Trapping dynamics in nonlinear wave scattering by local guiding defects.
We study numerically the trapping dynamics of nonlinear waves scattered by local guiding photonic centers with normal eigenmodes which are embedded in uniform nonlinear Kerr waveguides. The linear and nonlinear scattering from a local defect may be treated from either a wave optics approach or a ray optics approach. The former provides a better understanding of the wave dynamics while the latter enables one to perform quasi-analytical estimates of the extent of trapping in a given structure. In the presence of a single-site multi-mode local scattering center, power may localize in a certain normal mode of the center, or periodically oscillate between different normal modes. The degree of trapping and mode of localization can be controlled as function of both the input power and the angle of incidence. With multi-site local scattering centers, the trapping dynamics are strongly dependent on the degree of coupling between the neighboring sites. In the scattering by a local multi-site defect with strongly coupled adjacent sites, two possibilities for nonlinear trapping arise. At intermediate nonlinear powers, periodic tunneling of power between adjacent sites and their normal modes is observed. At highly nonlinear powers, but still within experimental feasibility, the radiation can become strongly localized in a single site. The scattering and trapping dynamics are also described in the context of nonlinear Fabry-Perot etalons, as a function of the local defect's refractive index.


Crystal structures of DntR inducer binding domains in complex with salicylate offer insights into the activation of LysR-type transcriptional regulators.
Activation of LysR-type transcription factors (LTTRs) is thought to result from conformational changes that occur when inducer molecules bind to their Inducer Binding Domains (IBDs). However, the exact nature of these changes remains to be fully elucidated. We present the crystal structures of two truncated constructs of the LTTR DntR in their apo- forms and in complex with its natural inducer molecule, salicylate. These provide a fuller picture of the conformational changes that can occur in LTTR IBDs and offer insights that may be relevant when considering the mechanism of activation of LTTRs. Two of the crystal structures show that DntR IBDs can bind up to two inducer molecules. The full extent of conformational changes observed is achieved only when inducer molecules are bound in both binding sites identified. Point mutations disrupting the putative secondary binding site produce DntR variants with a reduced response to salicylate in a whole cell system, suggesting that this site is functionally relevant.


Skeletal diversity in Pt- and Au-catalyzed annulations of allenedienes: dissecting unconventional mechanistic pathways.
We describe the discovery of unprecedented annulation processes of 1,7-allenedienes, promoted by Pt or Au catalysts. These transformations revealed mechanistic pathways that had not been previously observed in reactions involving carbophilic catalysis. In particular, we have found that allenedienes bearing a silyl ether in the carbon tether connecting the diene and the allene divergently afford cyclopropane-embedded tricyclic derivatives, 6,6-fused bicarbocyclic products or 5,6-fused bicarbocyclic systems, depending on the type of Au or Pt catalyst used. We have carried out experimental and computational studies that shed light on the mechanistic reasons behind this rich and unusual skeletal divergence, and provide new lessons on the drastic influence of platinum ancillary ligands on the reaction outcome.


An overview of the NCI precision medicine trials-NCI MATCH and MPACT.
The concept of oncogene addiction was first proposed by Weinstein in 2002, postulating that tumors rely on a single dominant mutation, the oncogenic "driver", for growth and survival. We have since come to realize that the genomic landscape of tumors is heterogeneous and more complex than previously thought. Advances in biotechnology and bioinformatics over the past decade have shifted treatment paradigms with regard to the development of molecular targeted therapeutics to identify and target the presumptive dominant lesion. As such, the decision of choosing targeted treatment strategies has become increasingly more reliant on the reporting of genomic screens of patients' tumor tissue. Whether this change in treatment paradigm will translate into improved clinical benefit, remains to be seen. To this end, the United States National Cancer Institute (NCI) has launched precision-based medicine trials to address this question. NCI Molecular Analysis for Therapy Choice (MATCH), a genomic pre-screening study, was designed to explore the efficacy of using targeted agents to target specific molecular aberrations and whether these same therapies have comparable activity across different tumor subtypes. Molecular Profiling-based Assignment of Cancer Therapy (MPACT), is a smaller, provocative trial designed to address whether targeting an oncogenic "driver" would be more efficacious than one not. The Exceptional Responders' initiative further aims to evaluate patients who have derived an unexpected durable benefit to these therapies, with retrospective analysis of their tumors to delineate potential predictive biomarkers which could predict response. The results of these trials will serve to help guide the field of precision medicine and personalized care.


The neurosteroid allopregnanolone protects retinal neurons by effects on autophagy and GABRs/GABAA receptors in rat glaucoma models.
In an ex vivo rat glaucoma model using dissected retinas, the neurosteroid allopregnanolone (AlloP) protects retinal ganglion cells (RGCs) via GABR/GABAA receptors. To determine the involvement of macroautophagy/autophagy in neuroprotection by AlloP, we examined the effects of autophagy activators, rapamycin and torin 2, and autophagy inhibitors, bafilomycin A1 and SAR405, on retinal retinal morphology and expression of MAP1 LC3B/LC3B (microtubule-associated protein 1 light chain 3 beta) and SQSTM1 (sequestosome 1). Administration of rapamycin or torin 2 exerted partial histological neuroprotection, while combined administration of AlloP with bafilomycin A1 or SAR405 induced severe degeneration in a hyperbaric condition. Electron microscopic analyses showed that the addition of AlloP significantly increased autophagosomes and degenerative autophagic vacuoles in the retinal nerve fiber layer. Immunoblotting showed that the addition of AlloP or autophagic activators increased the lipidated form of LC3B (LC3B-II) and suppressed SQSTM1. Moreover, bafilomycin A1 increased LC3B-II and SQSTM1 protein levels in the presence of AlloP without changes in corresponding mRNAs compared to AlloP-treated retinas in a hyperbaric condition. These data indicate that AlloP likely induces a protective form of autophagy in this model. In an in vivo rat model of glaucoma, we also observed neuroprotective effects of AlloP. Injection of polystyrene microbeads into the anterior chamber increased intraocular pressure about 3-fold and induced RGC apoptosis. A single intravitreal injection of AlloP or autophagy activators prevented apoptosis and protected RGCs with autophagy activation. We conclude that AlloP may serve as a potential therapeutic agent for the treatment of glaucoma via diverse mechanisms.Abbreviations: 2HBCD: 2-Hydroxypropyl)-β-cyclodextrin; 3-MA: 3-methyladenine; AlloP: allopregnanolone; AP: autophagosome; AVd: degradative autophagic vacuoles; GCL: ganglion cell layer; INL: inner nuclear layer; IOP: intraocular pressure; IPL: inner plexiform layer; LC3B-I: cytosolic form of LC3B; LCB-II: lipidated form of LC3B; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; mPTP: mitochondrial permeability transition pore; NDS: neuronal damage score; NFL: nerve fiber layer; OH: ocular hypertension; ON: optic nerve; ONL: outer nuclear layer; OPL: outer plexiform layer; p-STR: scotopic threshold response; RGC: retinal ganglion cells; RT-PCR: real-time reverse transcription polymerase chain reaction; SQSTM1: sequestosome 1; TUNEL: TdT-mediated dUTP Nick End Labeling.


Distributed fiber strain and vibration sensor based on Brillouin optical time-domain reflectometry and polarization optical time-domain reflectometry.
A distributed fiber strain and vibration sensor which effectively combines Brillouin optical time-domain reflectometry and polarization optical time-domain reflectometry is proposed. Two reference beams with orthogonal polarization states are, respectively, used to perform the measurement. By using the signal obtained from either reference beam, the vibration of fiber can be measured from the polarization effect. After combining the signals obtained by both reference beams, the strain can be measured from the Brillouin effect. In the experiment, 10 m spatial resolution, 0.6 kHz frequency measurement range, 2.5 Hz frequency resolution, and 0.2 MHz uncertainty of Brillouin frequency measurement are realized for a 4 km sensing distance.


Complex absorbing potentials within EOM-CC family of methods: theory, implementation, and benchmarks.
A production-level implementation of equation-of-motion coupled-cluster singles and doubles (EOM-CCSD) for electron attachment and excitation energies augmented by a complex absorbing potential (CAP) is presented. The new method enables the treatment of metastable states within the EOM-CC formalism in a similar manner as bound states. The numeric performance of the method and the sensitivity of resonance positions and lifetimes to the CAP parameters and the choice of one-electron basis set are investigated. A protocol for studying molecular shape resonances based on the use of standard basis sets and a universal criterion for choosing the CAP parameters are presented. Our results for a variety of π(*) shape resonances of small to medium-size molecules demonstrate that CAP-augmented EOM-CCSD is competitive relative to other theoretical approaches for the treatment of resonances and is often able to reproduce experimental results.


Controlled ovarian hyperstimulation and intrauterine insemination cycles in patients with unilateral tubal blockage diagnosed by hysterosalpingography.
Controlled ovarian hyperstimulation and intrauterine insemination (IUI) cycle is an ideal protocol for some subfertile patients. So, we decided to try this therapeutic protocol for the patients with unilateral tubal blockage diagnosed by hysterosalpingography (HSG). To evaluate the effect of unilateral tubal blockage diagnosed by HSG on cumulative pregnancy rate (CPR) of the stimulated IUI cycles. A cross-sectional analysis was performed between October 2006 and October 2009 in an academic reproductive endocrinology and infertility center. Two groups of patients undergoing stimulated IUI cycles were compared. Sixty-four infertile couples with unilateral tubal blockage diagnosed by HSG as the sole cause of infertility in the group (І), and two hundred couples with unexplained infertility in the group (II). The patients underwent 3 consecutive ovarian hyperstimulation (Clomiphen citrate and human menopausal gonadotropin) and IUI cycles. The main outcome measurements were the CPRs per patients for 3 consecutive stimulated IUI cycles. Cycle characteristics were found to be homogenous between the both groups. CPRs were similar in group І (26.6%) and group II (28%) (p=0.87; OR=1.075; 95% CI: 0.57 -2.28). Unilateral tubal blockage (diagnosed on HSG) has no effect on success rate of stimulated IUI cycles, so COH and IUI could be recommended as the initial therapeutic protocol in these patients.


Altered dynamics of the circadian relationship between systemic arterial pressure and cardiac sympathetic drive early on in mild hypertension.
1. This study was designed to test the hypothesis that simultaneous non-invasive assessment of the circadian variations in both intermittent arterial pressure and the continuous 24 h changes of spectral markers of cardiac neural control could provide new information on cardiovascular regulatory mechanisms, in hypertensive patients and normotensive subjects. To test this hypothesis we studied 18 subjects with mild hypertension and 11 normotensive subjects in whom we recorded simultaneously non-invasive intermittent arterial pressure and Holter electrocardiogram for 24 h. We also studied the same subjects during resting and standing conditions in the clinical laboratory. 2. The normalized power of the low-frequency (approximately 0.1 Hz) spectral component of R-R interval variability, considered mainly a marker of sympathetic drive to the sino-atrial node, was, at rest, significantly higher in the hypertensive than in the normotensive subjects, as already reported. Moreover, the values of the low-frequency component at rest recorded in the clinical laboratory were significantly correlated with those obtained from ambulatory recording during night rest. The decrease in the values of arterial pressure during the night-time was accompanied by a reduction in the power of the low-frequency component only in the case of normotensive subjects. Accordingly, the slope of the regression of the low-frequency component as a function of systolic arterial pressure during ambulatory recordings was steep in normotensive subjects and flat in hypertensive subjects.(ABSTRACT TRUNCATED AT 250 WORDS)


Palliative care in Africa since 2005: good progress, but much further to go.
There has been rapid progress in palliative care in Africa since the World Health Assembly in 2005 which identified palliative care as an urgent humanitarian need. Palliative care is now recognised as a basic human right, and momentum has gathered to translate this into action. From being significantly present in only five countries in 2004, palliative care is now delivered in nearly 50% of African countries. Even so, still less than 5% of people in need currently receive it, and with an estimated 300% increase in the need for palliative care for people with non-communicable diseases over the next 20 years, and with those living with HIV needing more prolonged support, the demand for palliative care will continue to outpace supply. African countries adopting a public health approach and networking together through palliative care associations are beginning to embed and integrate palliative care into health systems and communities. Current challenges are to increase coverage while maintaining quality, to develop dynamic and flexible responses to the changing illness patterns in Africa, and to counter false beliefs. Resourcefulness and harnessing new technologies such as mobile phones while respecting cultural traditions, may be the way forward. The authors review recent progress in policy, service provision and training initiatives in Africa, illustrate the current situation at grass roots level from a recent evaluation of programmes in Kenya, Malawi and Uganda, analyse the current urgent challenges and suggest some ways ahead.


Fungiculture or Termite Husbandry? The Ruminant Hypothesis.
We present a new perspective for the role of Termitomyces fungi in the mutualism with fungus-growing termites. According to the predominant view, this mutualism is as an example of agriculture with termites as farmers of a domesticated fungus crop, which is used for degradation of plant-material and production of fungal biomass. However, a detailed study of the literature indicates that the termites might as well be envisioned as domesticates of the fungus. According to the "ruminant hypothesis" proposed here, termite workers, by consuming asexual fruiting bodies not only harvest asexual spores, but also lignocellulolytic enzymes, which they mix with foraged plant material and enzymes of termite and possibly bacterial origin. This mixture is the building material of the fungus garden and facilitates efficient degradation of plant material. The fungus garden thus functions as an external rumen for termites and primarily the fungi themselves benefit from their own, and gut-derived, lignocellulolytic enzymes, using the termites to efficiently mix these with their growth substrate. Only secondarily the termites benefit, when they consume the degraded, nitrogen-enriched plant-fungus mixture a second time. We propose that the details of substrate use, and the degree of complementarity and redundancy among enzymes in food processing, determine selection of horizontally transmitted fungal symbionts at the start of a colony: by testing spores on a specific, mechanically and enzymatically pre-treated growth substrate, the termite host has the opportunity to select specific fungal symbionts. Potentially, the gut-microbiota thus influence host-fungus specificity, and the selection of specific fungal strains at the start of a new colony. We argue that we need to expand the current bipartite insect-biased view of the mutualism of fungus-growing termites and include the possible role of bacteria and the benefit for the fungi to fully understand the division of labor among partners in substrate degradation.


Prognostic value of p53, proliferating cell nuclear antigen, and Ki-67 expression in undifferentiated nasopharyngeal carcinomas.
In this study the prognostic importance of p53, proliferating cell nuclear antigen (PCNA), and Ki-67 expression was analyzed along with the clinical parameters in 35 consecutive patients with undifferentiated nasopharyngeal carcinomas. Immunohistochemistry was used to detect p53, PCNA, and Ki-67 staining. Among the clinical findings, stage IV disease (P = 0.01), cranial nerve paralysis (P = 0.02), and lymph node metastasis (P = 0.06) were associated with shorter survival. The p53 positivity correlated with the presence of lymph nodes, but it was not a significant factor to predict the outcome. PCNA expression was not found to be a prognostic indicator. On the other hand, the proliferative value of Ki-67 staining was suggestive of prognosis. A proliferation index of Ki-67 less than 10% indicated longer survival (P = 0.03). There was no correlation between Ki-67 staining and PCNA index. As a result, the prognostic value of Ki-67 may alert the physician to more aggressive and adjuvant treatment modalities.


Four Experiments on the Perception of Bar Charts.
Bar charts are one of the most common visualization types. In a classic graphical perception paper, Cleveland & McGill studied how different bar chart designs impact the accuracy with which viewers can complete simple perceptual tasks. They found that people perform substantially worse on stacked bar charts than on aligned bar charts, and that comparisons between adjacent bars are more accurate than between widely separated bars. However, the study did not explore why these differences occur. In this paper, we describe a series of follow-up experiments to further explore and explain their results. While our results generally confirm Cleveland & McGill's ranking of various bar chart configurations, we provide additional insight into the bar chart reading task and the sources of participants' errors. We use our results to propose new hypotheses on the perception of bar charts.


Informant-based hearing difficulties and the risk for mild cognitive impairment and dementia.
hearing loss has been associated with mild cognitive impairment (MCI) and dementia. Studies have not assessed whether hearing difficulties (HD) that interfere with daily activities as reported by partners can be a marker for increased risk for cognitive decline and impairment. to assess the cross-sectional and longitudinal associations between informant-based HD, which interfere with daily activities and the risk for MCI and dementia. the study included 4812 participants without dementia, enrolled in the Mayo Clinic Study of Aging (mean age (SD) 73.7 (9.6) years) with cognitive evaluation and informant-based report on participant's HD that interfere significantly with daily activities at baseline and for every 15 months. Cox proportional hazards models (utilising time-dependent HD status and age as the time scale) were used to examine HD and the risk for MCI or dementia, and mixed-effects models (allowing for random subject-specific intercepts and slopes) were used to examine the relationship between HD and cognitive decline. about, 981 participants had HD and 612 (12.7%) had prevalent MCI at baseline; 759 participants developed incident MCI and 273 developed incident dementia. In cognitively unimpaired participants at baseline, those with HD had higher risk for MCI (hazard ratio [HR] = 1.29, 95% confidence interval [CI] (1.10, 1.51), P = 0.002; adjusting for sex, years of education). In participants without dementia, those with HD had higher risk for dementia (HR: 1.39, 95% CI, (1.08-1.79), P = 0.011; adjusting sex and education). In individuals with MCI, HD was associated with modestly greater cognitive decline. informant-based HD was associated with increased risk for MCI and dementia.


Transfection of human pancreatic islets with an anti-apoptotic gene (bcl-2) protects beta-cells from cytokine-induced destruction.
Apoptosis has been identified as a mechanism of pancreatic islet beta-cell death in autoimmune diabetes. Proinflammatory cytokines are candidate mediators of beta-cell death in autoimmune diabetes, and these cytokines can induce beta-cell death by apoptosis. In the present study, we examined whether transfection of human islet beta-cells with an anti-apoptotic gene, bcl-2, can prevent cytokine-induced beta-cell destruction. Human islet beta-cells were transfected by a replication-defective herpes simplex virus (HSV) amplicon vector that expressed the bcl-2 gene (HSVbcl-2) and, as a control, the same HSV vector that expressed a beta-galactosidase reporter gene (HSVlac). Two-color immunohistochemical staining revealed that 95+/-3% of beta-cells transfected with HSVbcl-2 expressed Bcl-2 protein compared with 14+/-3% of beta-cells transfected with HSVlac and 19+/-4% of nontransfected beta-cells. The bcl-2-transfected beta-cells were fully protected from impaired insulin secretion and destruction resulting from incubation for 5 days with the cytokine combination of interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma. In addition, the bcl-2-transfected islet cells were significantly protected from cytokine-induced lipid peroxidation and DNA fragmentation. These results demonstrate that cytokine-induced beta-cell dysfunction and death involve mechanisms subject to regulation by an anti-apoptotic protein, Bcl-2. Therefore, bcl-2 gene therapy has the potential to protect human beta-cells in pancreatic islets, or islet grafts, from immune-mediated damage in type 1 diabetes.


Bauhinia purpurea--a new paraffin section marker for Reed-Sternberg cells of Hodgkin's disease. A comparison with Leu-M1 (CD15), LN2 (CD74), peanut agglutinin, and Ber-H2 (CD30).
Thirty-three cases of Hodgkin's disease (thirteen nodular sclerosis, four diffuse, lymphocyte predominance, and sixteen mixed cellularity) were studied with Bauhinia purpurea (BPA), peanut agglutinin (PNA), anti-Leu-M1, LN2, and Ber-H2 by the avidinbiotin-peroxidase complex (ABC) method in paraffin sections. Reed-Sternberg (RS) cells and variants were stained positively with one or more of the reagents in all cases. BPA staining was positive in 32 of 33 cases (97.0%), PNA staining was positive in 23 of 33 cases (69.7%), Leu-M1 was positive in 13 of 33 cases (39.4%), LN2 was positive in 14 of 33 cases (42.4%), and Ber-H2 was positive in 24 of 33 cases (72.7%). Many RS cells were stained moderately to strongly and were readily recognized in 31 cases (96.9%) of BPA+, 10 (43.5%) of PNA+, 8 (61.5%) of Leu-M1+, 6 (42.9%) of LN2+, and 22 (91.7%) of Ber-H2+ cases; in the remaining positive cases, the RS cells were found only after careful searching. Three staining patterns were recognized: paranuclear, diffuse cytoplasmic, and membranous. These three patterns were obtained with all markers except for LN2. LN2 showed diffuse cytoplasmic staining in most of the positive cells, and a few cells showed paranuclear deposits. BPA reactivity was not affected by formalin fixation or paraffin embedding. Except for RS cells, BPA also showed dense cytoplasmic staining reaction with macrophage-histiocytes. Sixty cases of non-Hodgkin's diffuse lymphomas (30 T- and 30 B-cell origin) were also studied. Tumor cells were not stained with BPA, PNA, and Leu-M1, but stained positively with LN2 in six T-cell lymphomas and thirteen B-cell lymphomas, and with Ber-H2 in six T-cell lymphomas and one B-cell lymphoma. In conclusion, to facilitate the detection of RS cells and related variants in paraffin sections, BPA can be accepted as a useful marker due to its high-detection rate, reproducible staining pattern, and resistance to fixatives.


Transcriptome profiling of archived sectioned formalin-fixed paraffin-embedded (AS-FFPE) tissue for disease classification.
Archived tissues from previously completed prospective trials represent invaluable resource for biomarker development. However, such specimens are often stored as sections on glass slides, in which RNA is severely degraded due to prolonged air exposure. We evaluated whether a proportion of archived sectioned formalin-fixed paraffin-embedded (AS-FFPE) tissues yield transcriptome profiles comparable to freshly cut (FC) FFPE tissues, which can be used for retrospective class prediction analysis. Genome-wide transcriptome profiles of 6 to 7-year-old AS-FFPE tissue sections (generated from 5 to 16-year-old blocks) of 83 hepatocellular carcinoma (HCC) and 47 liver cirrhosis samples were generated by using whole-genome DASL assay (Illumina) and digital transcript counting (nCounter) assay (NanoString), and gene signature-based prediction of HCC subclasses and prognosis was compared with previously generated FC-FFPE profiles from the same tissue blocks. RNA quality and assay reproducibility of AS-FFPE RNA were comparable to intermediate to poor quality FC-FFPE samples (RNA Integrity Number: up to 2.50, R-square for technical replicates: up to 0.93). Analyzable transcriptome profiles were obtained in 64 (77%) HCC and 36 (77%) cirrhosis samples. Statistically more confident predictions based on random resampling-based method (nearest template prediction) were obtained in 37 (58%) HCC and 13 (36%) cirrhosis samples. Predictions made in FC-FFPE profiles were reproduced in 36 (97%) HCC and 11 (85%) cirrhosis AS-FFPE profiles. nCounter assay was tested in 24 cirrhosis samples, which yielded confident prediction in 15 samples (63%), of which 10 samples (67%) showed concordant predictions with FC-FFPE profiles. AS-FFPE tissues yielded poorer quality RNA and transcriptome profiles compared to FC-FFPE tissues. Statistically more confident class prediction was feasible in 37 of 83 HCC samples and 13 of 47 cirrhosis samples. These results suggest that AS-FFPE tissues can be regarded as a resource for retrospective transcriptome-based class prediction analysis when they are the only available materials.


Ordered dephosphorylation initiated by the selective proteolysis of cyclin B drives mitotic exit.
APC/C-mediated proteolysis of cyclin B and securin promotes anaphase entry, inactivating CDK1 and permitting chromosome segregation, respectively. Reduction of CDK1 activity relieves inhibition of the CDK1-counteracting phosphatases PP1 and PP2A-B55, allowing wide-spread dephosphorylation of substrates. Meanwhile, continued APC/C activity promotes proteolysis of other mitotic regulators. Together, these activities orchestrate a complex series of events during mitotic exit. However, the relative importance of regulated proteolysis and dephosphorylation in dictating the order and timing of these events remains unclear. Using high temporal-resolution proteomics, we compare the relative extent of proteolysis and protein dephosphorylation. This reveals highly-selective rapid proteolysis of cyclin B, securin and geminin at the metaphase-anaphase transition, followed by slow proteolysis of other substrates. Dephosphorylation requires APC/C-dependent destruction of cyclin B and was resolved into PP1-dependent categories with unique sequence motifs. We conclude that dephosphorylation initiated by selective proteolysis of cyclin B drives the bulk of changes observed during mitotic exit.


Improved and standardized method for assessing years lived with disability after burns and its application to estimate the non-fatal burden of disease of burn injuries in Australia, New Zealand and the Netherlands.
Burden of disease estimates are an important resource in public health. Currently, robust estimates are not available for the burn population. Our objectives are to adapt a refined methodology (INTEGRIS method) to burns and to apply this new INTEGRIS-burns method to estimate, and compare, the burden of disease of burn injuries in Australia, New Zealand and the Netherlands. Existing European and Western-Australian health-related quality of life (HRQL) datasets were combined to derive disability weights for three homogenous burn injury groups based on percentage total body surface area (%TBSA) burned. Subsequently, incidence data from Australia, New Zealand, and the Netherlands from 2010 to 2017 were used to compute annual non-fatal burden of disease estimates for each of these three countries. Non-fatal burden of disease was measured by years lived with disability (YLD). The combined dataset included 7159 HRQL (EQ-5D-3 L) outcomes from 3401 patients. Disability weights ranged from 0.046 (subgroup < 5% TBSA burned > 24 months post-burn) to 0.497 (subgroup > 20% TBSA burned 0-1 months post-burn). In 2017 the non-fatal burden of disease of burns for the three countries (YLDs/100,000 inhabitants) was 281 for Australia, 279 for New Zealand and 133 for the Netherlands. This project established a method for more precise estimates of the YLDs of burns, as it is the only method adapted to the nature of burn injuries and their recovery. Compared to previous used methods, the INTEGRIS-burns method includes improved disability weights based on severity categorization of burn patients; a better substantiated proportion of patients with lifelong disability based; and, the application of burn specific recovery timeframes. Information derived from the adapted method can be used as input for health decision making at both the national and international level. Future studies should investigate whether the application is valid in low- and middle- income countries.


Prevalence, predictors and perinatal outcomes of peri-conceptional alcohol exposure--retrospective cohort study in an urban obstetric population in Ireland.
Evidence-based advice on alcohol consumption is required for pregnant women and women planning a pregnancy. Our aim was to investigate the prevalence, predictors and perinatal outcomes associated with peri-conceptional alcohol consumption. A cohort study of 61,241 women who booked for antenatal care and delivered in a large urban maternity hospital between 2000 and 2007. Self-reported alcohol consumption at the booking visit was categorised as low (0-5 units per week), moderate (6-20 units per week) and high (>20 units per week). Of the 81% of women who reported alcohol consumption during the peri-conceptional period, 71% reported low intake, 9.9% moderate intake and 0.2% high intake. Factors associated with moderate alcohol consumption included being in employment OR 4.47 (95% CI 4.17 to 4.80), Irish nationality OR 16.5 (95% CI 14.9 to 18.3), private health care OR 5.83 (95% CI 5.38 to 6.31) and smoking OR 1.86 (95% CI 1.73 to 2.01). Factors associated with high consumption included maternal age less than 25 years OR 2.70 (95% CI 1.86 to 3.91) and illicit drug use OR 6.46 (95% CI 3.32 to 12.60). High consumption was associated with very preterm birth (<32 weeks gestation) even after controlling for socio-demographic factors, adjusted OR 3.15 (95% CI 1.26-7.88). Only three cases of Fetal Alcohol Syndrome were recorded (0.05 per 1000 total births), one each in the low, moderate and high consumption groups. Public Health campaigns need to emphasise the importance of peri-conceptional health and pre-pregnancy planning. Fetal Alcohol Syndrome is likely to be under-reported despite the high prevalence of alcohol consumption in this population.


Modulation of MMP-2 and MMP-9 secretion by cytokines, inducers and inhibitors in human glioblastoma T-98G cells.
Brain tumors are highly aggressive, characterized by the secretion of high levels of matrix metalloproteinase (MMP)-2 and MMP-9 that degrade the extracellular matrix and basement membrane, allowing cancer cells to spread to distal organs. Various cytokines, mitogens, growth factors, inducers and inhibitors control MMP activity. We investigated the roles of these in the regulation of MMP-2 and MMP-9 in human glioblastoma T-98G cells. Human T-98G cells were grown in DME supplemented with 15% fetal bovine serum and antibiotics in 24-well tissue culture plates. At near confluence, cells were washed with phosphate-buffered saline and incubated in serum-free media with: phorbol 12-myristate 13-acetate (PMA) at 10, 25, 50 and 100 ng/ml; tumor necrosis factor (TNF)-α and interleukin (IL)-1β at 0.1, 1, 10 and 25 ng/ml; lipopolysaccharide (LPS) at 10, 25, 50 and 100 µg/ml; epigallocatechin gallate (EGCG) and doxycycline (Dox) at 10, 25, 50 and 100 µM without and with PMA; a nutrient mixture (NM) containing lysine, proline, ascorbic acid and green tea extract without and with PMA at 10, 50, 100, 500 and 1,000 µg/ml; actinomycin D and cyclohexamide at 2 and 4 µM; retinoic acid and dexamethasone at 50 µM. After 24 h the media were removed and analyzed for MMP-2 and MMP-9 by zymography and densitometry. Glioblastoma T-98G cells expressed only one band corresponding to MMP-2. PMA treatment showed increased MMP-2 and MMP-9 secretions up to 25 ng/ml and decreased levels of secretions at 50 and 100 ng/ml, with no significant overall effect. TNF-α induced an up and down effect on MMP-2 and a slight induction of MMP-9. IL-1β demonstrated a slight dose-dependent increase in T-98G secretion of MMP-2, but no induction of MMP-9. LPS showed dose-dependent decreased inactive MMP-2 secretion, increased active MMP-2 secretion and no effect on MMP-9. EGCG, Dox and NM, without and with PMA, downregulated the expression of MMP-2 and MMP-9 in a dose-dependent manner. Actinomycin D, cyclohexamide, retinoic acid and dexamethasone also had inhibitory effects on MMP-2. Our results showed that cytokines, mitogens and inhibitors modulated T-98G cell MMP-2 and MMP-9 expression, suggesting the clinical use of MMP inhibitors, particularly such potent and non-toxic ones as the nutrient mixture and its component EGCG in the management of glioblastoma cancers.


Progenitor cell release plus exercise to improve functional performance in peripheral artery disease: the PROPEL Study.
Functional impairment, functional decline, and mobility loss are major public health problems in people with lower extremity peripheral artery disease (PAD). Few medical therapies significantly improve walking performance in PAD. We describe methods for the PROgenitor cell release Plus Exercise to improve functionaL performance in PAD (PROPEL) Study, a randomized controlled clinical trial designed to determine whether granulocyte-macrophage colony stimulating factor (GM-CSF) combined with supervised treadmill walking exercise improves six-minute walk distance more than GM-CSF alone, more than supervised treadmill exercise alone, and more than placebo plus attention control in participants with PAD, respectively. PROPEL Study participants are randomized to one of four arms in a 2 by 2 factorial design. The four study arms are GM-CSF plus supervised treadmill exercise, GM-CSF plus attention control, placebo plus supervised exercise therapy, or placebo plus attention control. The primary outcome is change in six-minute walk distance at 12-week follow-up. Secondary outcomes include change in brachial artery flow-mediated dilation (FMD), change in maximal treadmill walking time, and change in circulating CD34+ cells at 12-week follow-up. Outcomes are also measured at six-week and six-month follow-up. Results of the PROPEL Study will have important implications for understanding mechanisms of improving walking performance and preventing mobility loss in the large and growing number of men and women with PAD.


The rise in health care coverage and affordability since health reform took effect: findings from the Commonwealth Fund Biennial Health Insurance Survey, 2014.
New results from the Commonwealth Fund Biennial Health Insurance Survey, 2014, indicate that the Affordable Care Act's subsidized insurance options and consumer protections reduced the number of uninsured working-age adults from an estimated 37 million people, or 20 percent of the population, in 2010 to 29 million, or 16 percent, by the second half of 2014. Conducted from July to December 2014, for the first time since it began in 2001, the survey finds declines in the number of people who report cost-related access problems and medical-related financial difficulties. The number of adults who did not get needed health care because of cost declined from 80 million people, or 43 percent, in 2012 to 66 million, or 36 percent, in 2014. The number of adults who reported problems paying their medical bills declined from an estimated 75 million people in 2012 to 64 million people in 2014.


Exploring redundant research into the effect of tranexamic acid on surgical bleeding: further analysis of a systematic review of randomised controlled trials.
We examined whether apparent redundancy in a cumulative meta-analysis of trials is justified by concern about bias, random error or generalisability of the results. Cumulative meta-analysis, risk of bias assessment, trial sequential analysis, description of study participants over time and a review of rationales for conducting trials. 126 randomised trials included in a systematic review assessing of tranexamic acid on blood transfusion in surgery. The cumulative meta-analysis including all trials shows that the pooled estimate first reached statistical significance after the second trial in 1993. When the analysis was limited to the 38 high-quality trials and adjusted to account for potential systematic and random errors, the uncertainty was resolved after the 22nd trial in 2008. When the analysis was restricted to the two high-quality, prospectively registered trials, the cumulative z-curve crossed p=0.05 but not the monitoring boundary, suggesting an early potentially spurious statistically significant result. As precision of the pooled estimate increased, the number of trials initiated increased, although trial activity appeared to move to other surgery types. Most (62%) reports cited at least one systematic review. Of 118 reports examined, concern about generalisability was the reason for initiating the trial in 60%. Other reasons were to address a question other than the effect on bleeding (26%) and to confirm previously observed results (4%). Unawareness of previous research was apparent in 4% trials, while the rationale was unclear in 3%. Our results indicate that poor quality is a more important cause of redundant research than the failure to review existing evidence. Concerns about generalisability of results is the main motivation for new trials. Contrary to previous claims, our results suggest that systematic reviews showing treatment effects can stimulate an increase in trial activity rather than reduce it.


A molecular and neuronal basis for amino acid sensing in the Drosophila larva.
Amino acids are important nutrients for animals, reflected in conserved internal pathways in vertebrates and invertebrates for monitoring cellular levels of these compounds. In mammals, sensory cells and metabotropic glutamate receptor-related taste receptors that detect environmental sources of amino acids in food are also well-characterised. By contrast, it is unclear how insects perceive this class of molecules through peripheral chemosensory mechanisms. Here we investigate amino acid sensing in Drosophila melanogaster larvae, which feed ravenously to support their rapid growth. We show that larvae display diverse behaviours (attraction, aversion, neutral) towards different amino acids, which depend upon stimulus concentration. Some of these behaviours require IR76b, a member of the variant ionotropic glutamate receptor repertoire of invertebrate chemoreceptors. IR76b is broadly expressed in larval taste neurons, suggesting a role as a co-receptor. We identify a subpopulation of these neurons that displays physiological activation by some, but not all, amino acids, and which mediate suppression of feeding by high concentrations of at least a subset of these compounds. Our data reveal the first elements of a sophisticated neuronal and molecular substrate by which these animals detect and behave towards external sources of amino acids.


Paraplegia caused by aortic coarctation complicated with spinal epidural hemorrhage.
Aortic coarctation complicated with spinal artery aneurysm rupture is exceptionally rare and can be source of intraspinal hemorrhage with markedly poor prognosis. A 21-year-old man visited the emergency department because of chest and back pain along with immobility of bilateral lower limbs immediately after he woke up in the morning. Complete flaccid paraplegia and hypoesthesia in dermatome below bilateral T3 level and pain over axial region from neck to lumbar region were noted. A computed tomography excluded aortic dissection. Magnetic resonance imaging revealed a fusiform lesion involving the anterior epidural space from C7 to T2 level suspected of epidural hemorrhage, causing compression of spinal cord. He started intravenous corticosteroid but refused operation concerning the surgical benefits. Severe chest pain occurred with newly onset right bundle branch block that developed the other day. Coronary artery angiography revealed myocardial bridge of left anterior descending coronary artery at middle third and coarctation of aorta. He underwent thoracic endovascular aortic repair uneventfully. The patient was hemodynamically stable but with slow improvement in neurologic recovery of lower limbs. Aortic coarcation can cause paralysis by ruptured vascular aneurysms with spinal hemorrhage and chest pain that mimics acute aortic dissection. A history of hypertension at young age and aortic regurgitated murmurs may serve as clues for further diagnostic studies. Cautious and prudent evaluation and cross disciplines cares are essential for diagnosis and successful management of the disease.


Young Blood Rejuvenates Old Bodies: A Call for Reflection when Moving from Mice to Men.
Connecting the circulatory system of old and young mice (parabiosis) is documented to have rejuvenating effects on cells, tissues, organs, and functions. A wide range of benefits are envisioned. Blood-based rejuvenation can come to totally change population health and aging. The first blood rejuvenation studies on humans with Alzheimer's disease have started. It puts blood at the center of therapy and revitalizes the historical line of humoral pathology from Hippocrates and Harvey, creating a new type of 'bloodletting.' However, moving from mice to men requires careful consideration. Parabiosis actualizes well-known ethical challenges, such as just distribution of health care, avoiding disparities, and providing equal access to health care resources, as well as issues of human enhancement. However, it also poses new problems. Using internal substances in some persons as means to rejuvenate others calls for ethical reflection. New type of 'blood bonds' may result from the continuous demand for specific types of blood. Even if rejuvenating substances from blood may be artificially and cheaply produced and justly distributed, problems arise: survival may have to be balanced against reproduction, as reproductive age increases. Eternal youth and endless bliss have always been vital human dreams. Although parabiosis may bring us closer to the fountain of youth than ever, it is still too early to provide full-fledged assessments of its implications or to foresee how it will change health, aging, medicine, and society. However, in order to bring our reflective abilities on par with our technical skills, we need to start reflection now.


The imprinted brain: how genes set the balance between autism and psychosis.
The imprinted brain theory proposes that autism spectrum disorder (ASD) represents a paternal bias in the expression of imprinted genes. This is reflected in a preference for mechanistic cognition and in the corresponding mentalistic deficits symptomatic of ASD. Psychotic spectrum disorder (PSD) would correspondingly result from an imbalance in favor of maternal and/or X-chromosome gene expression. If differences in gene expression were reflected locally in the human brain as mouse models and other evidence suggests they are, ASD would represent not so much an 'extreme male brain' as an extreme paternal one, with PSD correspondingly representing an extreme maternal brain. To the extent that copy number variation resembles imprinting and aneuploidy in nullifying or multiplying the expression of particular genes, it has been found to conform to the diametric model of mental illness peculiar to the imprinted brain theory. The fact that nongenetic factors such as nutrition in pregnancy can mimic and/or interact with imprinted gene expression suggests that the theory might even be able to explain the notable effect of maternal starvation on the risk of PSD - not to mention the 'autism epidemic' of modern affluent societies. Finally, the theory suggests that normality represents balanced cognition, and that genius is an extraordinary extension of cognitive configuration in both mentalistic and mechanistic directions. Were it to be proven correct, the imprinted brain theory would represent one of the biggest single advances in our understanding of the mind and of mental illness that has ever taken place, and would revolutionize psychiatric diagnosis, prevention and treatment - not to mention our understanding of epigenomics.


Obesity is Independently Associated With Increased Risk of Hepatocellular Cancer-related Mortality: A Systematic Review and Meta-Analysis.
Excess body weight is associated with increased risk of developing hepatocellular cancer (HCC), but its effect on HCC-related mortality remains unclear. We performed a systematic review and meta-analysis to assess the association between premorbid obesity and HCC-related mortality. Through a systematic literature search-up to March 2016, we identified 9 observational studies (1,599,453 individuals, 5705 HCC-related deaths) reporting the association between premorbid body mass index (BMI), and HCC-related mortality. We estimated summary adjusted hazard ratio (aHR) with 95% confidence intervals (CIs), comparing obese (BMI>30 kg/m(2)) and overweight (BMI, 25 to 29.9 kg/m(2)) individuals with normal BMI individuals using random-effects model. On meta-analysis, compared with individuals with normal BMI, obese (aHR, 1.95; 95% CI, 1.46-2.46), but not overweight individuals (aHR, 1.08; 95% CI, 0.97-1.21), had higher HCC-related mortality, with moderate heterogeneity. On subgroup analysis, magnitude of increased mortality was higher in obese men (aHR, 2.50; 95% CI, 2.02-3.09; 3 studies) as compared with obese women (aHR, 1.45; 95% CI, 1.08-1.97; 2 studies). The impact of premorbid obesity on HCC-related mortality was observed only in western populations (aHR, 2.10; 95% CI, 1.77-2.48; 4 studies), but not Asian populations (aHR, 1.10; 95% CI, 0.63-1.92; 1 study). There was limited assessment of competing risk because of advanced liver disease. On the basis of this meta-analysis, premorbid obesity may be independently associated with a 2-fold risk of HCC-related mortality. This association was more pronounced in men and western populations. Strategies targeting obesity-associated metabolic abnormalities may provide novel pathways for HCC therapy.


The placenta: phenotypic and epigenetic modifications induced by Assisted Reproductive Technologies throughout pregnancy.
Today, there is growing interest in the potential epigenetic risk related to assisted reproductive technologies (ART). Much evidence in the literature supports the hypothesis that adverse pregnancy outcomes linked to ART are associated with abnormal trophoblastic invasion. The aim of this review is to investigate the relationship between epigenetic dysregulation caused by ART and subsequent placental response. The dialogue between the endometrium and the embryo is a crucial step to achieve successful trophoblastic invasion, thus ensuring a non-complicated pregnancy and healthy offspring. However, as described in this review, ART could impair both actors involved in this dialogue. First, ART may induce epigenetic defects in the conceptus by modifying the embryo environment. Second, as a result of hormone treatments, ART may impair endometrial receptivity. In some cases, it results in embryonic growth arrest but, when the development of the embryo continues, the placenta could bring adaptive responses throughout pregnancy. Amongst the different mechanisms, epigenetics, especially thanks to a finely tuned network of imprinted genes stimulated by foetal signals, may modify nutrient transfer, placental growth and vascularization. If these coping mechanisms are overwhelmed, improper maternal-foetal exchanges occur, potentially leading to adverse pregnancy outcomes such as abortion, preeclampsia or intra-uterine growth restriction. But in most cases, successful placental adaptation enables normal progress of the pregnancy. Nevertheless, the risks induced by these modifications during pregnancy are not fully understood. Metabolic diseases later in life could be exacerbated through the memory of epigenetic adaptation mechanisms established during pregnancy. Thus, more research is still needed to better understand abnormal interactions between the embryo and the milieu in artificial conditions. As trophectoderm cells are in direct contact with the environment, they deserve to be studied in more detail. The ultimate goal of these studies will be to render ART protocols safer. Optimization of the environment will be the key to improving the dialogue between the endometrium and embryo, so as to ensure that placentation after ART is similar to that following natural conception.


Lack of G protein-coupled estrogen receptor (GPER) in the plasma membrane is associated with excellent long-term prognosis in breast cancer.
G protein-coupled estrogen receptor (GPER), or GPR30, is a membrane receptor reported to mediate non-genomic estrogen responses. Tamoxifen is a partial agonist at GPER in vitro. Here, we investigated if GPER expression is prognostic in primary breast cancer, if the receptor is treatment-predictive for adjuvant tamoxifen, and if receptor subcellular localization has any impact on the prognostic value. Total and plasma membrane (PM) GPER expression was analyzed by immunohistochemistry in breast tumors from 742 postmenopausal lymph node-negative patients subsequently randomized for tamoxifen treatment for 2-5 years versus no systemic treatment, regardless of estrogen receptor (ER) status, and with a median follow-up of 17 years for patients free of event. PM GPER expression was a strong independent prognostic factor for poor prognosis in breast cancer without treatment-predictive information for tamoxifen. In the tamoxifen-treated ER-positive and progesterone receptor (PgR)-positive patient subgroup, the absence of PM GPER (53 % of all ER-positive tumors) predicted 91 % 20-year distant disease-free survival, compared to 73 % in the presence of GPER (p = 0.001). Total GPER expression showed positive correlations with ER and PgR and negative correlation with histological grade, but the correlations were biphasic. On the other hand, PM GPER expression showed strong negative correlations with ER and PgR, and strong positive correlation with HER2 overexpression and high histological grade. GPER overexpression and PM localization are critical events in breast cancer progression, and lack of GPER in the PM is associated with excellent long-term prognosis in ER-positive and PgR-positive tamoxifen-treated primary breast cancer.


A genetically modified protein-based hydrogel for 3D culture of AD293 cells.
Hydrogels have strong application prospects for drug delivery, tissue engineering and cell therapy because of their excellent biocompatibility and abundant availability as scaffolds for drugs and cells. In this study, we created hybrid hydrogels based on a genetically modified tax interactive protein-1 (TIP1) by introducing two or four cysteine residues in the primary structure of TIP1. The introduced cysteine residues were crosslinked with a four-armed poly (ethylene glycol) having their arm ends capped with maleimide residues (4-armed-PEG-Mal) to form hydrogels. In one form of the genetically modification, we incorporated a peptide sequence 'GRGDSP' to introduce bioactivity to the protein, and the resultant hydrogel could provide an excellent environment for a three dimensional cell culture of AD293 cells. The AD293 cells continued to divide and displayed a polyhedron or spindle-shape during the 3-day culture period. Besides, AD293 cells could be easily separated from the cell-gel constructs for future large-scale culture after being cultured for 3 days and treating hydrogel with trypsinase. This work significantly expands the toolbox of recombinant proteins for hydrogel formation, and we believe that our hydrogel will be of considerable interest to those working in cell therapy and controlled drug delivery.


Brain expression of the vascular endothelial growth factor gene family in cognitive aging and alzheimer's disease.
Vascular endothelial growth factor (VEGF) is associated with the clinical manifestation of Alzheimer's disease (AD). However, the role of the VEGF gene family in neuroprotection is complex due to the number of biological pathways they regulate. This study explored associations between brain expression of VEGF genes with cognitive performance and AD pathology. Genetic, cognitive, and neuropathology data were acquired from the Religious Orders Study and Rush Memory and Aging Project. Expression of ten VEGF ligand and receptor genes was quantified using RNA sequencing of prefrontal cortex tissue. Global cognitive composite scores were calculated from 17 neuropsychological tests. β-amyloid and tau burden were measured at autopsy. Participants (n = 531) included individuals with normal cognition (n = 180), mild cognitive impairment (n = 148), or AD dementia (n = 203). Mean age at death was 89 years and 37% were male. Higher prefrontal cortex expression of VEGFB, FLT4, FLT1, and PGF was associated with worse cognitive trajectories (p ≤ 0.01). Increased expression of VEGFB and FLT4 was also associated with lower cognition scores at the last visit before death (p ≤ 0.01). VEGFB, FLT4, and FLT1 were upregulated among AD dementia compared with normal cognition participants (p ≤ 0.03). All four genes associated with cognition related to elevated β-amyloid (p ≤ 0.01) and/or tau burden (p ≤ 0.03). VEGF ligand and receptor genes, specifically genes relevant to FLT4 and FLT1 receptor signaling, are associated with cognition, longitudinal cognitive decline, and AD neuropathology. Future work should confirm these observations at the protein level to better understand how changes in VEGF transcription and translation relate to neurodegenerative disease.


Helix-sense-selective co-precipitation for preparing optically active helical polymer nanoparticles/graphene oxide hybrid nanocomposites.
Constructing optically active helical polymer based nanomaterials without using expensive and limited chirally helical polymers has become an extremely attractive research topic in both chemical and materials science. In this study, we prepared a series of optically active helical polymer nanoparticles/graphene oxide (OAHPNs/GO) hybrid nanocomposites through an unprecedented strategy-the co-precipitation of optically inactive helical polymers and chirally modified GO. This approach is named helix-sense-selective co-precipitation (HSSCP), in which the chirally modified GO acted as a chiral source for inducing and further stabilizing the predominantly one-handed helicity in the optically inactive helical polymers. SEM and TEM images show quite similar morphologies of all the obtained OAHPNs/GO nanocomposites; specifically, the chirally modified GO sheets were uniformly decorated with spherical polymer nanoparticles. Circular dichroism (CD) and UV-vis absorption spectra confirmed the preferentially induced helicity in the helical polymers and the optical activity of the nanocomposites. The established HSSCP strategy is thus proven to be widely applicable and is expected to produce numerous functional OAHPNs/GO nanocomposites and even the analogues.


Longitudinal study of cone photoreceptors during retinal degeneration and in response to ciliary neurotrophic factor treatment.
To study cone photoreceptor structure and function in patients with inherited retinal degenerations treated with sustained-release ciliary neurotrophic factor (CNTF). Two patients with retinitis pigmentosa and one with Usher syndrome type 2 who participated in a phase 2 clinical trial received CNTF delivered by an encapsulated cell technology implant in one eye and sham surgery in the contralateral eye. Patients were followed longitudinally over 30 to 35 months. Adaptive optics scanning laser ophthalmoscopy (AOSLO) provided high-resolution images at baseline and at 3, 6, 12, 18, and 24 months. AOSLO measures of cone spacing and density and optical coherence tomography measures of retinal thickness were correlated with visual function, including visual acuity (VA), visual field sensitivity, and full-field electroretinography (ERG). No significant changes in VA, visual field sensitivity, or ERG responses were observed in either eye of the three patients over 24 months. Outer retinal layers were significantly thicker in CNTF-treated eyes than in sham-treated eyes (P < 0.005). Cone spacing increased by 2.9% more per year in sham-treated eyes than in CNTF-treated eyes (P < 0.001, linear mixed model), and cone density decreased by 9.1%, or 223 cones/degree(2) more per year in sham-treated than in CNTF-treated eyes (P = 0.002, linear mixed model). AOSLO images provided a sensitive measure of disease progression and treatment response in patients with inherited retinal degenerations. Larger studies of cone structure using high-resolution imaging techniques are urgently needed to evaluate the effect of CNTF treatment in patients with inherited retinal degenerations.


Spectrum of Rift Valley fever virus transmission in Kenya: insights from three distinct regions.
Rift Valley fever virus (RVFV) is an emerging pathogen that maintains high biodefense priority based on its threat to livestock, its ability to cause human hemorrhagic fever, and its potential for aerosol spread. To define the range of human transmission during inter-epidemic and epidemic periods in Kenya, we tested archived sera from defined populations (N = 1,263) for anti-RVFV IgG by ELISA and plaque reduction neutralization testing. RVFV seroprevalence was 10.8% overall and varied significantly by location, sex, and age. In NW Kenya, high seroprevalence among those born before 1980 indicates that an undetected epidemic may have occurred then. Seroconversion documented in highland areas suggests previously unsuspected inter-epidemic transmission. RVFV seroprevalence is strikingly high in certain Kenyan areas, suggesting endemic transmission patterns that may preclude accurate estimation of regional acute outbreak incidence. The extent of both epidemic and inter-epidemic RVFV transmission in Kenya is greater than previously documented.


Automatic spike sorting for extracellular electrophysiological recording using unsupervised single linkage clustering based on grey relational analysis.
Automatic spike sorting is a prerequisite for neuroscience research on multichannel extracellular recordings of neuronal activity. A novel spike sorting framework, combining efficient feature extraction and an unsupervised clustering method, is described here. Wavelet transform (WT) is adopted to extract features from each detected spike, and the Kolmogorov-Smirnov test (KS test) is utilized to select discriminative wavelet coefficients from the extracted features. Next, an unsupervised single linkage clustering method based on grey relational analysis (GSLC) is applied for spike clustering. The GSLC uses the grey relational grade as the similarity measure, instead of the Euclidean distance for distance calculation; the number of clusters is automatically determined by the elbow criterion in the threshold-cumulative distribution. Four simulated data sets with four noise levels and electrophysiological data recorded from the subthalamic nucleus of eight patients with Parkinson's disease during deep brain stimulation surgery are used to evaluate the performance of GSLC. Feature extraction results from the use of WT with the KS test indicate a reduced number of feature coefficients, as well as good noise rejection, despite similar spike waveforms. Accordingly, the use of GSLC for spike sorting achieves high classification accuracy in all simulated data sets. Moreover, J-measure results in the electrophysiological data indicating that the quality of spike sorting is adequate with the use of GSLC.


In vivo analysis of MEF2 transcription factors in synapse regulation and neuronal survival.
MEF2 (A-D) transcription factors govern development, differentiation and maintenance of various cell types including neurons. The role of MEF2 isoforms in the brain has been studied using in vitro manipulations with only MEF2C examined in vivo. In order to understand specific as well as redundant roles of the MEF2 isoforms, we generated brain-specific deletion of MEF2A and found that Mef2aKO mice show normal behavior in a range of paradigms including learning and memory. We next generated Mef2a and Mef2d brain-specific double KO (Mef2a/dDKO) mice and observed deficits in motor coordination and enhanced hippocampal short-term synaptic plasticity, however there were no alterations in learning and memory, Schaffer collateral pathway long-term potentiation, or the number of dendritic spines. Since previous work has established a critical role for MEF2C in hippocampal plasticity, we generated a Mef2a, Mef2c and Mef2d brain-specific triple KO (Mef2a/c/dTKO). Mef2a/c/d TKO mice have early postnatal lethality with increased neuronal apoptosis, indicative of a redundant role for the MEF2 factors in neuronal survival. We examined synaptic plasticity in the intact neurons in the Mef2a/c/d TKO mice and found significant impairments in short-term synaptic plasticity suggesting that MEF2C is the major isoform involved in hippocampal synaptic function. Collectively, these data highlight the key in vivo role of MEF2C isoform in the brain and suggest that MEF2A and MEF2D have only subtle roles in regulating hippocampal synaptic function.


Impulsive reactivity to emotion and vulnerability to psychopathology.
Impulsiveness has been studied as an aspect of personality and psychopathology for generations. There are longstanding disagreements about how to define it and whether it should be viewed as one construct or several. This article begins by briefly reviewing some earlier and some more recent work on impulsiveness. Several approaches have recently converged to focus on a distinction between impulsive reactions to emotion and impulsive properties that are not initiated by emotion. From this review, we turn to psychopathology. It is well known that impulsiveness is related to externalizing psychopathology, but some have concluded that a similar relation does not exist for internalizing psychopathology. A recent literature is described that challenges the latter conclusion, linking impulsive reactivity to emotion to both externalizing and internalizing aspects of psychopathology. Discussion then turns to emotion-related impulsiveness and other constructs to which it is conceptually and empirically related, reexamining whether other conceptual targets should be added to the discussion. The article closes with a consideration of how important it is to continue to remain open to new conceptual perspectives. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Effects of gossypol on fitness costs associated with resistance to Bt cotton in pink bollworm.
Fitness costs associated with insect resistance to Bacillus thuringiensis (Bt) crops may help to delay or prevent the spread of resistance alleles, especially when refuges of non-Bt host plants are present. The potential for such delays increases as the magnitude and dominance of fitness costs increase. Here, we examined the idea that plant secondary chemicals affect expression of fitness costs associated with resistance to Bt cotton in Pectinophora gossypiella (Saunders). Specifically, we tested the hypotheses that gossypol affects the magnitude or dominance of fitness costs, by measuring performance of three independent sets of pink bollworm populations fed artificial diet with and without gossypol. Each set had an unselected susceptible population, a resistant population derived by selection from the susceptible population, and the F1 progeny of the susceptible and resistant populations. No individuals completed development on diets with gossypol in one set, suggesting that these individuals partially lost the ability to detoxify this chemical. In the other two sets, costs affecting survival did not support the hypotheses, but costs affecting pupal weight did. Adding gossypol to diet increased the magnitude and dominance of costs affecting pupal weight. In one of the two sets with survivors on diet with gossypol, costs affecting development time were less recessive when gossypol was present in diet. These results indicate that gossypol increased the magnitude and dominance of some fitness costs. Better understanding of the effects of natural plant defenses on fitness costs could improve our ability to design refuges for managing insect resistance to Bt crops.


Cortical neurons gradually attain a post-mitotic state.
Once generated, neurons are thought to permanently exit the cell cycle and become irreversibly differentiated. However, neither the precise point at which this post-mitotic state is attained nor the extent of its irreversibility is clearly defined. Here we report that newly born neurons from the upper layers of the mouse cortex, despite initiating axon and dendrite elongation, continue to drive gene expression from the neural progenitor tubulin α1 promoter (Tα1p). These observations suggest an ambiguous post-mitotic neuronal state. Whole transcriptome analysis of sorted upper cortical neurons further revealed that neurons continue to express genes related to cell cycle progression long after mitotic exit until at least post-natal day 3 (P3). These genes are however down-regulated thereafter, associated with a concomitant up-regulation of tumor suppressors at P5. Interestingly, newly born neurons located in the cortical plate (CP) at embryonic day 18-19 (E18-E19) and P3 challenged with calcium influx are found in S/G2/M phases of the cell cycle, and still able to undergo division at E18-E19 but not at P3. At P5 however, calcium influx becomes neurotoxic and leads instead to neuronal loss. Our data delineate an unexpected flexibility of cell cycle control in early born neurons, and describe how neurons transit to a post-mitotic state.


Hospital reorganization after merger.
Major organizational changes among hospitals, like system affiliation, merger, and closure, would seem to offer substantial opportunities for hospitals and health systems to be strategic in the local reconfiguration of health services. This report presents the results of a unique survey on what happened to hospitals after mergers occurring between 1983 and 1988, inclusive. Building on an ongoing verification process of the American Hospital Association, surviving institutions from all 74 mergers that occurred during the study frame were surveyed in the fall of 1991. Responses were received from 60 of the 74 mergers (81%), regarding the primary, postmerger use of the hospitals involved. Topics surveyed included the premerger competition between the hospitals and in their environment, and what happened to the hospitals after their mergers. Mergers frequently served to convert acute, inpatient capacity to other functions, with less than half of acquired hospitals continuing acute services after merger. In the context of health care reform, mergers may offer an expeditious way locally to restructure health services. Evidence on the postmerger uses of hospitals and about the reasons given for merger suggests that mergers may reflect two general strategies: elimination of direct acute competitors or expansion of acute care networks.


Risk factors for upper gastrointestinal rebleeding in critically ill patients.
To determine the risk factors for rebleeding after upper gastrointestinal bleeding in critically ill patients. We retrospectively analyzed the medical records of consecutive 60 patients undergoing bedside esophagogastroduodenoscopy between January 2000 and December 2004 for upper gastrointestinal bleeding that developed while in the ICU. Eight of the 60 patients died within 7 days after initial bleeding and two of the eight died due to upper gastrointestinal bleeding. Seven-day rebleeding rate was 34.6% (18/52). An additional 7 patients died within 30 days, none of whom died of upper gastrointestinal bleeding. Thirty-day rebleeding rate was 51.1% (23/45). In multiple logistic regression using selected significant variables, anemia (Hb < 9.0g/dL), and hypoalbuminemia (albumin < 3.0g/dL) for 7-day rebleeding, and hypoxia (PaO2 < 80mmHg), anemia (Hb < 9.0g/dL), and units of blood transfused (> or = 3) for 30-day rebleeding were the significant independent risk factors in critically ill patients. The results of this study suggest that underlying patients' conditions or the severity of initial upper gastrointestinal bleeding affect rebleeding in the ICU setting. Adequate general ICU care including the prevention of initial bleeding and correction of hypoxia, anemia, and hypoalbuminemia after bleeding could reduce the rebleeding risk.


Single site-specific integration targeting coupled with embryonic stem cell differentiation provides a high-throughput alternative to in vivo enhancer analyses.
Comprehensive analysis of cis-regulatory elements is key to understanding the dynamic gene regulatory networks that control embryonic development. While transgenic animals represent the gold standard assay, their generation is costly, entails significant animal usage, and in utero development complicates time-course studies. As an alternative, embryonic stem (ES) cells can readily be differentiated in a process that correlates well with developing embryos. Here, we describe a highly effective platform for enhancer assays using an Hsp68/Venus reporter cassette that targets to the Hprt locus in mouse ES cells. This platform combines the flexibility of Gateway® cloning, live cell trackability of a fluorescent reporter, low background and the advantages of single copy insertion into a defined genomic locus. We demonstrate the successful recapitulation of tissue-specific enhancer activity for two cardiac and two haematopoietic enhancers. In addition, we used this assay to dissect the functionality of the highly conserved Ets/Ets/Gata motif in the Scl+19 enhancer, which revealed that the Gata motif is not required for initiation of enhancer activity. We further confirmed that Gata2 is not required for endothelial activity of the Scl+19 enhancer using Gata2(-/-) Scl+19 transgenic embryos. We have therefore established a valuable toolbox to study gene regulatory networks with broad applicability.


Studies on the mechanism of bacterial resistance to complement-mediated killing. I. Terminal complement components are deposited and released from Salmonella minnesota S218 without causing bacterial death.
The mechanism of resistance of gram-negative bacteria to killing by complement was investigated. Complement consumption and uptake of purified, radiolabeled complement components on bacteria was studied using a serum- sensitive and a serum-resistant strain of Salmonella minnesota. Twice as many molecules of (125)I C3 were bound per colony-forming unit (CFU) of the smooth, serum-resistant S. minnesota S218 as were bound per CFU of the rough, serum-sensitive S. minnesota Re595 in 10 percent pooled normal human serum (PNHS), although 75-80 percent of C3 was consumed by both organisms. Hemolytic titrations documented total consumption of C9 by 5 min and more than 95 percent consumption of C5 and C7 by 15 min in the reaction with S218 with 10 percent PNHS. In contrast, negligible C5 depletion, 10 percent C7 consumption, and only a 26 percent decrease in C9 titer occurred with the serum-sensitive Re595. Binding of (125)I C5, (125)I C7, and (125)I C9 to S218 and Re595 was measured in 10 percent PNHS. A total of 6,600 molecules C5/CFU, 5,200 molecules C7/CFU, and 3,100 molecules C9/CFU bound to S218 after 5-10 min of incubation at 37 degrees C, but 50-70 percent of the C5, C7, and C9 bound to S218 was released from the organism during incubation at 37 degrees C for 60 min. Binding of 2,000 molecules C5/CFU, 1,900 molecules C7/CFU, and 9,000 molecules C9/CFU to Re595 was achieved by 20 min and was stable. The ratio of bound C9 molecules to bound C7 molecules, measured using (131)I C9 and (125)I C7, was constant for both organisms after 15 min and was 4.3:1 on Re595 and 0.65:1 on S218 in 10 percent PNHS. With addition of increasing amounts of purified, unlabeled (29 to 10 percent PNHS, there was no change in the C9:C7 ratio on Re595. However, with S218 there was a linear increase of the C9:C7 ratio, which approached the ratio on Re595. There was no (14)C release from S218 incubated in PNHS, nor was there evidence by electron microscopy of outer membrane damage to S218. Therefore, S. minnesota S218 is resistant to killing by PNHS, despite the fact that the organism consumes terminal complement components efficiently and that terminal components are deposited on the surface in significant amounts. The C5b-9 complex is released from the surface of S218 without causing lethal outer membrane damage.


Review of the Clinical Approaches to the Use of Urine-based Tumor Markers in Bladder Cancer.
Bladder cancer is a common disease with a stable incidence for the past few decades despite advancements in molecular and genetic determinants of cancer development and progression. Cystoscopy remains the standard for detection and surveillance of bladder cancer, but it is an invasive and potentially costly procedure. With the knowledge of molecular alterations associated with bladder cancer numerous urine-based tumor markers have become commercially available. These urine markers have been evaluated in all clinical scenarios for the detection of bladder cancer including screening, hematuria, atypical cytology evaluation, and surveillance, but given the relative lack of impactful trials they are not routinely utilized. The efforts to develop markers with increased sensitivity to replace cystoscopy for the detection of bladder cancer have thus far been unsuccessful as well. This review addresses role of urine markers for screening, detection, and surveillance of bladder cancer.


Implementation of a program for surgical education in laryngology.
To describe the implementation of a program for surgical education in laryngology. Items necessary to modify a temporal bone lab for laryngeal dissection purposes were identified, and costs to do so were calculated. The prices and availability of human and canine laryngeal specimens to be used for teaching purposes were then compared. Endoscopic and open laryngeal surgery were performed on canine larynges to determine suitability as a teaching model. A laryngeal dissection course with teaching objectives was created and instituted in an Otolaryngology-Head and Neck Surgery residency training program. Modifications to convert an existing temporal bone lab into a laryngeal dissection lab cost $7,425. Canine larynges were found to strongly resemble human larynges and were easily used in a teaching model. They were more easily acquired and less expensive than human larynges. A novel dissection approach was created to maximize utility of a single cadaveric laryngeal specimen. Development of a laryngeal dissection manual facilitated a laryngeal dissection course. A laryngeal dissection educational course can be instituted with simple and relatively inexpensive modifications to an existing temporal bone laboratory. Canine larynges can be substituted for human larynges for a substantial cost savings without educational compromise. The educational methods demonstrated can be easily duplicated at other training sites.


Naturally processed peptides from two disease-resistance-associated HLA-DR13 alleles show related sequence motifs and the effects of the dimorphism at position 86 of the HLA-DR beta chain.
HLA-DR13 has been associated with resistance to two major infectious diseases of humans. To investigate the peptide binding specificity of two HLA-DR13 molecules and the effects of the Gly/Val dimorphism at position 86 of the HLA-DR beta chain on natural peptide ligands, these peptides were acid-eluted from immunoaffinity-purified HLA-DRB1*1301 and -DRB1*1302, molecules that differ only at this position. The eluted peptides were subjected to pool sequencing or individual peptide sequencing by tandem MS or Edman microsequencing. Sequences were obtained for 23 peptides from nine source proteins. Three pool sequences for each allele and the sequences of individual peptides were used to define binding motifs for each allele. Binding specificities varied only at the primary hydrophobic anchor residue, the differences being a preference for the aromatic amino acids Tyr and Phe in DRB1*1302 and a preference for Val in DRB1*1301. Synthetic analogues of the eluted peptides showed allele specificity in their binding to purified HLA-DR, and Ala-substituted peptides were used to identify the primary anchor residues for binding. The failure of some peptides eluted from DRB1*1302 (those that use aromatic amino acids as primary anchors) to bind to DRB1*1301 confirmed the different preferences for peptide anchor residues conferred by the Gly-->Val change at position 86. These data suggest a molecular basis for the differential associations of HLA-DRB1*1301 and DRB1*1302 with resistance to severe malaria and clearance of hepatitis B virus infection.


Effects of metallothionein-1 genetic polymorphism and cigarette smoking on the development of hepatocellular carcinoma.
A low expression of metallothionein (MT) has been observed in liver cancer. Such a phenomenon might be influenced by oxidative stress, thus resulting in the cells being more susceptible to DNA damage and apoptotic death. In particular, oxidative stress induced by cigarette smoking might affect MT-1 expression. We designed a hospital-based case-control study to evaluate the effects of MT-1 genotypes and smoking on hepatocellular carcinoma (HCC) occurrence. A total of 102 HCC patients and 191 matched healthy control subjects were recruited, and epidemiological information was collected. Six genotypes of MT-1 were determined with TaqMan single-nucleotide polymorphism genotyping assays. Individuals possessing MT-1 rs8052394 A, rs964372 G, and rs8052334 T alleles as well as engaging in cigarette smoking had increased risks of HCC; these alleles also had higher linkage disequilibrium. Carriers with MT-1 rs8052394, rs964372, and rs8052334 A-G-T haplotype had a 2.25-fold (95 % confidence interval [CI] 1.46-3.26) risk for HCC development than the control group (A-C-T, the most common haplotype). Compared to nonsmokers with other haplotypes (A-C-T, G-G-C, A-G-C, G-G-T, G-C-T, and G-C-C), nonsmokers with A-G-T haplotype had a 1.93-fold (95 % CI 1.01-3.71) increased risk, and smokers with other haplotypes had a 3.66-fold (95 % CI 1.78-7.54) increased risk, whereas smokers carrying the A-G-T haplotype had the highest risk (matched relative risk 6.72; 95 % CI 2.86-15.79) of developing HCC. The MT-1 A-G-T haplotypes are associated with increased risk of HCC, especially in those who smoke.


Emergence and treatment of multidrug resistant (MDR) and extensively drug-resistant (XDR) tuberculosis in South Africa.
Drug resistant tuberculosis (TB) has reached alarming proportions in South Africa, draining valuable resources that are needed to fight drug susceptible TB. It is currently estimated that 9.6% of all TB cases have multi-drug resistant (MDR)-TB, thereby ranking South Africa as one of the highest MDR-TB burden countries in the world. Molecular epidemiological studies have demonstrated the complexity of the epidemic and have clearly shown that the epidemic is driven by transmission as a consequence of low cases detection and diagnostic delay. The latter has in turn fueled the amplification of drug resistance, ultimately leading to the emergence of extensively drug resistant (XDR)-TB. Despite the introduction of new drugs to combat this scourge, culture conversion rates for XDR-TB remain below 20%. Failure to achieve cure may be explained from DNA sequencing results which have demonstrated mutations in 7 genes encoding resistance to at least 8 anti-TB drugs. This review shows how molecular epidemiology has provided novel insights into the MDR-TB epidemic in South Africa and thereby has highlighted the challenges that need to be addressed regarding the diagnosis and treatment of MDR-TB. An important step towards for curbing this epidemic will be collaboration between clinicians, laboratories and researchers to establish scientific knowledge and medical expertise to more efficiently guide public health policy.


Just dying: the futility of futility.
I argue that Brierley et al are wrong to claim that parents who request futile treatment are acting against the interests of their child. A better ethical ground for withholding or withdrawing life-prolonging treatment is not that it is in the interests of the patient to die, but rather on grounds of the limitation of resources and the requirements of distributive justice. Put simply, not all treatment that might be in a person's interests must ethically be provided.


The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis.
Endothelial cells play essential roles in maintenance of vascular integrity, angiogenesis, and wound repair. We show that an endothelial cell-restricted microRNA (miR-126) mediates developmental angiogenesis in vivo. Targeted deletion of miR-126 in mice causes leaky vessels, hemorrhaging, and partial embryonic lethality, due to a loss of vascular integrity and defects in endothelial cell proliferation, migration, and angiogenesis. The subset of mutant animals that survives displays defective cardiac neovascularization following myocardial infarction. The vascular abnormalities of miR-126 mutant mice resemble the consequences of diminished signaling by angiogenic growth factors, such as VEGF and FGF. Accordingly, miR-126 enhances the proangiogenic actions of VEGF and FGF and promotes blood vessel formation by repressing the expression of Spred-1, an intracellular inhibitor of angiogenic signaling. These findings have important therapeutic implications for a variety of disorders involving abnormal angiogenesis and vascular leakage.


Genetic evidence for unequal effective population sizes of human females and males.
The time to the most recent common ancestor (TMRCA) of the human mitochondria (mtDNA) is estimated to be older than that of the nonrecombining portion of the Y chromosome (NRY). Surveys of variation in globally distributed humans typically result in mtDNA TMRCA values just under 200 thousand years ago (kya), whereas those for the NRY range between 46 and 110 kya. A favored hypothesis for this finding is that natural selection has acted on the NRY, leading to a recent selective sweep. An alternate hypothesis is that sex-biased demographic processes are responsible. Here, we re-examine the disparity between NRY and mtDNA TMRCAs using data collected from individual human populations--a sampling strategy that minimizes the confounding influence of population subdivision in global data sets. We survey variation at 782 bp of the mitochondrial cytochrome c oxidase subunit 3 gene as well as at 26.5 kb of noncoding DNA from the NRY in a sample of 25 Khoisan, 24 Mongolians, and 24 Papua New Guineans. Data from both loci in all populations are best described by a model of constant population size, with the exception of Mongolian mtDNA, which appears to be experiencing rapid population growth. Taking these demographic models into account, we estimate the TMRCAs for each locus in each population. A pattern that is remarkably consistent across all three populations is an approximately twofold deeper coalescence for mtDNA than for the NRY. The oldest TMRCAs are observed for the Khoisan (73.6 kya for the NRY and 176.5 kya for mtDNA), whereas those in the non-African populations are consistently lower (averaging 47.7 kya for the NRY and 92.8 kya for mtDNA). Our data do not suggest that differential natural selection is the cause of this difference in TMRCAs. Rather, these results are most consistent with a higher female effective population size.


Characterization of the vaginal microbiota among sexual risk behavior groups of women with bacterial vaginosis.
The pathogenesis of bacterial vaginosis (BV) remains elusive. BV may be more common among women who have sex with women (WSW). The objective of this study was to use 454 pyrosequencing to investigate the vaginal microbiome of WSW, women who have sex with women and men (WSWM), and women who have sex with men (WSM) with BV to determine if there are differences in organism composition between groups that may inform new hypotheses regarding the pathogenesis of BV. Vaginal swab specimens from eligible women with BV at the Mississippi State Department of Health STD Clinic were used. After DNA extraction, 454 pyrosequencing of PCR-amplified 16S rRNA gene sequences was performed. Sequence data was classified using the Ribosomal Database Program classifer. Complete linkage clustering analysis was performed to compare bacterial community composition among samples. Differences in operational taxonomic units with an abundance of ≥ 2% between risk behavior groups were determined. Alpha and beta diversity were measured using Shannon's Index implemented in QIIME and Unifrac analysis, respectively. 33 WSW, 35 WSWM, and 44 WSM were included. The vaginal bacterial communities of all women clustered into four taxonomic groups with the dominant taxonomic group in each being Lactobacillus, Lachnospiraceae, Prevotella, and Sneathia. Regarding differences in organism composition between risk behavior groups, the abundance of Atopobium (relative ratio (RR)=0.24; 95%CI 0.11-0.54) and Parvimonas (RR=0.33; 95%CI 0.11-0.93) were significantly lower in WSW than WSM, the abundance of Prevotella was significantly higher in WSW than WSWM (RR=1.77; 95%CI 1.10-2.86), and the abundance of Atopobium (RR=0.41; 95%CI 0.18-0.88) was significantly lower in WSWM than WSM. Overall, WSM had the highest diversity of bacterial taxa. The microbiology of BV among women in different risk behavior groups is heterogeneous. WSM in this study had the highest diversity of bacterial taxa. Additional studies are needed to better understand these differences.


Pharmacological agents that directly modulate insulin secretion.
Blood glucose levels are sensed and controlled by the release of hormones from the islets of Langerhans in the pancreas. The beta-cell, the insulin-secreting cell in the islet, can detect subtle increases in circulating glucose levels and a cascade of molecular events spanning the initial depolarization of the beta-cell membrane culminates in exocytosis and optimal insulin secretion. Here we review these processes in the context of pharmacological agents that have been shown to directly interact with any stage of insulin secretion. Drugs that modulate insulin secretion do so by opening the K(ATP) channels, by interacting with cell-surface receptors, by altering second-messenger responses, by disrupting the beta-cell cytoskeletal framework, by influencing the molecular reactions at the stages of transcription and translation of insulin, and/or by perturbing exocytosis of the insulin secretory vesicles. Drugs acting primarily at the K(ATP) channels are the sulfonylureas, the benzoic acid derivatives, the imidazolines, and the quinolines, which are channel openers, and finally diazoxide, which closes these channels. Methylxanthines also work at the cell membrane level by antagonizing the purinergic receptors and thus increase insulin secretion. Other drugs have effects at multiple levels, such as the calcineurin inhibitors and somatostatin. Some drugs used extensively in research, e.g., colchicine, which is used to study vesicular transport, have no effect at the pharmacological doses used in clinical practice. We also briefly discuss those drugs that have been shown to disrupt beta-cell function in a clinical setting but for which there is scant information on their mechanism of action.


Subjective data, objective data and the role of bias in predictive modelling: Lessons from a dispositional learning analytics application.
For decades, self-report measures based on questionnaires have been widely used in educational research to study implicit and complex constructs such as motivation, emotion, cognitive and metacognitive learning strategies. However, the existence of potential biases in such self-report instruments might cast doubts on the validity of the measured constructs. The emergence of trace data from digital learning environments has sparked a controversial debate on how we measure learning. On the one hand, trace data might be perceived as "objective" measures that are independent of any biases. On the other hand, there is mixed evidence of how trace data are compatible with existing learning constructs, which have traditionally been measured with self-reports. This study investigates the strengths and weaknesses of different types of data when designing predictive models of academic performance based on computer-generated trace data and survey data. We investigate two types of bias in self-report surveys: response styles (i.e., a tendency to use the rating scale in a certain systematic way that is unrelated to the content of the items) and overconfidence (i.e., the differences in predicted performance based on surveys' responses and a prior knowledge test). We found that the response style bias accounts for a modest to a substantial amount of variation in the outcomes of the several self-report instruments, as well as in the course performance data. It is only the trace data, notably that of process type, that stand out in being independent of these response style patterns. The effect of overconfidence bias is limited. Given that empirical models in education typically aim to explain the outcomes of learning processes or the relationships between antecedents of these learning outcomes, our analyses suggest that the bias present in surveys adds predictive power in the explanation of performance data and other questionnaire data.


Mechanisms of xenogeneic baboon platelet aggregation and phagocytosis by porcine liver sinusoidal endothelial cells.
Baboons receiving xenogeneic livers from wild type and transgenic pigs survive less than 10 days. One of the major issues is the early development of profound thrombocytopenia that results in fatal hemorrhage. Histological examination of xenotransplanted livers has shown baboon platelet activation, phagocytosis and sequestration within the sinusoids. In order to study the mechanisms of platelet consumption in liver xenotransplantation, we have developed an in vitro system to examine the interaction between pig endothelial cells with baboon platelets and to thereby identify molecular mechanisms and therapies. Fresh pig hepatocytes, liver sinusoidal and aortic endothelial cells were isolated by collagenase digestion of livers and processing of aortae from GTKO and Gal+ MGH-miniature swine. These primary cell cultures were then tested for the differential ability to induce baboon or pig platelet aggregation. Phagocytosis was evaluated by direct observation of CFSE labeled-platelets, which are incubated with endothelial cells under confocal light microscopy. Aurintricarboxylic acid (GpIb antagonist blocking interactions with von Willebrand factor/vWF), eptifibatide (Gp IIb/IIIa antagonist), and anti-Mac-1 Ab (anti-α(M)β(2) integrin Ab) were tested for the ability to inhibit phagocytosis. None of the pig cells induced aggregation or phagocytosis of porcine platelets. However, pig hepatocytes, liver sinusoidal and aortic endothelial cells (GTKO and Gal+) all induced moderate aggregation of baboon platelets. Importantly, pig liver sinusoidal endothelial cells efficiently phagocytosed baboon platelets, while pig aortic endothelial cells and hepatocytes had minimal effects on platelet numbers. Anti-MAC-1 Ab, aurintricarboxylic acid or eptifibatide, significantly decreased baboon platelet phagocytosis by pig liver endothelial cells (P<0.01). Although pig hepatocytes and aortic endothelial cells directly caused aggregation of baboon platelets, only pig liver endothelial cells efficiently phagocytosed baboon platelets. Blocking vWF and integrin adhesion pathways prevented both aggregation and phagocytosis.


Iodine binding with thiophene and furan based dyes for DSCs.
Iodine binding to thiophene rings in dyes for dye-sensitized solar cells (DSCs) has been hypothesized to be performance degrading in a number of literature cases. Binding of iodine to dyes near the semiconductor surface can promote undesirable electron transfers and lower the overall efficiency of devices. Six thiophene or furan containing dye analogs were synthesized to analyze iodine binding to the dyes via Raman spectroscopy, UV-Vis studies, device performance metrics and density functional theory (DFT) based computations. Evidence suggests I2 binds thiophene-based dyes stronger than furan-based dyes. This leads to higher DSC device currents and voltages from furan analogues, and longer electron lifetimes in DSC devices using furan based dyes. Raman spectrum of the TiO2 surface-bound dyes reveals additional and more instense peaks for thiophene dyes in the presence of I2 relative to no I2. Additionally, broader and shifted UV-Vis peaks are observed for thiophene dyes in the presence of I2 on TiO2 films suggesting significant interaction between the dye molecules and I2. These observations are also supported by DFT and TD-DFT calculations which indicate the absence of a key geometric energy minimum in the dye-I2 ground state for furan dyes which are readily observed for the thiophene based analogues.


Cannabinoid WIN-55,212-2 mesylate inhibits interleukin-1β induced matrix metalloproteinase and tissue inhibitor of matrix metalloproteinase expression in human chondrocytes.
Interleukin-1β (IL-1β) is involved in the up-regulation of matrix metalloproteinases (MMPs) leading to cartilage degradation. Cannabinoids are anti-inflammatory and reduce joint damage in animal models of arthritis. This study aimed to determine a mechanism whereby the synthetic cannabinoid WIN-55,212-2 mesylate (WIN-55) may inhibit cartilage degradation. Effects of WIN-55 were studied on IL-1β stimulated production of MMP-3 and -13 and their inhibitors TIMP-1 and -2 in human chondrocytes. Chondrocytes were obtained from articular cartilage of patients undergoing total knee replacement. Chondrocytes were grown in monolayer and 3D alginate bead cultures. Real-time polymerase chain reaction (PCR) was used to determine the gene expression of MMP-3, -13, TIMP-1 and -2 and Enzyme Linked Immunosorbent Assay (ELISA) to measure the amount of MMP-3 and MMP-13 protein released into media. Immunocytochemistry was used to investigate the expression of cannabinoid receptors in chondrocyte cultures. Treatment with WIN-55 alone or in combination with IL-1β, decreased or abolished MMP-3, -13, TIMP-1 and -2 gene expression in human chondrocyte monolayer and alginate bead cultures in both a concentration and time dependent manner. WIN-55 treatment alone, and in combination with IL-1β, reduced MMP-3 and -13 protein production by chondrocytes cultured in alginate beads. Immunocytochemistry demonstrated the expression of cannabinoid receptors in chondrocyte cultures. Cannabinoid WIN-55 can reduce both basal and IL-1β stimulated gene and protein expression of MMP-3 and -13. However WIN-55 also decreased basal levels of TIMP-1 and -2 mRNA. These actions of WIN-55 suggest a mechanism by which cannabinoids may act to prevent cartilage breakdown in arthritis.


Masculinities, practices and meanings: A critical analysis of recent literature on the use of performance- and image-enhancing drugs among men.
The use of performance- and image-enhancing drugs (PIEDs) has been a topic of considerable research interest since the 1980s, with the vast majority of PIED consumers being men. In this article, our departure point is a 2005 article by Helen Keane, in which she critically analyses 'the discursive constitution of male steroid users' as psychologically disordered subjects. We extend Keane's insightful feminist analysis by examining the constitution of masculinity in post-2005 social science research on PIEDs. We ask (1) to what extent do the discursive trends identified by Keane persist in the more recent literature on PIED use among men? (2) how have her insights been taken up in the post-2005 literature, and (3) to what extent does this work attend to the specificity and varied meanings of steroid practices? We argue that men who use PIEDs continue to be pathologised as insecure, inadequate and vulnerable, and marked by 'obsession', 'compensatory behaviours' and crisis. In some of the analysed texts, the male steroid user becomes doubly disordered as both insecure in his masculine body and at risk of drug dependence. Of the articles that engage with Keane's work, only two recognise the value of her insights. The others misinterpret or apply Keane's argument in inconsistent or incoherent ways. Finally, in some of the post-2005 texts, we begin to see attention to the wide variety of practices and meanings encompassed by the term 'PIED use' although much remains to be learned.