variant is dominant. Furthermore, the comparative protection against the infection persists for at least six months among the fully vaccinated, suggesting no differential waning between the two vaccines. These findings can inform evidence-based Covid-19 vaccination campaigns and booster strategies.


Acute effects of interleukin-6 infusion on apo-B-containing lipoprotein subclasses in humans.
IL-6 is believed to mediate the elevation in plasma TG and VLDL lipids in patients with sepsis. Previous studies of lipoprotein density fractions do not reveal the extent to which cytokines change the immunochemically distinct TG-rich (LpB:C, LpB:C:E, LpAII:B:C:D:E) and cholesterol-rich (LpB, LpB:E) apoB-containing subclasses present in VLDL. Therefore, we have directly measured these subclasses following their isolation by sequential immunoprecipitation in seven healthy male subjects during a 3-h infusion with recombinant human (rh) IL-6. Though plasma TG and apoB-containing particle number were unchanged by IL-6, the distribution of TG-rich subclasses was significantly altered. Compared to baseline values, LpB:E + LpB:C:E increased significantly at 0.5 h (p < 0.02) and were higher than saline-infused controls at 0.5 and 1 h (p < 0.05). At 0.5 h LpAII:B:C:D:E reciprocally declined from baseline (p < 0.01). While the pattern of change for total apoB showed an overall decline (p < 0.05), these changes in LpB:E + LpB:C:E and LpAII:B:C:D:E in IL-6 subjects differed from controls (p < 0.05; p < 0.01, respectively). These findings indicate that physiologic concentrations of IL-6 rapidly and selectively regulate the transport of apoB particles that contain apoE. Since apoE has immunomodulatory and host defense functions, these changes may be a previously unrecognized early step in the innate immune response.


Distribution and movement of sludge-derived trace metals in selected Nigerian soils.
Use of metal-rich sewage sludge as soil fertilizer may result in trace- metal contamination of soils. This study was conducted to evaluate the effects of long-term sludge application on trace-metal (Zn, Cu, Pb, and Ni) distribution and potential bioavailability in Nigerian soils under a tropical wet-dry climate. Total metal analyses, sequential chemical fractionation, and DTPA extractions were carried out on samples of control and sludge-amended pedons in Nigeria (a Rhodic Kandiustult and two Rhodic Kandiustalfs from Nigeria, respectively). The sewage sludge applied to the soils contained higher levels of Zn and Cu than Pb and Ni. The control pedon contained low levels of all four metals. Soil enrichment factors (EF) were calculated for each metal in the sludge-amended pedons. Compared with the control soil, the sludge-amended pedons showed elevated levels of Zn and Cu, reflecting the trace-metal composition of the sewage sludge. Zinc and Cu in the sludge-amended soils were strongly enriched at all depths in the profile, indicating that they had moved below the zone of sludge application. The sequential extraction and DTPA analyses indicated that the sludge-amended soils contained more readily extractable and bioavailable metal ions than the unamended soil.


MammaPrint Pre-screen Algorithm (MPA) reduces chemotherapy in patients with early-stage breast cancer.
Clinical and pathological parameters may overestimate the need for chemotherapy in patients with early-stage breast cancer. More accurate determination of the risk of distant recurrence is now possible with use of genetic tests, such as the 70-gene MammaPrint profile. A health technology assessment performed by a medical insurer in 2009 introduced a set of test eligibility criteria - the MammaPrint Pre-screen Algorithm (MPA) - applied in this study to determine the clinical usefulness of a pathology-supported genetic testing strategy, aimed at the reduction of healthcare costs.Methods. An implementation study was designed to take advantage of the fact that the 70-gene profile excludes analysis of hormone receptor and human epidermal growth factor receptor 2 (HER2) status, which form part of the MPA based partly on immunohistochemistry routinely performed in all breast cancer patients. The study population consisted of 104 South African women with early-stage breast carcinoma referred for MammaPrint. For the MammaPrint test, RNA was extracted from 60 fresh tumours (in 58 patients) and 46 formalin-fixed, paraffin-embedded (FFPE) tissue samples. When applying the MPA for selection of patients eligible for MammaPrint testing, 95 of the 104 patients qualified. In this subgroup 62% (59/95) were classified as low risk. Similar distribution patterns for risk classification were obtained for RNA extracted from fresh tumours v. FFPE tissue samples. The 70-gene profile classifies approximately 40% of early-stage breast cancer patients as low-risk compared with 15% using conventional criteria. In comparison, more than 60% were shown to be low risk with use of the MPA validated in this study as an appropriate strategy to prevent chemotherapy overtreatment in patients with early-stage breast cancer.


Reply to the 'Comment on "Discovery of a tetracontinuous, aqueous lyotropic network phase with unusual 3D-hexagonal symmetry"' by G. Schröder-Turk, M. Fischer and S. Hyde.
A new calculation by Fischer et al. suggests that the 3etc network phase with 3D-hexagonal symmetry (space group #193: P63/mcm) may be a generic structure adopted by self-assembling soft materials, thereby broadening the context for our recent report of its spontaneous formation in lyotropic liquid crystals. The experimental observation of the 3etc phase further validates previous theoretical models used to predict its stability, provocatively suggesting that other polycontinuous network phases predicted by these methods may be discovered in the future. While these network phase morphologies are often mathematically described in terms of their underlying triply periodic minimal surfaces (TPMS), the numerous potential applications of these functional nanostructured soft materials require the development of a concise, consistent, and unambiguous nomenclature for their complete description. In this comment, we propose adoption of a nomenclature that describes each mesophase more generally in terms of the total number of non-intersecting domains into which three-dimensional space is partitioned.


Color demosaicing using variance of color differences.
This paper presents an adaptive demosaicing algorithm. Missing green samples are first estimated based on the variances of the color differences along different edge directions. The missing red and blue components are then estimated based on the interpolated green plane. This algorithm can effectively preserve the details in texture regions and, at the same time, it can significantly reduce the color artifacts. As compared with the latest demosaicing algorithms, the proposed algorithm produces the best average demosaicing performance both objectively and subjectively.


Ecological memory of daily carbon exchange across the globe and its importance in drylands.
How do antecedent (past) conditions influence land-carbon dynamics after those conditions no longer persist? In particular, quantifying such memory effects associated with the influence of past environmental (exogenous) and biological (endogenous) conditions is crucial for understanding and predicting the carbon cycle. Here we show, using data from 42 eddy covariance sites across six major biomes, that ecological memory-decomposed into environmental and biological memory components-of daily net carbon exchange (NEE) is critical for understanding the land-carbon metabolism, especially in drylands for which memory explains ~ 32% of the variation in NEE. The strong environmental memory in drylands was primarily driven by short- and long-term moisture status. Moreover, the strength of environmental memory scales with increasing water stress. This universal scaling relationship, emerging within and among major biomes, suggests a potential adaptive response to water limitation. Our findings underscore the necessity of considering ecological memory in experiments, observations and modelling.


Multiplex immunoassay platforms based on shape-coded poly(ethylene glycol) hydrogel microparticles incorporating acrylic acid.
A suspension protein microarray was developed using shape-coded poly(ethylene glycol) (PEG) hydrogel microparticles for potential applications in multiplex and high-throughput immunoassays. A simple photopatterning process produced various shapes of hydrogel micropatterns that were weakly bound to poly(dimethylsiloxane) (PDMS)-coated substrates. These micropatterns were easily detached from substrates during the washing process and were collected as non-spherical microparticles. Acrylic acids were incorporated into hydrogels, which could covalently immobilize proteins onto their surfaces due to the presence of carboxyl groups. The amount of immobilized protein increased with the amount of acrylic acid due to more available carboxyl groups. Saturation was reached at 25% v/v of acrylic acid. Immunoassays with IgG and IgM immobilized onto hydrogel microparticles were successfully performed with a linear concentration range from 0 to 500 ng/mL of anti-IgG and anti-IgM, respectively. Finally, a mixture of two different shapes of hydrogel microparticles immobilizing IgG (circle) and IgM (square) was prepared and it was demonstrated that simultaneous detection of two different target proteins was possible without cross-talk using same fluorescence indicator because each immunoassay was easily identified by the shapes of hydrogel microparticles.


Prediction and control of brucellosis transmission of dairy cattle in Zhejiang Province, China.
Brucellosis is a bacterial disease caused by brucella; mainly spread by direct contact transmission through the brucella carriers, or indirect contact transmission by the environment containing large quantities of bacteria discharged by the infected individuals. At the beginning of 21st century, the epidemic among dairy cows in Zhejiang province, began to come back and has become a localized prevalent epidemic. Combining the pathology of brucellosis, the reported positive data characteristics, and the feeding method in Zhejiang province, this paper establishes an SEIV dynamic model to excavate the internal transmission dynamics, fit the real disease situation, predict brucellosis tendency and assess control measures in dairy cows. By careful analysis, we give some quantitative results as follows. (1) The external input of dairy cows from northern areas may lead to high fluctuation of the number of the infectious cows in Zhejiang province that can reach several hundreds. In this case, the disease cannot be controlled and the infection situation cannot easily be predicted. Thus, this paper encourages cows farms to insist on self-supplying production of the dairy cows. (2) The effect of transmission rate of brucella in environment to dairy cattle on brucellosis spreading is greater than transmission rate of the infectious dairy cattle to susceptible cattle. The prevalence of the epidemic is mainly aroused by environment transmission. (3) Under certain circumstances, the epidemic will become a periodic phenomenon. (4) For Zhejiang province, besides measures that have already been adopted, sterilization times of the infected regions is suggested as twice a week, and should be combined with management of the birth rate of dairy cows to control brucellosis spread.


A retrospective analysis of trabectedin infusion by peripherally inserted central venous catheters: a multicentric Italian experience.
The European Medicines Agency strongly recommends administration of trabectedin through a central venous catheter (CVC) to minimize the risk of extravasation. However, CVCs place patients at risk of catheter-related complications and have a significant budgetary impact for oncology departments. The most frequently used CVCs are subcutaneously implanted PORT-chamber catheters (PORTs); peripherally inserted central venous catheters (PICCs) are relatively new. We reviewed data of trabectedin-treated patients to evaluate the relative cost-effectiveness of the use of PORTs and PICCs in six Italian centres. Data on 102 trabectedin-treated patients (20 with sarcoma, 80 with ovarian cancer and two with cervical cancer) were evaluated. Forty-five patients received trabectedin by a PICC, inserted by trained nurses using an ultrasound-guided technique at the bedside, whereas 57 patients received trabectedin infusion by a PORT, requiring a day surgery procedure in the hospital by a surgeon. Device dislocation and infections were reported in four patients, equally distributed between PORT or PICC users. Thrombosis occurred in a single patient with a PORT. Complications requiring devices removal were not reported during any of the 509 cycles of therapy (median 5; range 1-20). PICC misplacement or early malfunctions were not reported during trabectedin infusion. The cost-efficiency ratio favours PORT over PICC only when the device is used for more than 1 year. Our data suggest that trabectedin infusion by PICC is safe and well accepted, with a preferable cost-efficiency ratio compared with PORT in patients requiring short-term use of the device (≤1 year).


The Malmö International Brother Study (MIBS). Genetic defects and inhibitor development in siblings with severe hemophilia A.
The strongest risk factor identified for inhibitor development in people with severe hemophilia A is the type of factor VIII gene mutation. The objective of this study was to evaluate the mutation type dependent concordance rate of inhibitor formation in siblings. The gene defect, treatment and inhibitor history were evaluated in 113 families in which two or more siblings had severe hemophilia A. Seventy-nine of the families (69.9%) were concordant in that either all or none of the siblings had a history of inhibitors. The concordance in 59 families with inhibitors was 42.4%. The corresponding figures for the 74 families with intron 22 inversion were 63.5% and 40.0%, respectively, and the overall concordance within 14 families with nonsense mutations was 78.6%. The siblings in two families with large gene deletions had no inhibitor history. A small proportion of the families with missense mutations, small deletions/insertions and splice site mutations developed inhibitors, but in four of the families two or more siblings developed high-responding inhibitors. In 18 of the 25 concordant families (72.0%) with inhibitors, the inhibitor was also of the same type (high-responding). This is the first study of the association between inhibitor formation and the causative factor VIII gene mutation in siblings. The data show that the type of mutation provides, to some extent, the basis for this relationship, but the mutation itself is not enough to predict the risk for therapy-induced inhibitor formation.


Objective measures of the environment and physical activity--results of the environment and physical activity study in English adults.
Physical activity has been positively associated with a range of objectively measured environmental variables. We explored the relationship of walking and other categories of physical activity with objectively measured activity specific environmental variables in a U.K. population. We used a geographical information system (GIS) and gender specific multivariate models to relate 13,927 participants' reported levels of physical activity with a range of measures of the environment. Access to green space and area levels of crime were not associated with walking for recreation. Distance to facilities had either no or only a small effect on the uptake of different activities. Odds ratios of cycling for leisure dropped as local traffic density increased for both genders. Compared with the lowest quartile for traffic density the likelihood of reporting any cycling for leisure was OR 0.42, (95% CI 0.32 to 0.52, P < .001) for women and OR 0.41, (95% CI 0.33 to 0.50, P < .001) for men in the highest quartile. We were unable to reproduce results observed in previous studies. Future research should use large representative population samples from multiple areas to maximize environmental variability and if feasible use both objective and subjective measures of physical activity and the environment.


Safety, pharmacokinetics, and antimalarial activity of the novel plasmodium eukaryotic translation elongation factor 2 inhibitor M5717: a first-in-human, randomised, placebo-controlled, double-blind, single ascending dose study and volunteer infection study.
M5717 is the first plasmodium translation elongation factor 2 inhibitor to reach clinical development as an antimalarial. We aimed to characterise the safety, pharmacokinetics, and antimalarial activity of M5717 in healthy volunteers. This first-in-human study was a two-part, single-centre clinical trial done in Brisbane, QLD, Australia. Part one was a double-blind, randomised, placebo-controlled, single ascending dose study in which participants were enrolled into one of nine dose cohorts (50, 100, 200, 400, 600, 1000, 1250, 1800, or 2100 mg) and randomly assigned (3:1) to M5717 or placebo. A sentinel dosing strategy was used for each dose cohort whereby two participants (one assigned to M5717 and one assigned to placebo) were initially randomised and dosed. Randomisation schedules were generated electronically by independent, unblinded statisticians. Part two was an open-label, non-randomised volunteer infection study using the Plasmodium falciparum induced blood-stage malaria model in which participants were enrolled into three dose cohorts. Healthy men and women of non-childbearing potential aged 18-55 years were eligible for inclusion; individuals in the volunteer infection study were required to be malaria naive. Safety and tolerability (primary outcome of the single ascending dose study and secondary outcome of the volunteer infection study) were assessed by frequency and severity of adverse events. The pharmacokinetic profile of M5717 was also characterised (primary outcome of the volunteer infection study and secondary outcome of the single ascending dose study). Parasite clearance kinetics (primary outcome of the volunteer infection study) were assessed by the parasite reduction ratio and the corresponding parasite clearance half-life; the incidence of recrudescence up to day 28 was determined (secondary outcome of the volunteer infection study). Recrudescent parasites were tested for genetic mutations (exploratory outcome). The trial is registered with ClinicalTrials.gov (NCT03261401). Between Aug 28, 2017, and June 14, 2019, 221 individuals were assessed for eligibility, of whom 66 men were enrolled in the single ascending dose study (eight per cohort for 50-1800 mg cohorts, randomised three M5717 to one placebo, and two in the 2100 mg cohort, randomised one M5717 to one placebo) and 22 men were enrolled in the volunteer infection study (six in the 150 mg cohort and eight each in the 400 mg and 800 mg cohorts). No adverse event was serious; all M5717-related adverse events were mild or moderate in severity and transient, with increased frequency observed at doses above 1250 mg. In the single ascending dose study, treatment-related adverse events occurred in three of 17 individuals in the placebo group; no individual in the 50 mg, 100 mg, or 200 mg groups; one of six individuals in each of the 400 mg, 1000 mg, and 1250 mg groups; two of six individuals in the 600 mg group; and in all individuals in the 1800 mg and 2100 mg groups. In the volunteer infection study, M5717-related adverse events occurred in no participants in the 150 mg or 800 mg groups and in one of eight participants in the 400 mg group. Transient oral hypoesthesia (in three participants) and blurred vision (in four participants) were observed in the 1800 mg or 2100 mg groups and constituted an unknown risk; thus, further dosing was suspended after dosing of the two sentinel individuals in the 2100 mg cohort. Maximum blood concentrations occurred 1-7 h after dosing, and a long half-life was observed (146-193 h at doses ≥200 mg). Parasite clearance occurred in all participants and was biphasic, characterised by initial slow clearance lasting 35-55 h (half-life 231·1 h [95% CI 40·9 to not reached] for 150 mg, 60·4 h [38·6 to 138·6] for 400 mg, and 24·7 h [20·4 to 31·3] for 800 mg), followed by rapid clearance (half-life 3·5 h [3·1 to 4·0] for 150 mg, 3·9 h [3·3 to 4·8] for 400 mg, and 5·5 h [4·8 to 6·4] for 800 mg). Recrudescence occurred in three (50%) of six individuals dosed with 150 mg and two (25%) of eight individuals dosed with 400 mg. Genetic mutations associated with resistance were detected in four cases of parasite recrudescence (two individuals dosed with 150 mg and two dosed with 400 mg). The safety, pharmacokinetics, and antimalarial activity of M5717 support its development as a component of a single-dose antimalarial combination therapy or for malaria prophylaxis. Wellcome Trust and the healthcare business of Merck KGaA, Darmstadt, Germany.


Optimality approaches to describe characteristic fluvial patterns on landscapes.
Mother Nature has left amazingly regular geomorphic patterns on the Earth's surface. These patterns are often explained as having arisen as a result of some optimal behaviour of natural processes. However, there is little agreement on what is being optimized. As a result, a number of alternatives have been proposed, often with little a priori justification with the argument that successful predictions will lend a posteriori support to the hypothesized optimality principle. Given that maximum entropy production is an optimality principle attempting to predict the microscopic behaviour from a macroscopic characterization, this paper provides a review of similar approaches with the goal of providing a comparison and contrast between them to enable synthesis. While assumptions of optimal behaviour approach a system from a macroscopic viewpoint, process-based formulations attempt to resolve the mechanistic details whose interactions lead to the system level functions. Using observed optimality trends may help simplify problem formulation at appropriate levels of scale of interest. However, for such an approach to be successful, we suggest that optimality approaches should be formulated at a broader level of environmental systems' viewpoint, i.e. incorporating the dynamic nature of environmental variables and complex feedback mechanisms between fluvial and non-fluvial processes.


Fresnel and Fourier hologram generation using orthographic projection images.
A novel technique for synthesizing a hologram of three-dimensional objects from multiple orthographic projection view images is proposed. The three-dimensional objects are captured under incoherent white illumination and their orthographic projection view images are obtained. The orthographic projection view images are multiplied by the corresponding phase terms and integrated to form a Fourier or Fresnel hologram. Using simple manipulation of the orthographic projection view images, it is also possible to shift the three-dimensional objects by an arbitrary amount along the three axes in the reconstruction space or invert their depths with respect to the given depth plane. The principle is verified experimentally.


Tailoring the water structure and transport in nanotubes with tunable interiors.
Self-assembly of cyclic peptide nanotubes (CPNs) in polymer thin films has opened up the possibility of creating separation membranes with tunable nanopores that can differentiate molecules at the sub-nanometer level. While it has been demonstrated that the interior chemistry of the CPNs can be tailored by inserting functional groups in the nanopore lumen (mCPNs), a design strategy for picking the chemical modifications that lead to particular transport properties has not been established. Drawing from the knowledgebase of functional groups in natural amino acids, here we use molecular dynamics simulations to elucidate how bioinspired mutations influence the transport of water through mCPNs. We show that, at the nanoscale, factors besides the pore size, such as electrostatic interactions and steric effects, can dramatically change the transport properties. We recognize a novel asymmetric structure of water under nanoconfinement inside the chemically functionalized nanotubes and identify that the small non-polar glycine-mimic groups that minimize the steric constraints and confer a hydrophobic character to the nanotube interior are the fastest transporters of water. Our computationally developed experiments on a realistic material system circumvent synthetic challenges, and lay the foundation for bioinspired principles to tailor artificial nanochannels for separation applications such as desalination, ion-exchange and carbon capture.


Cross sectional observation of the effects of carbon disulphide on the nervous system, endocrine system, and subjective symptoms in rayon manufacturing workers.
A prospective cohort study was initiated to clarify whether the current level of exposure to carbon disulphide (CS2) is low enough to prevent occurrence of subclinical health impairments or to ameliorate health effects due to past high exposure. This paper describes the effects of exposure to CS2 on the nervous and endocrine systems, and the subjective symptoms in a baseline observation. The effects were evaluated of CS2 on the median nerve conduction velocity, neurobehavioural and psychological tests, and subjective symptoms related to solvents in 432 male workers exposed to CS2 and 402 reference workers from 11 rayon factories in Japan. Adjustment was made for potential confounding factors such as age or alcohol drinking. Exposure to CS2 was either dichotomised or categorised into three groups by job type. Reductions were observed in motor (-1.9 m/s) and sensory (-0.91 m/s for orthodromic and -1.1 m/s for antidromic) nerve conduction velocities in the workers exposed to CS2 at the spinning and refining processes. Small but significant increases were found in self rated depression scale score and decrease in digit span (backward) in the workers exposed to CS2. Of 54 subjective symptoms many were increased--namely, heavy feeling in the head, light headedness, fainting after suddenly standing up, tremor, dullness, and increased sensitivity of skin in the extremities, reduced grasping power, reduced sexual desire, and increased rough skin. The endocrinological indicator--the concentration of glycosylated haemoglobin--was also increased in the workers exposed to CS2. Subclinical effects on the nervous system and on glucose metabolism were found in the workers exposed to CS2. One interpretation is that relatively higher exposure to CS2 in the past may induce these, but the effects are still not entirely ameliorated under the current exposure to CS2. Another possibility is that the current exposure to CS2 may cause these positive findings. A follow up observation is necessary to clarify these questions.


Using information communication technology in models of integrated community-based primary health care: learning from the iCOACH case studies.
Information communication technology (ICT) is a critical enabler of integrated models of community-based primary health care; however, little is known about how existing technologies have been used to support new models of integrated care. To address this gap, we draw on data from an international study of integrated models, exploring how ICT is used to support activities of integrated care and the organizational and environmental barriers and enablers to its adoption. We take an embedded comparative multiple-case study approach using data from a study of implementation of nine models of integrated community-based primary health care, the Implementing Integrated Care for Older Adults with Complex Health Needs (iCOACH) study. Six cases from Canada, three each in Ontario and Quebec, and three in New Zealand, were studied. As part of the case studies, interviews were conducted with managers and front-line health care providers from February 2015 to March 2017. A qualitative descriptive approach was used to code data from 137 interviews and generate word tables to guide analysis. Despite different models and contexts, we found strikingly similar accounts of the types of activities supported through ICT systems in each of the cases. ICT systems were used most frequently to support activities like care coordination by inter-professional teams through information sharing. However, providers were limited in their ability to efficiently share patient data due to data access issues across organizational and professional boundaries and due to system functionality limitations, such as a lack of interoperability. Even in innovative models of care, managers and providers in our cases mainly use technology to enable traditional ways of working. Technology limitations prevent more innovative uses of technology that could support disruption necessary to improve care delivery. We argue the barriers to more innovative use of technology are linked to three factors: (1) information access barriers, (2) limited functionality of available technology, and (3) organizational and provider inertia.


Hepatitis C virus coinfection does not influence the CD4 cell recovery in HIV-1-infected patients with maximum virologic suppression.
Conflicting data exist whether hepatitis C virus (HCV) affects the CD4 cell recovery in patients with HIV starting antiretroviral treatment. To investigate the influence of HCV coinfection on the CD4 recovery in patients with maximum virologic suppression within the EuroSIDA cohort. Patients tested for anti-HCV antibodies and with at least 2 consecutive HIV viral loads (VLs) <50 copies per milliliter after starting combination antiretroviral therapy were eligible for inclusion. For each pair of VL <50 copies per milliliter, the annual change in CD4 count was calculated and compared between (1) HCV-seronegative vs. HCV-seropositive patients, (2) HCV genotypes 1-4 in HCV-RNA+ patients, and (3) viremic vs. aviremic (HCV-RNA < 615 IU/mL) in HCV-seropositive patients. Results were adjusted for known confounders. Four thousand two hundred eight patients were included, representing 39,474 pairs of HIV VL measurements with VL <50 copies per milliliter and 12,492 person-years of follow-up. The unadjusted annual change in CD4 count for HCV-seropositive and HCV-seronegative patients was 35.5 cells per milliliter (95% confidence interval 27.2 to 43.9) and 38.3 cells per milliliter (95%confidence interval 34.8 to 41.9), respectively. After adjustment, there was no difference in CD4 change when comparing, according to HCV serostatus (P = 0.17), between genotypes (P = 0.23) or when comparing HCV viremic vs. aviremic patients (P = 0.57). Adjusting additionally for HCV treatment and HCV-RNA VL did not change the findings. HCV serostatus did not influence the CD4 recovery in patients with HIV with maximum virologic suppression after starting combination antiretroviral therapy. Furthermore, no difference in CD4 gain was found when comparing distinct HCV genotypes in HCV-RNA+ patients or when comparing HCV viremic vs. aviremic HCV-seropositive patients.


Structural modeling of an outer membrane electron conduit from a metal-reducing bacterium suggests electron transfer via periplasmic redox partners.
Many subsurface microorganisms couple their metabolism to the reduction or oxidation of extracellular substrates. For example, anaerobic mineral-respiring bacteria can use external metal oxides as terminal electron acceptors during respiration. Porin-cytochrome complexes facilitate the movement of electrons generated through intracellular catabolic processes across the bacterial outer membrane to these terminal electron acceptors. In the mineral-reducing model bacterium Shewanella oneidensis MR-1, this complex is composed of two decaheme cytochromes (MtrA and MtrC) and an outer-membrane β-barrel (MtrB). However, the structures and mechanisms by which porin-cytochrome complexes transfer electrons are unknown. Here, we used small-angle neutron scattering (SANS) to study the molecular structure of the transmembrane complexes MtrAB and MtrCAB. Ab initio modeling of the scattering data yielded a molecular envelope with dimensions of ∼105 × 60 × 35 Å for MtrAB and ∼170 × 60 × 45 Å for MtrCAB. The shapes of these molecular envelopes suggested that MtrC interacts with the surface of MtrAB, extending ∼70 Å from the membrane surface and allowing the terminal hemes to interact with both MtrAB and an extracellular acceptor. The data also reveal that MtrA fully extends through the length of MtrB, with ∼30 Å being exposed into the periplasm. Proteoliposome models containing membrane-associated MtrCAB and internalized small tetraheme cytochrome (STC) indicate that MtrCAB could reduce Fe(III) citrate with STC as an electron donor, disclosing a direct interaction between MtrCAB and STC. Taken together, both structural and proteoliposome experiments support porin-cytochrome-mediated electron transfer via periplasmic cytochromes such as STC.


Binocular interaction: contrast matching and contrast discrimination are predicted by the same model.
How do signals from the 2 eyes combine and interact? Our recent work has challenged earlier schemes in which monocular contrast signals are subject to square-law transduction followed by summation across eyes and binocular gain control. Much more successful was a new 'two-stage' model in which the initial transducer was almost linear and contrast gain control occurred both pre- and post-binocular summation. Here we extend that work by: (i) exploring the two-dimensional stimulus space (defined by left- and right-eye contrasts) more thoroughly, and (ii) performing contrast discrimination and contrast matching tasks for the same stimuli. Twenty-five base-stimuli made from 1 c/deg patches of horizontal grating, were defined by the factorial combination of 5 contrasts for the left eye (0.3-32%) with five contrasts for the right eye (0.3-32%). Other than in contrast, the gratings in the two eyes were identical. In a 2IFC discrimination task, the base-stimuli were masks (pedestals), where the contrast increment was presented to one eye only. In a matching task, the base-stimuli were standards to which observers matched the contrast of either a monocular or binocular test grating. In the model, discrimination depends on the local gradient of the observer's internal contrast-response function, while matching equates the magnitude (rather than gradient) of response to the test and standard. With all model parameters fixed by previous work, the two-stage model successfully predicted both the discrimination and the matching data and was much more successful than linear or quadratic binocular summation models. These results show that performance measures and perception (contrast discrimination and contrast matching) can be understood in the same theoretical framework for binocular contrast vision.


The UvsY protein of bacteriophage T4 modulates recombination-dependent DNA synthesis in vitro.
An in vitro system containing the T4 gene 43, 45, 44/62, 32, dda, and uvsX proteins catalyzes DNA synthesis that is dependent on the synapsis step of homologous genetic recombination. The rate of DNA synthesis in this system is highly dependent on the concentration of the uvsX recombinase (a recA-like protein). Here we report the effect of the T4 uvsY protein, a recombination accessory protein, on this reaction. Low concentrations of uvsY protein greatly stimulate DNA synthesis at low concentrations of uvsX protein, but these same concentrations inhibit DNA synthesis at high concentrations of uvsX protein. As a result, the addition of small amounts of uvsY protein lowers the minimum concentration of uvsX protein needed for the reaction 8-fold, and it lowers the uvsX protein concentration for maximum activity 4-fold. The uvsY protein can affect either the initiation or elongation phase of DNA synthesis, depending on the concentration of uvsX protein present. The implications of these results for the function of the uvsY protein in T4 DNA replication in vivo are discussed.


PTEN Inhibition Facilitates Diabetic Corneal Epithelial Regeneration by Reactivating Akt Signaling Pathway.
To investigate the contribution of phosphatase and tensin homologue (PTEN) on the delayed epithelial regeneration and impaired Akt activation in diabetic mice. The expression of PTEN on cornea was compared between normal and diabetic mice. The corneal epithelial and nerve regeneration rate was evaluated in diabetic mice after the treatment with PTEN small interfering RNA (siRNA), PTEN inhibitors, or Akt inhibitor. The reactivation of epithelial regeneration-related signaling, including phosphorylated (p)-Akt, p-Stat3, Sirt1, and Parkin, were assessed with Western blot and immunofluorescence staining. The effects of PTEN inhibition on cellular proliferation and migration were further evaluated in cultured mouse corneal epithelial cells. PTEN messenger RNA and protein levels exhibited up-regulation in diabetic cornea. Upon central epithelial debridement, the epithelial regeneration rate was significantly promoted in diabetic mice with the treatment of PTEN inhibition than that of vehicle control (P < 0.05), which accompanied with the recovered levels of p-Akt, p-Stat3, Sirt1, and Parkin. However, the promotion of diabetic corneal epithelial regeneration rate and Akt reactivation was completed reversed by Akt inhibitor. In vitro, PTEN inhibition promoted their migration, but not the proliferation capacity. In addition, PTEN inhibitor treatment also improved the recovery of corneal nerve fiber density and sensitivity that was impaired in diabetic mice. Elevated PTEN expression contributes to the impaired corneal epithelial regeneration and Akt activation in diabetic mice, which can be improved with PTEN inhibition. Our study suggests that PTEN inhibition may serve as a new strategy for restoring the impaired corneal epithelial regeneration ability in patients with diabetes.


Unsupervised Local Feature Hashing for Image Similarity Search.
The potential value of hashing techniques has led to it becoming one of the most active research areas in computer vision and multimedia. However, most existing hashing methods for image search and retrieval are based on global feature representations, which are susceptible to image variations such as viewpoint changes and background cluttering. Traditional global representations gather local features directly to output a single vector without the analysis of the intrinsic geometric property of local features. In this paper, we propose a novel unsupervised hashing method called unsupervised bilinear local hashing (UBLH) for projecting local feature descriptors from a high-dimensional feature space to a lower-dimensional Hamming space via compact bilinear projections rather than a single large projection matrix. UBLH takes the matrix expression of local features as input and preserves the feature-to-feature and image-to-image structures of local features simultaneously. Experimental results on challenging data sets including Caltech-256, SUN397, and Flickr 1M demonstrate the superiority of UBLH compared with state-of-the-art hashing methods.