Transduction of Recombinant M3-p53-R12 Protein Enhances Human Leukemia Cell Apoptosis.
Tumor suppressor protein p53 plays important roles in initiating cell cycle arrest and promoting tumor cell apoptosis. Previous studies have shown that p53 is either mutated or defective in approximately 50% of human cancers; therefore restoring normal p53 activity in cancer cells might be an effective anticancer therapeutic approach. Herein, we designed a chimeric p53 protein flanked with the MyoD N-terminal transcriptional activation domain (amino acids 1-62, called M3) and a poly-arginine (R12) cell penetrating signal in its N-and C-termini respectively. This chimeric protein, M3-p53-R12, can be expressed in E. coli and purified using immobilized metal ion chromatography followed by serial refolding dialysis. The purified M3-p53-R12 protein retains DNA-binding activity and gains of cell penetrating ability. Using MTT assay, we demonstrated that M3-p53-R12 inhibited the growth of K562, Jurkat as well as HL-60 leukemia cells carrying mutant p53 genes. Results from FACS analysis also demonstrated that transduction of M3-p53-R12 protein induced cell cycle arrest of these leukemia cells. Of special note, M3-p53-R12 has no apoptotic effect on normal mesenchymal stem cells (MSC) and leukocytes, highlighting its differential effects on normal and tumor cells. To sum up, our results reveal that purified recombinant M3-p53-R12 protein has functions of suppressing the leukemia cell lines' proliferation and launching cell apoptosis, suggesting the feasibility of using M3-p53-R12 protein as an anticancer drug. In the future we will test whether this chimeric protein can preferentially trigger the death of malignant cancer cells without affecting normal cells in animals carrying endogenous or xenographic tumors.


Play along: effects of music and social interaction on word learning.
Learning new words is an increasingly common necessity in everyday life. External factors, among which music and social interaction are particularly debated, are claimed to facilitate this task. Due to their influence on the learner's temporal behavior, these stimuli are able to drive the learner's attention to the correct referent of new words at the correct point in time. However, do music and social interaction impact learning behavior in the same way? The current study aims to answer this question. Native German speakers (N = 80) were requested to learn new words (pseudo-words) during a contextual learning game. This learning task was performed alone with a computer or with a partner, with or without music. Results showed that music and social interaction had a different impact on the learner's behavior: Participants tended to temporally coordinate their behavior more with a partner than with music, and in both cases more than with a computer. However, when both music and social interaction were present, this temporal coordination was hindered. These results suggest that while music and social interaction do influence participants' learning behavior, they have a different impact. Moreover, impaired behavior when both music and a partner are present suggests that different mechanisms are employed to coordinate with the two types of stimuli. Whether one or the other approach is more efficient for word learning, however, is a question still requiring further investigation, as no differences were observed between conditions in a retrieval phase, which took place immediately after the learning session. This study contributes to the literature on word learning in adults by investigating two possible facilitating factors, and has important implications for situations such as music therapy, in which music and social interaction are present at the same time.


Trans-mastoid approach to otogenic brain abscess.
The treatment of otogenic brain abscess initially involves excision or aspiration of the abscess through a temporal or sub-occipital route depending on its location. This is followed by a mastoidectomy by the ENT surgeon to eradicate the primary source of infection. During the last three years, we have approached such lesions through a mastoidectomy followed by excision of the abscess through the same approach. This trans-mastoid approach is technically feasible in following the tract of suppuration, and clearing the cause and effect of pathology, at the same sitting. This paper describes our initial experience with the trans-mastoid approach to otogenic brain abscesses. On the basis of our results, we believe that transmastoid approach is an effective and logical option for the treatment of otogenic brain abscess, and merits further investigation in the form of a prospective study.


Oncologic manifestations in children with neurofibromatosis type 1 in Turkey.
Children with neurofibromatosis type 1 (NF1) are predisposed to malignancies such as brain tumors, leukemia, and pheochromocytomas. The aim of this study was to evaluate malignancy in patients with NF1. We studied 120 patients with NF1 in this study. Demographic data from these patients were retrospectively reviewed. We found 20 malignancies in 19 patients in our study. Ten children with NF1 had optic glioma. Four children had solid central nervous system tumors (3 pilocytic astrocytomas, 1 glioblastoma multiforme). Three patients had myeloid malignancies (1 juvenile myelomonocytic leukemia, 1 acute myeloid leukemia, 1 acute lymphocytic leukemia). Hodgkin lymphoma, T-cell lymphoblastic lymphoma, and malignant triton tumor were found in one patient each. Patients with NF1 are predisposed to both benign and malignant tumors of neurogenic and non-neurogenic origin. Therefore, systematic medical follow-up in patients with NF1 is important.


Towards an integration of the health promotion models of self-determination theory and theory of planned behavior among people with chronic pain.
People with chronic pain and related disability often report motivational difficulties with engaging in health-promoting behaviors. Although health promotion models of self-determination theory (SDT) and theory of planned behavior (TPB) have been shown to explain the motivational processes behind health behaviors in the general population, there is limited theoretical research among persons with chronic pain. This study examined the integration of such theories relevant to physical activity and exercise behavior among pain populations. Secondary data analyses were conducted using cross-sectional surveys from 198 participants with chronic musculoskeletal pain recruited from U.S. clinics and community networks. The primary outcome was self-reported physical activity and exercise participation. Predictor variables included pain intensity, functional disability, and SDT and TPB measures. Hierarchical regression analysis was conducted to examine the associations between these variables. Findings demonstrated that in the first step, functional disability was associated with physical activity and exercise; and in the second step, all SDT factors were associated with physical activity and exercise. In the final step of the model, only certain SDT and TPB factors were associated with physical activity and exercise. Despite preexisting pain and functional disability, the findings suggest that health behavior factors from both SDT and TPB are associated with physical activity and exercise participation. This line of research should encourage rehabilitation professionals to recommend regular physical activity and exercise, while simultaneously addressing and monitoring the SDT and TPB factors that are well-timed and appropriate for persons with chronic pain through motivation-oriented rehabilitation approaches. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Integrating a newly developed BAC-based physical mapping resource for Lolium perenne with a genome-wide association study across a L. perenne European ecotype collection identifies genomic contexts associated with agriculturally important traits.
Lolium perenne (perennial ryegrass) is the most widely cultivated forage and amenity grass species in temperate areas worldwide and there is a need to understand the genetic architectures of key agricultural traits and crop characteristics that deliver wider environmental services. Our aim was to identify genomic regions associated with agriculturally important traits by integrating a bacterial artificial chromosome (BAC)-based physical map with a genome-wide association study (GWAS). BAC-based physical maps for L. perenne were constructed from ~212 000 high-information-content fingerprints using Fingerprint Contig and Linear Topology Contig software. BAC clones were associated with both BAC-end sequences and a partial minimum tiling path sequence. A panel of 716 L. perenne diploid genotypes from 90 European accessions was assessed in the field over 2 years, and genotyped using a Lolium Infinium SNP array. The GWAS was carried out using a linear mixed model implemented in TASSEL, and extended genomic regions associated with significant markers were identified through integration with the physical map. Between ~3600 and 7500 physical map contigs were derived, depending on the software and probability thresholds used, and integrated with ~35 k sequenced BAC clones to develop a resource predicted to span the majority of the L. perenne genome. From the GWAS, eight different loci were significantly associated with heading date, plant width, plant biomass and water-soluble carbohydrate accumulation, seven of which could be associated with physical map contigs. This allowed the identification of a number of candidate genes. Combining the physical mapping resource with the GWAS has allowed us to extend the search for candidate genes across larger regions of the L. perenne genome and identified a number of interesting gene model annotations. These physical maps will aid in validating future sequence-based assemblies of the L. perenne genome.


Training-induced changes in subsequent-memory effects: No major differences among children, younger adults, and older adults.
The neural correlates of encoding mode, or the state of forming new memory episodes, have been found to change with age and mnemonic training. However, it is unclear whether neural correlates of encoding success, termed subsequent-memory (SM) effects, also differ by age and mnemonic skill. In a multi-session training study, we investigated whether SM effects are altered by instruction and training in a mnemonic skill, and whether such alterations differ among children, younger adults, and older adults. Before and after strategy training, fMRI data were collected while participants were memorizing word pairs. In all age groups, participants receiving training showed greater performance gains than control group participants. Analysis of task-relevant regions showed training-induced reductions in SM effects in left frontal regions. Reductions in SM effects largely generalized across age and primarily reflected greater training-induced activation increases for omissions than for remembered items, indicating that training resulted in more consistent use of the mnemonic strategy. The present results reveal no major age differences in SM effects in children, younger adults, and older adults.


Phase II presurgical feasibility study of bevacizumab in untreated patients with metastatic renal cell carcinoma.
To assess safety and efficacy of presurgical bevacizumab in patients with metastatic renal cell carcinoma (mRCC), and to explore the hypothesis that pretreatment of patients with antiangiogenic therapy will select patients who benefit most from cytoreductive nephrectomy. Patients with newly diagnosed, clear cell mRCC whose primary tumors were considered resectable were enrolled. In this single-arm, phase II trial, patients received bevacizumab plus erlotinib (first patients, n = 23) or bevacizumab alone (n = 27 patients) for 8 weeks followed by restaging. If patients demonstrated progressive disease and had declining performance statuses after 8 weeks, nephrectomy procedures were deferred. Postoperatively, patients continued on the study drug or drugs if disease stabilization or regression had occurred. Between March 2005 and March 2008, 52 patients were enrolled on study, and 50 were included in the analysis. By Memorial Sloan-Kettering Cancer Center criteria, 82% of patients had intermediate-risk, and 18% had poor-risk, features. Forty-two patients underwent nephrectomy. Median progression-free survival was 11.0 months (95% CI, 5.5 to 15.6 months). Median overall survival was 25.4 months (95% CI, 11.4 months to not estimable). Two perioperative deaths occurred; neither was attributable to study drug. Wound dehiscence resulted in treatment discontinuation for three patients and treatment delay for two others. Presurgical treatment with bevacizumab therapy yields clinical outcomes comparable to post-surgical treatment with antiangiogenic therapy in patients with mRCC, but it may result in wound-healing delays. Prospective, randomized trials to test the use of presurgical therapy as a method to select appropriate patients for cytoreductive nephrectomy are warranted.


Alteromonas flava sp. nov. and Alteromonas facilis sp. nov., two novel copper tolerating bacteria isolated from a sea cucumber culture pond in China.
Two bacterial strains, P0211T and P0213T, were isolated from a sea cucumber culture pond in China. The strains were able to resist high copper levels. These two strains were characterized at the phenotypic, chemotaxonomic, and genomic level. They were completely different colors, but the 16S rRNA genes showed 99.30% similarity. Phylogenetic analysis based on the sequences of the 16S rRNA gene and five housekeeping genes (dnaK, sucC, rpoB, gyrB, and rpoD) supported the inclusion of these strains within the genus Alteromonas, and the two isolated strains formed a group separated from the closest species Alteromonas aestuariivivens KCTC 52655T. Genomic analyses, including average nucleotide identity (ANIb and ANIm), DNA-DNA hybridization (DDH), and the percentage of conserved proteins (POCP), clearly separated strains P0211T and P0213T from the other species within the genus Alteromonas with values below the thresholds for species delineation. The chemotaxonomic features (including fatty acid and polar lipid analysis) of strains P0211T and P0213T also confirmed their differentiation from the related taxa. The results demonstrated that strains P0211T and P0213T represented two novel species in the genus Alteromonas, for which we propose the names Alteromonas flava sp. nov., type strain P0211T (=KCTC 62078T=MCCC 1H00242T), and Alteromonas facilis sp. nov., type strain P0213T (=KCTC 62079T=MCCC 1H00243T).


Aggregation-caused quenching versus crystallization induced emission in thiazolo[5,4-b]thieno[3,2-e]pyridine (TTP) derivatives: theoretical insights.
We report a QM (TD-DFT) and QM/QM' (ONIOM) study of the modulation of emission in a series of thiazolo[5,4,b]thieno[3,2-e]pyridine (TTP) derivatives [Huang et al., J. Mater. Chem. C, 2017, 14, 3456]. By computing the excitation energy transfer couplings and the Huang-Rhys (HR) factors, we rationalize the aggregation-caused quenching (ACQ) observed for the parent molecule and the crystallization-induced emission (CIE) observed for the derivatives presenting intra-molecular H-bonding. We also show that the CIE strategy relying on the rigidification of the arch-bridge-like stator should be considered with caution since it can promote the energy dissipation through vibrational motions.


Role of transforming growth factor-[beta]1 in inhibiting endothelial cell proliferation in experimental alcoholic liver disease.
We used the intragastric feeding rat model for alcoholic liver disease to investigate the relationship between transforming growth factor (TGF)-beta 1 and inhibition of endothelial cell proliferation. Twelve groups of male Wistar rats (four to five rats per group) were fed ethanol or dextrose with either corn oil or saturated fat for 1-, 2-, and 4-week periods. All control animals were pair fed the same diets as ethanol-fed rats except that ethanol was isocalorically replaced by dextrose. In the ethanol-fed groups, nonparenchymal cells were isolated and TGF-beta 1 was measured in the nonparenchymal cell supernatant. Liver pathology and endothelial cell proliferation with an antibody to proliferating cell nuclear antigen were studied in all groups. Plasma TGF-beta 1 was measured in all rats. Pathological changes (fatty liver, necrosis, and inflammation) were observed only in the corn oil/ethanol-fed rats at 4 weeks. Significantly higher levels of TGF-beta 1 were seen in both plasma and nonparenchymal cell supernatant in rats fed corn oil and ethanol; plasma levels of TGF-beta 1 were not significantly different between the dextrose-fed controls and saturated fat/ethanol-fed rats. A significant inverse correlation (r = -0.89, P < 0.01) was seen between plasma TGF-beta 1 and the number of endothelial cells arrested at G1/S. Immunohistochemistry revealed the presence of TGF-beta 1 staining in interstitial macrophages only in rats fed corn oil and ethanol. The present study provides evidence for a role for TGF-beta 1 in inhibiting endothelial cell proliferation in experimental alcoholic liver disease. Arrest of endothelial cells may lead to their differentiation and/or to produce mediators that could stimulate other cells such as Ito cells. Sustained TGF-beta 1 may also lead to Ito cell production of extracellular matrix.


A Conversation with John McKetta.
John J. McKetta, Jr. is a foundational figure in chemical engineering education and energy policy in the United States. An authority on the thermodynamic properties of hydrocarbons and an energy adviser to several US presidents, McKetta helped to educate and mentor thousands of students at the University of Texas at Austin for over 40 years, many of whom became leading figures in the energy and petrochemical industries, as well as in academia. As dean of the College of Engineering, McKetta helped to establish a bioengineering program, which later became the Biomedical Engineering Department, at the University of Texas at Austin, and was a tireless advocate for excellence and a focus on the student. At age 100, McKetta recalls the challenges and opportunities he faced in childhood, his memories of the emergence of petrochemical engineering, and his views on chemical engineering education and the people it has impacted in the United States over the past 100 years.


Management of common musculoskeletal problems: a survey of Ontario primary care physicians.
In Canada, primary care physicians manage most musculoskeletal problems. However, their training in this area is limited, and some aspects of management may be suboptimal. This study was conducted to examine primary care physicians' management of 3 common musculoskeletal problems, ascertain the determinants of management and compare management with that recommended by a current practice panel. A stratified computer-generated random sample of 798 Ontario members of the College of Family Physicians of Canada received a self-administered questionnaire by mail. Respondents selected various items in the management of 3 hypothetical patients: a 77-year-old woman with a shoulder problem, a 64-year-old man with osteoarthritis of the knee and a 30-year-old man with an acutely hot, swollen knee. Scores reflecting the proportion of recommended investigations, interventions and referrals selected for each scenario were calculated and examined for their association with physician and practice characteristics and physician attitudes. The response rate was 68.3% (529/775 eligible physicians). For the shoulder problem, all of the recommended items were chosen by the majority of respondents. However, of the items not recommended, ordering blood tests was selected by almost half (242 [45.7%]) as was prescribing an NSAID (236 [44.7%]). For the knee osteoarthritis the majority of respondents chose the recommended items except exercise (selected by only 175 [33.1%]). Of the items not recommended, tests were chosen by about half of the respondents and inappropriate referrals (chiefly for orthopedic surgery) were chosen by a quarter. For the acutely hot knee, the majority of physicians chose all of the recommended items except use of ice or heat (selected by only 188 [35.6%]). Although most (415 [78.5%]) of the respondents selected the recommended joint aspiration for this scenario, 84 (15.9%) omitted this investigation or referral to a specialist. The selection of recommended items was strongly associated with training in musculoskeletal specialties during medical school and residency. Primary care physicians' management of 3 common musculoskeletal problems was for the most part in accord with panel recommendations. However, the unnecessary use of diagnostic tests, inappropriate prescribing of NSAIDs, low use of patient-centred options such as exercise, and lack of diagnostic suspicion of infectious arthritis are cause for concern. The results point to the need for increased exposure to musculoskeletal problems during undergraduate and residency training and in continuing medical education.


Direct determination of nucleosides in the urine of patients with breast cancer using column-switching liquid chromatography-tandem mass spectrometry.
We developed an analytical method for a simple, sensitive and simultaneous determination of oxidized nucleosides in urine using column-switching liquid chromatography-electrospray/tandem mass spectrometry (LC-ESI/MS/MS). We connected two columns through a six-way switching valve and effectively separated nucleosides in the urine from the interference by column-switching liquid chromatography. We monitored separated nucleosides using positive ionization tandem mass spectrometry in selective reaction monitoring (SRM) mode. The calibration ranges of nucleosides were 0.2-100 nmol/mL. The linearity of the method was 0.994-0.999, and the limits-of-detection (LOD) at a signal-to-noise (S/N) ratio of 3 were 0.1-0.2 nmol/mL. The coefficients of variation were in the range 2.28-11.74% for within-day variation and 4.36-11.15% for day-to-day variation, respectively. To explore the relationship between breast cancer and the nucleosides level in human urine, we measured the concentrations of nucleosides in female patients with breast cancer (n = 30) and in normal female subjects (n = 30). The concentration of nucleosides was significantly increased in patients with breast cancer when compared with the normal controls (1-methyladenosine; p < 0.005, N(2),N(2)-dimethylguanosine; p < 0.01, 5-hydroxymethyl-2'-deoxyuridine; p < 0.001, 8-hydroxy-2-deoxyguanosine; p < 0.001). Therefore, the elevated levels of nucleosides could be used as an important biomarker for breast-cancer research.


Validation of image segmentation by estimating rater bias and variance.
The accuracy and precision of segmentations of medical images has been difficult to quantify in the absence of a 'ground truth' or reference standard segmentation for clinical data. Although physical or digital phantoms can help by providing a reference standard, they do not allow the reproduction of the full range of imaging and anatomical characteristics observed in clinical data. An alternative assessment approach is to compare with segmentations generated by domain experts. Segmentations may be generated by raters who are trained experts or by automated image analysis algorithms. Typically, these segmentations differ due to intra-rater and inter-rater variability. The most appropriate way to compare such segmentations has been unclear. We present here a new algorithm to enable the estimation of performance characteristics, and a true labelling, from observations of segmentations of imaging data where segmentation labels may be ordered or continuous measures. This approach may be used with, among others, surface, distance transform or level-set representations of segmentations, and can be used to assess whether or not a rater consistently overestimates or underestimates the position of a boundary.


Biogeochemistry at a wetland sediment-alluvial aquifer interface in a landfill leachate plume.
The biogeochemistry at the interface between sediments in a seasonally ponded wetland (slough) and an alluvial aquifer contaminated with landfill leachate was investigated to evaluate factors that can effect natural attenuation of landfill leachate contaminants in areas of groundwater/surface-water interaction. The biogeochemistry at the wetland-alluvial aquifer interface differed greatly between dry and wet conditions. During dry conditions (low water table), vertically upward discharge was focused at the center of the slough from the fringe of a landfill-derived ammonium plume in the underlying aquifer, resulting in transport of relatively low concentrations of ammonium to the slough sediments with dilution and dispersion as the primary attenuation mechanism. In contrast, during wet conditions (high water table), leachate-contaminated groundwater discharged upward near the upgradient slough bank, where ammonium concentrations in the aquifer where high. Relatively high concentrations of ammonium and other leachate constituents also were transported laterally through the slough porewater to the downgradient bank in wet conditions. Concentrations of the leachate-associated constituents chloride, ammonium, non-volatile dissolved organic carbon, alkalinity, and ferrous iron more than doubled in the slough porewater on the upgradient bank during wet conditions. Chloride, non-volatile dissolved organic carbon (DOC), and bicarbonate acted conservatively during lateral transport in the aquifer and slough porewater, whereas ammonium and potassium were strongly attenuated. Nitrogen isotope variations in ammonium and the distribution of ammonium compared to other cations indicated that sorption was the primary attenuation mechanism for ammonium during lateral transport in the aquifer and the slough porewater. Ammonium attenuation was less efficient, however, in the slough porewater than in the aquifer and possibly occurred by a different sorption mechanism. A stoichiometrically balanced increase in magnesium concentration with decreasing ammonium and potassium concentrations indicated that cation exchange was the sorption mechanism in the slough porewater. Only a partial mass balance could be determined for cations exchanged for ammonium and potassium in the aquifer, indicating that some irreversible sorption may be occurring. Although wetlands commonly are expected to decrease fluxes of contaminants in riparian environments, enhanced attenuation of the leachate contaminants in the slough sediment porewater compared to the aquifer was not observed in this study. The lack of enhanced attenuation can be attributed to the fact that the anoxic plume, comprised largely of recalcitrant DOC and reduced inorganic constituents, interacted with anoxic slough sediments and porewaters, rather than encountering a change in redox conditions that could cause transformation reactions. Nevertheless, the attenuation processes in the narrow zone of groundwater/surface-water interaction were effective in reducing ammonium concentrations by a factor of about 3 during lateral transport across the slough and by a factor of 2 to 10 before release to the surface water. Slough porewater geochemistry also indicated that the slough could be a source of sulfate in dry conditions, potentially providing a terminal electron acceptor for natural attenuation of organic compounds in the leachate plume.


Analyzing Visibility Configurations.
Many algorithms, such as level of detail rendering and occlusion culling methods, make decisions based on the degree of visibility of an object, but do not analyze the distribution, or structure, of the visible and occluded regions across surfaces. We present an efficient method to classify different visibility configurations and show how this can be used on top of existing methods based on visibility determination. We adapt co-occurrence matrices for visibility analysis and generalize them to operate on clusters of triangular surfaces instead of pixels. We employ machine learning techniques to reliably classify the thus extracted feature vectors. Our method allows perceptually motivated level of detail methods for real-time rendering applications by detecting configurations with expected visual masking. We exemplify the versatility of our method with an analysis of area light visibility configurations in ray tracing and an area-to-area visibility analysis suitable for hierarchical radiosity refinement. Initial results demonstrate the robustness, simplicity, and performance of our method in synthetic scenes, as well as real applications.


Abnormalities in the pulmonary innate immune system in cystic fibrosis.
Pulmonary infection is the dominant clinical feature of cystic fibrosis (CF), but the basis for this susceptibility remains incompletely understood. One hypothesis is that CF airway surface liquid (ASL) is abnormal and interferes with neutrophil function. To study this possibility, we developed an in vitro system in which we collected ASL from primary cultures of normal and CF airway epithelial cells. Microbial killing was less efficient when bacteria were incubated with neutrophils in the presence of ASL from CF epithelia compared with normal ASL. Antimicrobial functions of human neutrophils were assessed in ASL from CF and normal epithelia using a combination of quantitative bacterial culture, flow cytometry, and microfluorescence imaging. The results of these assays of neutrophil function were indistinguishable in CF and normal ASL. In contrast, the direct bactericidal activity of ASL to Escherichia coli and to clinical isolates of Staphylococcus aureus and Pseudomonas aeruginosa was substantially less in CF than in normal ASL, even when highly diluted in media of identical ionic strength. Together, these observations indicate that the antimicrobial properties of ASL in CF are compromised in a manner independent of ionic strength of the ASL, and that this effect is not mediated through a direct effect of the ASL on phagocyte function.


Calcium plus vitamin D supplementation and the risk of nonmelanoma and melanoma skin cancer: post hoc analyses of the women's health initiative randomized controlled trial.
In light of inverse relationships reported in observational studies of vitamin D intake and serum 25-hydroxyvitamin D levels with risk of nonmelanoma skin cancer (NMSC) and melanoma, we evaluated the effects of vitamin D combined with calcium supplementation on skin cancer in a randomized placebo-controlled trial. Postmenopausal women age 50 to 79 years (N = 36,282) enrolled onto the Women's Health Initiative (WHI) calcium/vitamin D clinical trial were randomly assigned to receive 1,000 mg of elemental calcium plus 400 IU of vitamin D3 (CaD) daily or placebo for a mean follow-up period of 7.0 years. NMSC and melanoma skin cancers were ascertained by annual self-report; melanoma skin cancers underwent physician adjudication. Neither incident NMSC nor melanoma rates differed between treatment (hazard ratio [HR], 1.02; 95% CI, 0.95 to 1.07) and placebo groups (HR, 0.86; 95% CI, 0.64 to 1.16). In subgroup analyses, women with history of NMSC assigned to CaD had a reduced risk of melanoma versus those receiving placebo (HR, 0.43; 95% CI, 0.21 to 0.90; P(interaction) = .038), which was not observed in women without history of NMSC. Vitamin D supplementation at a relatively low dose plus calcium did not reduce the overall incidence of NMSC or melanoma. However, in women with history of NMSC, CaD supplementation reduced melanoma risk, suggesting a potential role for calcium and vitamin D supplements in this high-risk group. Results from this post hoc subgroup analysis should be interpreted with caution but warrant additional investigation.


Polarizability is a key parameter for molecular electronics.
Identifying descriptors that govern charge transport in molecular electronics is of prime importance for the elaboration of devices. The effects of molecule characteristics, such as size, bulkiness or charge, have been widely reported. Herein, we show that the molecule polarizability can be a crucial parameter to consider. To this end, platinum nanoparticle self-assemblies (PtNP SAs) are synthesized in solution, including a series of polyoxometalates (POMs). The charge of the POM unit can be modified according to the nature of the central heteroatom while keeping its size constant. POM hybrids that display remote terminal thiol functions strongly anchor the PtNP surface to form robust SAs. IV curves, recorded by conductive AFM, show a decrease in Coulomb blockade as the dielectric constant of the POMs increases. In this system, charge transport across molecular junctions can be interpreted as variations in polarizability, which is directly related to the dielectric constant.


Prevalence of symptoms of dyspepsia in the community.
To study the prevalence of dyspepsia in the community a postal questionnaire was sent to 2697 patients who were selected at random from the lists of patients registered in two health centres in Hampshire. A total of 2066 returned questionnaires were suitable for analysis (response rate 77%). It was found that the six month prevalence of dyspepsia was 38%. There was considerable overlap between symptoms of heartburn and upper abdominal pain, with over half of patients with dyspepsia experiencing both. One in four of these patients had consulted their general practitioner during that time. The proportion of patients with dyspepsia who consulted their general practitioner varied widely among the eight doctors who participated in the study, from 17% to 45%. Frequency of symptoms tended to fall with age, particularly in men, while the proportion of patients with dyspepsia who sought medical advice increased with age. Almost one in five of the 2066 patients had been investigated with radiology or endoscopy at some time, and 143 (7%) of them claimed to have had a diagnosis of peptic ulcer.


Borate inhibits activation of inactive dinitrogenase reductase from Rhodospirillum rubrum.
Borate and aminophenylboronic acid were tested as inhibitors of activation of inactive dinitrogenase reductase from Rhodospirillum rubrum. Inhibition was specific for activation because activity of the active form of the enzyme was not inhibited. Inhibition showed the pH-dependence expected if borate inhibits by binding to cis-hydroxy groups of the modifying group found on the inactive enzyme.


Success versus failure in cognitive control: meta-analytic evidence from neuroimaging studies on error processing.
Brain mechanisms of error processing have often been investigated using response interference tasks and focusing on the posterior medial frontal cortex, which is also implicated in resolving response conflict in general. Thereby, the role other brain regions may play has remained undervalued. Here, activation likelihood estimation meta-analyses were used to synthesize the neuroimaging literature on brain activity related to committing errors versus responding successfully in interference tasks and to test for commonalities and differences. The salience network and the temporoparietal junction were commonly recruited irrespective of whether responses were correct or incorrect, pointing towards a general involvement in coping with situations that call for increased cognitive control. The dorsal posterior cingulate cortex, posterior thalamus, and left superior frontal gyrus showed error-specific convergence, which underscores their consistent involvement when performance goals are not met. In contrast, successful responding revealed stronger convergence in the dorsal attention network and lateral prefrontal regions. Underrecruiting these regions in error trials may reflect failures in activating the task-appropriate stimulus-response contingencies necessary for successful response execution.


Severe hypoglycemia and mortality after cardiovascular events for type 1 diabetic patients in Sweden.
To examine whether previous severe hypoglycemic events were associated with the risk of all-cause mortality after major cardiovascular events (myocardial infarction [MI] or stroke) in patients with type 1 diabetes. This study is based on data from the Swedish National Diabetes Register linked to patient-level hospital records, prescription data, and death records. We selected patients with type 1 diabetes who visited a clinic during 2002-2010 and experienced a major cardiovascular complication after their clinic visit. We estimated a two-part model for all-cause mortality after a major cardiovascular event: logistic regression for death within the first month and a Cox proportional hazards model conditional on 1-month survival. At age 60 years, 5-year cumulative mortality risk was estimated from the models for patients with and without prior diabetes complications. A total of 1,839 patients experienced major cardiovascular events, of whom 403 had previously experienced severe hypoglycemic events and 703 died within our study period. A prior hypoglycemic event was associated with a significant increase in mortality after a cardiovascular event, with hazard ratios estimated at 1.79 (95% CI 1.37-2.35) within the first month and 1.25 (95% CI 1.02-1.53) after 1 month. Patients with prior hypoglycemia had an estimated 5-year cumulative mortality risk of 52.4% (95% CI 45.3-59.5) and 39.8% (95% CI 33.4-46.3) for MI and stroke, respectively. We have found evidence that patients with type 1 diabetes in Sweden with prior severe hypoglycemic events have increased risk of mortality after a cardiovascular event.


Scarring, stem cells, scaffolds and skin repair.
The treatment of full thickness skin loss, which can be extensive in the case of large burns, continues to represent a challenging clinical entity. This is due to an on-going inability to produce a suitable tissue engineered substrate that can satisfactorily replicate the epidermal and dermal in vivo niches to fulfil both aesthetic and functional demands. The current gold standard treatment of autologous skin grafting is inadequate because of poor textural durability, scarring and associated contracture, and because of a paucity of donor sites in larger burns. Tissue engineering has seen exponential growth in recent years with a number of 'off-the-shelf' dermal and epidermal substitutes now available. Each has its own limitations. In this review, we examine normal wound repair in relation to stem/progenitor cells that are intimately involved in this process within the dermal niche. Endothelial precursors, in particular, are examined closely and their phenotype, morphology and enrichment from multiple sources are described in an attempt to provide some clarity regarding the controversy surrounding their classification and role in vasculogenesis. We also review the role of the next generation of cellularized scaffolds and smart biomaterials that attempt to improve the revascularisation of artificial grafts, the rate of wound healing and the final cosmetic and functional outcome.


Social inequalities in childcare quality and their effects on children's development at school entry: findings from the Longitudinal Study of Australian Children.
Higher quality childcare in the years before school may help narrow developmental gaps between the richest and poorest children in our societies, but specific evidence is limited and inconsistent. We address this issue by examining whether higher quality childcare is associated with better developmental outcomes at school entry for children from lower than higher income families. The sample from the Longitudinal Study of Australian Children included children attending childcare from 2 to 3 years (n=980-1187, depending on outcome). Childcare quality was measured using carers assessment of their relationship with the child. Children's receptive vocabulary was directly assessed in the child's home, and behavioural difficulties were measured by teachers and parents at 4-5 years. We assessed additive and multiplicative income-related effect measure modification of the quality of carer-child relationship on developmental outcomes. After adjusting for confounding, there was some evidence of effect measure modification on the additive and multiplicative scales of childcare quality by income. Children experiencing higher quality relationships and lower income had almost the same risk of poorer receptive vocabulary as children in higher quality relationships and higher incomes (relative excess risk due to interaction=0.18; 95% CI -0.20 to 0.52), ratio of relative risks=1.11 (1.04 to 1.17)). These patterns were similar for teacher-reported and parent-reported behavioural difficulties. The effects of higher quality childcare, in terms of quality relationships with carers, on children's cognitive and behavioural development at school entry were stronger among children from lower income families. This provides some evidence that higher quality relationships in childcare may be especially important in helping reduce developmental gaps for children from lower income families.


Interactions "Candidatus Liberibacter solanacearum"-Bactericera cockerelli: Haplotype Effect on Vector Fitness and Gene Expression Analyses.
"Candidatus Liberibacter solanacearum" (Lso) has emerged as a serious threat world-wide. Five Lso haplotypes have been identified so far. Haplotypes A and B are present in the Americas and/or New Zealand, where they are vectored to solanaceous plants by the potato psyllid, Bactericera cockerelli (Šulc) (Hemiptera: Triozidae). The fastidious nature of these pathogens has hindered the study of the interactions with their eukaryotic hosts (vector and plant). To understand the strategies used by these pathogens to infect their vector, the effects of each Lso haplotype (A or B) on psyllid fitness was investigated, and genome-wide transcriptomic and RT-qPCR analyses were performed to evaluate Lso gene expression in association with its vector. Results showed that psyllids infected with haplotype B had significantly lower percentage of nymphal survival compared to psyllids infected with haplotype A. Although overall gene expression across Lso genome was similar between the two Lso haplotypes, differences in the expression of key candidate genes were found. Among the 16 putative type IV effector genes tested, four of them were differentially expressed between Lso haplotypes, while no differences in gene expression were measured by qPCR or transcriptomic analysis for the rest of the genes. This study provides new information regarding the pathogenesis of Lso haplotypes in their insect vector.


LUMINEX®: a new technology for the simultaneous identification of five Entamoeba spp. commonly found in human stools.
Six species of the genus Entamoeba, i.e., E. histolytica, E. dispar, E. moshkovskii, E. polecki, E. coli, and E. hartmanii can be found in human stools. Among these, only E. histolytica is considered to be pathogenic, causing intestinal and extra-intestinal disease, but it is morphologically identical to E. dispar and E. moshkovskii. In general, E. polecki, E. coli, and E. hartmanii can be differentiated morphologically from E. histolytica, but some of their diagnostic morphologic features may overlap creating issues for the differential diagnosis. Moreover, the previous inability to differentiate among Entamoeba species has limited epidemiologic information on E histolytica. The objective of this study was to develop a rapid, high-throughput screening method using Luminex technique for the simultaneous detection and differentiation of Entamoeba species. PCR amplification was performed with biotinylated Entamoeba sp 18S rRNA gene primers, designed to amplify a fragment ranging from 382 to 429 bp of the Entamoeba spp studied. Regions of this fragment that could differentiate among E. histolytica, E. moshkovskii, E. dispar, E. hartmanii and E. coli were selected to design hybridization probes to link to Luminex beads. The assay was standardized with cloned DNA samples of each species and evaluated with 24 DNA extracts from samples obtained from individuals diagnosed with these amebas in their stools. Using this approach we were able to correctly identify E. histoltyica, E. dispar, E hartmanni, E. coli and E. moshkovskii in all specimens studied. From twenty four samples tested by microscopy, PCR/DNA Sequencing and real-time PCR, 100% agreed with PCR-Luminex assay for identification of E. dispar, E. moshkovskii, E. hartmanni, E. histolytica, and E. coli. These results show that this method could be used in the diagnostic detection of Entamoeba spp in fecal samples. This diagnostic test was useful to clearly distinguish E histolytica from other species and also to strengthen epidemiologic data on Entamoeba spp.


Cardiovascular disease prevention in primary care.
Since the publication of the National Service Framework for coronary heart disease, there has been a move towards primary disease prevention with a greater focus on an individual's absolute risk. Meta-analysis and systematic reviews of the evidence for primary prevention are incomplete and the current guidelines and policy have led to considerable confusion in clinical practice. There is an increased use of risk assessment tools but no effective method of reviewing current activity with the limited integration into the existing Quality Outcome Framework. There is an inadequate evidence for some of the risk factors used to identify individuals at risk, the risk calculators used to quantify the degree of risk and the methods of communicating risk to patients are largely unproven or completely missing. There is a need for a co-ordinated vascular disease prevention programme which can be applied at the individual and at the population level but is also amenable to evaluation.


Predicting Protein-Protein Interactions by Combing Various Sequence-Derived.
Knowledge of protein-protein interactions (PPIs) plays an important role in constructing protein interaction networks and understanding the general machineries of biological systems. In this study, a new method is proposed to predict PPIs using a comprehensive set of 930 features based only on sequence information, these features measure the interactions between residues a certain distant apart in the protein sequences from different aspects. To achieve better performance, the principal component analysis (PCA) is first employed to obtain an optimized feature subset. Then, the resulting 67-dimensional feature vectors are fed to Support Vector Machine (SVM). Experimental results on Drosophila melanogaster and Helicobater pylori datasets show that our method is very promising to predict PPIs and may at least be a useful supplement tool to existing methods.


Hobson's choice: reproductive choices for women with learning disabilities.
This paper examines the present law in England and Wales concerning the sterilisation of women who are unable to give valid consent to medical treatment. In particular, it considers why sterilisation is frequently presented as the only meaningful reproductive choice that can be made by or on behalf of women with learning disabilities. In addition, the paper assesses the extent to which the best interests test, as formulated by the English courts, has been successful in the promotion of dignity and autonomy of women with learning disabilities. It is submitted that some of the issues presented to the courts have not received adequate consideration and others have been considered which are not relevant to the determination of the best interests of these patients. Furthermore, the best interests of the adult patient are determined by reference to the 'Bolam' test. This paper questions whether the Bolam test is the appropriate mechanism for determining the patient's best interests, having particular regard to the Australian model of decision-making for the intellectually impaired.


Pattern of polyphenol intake and the long-term risk of dementia in older persons.
To investigate the optimal combination of dietary polyphenols associated with the long-term risk of dementia in a large prospective French cohort of older persons, the Three-City (3C) Study. We included 1,329 older adults without dementia from the 3C study with assessment of intake of 26 polyphenol subclasses who were followed up for 12 years for dementia. Using partial least squares for Cox models, we identified a pattern of polyphenol intake associated with dementia risk. The pattern combined several flavonoids (dihydroflavonols, anthocyanins, isoflavonoids, flavanones), stilbenes (including resveratrol), lignans, and other subclasses (hydroxybenzaldehydes, naphthoquinones, furanocoumarins). Compared with participants in the lower quintile of pattern score, those in the higher quintile had a 50% lower risk of dementia (95% confidence interval 20%-68%, p for trend <0.01) in multivariate models. In this French cohort, a polyphenol pattern provided by a diet containing specific plant products (nuts, citrus, berries, leafy vegetables, soy, cereals, olive oil) accompanied by red wine and tea was associated with lower dementia risk.


Assessment of high-sensitivity C-reactive protein levels as diagnostic discriminator of maturity-onset diabetes of the young due to HNF1A mutations.
Despite the clinical importance of an accurate diagnosis in individuals with monogenic forms of diabetes, restricted access to genetic testing leaves many patients with undiagnosed diabetes. Recently, common variation near the HNF1 homeobox A (HNF1A) gene was shown to influence C-reactive protein levels in healthy adults. We hypothesized that serum levels of high-sensitivity C-reactive protein (hs-CRP) could represent a clinically useful biomarker for the identification of HNF1A mutations causing maturity-onset diabetes of the young (MODY). Serum hs-CRP was measured in subjects with HNF1A-MODY (n = 31), autoimmune diabetes (n = 316), type 2 diabetes (n = 240), and glucokinase (GCK) MODY (n = 24) and in nondiabetic individuals (n = 198). The discriminative accuracy of hs-CRP was evaluated through receiver operating characteristic (ROC) curve analysis, and performance was compared with standard diagnostic criteria. Our primary analyses excluded approximately 11% of subjects in whom the single available hs-CRP measurement was >10 mg/l. Geometric mean (SD range) hs-CRP levels were significantly lower (P <or= 0.009) for HNF1A-MODY individuals, 0.20 (0.03-1.14) mg/l, than for any other group: autoimmune diabetes 0.58 (0.10-2.75) mg/l, type 2 diabetes 1.33 (0.28-6.14) mg/l, GCK-MODY 1.01 (0.19-5.33) mg/l, and nondiabetic 0.48 (0.10-2.42) mg/l. The ROC-derived C-statistic for discriminating HNF1A-MODY and type 2 diabetes was 0.8. Measurement of hs-CRP, either alone or in combination with current diagnostic criteria, was superior to current diagnostic criteria alone. Sensitivity and specificity for the combined criteria approached 80%. Serum hs-CRP levels are markedly lower in HNF1A-MODY than in other forms of diabetes. hs-CRP has potential as a widely available, cost-effective screening test to support more precise targeting of MODY diagnostic testing.


Viral eukaryogenesis: was the ancestor of the nucleus a complex DNA virus?
In the theory of viral eukaryogenesis I propose here, the eukaryotic nucleus evolved from a complex DNA virus. It is proposed that the virus established a persistent presence in the cytoplasm of a methanogenic mycoplasma and evolved into the eukaryotic nucleus by acquiring a set of essential genes from the host genome and eventually usurping its role. It is proposed that several characteristic features of the eukaryotic nucleus derive from its viral ancestry. These include mRNA capping, linear chromosomes, and separation of transcription from translation. In the model, phagocytosis and other membrane fusion-based processes are derived from viral membrane fusion processes and evolved in concert with the nucleus. The coevolution of phagocytosis and the nucleus rendered much of the host archaeal genome redundant since the protoeukaryote could obtain raw materials and energy by engulfing bacterial syntrophs/prey. This redundancy allowed loss of the archaeal chromosome, generating an organism with eukaryotic features. The evolution of phagocytosis allowed the eukaryotes to be the first organisms to occupy the niche of predator.


The association of immigration and acculturation attributes with oral health among immigrants in New York City.
We examined associations between immigration and acculturation attributes and oral disease among immigrants. We conducted a large cross-sectional study of 1318 immigrants in New York City. We performed comprehensive interviews and oral examinations of the participants and used linear regression models to assess differences in oral disease levels among immigrant subgroups. We also constructed proportional odds models to evaluate the association of oral disease level with length of stay in the United States, age at immigration, and language preference. After we controlled for most known risk factors, country of birth and age at immigration were associated with variations in oral disease prevalence and need for oral health care. Length of stay was inversely associated with need for treatment of dental caries but not with any other indicator of oral disease. Language preference was not associated with any indicator of oral disease. Immigrants' country of birth, length of stay in the United States, and age at immigration played important roles in their oral disease prevalence, independently of most known risk factors for oral diseases. Our findings emphasize the need for more studies to elucidate the complex relationships of ethnicity, socioeconomic status, and culturally influenced factors that impact immigrants' oral health.


The prognostic significance of IDH2 mutations in AML depends on the location of the mutation.
We have investigated the prognostic significance of isocitrate dehydrogenase 2 (IDH2) mutations in 1473 younger adult acute myeloid leukemia patients treated in 2 United Kingdom Medical Research Council trials. An IDH2 mutation was present in 148 cases (10%), 80% at R140 and 20% at R172. Patient characteristics and outcome differed markedly between the 2 mutations. IDH2(R140) significantly correlated with nucleophosmin mutations (NPM1(MUT)), whereas IDH2(R172) cases generally lacked other molecular mutations. An IDH2(R140) mutation was an independent favorable prognostic factor for relapse (P = .004) and overall survival (P = .008), and there was no significant heterogeneity with regard to NPM1 or FLT3 internal tandem duplication (FLT3/ITD) genotype. Relapse in FLT3/ITD(WT)NPM1(MUT)IDH2(R140) patients was lower than in favorable-risk cytogenetics patients in the same cohort (20% and 38% at 5 years, respectively). The presence of an IDH2(R172) mutation was associated with a significantly worse outcome than IDH2(R140), and relapse in FLT3/ITD(WT)NPM1(WT)IDH2(R172) patients was comparable with adverse-risk cytogenetics patients (76% and 72%, respectively).


Chronic effects of air pollution on respiratory health in Southern California children: findings from the Southern California Children's Health Study.
Outdoor air pollution is one of the leading contributors to adverse respiratory health outcomes in urban areas around the world. Children are highly sensitive to the adverse effects of air pollution due to their rapidly growing lungs, incomplete immune and metabolic functions, patterns of ventilation and high levels of outdoor activity. The Children's Health Study (CHS) is a continuing series of longitudinal studies that first began in 1993 and has focused on demonstrating the chronic impacts of air pollution on respiratory illnesses from early childhood through adolescence. A large body of evidence from the CHS has documented that exposures to both regional ambient air and traffic-related pollutants are associated with increased asthma prevalence, new-onset asthma, risk of bronchitis and wheezing, deficits of lung function growth, and airway inflammation. These associations may be modulated by key genes involved in oxidative-nitrosative stress pathways via gene-environment interactions. Despite successful efforts to reduce pollution over the past 40 years, air pollution at the current levels still brings many challenges to public health. To further ameliorate adverse health effects attributable to air pollution, many more toxic pollutants may require regulation and control of motor vehicle emissions and other combustion sources may need to be strengthened. Individual interventions based on personal susceptibility may be needed to protect children's health while control measures are being implemented.


Health, functional status, and employment of adult survivors of bone marrow transplantation.
To determine the health, functional ability, and employment status of adults who survive bone marrow transplantation. Inception cohort study. Patients who received transplants at a single referral-based center. Adults of 18 years of age or older who had received bone marrow transplants at least 6 months previously and who were not in a life-threatening relapse were surveyed a mean of 47 months after transplant (median, 37 months; range, 6 to 149 months). Of 171 eligible patients, 157 were contacted and 135 (86%) responded. Patients completed a mailed survey. Medical records were also reviewed. Most patients (93%) reported they could do normal activities with minor or no physical problems (Karnofsky scores, greater than or equal to 80%). Global health was described as good to excellent by 67% of subjects. Most perceived social activities (80%) or physical functional abilities (67%) to be unimpaired or only slightly affected. Moderate or severe pain was uncommon (13%). Sixty-five percent had returned to full- or part-time employment, and one third of those who were not employed were attending school. Job discrimination and problems in obtaining insurance were reported by 23% and 39%, respectively. Among those who had been employed before illness, loss of employment was associated with lower social functioning, chronic graft-versus-host disease, greater job discrimination, and female gender using multivariate logistic regression. Most subjects surviving bone marrow transplant reported good to excellent health and functional ability. Three fourths were employed or enrolled in school. These outcomes are comparable to outcomes in survivors of cancer who received less intensive treatments.


New mixed quantumsemiclassical propagation method.
The authors developed a new method for calculating the quantum evolution of multidimensional systems, for cases in which the system can be assumed to consist of a quantum subsystem and a bath subsystem of heavier atoms. The method combines two ideas: starting from a simple frozen Gaussian description of the bath subsystem, then calculate quantum corrections to the propagation of the quantum subsystem. This follows from recent work by one of them, showing how one can calculate corrections to approximate evolution schemes, even when the Hamiltonian that corresponds to these approximate schemes is unknown. Then, they take the limit in which the width of the frozen Gaussians approaches zero, which makes the corrections to the evolution of the quantum subsystem depend only on classical bath coordinates. The test calculations they present use low-dimensional systems, in which comparison to exact quantum dynamics is feasible.


Molecular cloning and functional identification of a plant ornithine decarboxylase cDNA.
A cDNA for a plant ornithine decarboxylase (ODC), a key enzyme in putrescine and polyamine biosynthesis, has been isolated from root cultures of the solanaceous plant Datura stramonium. Reverse transcription-PCR employing degenerate oligonucleotide primers representing conserved motifs from other eukaryotic ODCs was used to isolate the cDNA. The longest open reading frame potentially encodes a peptide of 431 amino acids and exhibits similarity to other eukaryotic ODCs, prokaryotic and eukaryotic arginine decarboxylases (ADCs), prokaryotic meso-diaminopimelate decarboxylases and the product of the tabA gene of Pseudomonas syringae cv. tabaci. Residues involved at the active site of the mouse ODC are conserved in the plant enzyme. The plant ODC does not possess the C-terminal extension found in the mammalian enzyme, implicated in rapid turnover of the protein, suggesting that the plant ODC may have a longer half-life. Expression of the plant ODC in Escherichia coli and demonstration of ODC activity confirmed that the cDNA encodes an active ODC enzyme. This is the first description of the primary structure of a eukaryotic ODC isolated from an organism where the alternative ADC routine to putrescine is present.


Mesenchymal stem cell therapy: Two steps forward, one step back.
Mesenchymal stem cell (MSC) therapy is poised to establish a new clinical paradigm; however, recent trials have produced mixed results. Although MSC were originally considered to treat connective tissue defects, preclinical studies revealed potent immunomodulatory properties that prompted the use of MSC to treat numerous inflammatory conditions. Unfortunately, although clinical trials have met safety endpoints, efficacy has not been demonstrated. We believe the challenge to demonstrate efficacy can be attributed in part to an incomplete understanding of the fate of MSC following infusion. Here, we highlight the clinical status of MSC therapy and discuss the importance of cell-tracking techniques, which have advanced our understanding of the fate and function of systemically infused MSC and might improve clinical application.


Skin Disease Models In Vitro and Inflammatory Mechanisms: Predictability for Drug Development.
Investigative skin biology, analysis of human skin diseases, and numerous clinical and pharmaceutical applications rely on skin models characterized by reproducibility and predictability. Traditionally, such models include animal models, mainly rodents, and cellular models. While animal models are highly useful in many studies, they are being replaced by human cellular models in more and more approaches amid recent technological development due to ethical considerations. The culture of keratinocytes and fibroblasts has been used in cell biology for many years. However, only the development of co-culture and three-dimensional epidermis and full-skin models have fundamentally contributed to our understanding of cell-cell interaction and cell signalling in the skin, keratinocyte adhesion and differentiation, and mechanisms of skin barrier function. The modelling of skin diseases has highlighted properties of the skin important for its integrity and cutaneous development. Examples of monogenic as well as complex diseases including atopic dermatitis and psoriasis have demonstrated the role of skin models to identify pathomechanisms and drug targets. Recent investigations have indicated that 3D skin models are well suitable for drug testing and preclinical studies of topical therapies. The analysis of skin diseases has recognized the importance of inflammatory mechanisms and immune responses and thus other cell types such as dendritic cells and T cells in the skin. Current developments include the production of more complete skin models comprising a range of different cell types. Organ models and even multi-organ systems are being developed for the analysis of higher levels of cellular interaction and drug responses and are among the most recent innovations in skin modelling. They promise improved robustness and flexibility and aim at a body-on-a-chip solution for comprehensive pharmaceutical in vitro studies.


Systematic characterization of chromatin modifying enzymes identifies KDM3B as a critical regulator in castration resistant prostate cancer.
Androgen deprivation therapy (ADT) is the standard care for prostate cancer (PCa) patients who fail surgery or radiotherapy. While initially effective, the cancer almost always recurs as a more aggressive castration resistant prostate cancer (CRPC). Previous studies have demonstrated that chromatin modifying enzymes can play a critical role in the conversion to CRPC. However, only a handful of these potential pharmacological targets have been tested. Therefore, in this study, we conducted a focused shRNA screen of chromatin modifying enzymes previously shown to be involved in cellular differentiation. We found that altering the balance between histone methylation and demethylation impacted growth and proliferation. Of all genes tested, KDM3B, a histone H3K9 demethylase, was found to have the most antiproliferative effect. These results were phenocopied with a KDM3B CRISPR/Cas9 knockout. When tested in several PCa cell lines, the decrease in proliferation was remarkably specific to androgen-independent cells. Genetic rescue experiments showed that only the enzymatically active KDM3B could recover the phenotype. Surprisingly, despite the decreased proliferation of androgen-independent cell no alterations in the cell cycle distribution were observed following KDM3B knockdown. Whole transcriptome analyses revealed changes in the gene expression profile following loss of KDM3B, including downregulation of metabolic enzymes such as ARG2 and RDH11. Metabolomic analysis of KDM3B knockout showed a decrease in several critical amino acids. Overall, our work reveals, for the first time, the specificity and the dependence of KDM3B in CRPC proliferation.


Fostering innovation in contaminated sediments management through multicriteria technology assessment and public participation.
Management of contaminated sediments is problematic and costly. Several new technologies are under development that may in some cases reduce costs and environmental or ecological impacts. However, there are significant barriers to implementing new technologies, including the increased management complexity, the potential for introducing antagonistic or incommensurate objectives that are unfamiliar to stakeholders or regulators, and the difficulty of capturing private, commercial benefits from environmental improvements that may primarily benefit the public. This article identifies several innovative contaminated sediments technologies, discusses the difficulty of proving or quantifying the benefits of new technologies, and presents an agenda for research that would foster partnerships between scientific, government, and public communities of interest for the purpose of improving innovative technology assessment and environmental decision making.


Does childhood television viewing lead to attention problems in adolescence? Results from a prospective longitudinal study.
There is controversy over whether childhood television viewing causes attention problems. The findings from cross-sectional and longitudinal studies have been mixed. To our knowledge, no longitudinal studies have assessed the impact of children's television viewing on attention problems in adolescence. The objective of this study was to assess this association. Study members were a general population birth cohort of 1037 participants (502 female) born in Dunedin, New Zealand, between April 1972 and March 1973. Parental estimates of children's television-viewing time were obtained at ages 5, 7, 9, and 11 years. Self-, parent-, and teacher-reported attention problems in adolescence were obtained at ages 13 and 15 years. The mean of hours of television viewing during childhood was associated with symptoms of attention problems in adolescence. These associations remained significant after controlling for gender, attention problems in early childhood, cognitive ability at 5 years of age, and childhood socioeconomic status. This association was also independent of adolescent television viewing. Childhood television viewing was associated with attention problems in adolescence, independent of early attention problems and other confounders. These results support the hypothesis that childhood television viewing may contribute to the development of attention problems and suggest that the effects may be long-lasting.


Vitamin D Deficiency Prevalence in Late Neonatal Hypocalcemia: A Multicenter Study
Late neonatal hypocalcemia (LNH) is a common metabolic problem associated with hypoparathyroidism, high phosphate intake and vitamin D deficiency, often presenting with seizures. In this cross-sectional study, we aimed to evaluate the role of vitamin D deficiency in LNH in Turkey and to describe the characteristics of affected newborns. Conducted with a cross-sectional design and with the participation of 61 neonatal centers from December 2015 to December 2016, the study included term neonates with LNH (n=96) and their mothers (n=93). Data were registered on the FAVOR Web Registry System. Serum samples of newborns and mothers were analyzed for calcium, phosphate, magnesium, albumin, alkaline phosphatase, intact parathyroid hormone (iPTH) and 25 hydroxyvitamin D [25(OH)D] levels. The median (range) onset time of hypocalcemia was 5.0 (4.0-8.0) days of age, with a male preponderance (60.4%). The median (range) serum 25(OH)D levels of the neonates and their mothers were 6.3 (4.1-9.05) and 5.2 (4.7-8.8) ng/mL, respectively. The prevalence of vitamin D deficiency (<12 ng/mL) was high in both the neonates (86.5%) and mothers (93%). Serum 25(OH)D levels of the infants and mothers showed a strong correlation (p<0.001). While the majority (93.7%) of the neonates had normal/high phosphorus levels, iPTH levels were low or inappropriately normal in 54.2% of the patients. Vitamin D deficiency prevalence was found to be high in LNH. Efforts to provide vitamin D supplementation during pregnancy should be encouraged. Evaluation of vitamin D status should be included in the workup of LNH.


Rater reliability and construct validity of a mobile application for posture analysis.
[Purpose] Measurement of posture is important for those with a clinical diagnosis as well as researchers aiming to understand the impact of faulty postures on the development of musculoskeletal disorders. A reliable, cost-effective and low tech posture measure may be beneficial for research and clinical applications. The purpose of this study was to determine rater reliability and construct validity of a posture screening mobile application in healthy young adults. [Subjects and Methods] Pictures of subjects were taken in three standing positions. Two raters independently digitized the static standing posture image twice. The app calculated posture variables, including sagittal and coronal plane translations and angulations. Intra- and inter-rater reliability were calculated using the appropriate ICC models for complete agreement. Construct validity was determined through comparison of known groups using repeated measures ANOVA. [Results] Intra-rater reliability ranged from 0.71 to 0.99. Inter-rater reliability was good to excellent for all translations. ICCs were stronger for translations versus angulations. The construct validity analysis found that the app was able to detect the change in the four variables selected. [Conclusion] The posture mobile application has demonstrated strong rater reliability and preliminary evidence of construct validity. This application may have utility in clinical and research settings.


Mouse primordial germ cells lacking beta1 integrins enter the germline but fail to migrate normally to the gonads.
Primordial germ cells are the founder cells of the gametes. They are set aside at the initial stages of gastrulation in mammals, become embedded in the hind-gut endoderm, then actively migrate to the sites of gonad formation. The molecular basis of this migration is poorly understood. Here we sought to determine if members of the integrin family of cell surface receptors are required for primordial germ cell migration, as integrins have been implicated in the migration of several other motile cell types. We have established a line of mice which express green fluorescent protein in germline cells that has enabled us to efficiently purify primordial germ cells at different stages by flow cytometry. We have catalogued the spectrum of integrin subunit expression by primordial germ cells during and after migration, using flow cytometry, immunocytochemistry and RT-PCR. Through analysis of integrin beta1(-/-)-->wild-type chimeras, we show that embryonic cells lacking beta1 integrins can enter the germline. However, integrin beta1(-/-) primordial germ cells do not colonize the gonad efficiently. Embryos with targeted deletion of integrin subunit alpha3, alpha6, or alphaV show no major defects in primordial germ cell migration. These results demonstrate a role for beta1-containing integrins in the development of the germline, although an equivalent role for * integrin subunit(s) has yet to be established.


Imputation of variants from the 1000 Genomes Project modestly improves known associations and can identify low-frequency variant-phenotype associations undetected by HapMap based imputation.
Genome-wide association (GWA) studies have been limited by the reliance on common variants present on microarrays or imputable from the HapMap Project data. More recently, the completion of the 1000 Genomes Project has provided variant and haplotype information for several million variants derived from sequencing over 1,000 individuals. To help understand the extent to which more variants (including low frequency (1% ≤ MAF <5%) and rare variants (<1%)) can enhance previously identified associations and identify novel loci, we selected 93 quantitative circulating factors where data was available from the InCHIANTI population study. These phenotypes included cytokines, binding proteins, hormones, vitamins and ions. We selected these phenotypes because many have known strong genetic associations and are potentially important to help understand disease processes. We performed a genome-wide scan for these 93 phenotypes in InCHIANTI. We identified 21 signals and 33 signals that reached P<5×10(-8) based on HapMap and 1000 Genomes imputation, respectively, and 9 and 11 that reached a stricter, likely conservative, threshold of P<5×10(-11) respectively. Imputation of 1000 Genomes genotype data modestly improved the strength of known associations. Of 20 associations detected at P<5×10(-8) in both analyses (17 of which represent well replicated signals in the NHGRI catalogue), six were captured by the same index SNP, five were nominally more strongly associated in 1000 Genomes imputed data and one was nominally more strongly associated in HapMap imputed data. We also detected an association between a low frequency variant and phenotype that was previously missed by HapMap based imputation approaches. An association between rs112635299 and alpha-1 globulin near the SERPINA gene represented the known association between rs28929474 (MAF = 0.007) and alpha1-antitrypsin that predisposes to emphysema (P = 2.5×10(-12)). Our data provide important proof of principle that 1000 Genomes imputation will detect novel, low frequency-large effect associations.


[Effects of alpha lipoic acid and pirfenidone on liver cells antioxidant modulation against oxidative damage].
Liver fibrogenic processes are related to cellular redox state. Glutathione (GSH) is the major cellular antioxidant. GSH induced activation could be related to antifibrogenic effects. To explore the association between the antifibrogenic effect and pro-antioxidant mechanisms of alpha-lipoic acid (ALA) and pirfenidone (PFD). HepG2 cells and primary HSC cultures were exposed to menadione 0.1 μM (MEN) as oxidative stress inducer and treated to ALA (5 mM) or PFD (10 μM, 100 μM y 1000 μM). In HSC, PFD decreased cell proliferation and the expression of COL1A1, TGF-β1, TIMP1, IL6, TNFα and MCP1 induced by MEN. Furthermore it was confirmed that ALA and PFD activate diverse antioxidants mediators, however MEN decreases this response. Then, MEN, ALA and PFD induce an antioxidant response, the first one as a response to injury and the latter two as pro-antioxidant inducers. Therefore, when cells are exposed to oxidative stress, endogenous systems activate a battery of mediators that increase the antioxidant potential. When these cells are treated with ALA and PFD, de novo formation of protective genes decreases since previous elicited protection induced in response to injury, enhance ALA and PFD effects. Regardless of the route of action, ALA and PFD induce the biosynthesis of antioxidants mediators which is associated with modulation of fibrogenic processes.


Increased spring freezing vulnerability for alpine shrubs under early snowmelt.
Alpine dwarf shrub communities are phenologically linked with snowmelt timing, so early spring exposure may increase risk of freezing damage during early development, and consequently reduce seasonal growth. We examined whether environmental factors (duration of snow cover, elevation) influenced size and the vulnerability of shrubs to spring freezing along elevational gradients and snow microhabitats by modelling the past frequency of spring freezing events. We sampled biomass and measured the size of Salix herbacea, Vaccinium myrtillus, Vaccinium uliginosum and Loiseleuria procumbens in late spring. Leaves were exposed to freezing temperatures to determine the temperature at which 50% of specimens are killed for each species and sampling site. By linking site snowmelt and temperatures to long-term climate measurements, we extrapolated the frequency of spring freezing events at each elevation, snow microhabitat and per species over 37 years. Snowmelt timing was significantly driven by microhabitat effects, but was independent of elevation. Shrub growth was neither enhanced nor reduced by earlier snowmelt, but decreased with elevation. Freezing resistance was strongly species dependent, and did not differ along the elevation or snowmelt gradient. Microclimate extrapolation suggested that potentially lethal freezing events (in May and June) occurred for three of the four species examined. Freezing events never occurred on late snow beds, and increased in frequency with earlier snowmelt and higher elevation. Extrapolated freezing events showed a slight, non-significant increase over the 37-year record. We suggest that earlier snowmelt does not enhance growth in four dominant alpine shrubs, but increases the risk of lethal spring freezing exposure for less freezing-resistant species.


Gated fiber-optic-coupled detector for in vivo real-time radiation dosimetry.
Gated detection of the output of a fiber-optic-coupled radiation dosimeter effectively eliminated the direct contribution of Cerenkov radiation to the signal. The radiation source was an external beam radiotherapy machine that provided pulses of 6-MeV x rays. Gated detection was used to discriminate the signal collected during the radiation pulses, including Cerenkov interference, from the signal collected between the radiation pulses due only to phosphorescence from the Cu(1+)-doped glass detector. Gated detection of the long-lived phosphorescence of the Cu(1+)-doped glass provided real-time dose measurements that were linear with the absorbed dose and that were accurate for all field sizes studied.


A Stromal Cell Niche for Human and Mouse Type 3 Innate Lymphoid Cells.
Adaptive immunity critically depends on the functional compartmentalization of secondary lymphoid organs. Mesenchymal stromal cells create and maintain specialized niches that support survival, activation, and expansion of T and B cells, and integrated analysis of lymphocytes and their niche has been instrumental in understanding adaptive immunity. Lymphoid organs are also home to type 3 innate lymphoid cells (ILC3), innate effector cells essential for barrier immunity. However, a specialized stromal niche for ILC3 has not been identified. A novel lineage-tracing approach now identifies a subset of murine fetal lymphoid tissue organizer cells that gives rise exclusively to adult marginal reticular cells. Moreover, both cell types are conserved from mice to humans and colocalize with ILC3 in secondary lymphoid tissues throughout life. In sum, we provide evidence that fetal stromal organizers give rise to adult marginal reticular cells and form a dedicated stromal niche for innate ILC3 in adaptive lymphoid organs.


Steps Toward Technology Design to Beat Health Inequality - Participatory Design Walks in a Neighbourhood with High Health Risks.
This paper explores participatory design walks (PD walks) as a first step toward a participatory design of health information technology (HIT) aimed at tackling health inequality in a neighbourhood identified as a high-risk health area. Existing research shows that traditional methods for health promotion, such as campaigns and teaching, have little to no effect in high-risk health areas. Rather, initiatives must be locally anchored - integrated into the local culture, and based on social relationships and group activities. This paper explains how we conducted PD walks with residents and community workers in the neighbourhood and how this participatory approach supported a first step toward HIT design that tackles health inequality. This is important, as people in neighbourhoods with high health risks are not the target audience for the health technology innovation currently taking place despite the fact that this group suffers the most from health inequality and weigh most on the public healthcare services and costs. The study identifies social and cultural aspects that influence everyday health management and presents how a citizen-driven approach like PD walks, can contribute valuable insights for design of HIT. The paper provides concrete methodological recommendations on how to conduct PD walks that are valuable to HIT designers and developers who aim to do PD with neighbourhoods.


White matter hyperintensity as a factor associated with delayed mood disorders in patients with acute ischemic stroke.
Mood disorder is a frequent complication of stroke. Comorbid depressive and anxiety disorders are very common, indicating that it is advisable to assess both disorders at the same time. The aim of the present study was to examine the prevalence of post-stroke depression (PSD) and poststroke anxiety (PSA) at baseline and to evaluate factors related to delayed PSD and PSA at 3 months after stroke onset. This was a prospectively registered and retrospectively analyzed study of patients with acute ischemic stroke between January 2009 and March 2010. Patients included in this study were interviewed in order to evaluate their Hospital Anxiety and Depression Scale (HADS) scores. In this study, each depression and anxiety score was dichotomized into 'nondepressive and nonanxious' (HADS-D and HADS-A ≤7) and 'depressive and anxious' (HADS-D and HADS-A >7). Multiple logistic regression analysis was used to evaluate the independent factors of depressive and anxious symptoms 3 months after stroke onset. Of the 133 patients, 47.4% were 'depressive' and 56.4% were 'anxious' at baseline. The depressive and anxious groups had a significantly higher frequency of severe white matter hyperintensity (WMH) than the nondepressive and nonanxious groups (p < 0.05). The independent factors of PSD and PSA at 3 months were deep white matter hyperintensities (DWMH) and modified Rankin scale 0 to 1 at 3 months. In conclusions, the results of our study demonstrated that delayed depression and anxiety after ischemic stroke were related to the severity of DWMH and unfavorable outcomes at 3 months, regardless of anti-anxiety treatment. Our results suggested that WMH might be associated with pathomechanism of delayed depression and anxiety.


The indoor use of plastic sheeting pre-impregnated with insecticide for control of malaria vectors.
To evaluate the efficacy of permethrin-treated plastic sheeting (ITPS) applied as a lining to the ceiling or walls of rooms against pyrethroid-susceptible and pyrethroid-resistant Anopheles gambiae. Overnight tests were carried out in veranda-trap experimental huts in Vallée du Kou, where two molecular forms of A. gambiae, S and M, occur. The S form is mostly pyrethroid resistant due to the kdr mechanism, and the M form is mostly kdr susceptible. A variety of ITPS covered surfaces were tested, ranging from ceiling only to all walls plus ceiling covered. ITPS had a major effect on the mortality of mosquitoes, the proportion killed being dependent upon the surface area covered. Homozygotes for kdr resistance showed lower rates of mortality than did heterozygotes or homozygotes for susceptibility. Deterred entry of mosquitoes and inhibition of blood feeding were also correlated with surface area covered. The mode of action and efficacy of ITPS seems to bear closer resemblance to that induced by indoor residual spraying (IRS) than to that induced by insecticide-treated nets. ITPS might be conceived as being equivalent to long-lasting or permanent IRS but without some of the operational constraints normally associated with spraying. High coverage of ITPS could potentially have a mass population effect on mosquitoes and give rise to long-term community protection against malaria. A phase III trial is justified to assess the acceptability of ITPS and its efficacy against malaria.


Macrophage migration inhibitory factor inhibits the migration of cartilage end plate-derived stem cells by reacting with CD74.
Macrophage migration inhibitory factor (MIF) is a multifunctional cytokine that regulates inflammatory reactions and the pathophysiology of many inflammatory diseases. Intervertebral disc (IVD) degeneration is characterized by an inflammatory reaction, but the potential role of MIF in IVD degeneration has not been determined. Recent studies have shown that MIF and its receptor, CD74, are involved in regulating the migration of human mesenchymal stem cells (MSCs); Thus, MIF might impair the ability of mesenchymal stem cells (MSCs) to home to injured tissues. Our previous studies indicated that cartilage endplate (CEP)-derived stem cells (CESCs) as a type of MSCs exist in human degenerate IVDs. Here, we investigate the role of MIF in regulating the migration of CESCs. CESCs were isolated and identified. We have shown that MIF was distributed in human degenerate IVD tissues and was subject to regulation by the pro-inflammatory cytokine TNF-α. Furthermore, in vitro cell migration assays revealed that nucleus pulposus (NP) cells inhibited the migration of CESCs in a number-dependent manner, and ELISA assays revealed that the amount of MIF in conditioned medium (CM) was significantly increased as a function of increasing cell number. Additionally, recombinant human MIF (r-MIF) inhibited the migration of CESCs in a dose-dependent manner. CESCs migration was restored when an antagonist of MIF, (S, R)-3(4-hydroxyphenyl)-4, 5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1), was added. Finally, a CD74 activating antibody (CD74Ab) was used to examine the effect of CD74 on CESCs motility and inhibited the migration of CESCs in a dose-dependent manner. We have identified and characterized a novel regulatory mechanism governing cell migration during IVD degeneration. The results will benefit understanding of another possible mechanism for IVD degeneration, and might provide a new method to repair degenerate IVD by enhancing CESCs migration to degenerated NP tissues to exert their regenerative effects.


Physical and psychosocial factors associated with physical activity in patients with chronic obstructive pulmonary disease.
To assess physical activity and sitting time in patients with chronic obstructive pulmonary disease (COPD) and to investigate which physical and psychosocial factors are associated with physical activity and sitting time. Cross-sectional study. Patients were recruited at outpatient clinics of general hospitals and from general practitioners. Patients (N=113) with mild to very severe COPD. Not applicable. Physical activity and sitting time were measured with a triaxial accelerometer (24h/d). Mean locomotion time per 24 hours was 6.8% (range, 0.7%-20.4%). Elevated physical activity was independently associated with higher self-efficacy, higher functional exercise capacity, and lower lung hyperinflation. Decreased physical activity was strongest in more severe stages of COPD, in which the patients were mainly limited by physical disease-specific factors (higher lung hyperinflation, worse dyspnea severity, worse leg muscle function, and oxygen use). In less severe patients, physical activity was independently associated with more generic factors (higher self-efficacy and the spring/summer season). Sitting time did not differ between severity stages, and longer sitting time in the total group was independently associated with more positive perception of treatment control, less autonomous motivation to exercise, not using sleep medication, and oxygen use. Both physical and psychosocial factors were associated with physical activity in patients with COPD. The factors associated with physical activity differed between disease severity stages, raising the question of whether physical activity enhancement programs should differ as well. Sitting time should be investigated further.


DeepBound: accurate identification of transcript boundaries via deep convolutional neural fields.
Reconstructing the full-length expressed transcripts ( a.k.a. the transcript assembly problem) from the short sequencing reads produced by RNA-seq protocol plays a central role in identifying novel genes and transcripts as well as in studying gene expressions and gene functions. A crucial step in transcript assembly is to accurately determine the splicing junctions and boundaries of the expressed transcripts from the reads alignment. In contrast to the splicing junctions that can be efficiently detected from spliced reads, the problem of identifying boundaries remains open and challenging, due to the fact that the signal related to boundaries is noisy and weak. We present DeepBound, an effective approach to identify boundaries of expressed transcripts from RNA-seq reads alignment. In its core DeepBound employs deep convolutional neural fields to learn the hidden distributions and patterns of boundaries. To accurately model the transition probabilities and to solve the label-imbalance problem, we novelly incorporate the AUC (area under the curve) score into the optimizing objective function. To address the issue that deep probabilistic graphical models requires large number of labeled training samples, we propose to use simulated RNA-seq datasets to train our model. Through extensive experimental studies on both simulation datasets of two species and biological datasets, we show that DeepBound consistently and significantly outperforms the two existing methods. DeepBound is freely available at https://github.com/realbigws/DeepBound . email@example.com or firstname.lastname@example.com.


MIDAS (Minimally Invasive Drilling And Styptic) protocol - A modified approach to treating patients under therapeutic anticoagulants.
Patients with cardiac or allied medical conditions mandating long term oral anticoagulant therapy form a sizeable database in an implant practice today. The management of such patients during surgical and dental procedures has always been debatable. Literature has documented evidence that indicates towards stopping the anticoagulant for a finite period. However, discontinuing anticoagulants is not always possible, given the risks of greater significance than the edentulous state. In such patients a minimally invasive flapless approach is preferred, having the potential to reduce bleeding, surgical time and postoperative edema. The purpose of this case series is to show a possible modified approach for dental implant placement using a CAD-CAM stent guided flapless approach without stopping of therapeutic anticoagulant medication.


Preoperative opioid use and its association with perioperative opioid demand and postoperative opioid independence in patients undergoing spine surgery.
Prospective cohort. To assess whether preoperative opioid use is associated with increased perioperative opioid demand and postoperative opioid independence in patients undergoing spine surgery. Previous work has demonstrated increased opioid requirements during the intraoperative and immediate postoperative period in patients with high levels of preoperative opioid use. Despite this, they remain a common agent class used for the management of pain in patients prior to spine surgery. A total of 583 patients were included. Self-reported daily opioid consumption was obtained preoperatively and converted into morphine equivalent amounts and opioid use was recorded at the 12-month postoperative time. Intraoperative and immediate postoperative opioid demand was calculated. Linear regression analyses for intraoperative and immediate postoperative opioid demand while logistic regression analyses for opioid independence at 12 months including relevant covariates such as depression and anxiety were performed. The median preoperative morphine equivalent amount for the cohort was 8.75 mg, with 55% of patients reporting some degree of opioid use. Younger age, more invasive surgery, anxiety, and primary surgery were significantly associated with increased intraoperative opioid demand (P < 0.05). Younger age, anxiety, and greater preoperative opioid use were significantly associated with increased immediate postoperative opioid demand (P < 0.05). More invasive surgery, anxiety, revision surgery, and greater preoperative opioid use were significantly associated with a decreased incidence of opioid independence at 12 months postoperatively (P < 0.01). Greater preoperative opioid use prior to undergoing spine surgery predicts increased immediate postoperative opioid demand and decreased incidence of postoperative opioid independence. Psychiatric diagnoses in those using preoperative opioids were predictors of continued opioid use at 12 months. Patients may benefit from preoperative counseling that emphasizes minimizing opioid use prior to undergoing spine surgery. 2.


Penalized multimarker vs. single-marker regression methods for genome-wide association studies of quantitative traits.
The data from genome-wide association studies (GWAS) in humans are still predominantly analyzed using single-marker association methods. As an alternative to single-marker analysis (SMA), all or subsets of markers can be tested simultaneously. This approach requires a form of penalized regression (PR) as the number of SNPs is much larger than the sample size. Here we review PR methods in the context of GWAS, extend them to perform penalty parameter and SNP selection by false discovery rate (FDR) control, and assess their performance in comparison with SMA. PR methods were compared with SMA, using realistically simulated GWAS data with a continuous phenotype and real data. Based on these comparisons our analytic FDR criterion may currently be the best approach to SNP selection using PR for GWAS. We found that PR with FDR control provides substantially more power than SMA with genome-wide type-I error control but somewhat less power than SMA with Benjamini-Hochberg FDR control (SMA-BH). PR with FDR-based penalty parameter selection controlled the FDR somewhat conservatively while SMA-BH may not achieve FDR control in all situations. Differences among PR methods seem quite small when the focus is on SNP selection with FDR control. Incorporating linkage disequilibrium into the penalization by adapting penalties developed for covariates measured on graphs can improve power but also generate more false positives or wider regions for follow-up. We recommend the elastic net with a mixing weight for the Lasso penalty near 0.5 as the best method.


Female autonomy as a contributing factor to women's HIV-related knowledge and behaviour in three culturally contrasting States in India.
Factors contributing to India's vulnerability to the AIDS epidemic include pervasive poverty, low levels of education and high gender stratification. This study uses data collected in the 1998-99 National Family Health Survey-2 (NFHS-2) to investigate the relationship between aspects of women's autonomy and four measures of HIV-related knowledge and behaviour--awareness and knowledge of HIV/AIDS, condom awareness and condom use--in three culturally contrasting states in India: Kerala (n=2884), Karnataka (n=4357) and Uttar Pradesh (n=8981). The NFHS-2 is a nationally representative survey of India, with a sampling scheme that was designed such that each state sample can be generalized back to represent ever-married women aged 15-49 living in the state. Kerala scores highest in the four health outcome measures, followed by Karnataka and then Uttar Pradesh, but condom use is lowest in Karnataka. Kerala also leads in the four dimensions of autonomy examined and in socio-demographic status, followed again by Karnataka and Uttar Pradesh. Despite these observed differences, in all three states, women with greater autonomy as measured by this study were more likely to be knowledgeable about AIDS and condoms and to use condoms, after controlling for socio-demographic factors. These results concur with other studies focusing on women's autonomy and health outcomes around the world, and point to the importance of incorporating a gender-based approach to AIDS prevention programmes in India.


Ecological constraints on female fitness in a phytophagous insect.
Although understanding female reproduction is crucial for population demography, determining how and to what relative extent it is constrained by different ecological factors is complicated by difficulties in studying the links between individual behavior, life history, and fitness in nature. We present data on females in a natural population of the butterfly Leptidea sinapis. These data were combined with climate records and laboratory estimates of life-history parameters to predict the relative impact of different ecological constraints on female fitness in the wild. Using simulation models, we partitioned effects of male courtship, host plant availability, and temperature on female fitness. Results of these models indicate that temperature is the most constraining factor on female fitness, followed by host plant availability; the short-term negative effects of male courtship that were detected in the field study were less important in models predicting female reproductive success over the entire life span. In the simulations, females with more reproductive reserves were more limited by the ecological variables. Reproductive physiology and egg-laying behavior were therefore predicted to be co-optimized but reach different optima for females of different body sizes; this prediction is supported by the empirical data. This study thus highlights the need for studying behavioral and life-history variation in orchestration to achieve a more complete picture of both demographic and evolutionary processes in naturally variable and unpredictable environments.