Suicide Following Deliberate Self-Harm.
The authors sought to identify risk factors for repeat self-harm and completed suicide over the following year among adults with deliberate self-harm. A national cohort of Medicaid-financed adults clinically diagnosed with deliberate self-harm (N=61,297) was followed for up to 1 year. Repeat self-harm per 1,000 person-years and suicide rates per 100,000 person-years (based on cause of death information from the National Death Index) were determined. Hazard ratios of repeat self-harm and suicide were estimated by Cox proportional hazard models. During the 12 months after nonfatal self-harm, the rate of repeat self-harm was 263.2 per 1,000 person-years and the rate of completed suicide was 439.1 per 100,000 person-years, or 37.2 times higher than in a matched general population cohort. The hazard of suicide was higher after initial self-harm events involving violent as compared with nonviolent methods (hazard ratio=7.5, 95% CI=5.5-10.1), especially firearms (hazard ratio=15.86, 95% CI=10.7-23.4; computed with poisoning as reference), and to a lesser extent after events of patients who had recently received outpatient mental health care (hazard ratio=1.6, 95% CI=1.2-2.0). Compared with self-harm patients using nonviolent methods, those who used violent methods were at significantly increased risk of suicide during the first 30 days after the initial event (hazard ratio=17.5, 95% CI=11.2-27.3), but not during the following 335 days. Adults treated for deliberate self-harm frequently repeat self-harm in the following year. Patients who use a violent method for their initial self-harm, especially firearms, have an exceptionally high risk of suicide, particularly right after the initial event, which highlights the importance of careful assessment and close follow-up of this group.


Conformational and hydration effects of site-selective sodium, calcium and strontium ion binding to the DNA Holliday junction structure d(TCGGTACCGA)(4).
The role of metal ions in determining the solution conformation of the Holliday junction is well established, but to date the picture of metal ion binding from structural studies of the four-way DNA junction is very incomplete. Here we present two refined structures of the Holliday junction formed by the sequence d(TCGGTACCGA) in the presence of Na(+) and Ca(2+), and separately with Sr(2+) to resolutions of 1.85A and 1.65A, respectively. This sequence includes the ACC core found to promote spontaneous junction formation, but its structure has not previously been reported. Almost complete hydration spheres can be defined for each metal cation. The Na(+) sites, the most convincing observation of such sites in junctions to date, are one on either face of the junction crossover region, and stabilise the ordered hydration inside the junction arms. The four Ca(2+) sites in the same structure are at the CG/CG steps in the minor groove. The Sr(2+) ions occupy the TC/AG, GG/CC, and TA/TA sites in the minor groove, giving ten positions forming two spines of ions, spiralling through the minor grooves within each arm of the stacked-X structure. The two structures were solved in the two different C2 lattices previously observed, with the Sr(2+) derivative crystallising in the more highly symmetrical form with two-fold symmetry at its centre. Both structures show an opening of the minor groove face of the junction of 8.4 degrees in the Ca(2+) and Na(+) containing structure, and 13.4 degrees in the Sr(2+) containing structure. The crossover angles at the junction are 39.3 degrees and 43.3 degrees, respectively. In addition to this, a relative shift in the base pair stack alignment of the arms of 2.3A is observed for the Sr(2+) containing structure only. Overall these results provide an insight into the so-far elusive stabilising ion structure for the DNA Holliday junction.


A reduced-tillering trait shows small but important yield gains in dryland wheat production.
Reducing the number of tillers per plant using a tiller inhibition (tin) gene has been considered as an important trait for wheat production in dryland environments. We used a spatial analysis approach with a daily time-step coupled radiation and transpiration efficiency model to simulate the impact of the reduced-tillering trait on wheat yield under different climate change scenarios across Australia's arable land. Our results show a small but consistent yield advantage of the reduced-tillering trait in the most water-limited environments both under current and likely future conditions. Our climate scenarios show that whilst elevated [CO2 ] (e[CO2 ]) alone might limit the area where the reduced-tillering trait is advantageous, the most likely climate scenario of e[CO2 ] combined with increased temperature and reduced rainfall consistently increased the area where restricted tillering has an advantage. Whilst long-term average yield advantages were small (ranged from 31 to 51 kg ha-1 year-1 ), across large dryland areas the value is large (potential cost-benefits ranged from Australian dollar 23 to 60 MIL/year). It seems therefore worthwhile to further explore this reduced-tillering trait in relation to a range of different environments and climates, because its benefits are likely to grow in future dry environments where wheat is grown around the world.


Bowel Management and Quality of Life in Children With Spina Bifida in South Korea.
Bowel management is a concern in patients with spina bifida. We evaluated the status of bowel management in children with spina bifida (SB) and the effects on quality of life (QoL) of children and their caregivers. Data were collected from 173 children with SB between January and June 2011, whose bowel management status and QoL were assessed using a self-administered questionnaire. Of the 173 children, 38 (22.0%) reported normal defecation, 73 (42.2%) reported constipation only, and 62 (35.8%) reported fecal incontinence with/without constipation. For defecation, 59 children (34.1%) used digital stimulation or manual extraction, 28 (16.2%) used suppositories or enemas, 35 (20.3%) used laxatives, 4 (2.3%) used an antegrade continence enema, and 3 (1.7%) used transanal irrigation. There were significant differences in QoL, depending on defecation symptoms. Children with fecal incontinence and their caregivers had difficulties in travel and socialization (p < .0001), caregivers' emotions (p < .0001), family relationships (p < .0001), and finances (p < .0001). Constipation and fecal incontinence affect QoL of children with SB and their caregivers. Therefore, more attention should be paid to bowel problems and help should be provided to children and their caregivers to improve QoL.


A Probabilistic Approach to Cross-Region Matching-Based Image Retrieval.
With deep convolutional features, cross-region matching (CRM) has recently shown superior performance on image retrieval. It evaluates image similarity by comparing image regions at different locations and scales, and is, therefore, more robust to geometric variance of objects. This paper first scrutinizes CRM-based image retrieval to provide a rigorous probabilistic interpretation by following the probability ranking principle. In addition to manifesting the assumptions implicitly taken by CRM, our interpretation highlights a fundamental issue hindering the performance of CRM-when comparing two image regions, CRM ignores modeling the distribution of the visual concept class associated with an image region, making the similarity comparison less precise. Taking advantage of the unprecedented representation capability of deep convolutional features, this paper proposes one approach to tackle that issue. It treats locally clustered image regions as a pseudo-labeled class sharing the same visual concept and utilizes them to model the distribution of the visual concept class associated with an image region. Both non-parametric and parametric methods are developed for this purpose, with careful probabilistic justification. Extensive experimental study on multiple benchmark data sets demonstrates the superior performance of the proposed pseudo-label approach to CRM and other comparable methods, with the maximum improvement of more than 10 percentage points over CRM.


[Molecular evolution and structure of eukaryotic nuclear RNA polymerase subunits in light of the exon-intron organization of their genes].
Analysis of literary data (for Saccharomyces cerevisiae, Caenorhabditis elegans, Arabidopsis thaliana, Homo sapiens, and some other Eucarya) and our data (for Schizosaccharomyces pombe) on the exon-intron organization of the genes encoding subunits of nuclear RNA polymerases showed that introns in the orthologous genes from different organisms are arranged nonrandomly, namely, their positions, if projected on the map of the comparison of the amino acid sequences of the orthologous subunits, not infrequently coincide in evolutionarily distant species. As a rule, intron positions correspond to the boundaries of the structurally conserved regions (domains) or to the sites of possible turns of the polypeptide chain. For example, introns flank the secondary structure elements in the Rpb8 subunit with the known three-dimensional structure or the structure-function modules in subunits Rpb10 and Rpc10. These facts are in agreement with the idea of the ancient origin of introns, and with the notion of evolution of ancient protein sequences through the assembly of their genes from short protoexons selected by the nature as far back as the RNA world times. Comparative analysis of the primary structures of the subunits of eukaryotic RNA polymerases allowed us to reveal a nuclear localization signal in subunit Rpb10 and some hypothetical archaeal homologues of subunit Rpc10.


Direct visualization of protease action on collagen triple helical structure.
Enzymatic processing of extracellular matrix (ECM) macromolecules by matrix metalloproteases (MMPs) is crucial in mediating physiological and pathological cell processes. However, the molecular mechanisms leading to effective physiological enzyme-ECM interactions remain elusive. Only scant information is available on the mode by which matrix proteases degrade ECM substrates. An example is the enzymatic degradation of triple helical collagen II fragments, generated by the collagenase MMP-8 cleavage, during the course of acute inflammatory conditions by gelatinase B/MMP-9. As is the case for many other matrix proteases, it is not clear how MMP-9 recognizes, binds and digests collagen in this important physiological process. We used single molecule imaging to directly visualize this protease during its interaction with collagen fragments. We show that the initial binding is mediated by the diffusion of the protease along the ordered helix on the collagen (3/4) fragment, with preferential binding of the collagen tail. As the reaction progressed and prior to collagen degradation, gelatin-like morphologies resulting from the denaturation of the triple helical collagen were observed. Remarkably, this activity was independent of enzyme proteolysis and was accompanied by significant conformational changes of the working protease. Here we provide the first direct visualization of highly complex mechanisms of macromolecular interactions governing the enzymatic processing of ECM substrates by physiological protease.


Validating drug repurposing signals using electronic health records: a case study of metformin associated with reduced cancer mortality.
Drug repurposing, which finds new indications for existing drugs, has received great attention recently. The goal of our work is to assess the feasibility of using electronic health records (EHRs) and automated informatics methods to efficiently validate a recent drug repurposing association of metformin with reduced cancer mortality. By linking two large EHRs from Vanderbilt University Medical Center and Mayo Clinic to their tumor registries, we constructed a cohort including 32,415 adults with a cancer diagnosis at Vanderbilt and 79,258 cancer patients at Mayo from 1995 to 2010. Using automated informatics methods, we further identified type 2 diabetes patients within the cancer cohort and determined their drug exposure information, as well as other covariates such as smoking status. We then estimated HRs for all-cause mortality and their associated 95% CIs using stratified Cox proportional hazard models. HRs were estimated according to metformin exposure, adjusted for age at diagnosis, sex, race, body mass index, tobacco use, insulin use, cancer type, and non-cancer Charlson comorbidity index. Among all Vanderbilt cancer patients, metformin was associated with a 22% decrease in overall mortality compared to other oral hypoglycemic medications (HR 0.78; 95% CI 0.69 to 0.88) and with a 39% decrease compared to type 2 diabetes patients on insulin only (HR 0.61; 95% CI 0.50 to 0.73). Diabetic patients on metformin also had a 23% improved survival compared with non-diabetic patients (HR 0.77; 95% CI 0.71 to 0.85). These associations were replicated using the Mayo Clinic EHR data. Many site-specific cancers including breast, colorectal, lung, and prostate demonstrated reduced mortality with metformin use in at least one EHR. EHR data suggested that the use of metformin was associated with decreased mortality after a cancer diagnosis compared with diabetic and non-diabetic cancer patients not on metformin, indicating its potential as a chemotherapeutic regimen. This study serves as a model for robust and inexpensive validation studies for drug repurposing signals using EHR data.


Reduced or absent cyclin H expression is an independent prognostic marker for poor outcome in diffuse large B-cell lymphoma.
Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults, accounting for nearly 40% of all non-Hodgkin's lymphomas. As cell proliferation is essential for tumor growth, analysis of the cell cycle might give additional information on tumor progression. Although markers distinctive for cell-cycle regulation in DLBCL have been addressed, less attention has been paid to cyclin H in DLBCL with respect to its prognostic and potential therapeutic implications. Cyclin H occurs as a component of the cyclin H/Cdk 7/Mat 1 complex. Cyclin H is also a substrate of protein kinase 2, a ubiquitously expressed serine/threonine protein kinase required for cell viability and cell-cycle progression. We evaluated the expression of cyclin H by immunohistochemistry in 301 DLBCLs in a tissue microarray format. Validation was done by performing quantitative real-time polymerase chain reaction and Western blotting experiments for cyclin H. We studied the relationship between cyclin H expression in comparison to other cyclins (A, B1, D1, D3, and E) and the proliferation marker Ki-67. Reduced or absent cyclin H expression was seen in 14.5% of the DLBCL cases. Interestingly, reduced or absent cyclin H expression was correlated with lower expression of proliferation marker Ki-67 (P < .0001), cyclin B1 (P = .0001), cyclin D3 (P = .0007), and cyclin E (P < .0001). Reduced or absent cyclin H expression was significantly associated with poor overall survival, in both the univariate (P = .0286) and multivariate analysis with International Prognostic Index (P = .0180). Our study demonstrates the independent prognostic value of cyclin H expression in DLBCL and proposes its use as a prognostic marker.


Use of artificial neural networks to decision making in patients with lumbar spinal canal stenosis.
A lack of consensus exists regarding indications for surgery for lumbar spinal canal stenosis (LSCS). Hence, the aim of this study was to develop an artificial neural network (ANN) model that is designed to accurately select patients for surgery or non-surgical options and to compare such with the traditional clinical decision making approach in LSCS patients. An ANN model and a logistic regression (LR) model were used as predicting models. The data for a total of 346 of 379 patients (143 male, 203 female, mean age 59.5±11.5 years) were available for the analysis. The measured metrics included Visual Analog Scale (VAS) of leg pain/numbness, the Japanese Orthopedic Association (JOA) Score, the Neurogenic Claudication Outcome Score (NCOS), the Oswestry Disability Index (ODI), the Swiss Spinal Stenosis Score (SSS), the Stenosis Bothersomeness Index (SBI), the dural sac cross-sectional surface area (DSCA), the Stenosis Ratio (SR), the Self-Paced Walking Test (SPWT), morphology grade presented by Schizas et al. and grading system introduced by Lee et al. Successful outcome was recorded based on the criteria presented by Stucki et al. Twelve measures and age, gender, and duration of symptoms, were recorded as the input variables for the ANN and LR, and the ANN was fed with patients. A sensitivity analysis was applied to the developed ANN model to identify the important variables. Receiver operating characteristic (ROC) analysis, Hosmer-Lemeshow (H-L) statistics and accuracy rate were calculated for evaluating the two models. The study was not supported by a grant and the authors declare that they have no conflict of interest. The patient information was divided into training (N.=174), testing (N.=86), and validation (N.=86) data sets. Successful outcome were achieved in 93.4% of the patients selected for surgery and 89.4% for non-surgery at 1-year follow-up. The SR, morphology grade and grading system were important variables identified by the ANN. The ANN model displayed better accuracy rate (97.8 %), a better H-L statistic (41.1 %) which represented a good-fit calibration, and a better AUC (89.0%), compared to the LR model. The findings showed that an ANN model can predict the optimal treatment choice for LSCS patients in clinical setting and is superior to LR model. Our results will need to be confirmed with external validation studies.


The percutaneous penetration of prostaglandin E1 and its alkyl esters.
The percutaneous delivery of PGE1 and its alkyl esters in alcoholic saline solution through hairless mouse skin was compared. The quantification of alkyl esters was based on the same principle as that for PGE1, which was converted to PGB1 to enhance the sensitivity and minimize the interference. Results showed that it was PGE1 that appeared in the receiver compartment for all alkyl esters examined. The flux of all alkyl esters of PGE1 in the same concentration was higher than PGE1 itself at most of saline vehicle with various fractions of alcohol. The maximal flux for a fixed concentration of each alkyl ester appeared at different fractions of alcohol. When the fractions of alcohol was kept constant, the alkyl ester that showed the maximal flux at this concentration appeared to have a longer chain length with increasing the fraction of alcohol. But isopropyl ester deviated from this order. It was concluded that the alkyl ester derivatives promoted the penetration of PGE1 mainly as a result of enhancing the drug partitioning into the stratum corneum. The alcohol fraction that needed to achieve the maximal flux at the same concentration increased with the increase of alkyl chain length, which resulted in the decrease of solubility parameter. It is necessary to optimize the fraction of alcohol in the saline solution in order to achieve the maximal flux at a fixed concentration for these alkyl esters with different alkyl chain length.


MGMT expression predicts response to temozolomide in pancreatic neuroendocrine tumors.
Temozolomide (TEM) showed encouraging results in well-differentiated pancreatic neuroendocrine tumors (WDPNETs). Low O(6)-methylguanine-DNA methyltransferase (MGMT) expression and MGMT promoter methylation within tumors correlate with a better outcome under TEM-based chemotherapy in glioblastoma. We aimed to assess whether MGMT expression and MGMT promoter methylation could help predict the efficacy of TEM-based chemotherapy in patients with WDPNET. Consecutive patients with progressive WDPNET and/or liver involvement over 50% who received TEM between 2006 and 2012 were retrospectively studied. Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guidelines. Nuclear expression of MGMT was assessed by immunochemistry (H-score, 0-300) and MGMT promoter methylation by pyrosequencing. Forty-three patients (21 men, 58years (27-84)) with grade 1 WDPNET (n=6) or 2 (n=36) were analyzed. Objective response, stable disease, and progression rates were seen in 17 patients (39.5%), 18 patients (41.9%), and 8 patients (18.6%), respectively. Low MGMT expression (≤50) was associated with radiological objective response (P=0.04) and better progression-free survival (PFS) (HR=0.35 (0.15-0.81), P=0.01). Disease control rate at 18months of treatment remained satisfying with an MGMT score up to 100 (74%) but dropped with a higher expression. High MGMT promoter methylation was associated with a low MGMT expression and longer PFS (HR=0.37 (0.29-1.08), P=0.05). Low MGMT score (≤50) appears to predict an objective tumor response, whereas an intermediate MGMT score (50-100) seems to be associated with prolonged stable disease.


Lidar measurement of atmospheric aerosol extinction profiles: a comparison between two techniques-Klett inversion and pure rotational Raman scattering methods.
Two lidar methods of determining an atmospheric extinction coefficient profile are compared. The methods are the Klett inversion method for elastic lidar return and the log-derivative method for rotational Raman backscattered signal processing. The comparison includes numerical modeling and processing of lidar measurements when both the elastic and the rotational Raman backscattered signals are measured simultaneously. The suggested idea is that such a comparison can be used as a criterion for the reliability of the results of lidar measurements, similar to the comparison between the results of lidar and contact measurements.


Measurement of thromboxane and prostacyclin in valvulotomized human saphenous veins.
The present study was done to determine the effect of the modified Hall valvulotome technique on endothelial injury by measuring TxB2 and 6-keto PGF1alpha, the stable metabolites of thromboxane and prostacyclin, respectively. It was hypothesized that increased levels of these cyclooxygenase products would be an excellent indicator of vascular endothelial injury in the presence of the modified Hall valvulotome. Eight segments of human distal saphenous veins were obtained, each measuring approximately 4 cm in length, with diameters of approximately 2 to 3 mm. From these original vein segments, two groups of smaller vein segments were examined, with each group consisting of eight segments, each segment measuring 2 cm in length. The first group of vein segments was designated as the control group, and the second group of vessels had a modified Hall valvulotome (2.5 mm size) inserted into each segment to simulate valvulotomy. After this procedure, all vein segments were analyzed for levels of thromboxane and prostacyclin by a standard radioimmunoassay procedure. Results from the present study indicate that the modified Hall valvulotome technique in human saphenous veins does not significantly increase the levels of the cyclooxygenase metabolites thromboxane and prostacyclin relative to control conditions. However, the ratio of TxB2 formation 6-keto PGF1alpha production was increased in the valvulotomized vessel segments, indicating possible platelet release of thromboxane. Therefore, even though there was increased thromboxane production relative to prostacyclin levels in the modified Hall valvulotome technique, it still appears that this type of valvulotomy is relatively noninsulting to the endothelial cell lining.


The IGF-Trap: Novel Inhibitor of Carcinoma Growth and Metastasis.
The IGFI receptor promotes malignant progression and has been recognized as a target for cancer therapy. Clinical trials with anti-IGFIR antibodies provided evidence of therapeutic efficacy but exposed limitations due in part to effects on, and the compensatory function of, the insulin receptor system. Here, we report on the production, characterization, and biologic activity of a novel, IGF-targeting protein (the IGF-Trap) comprising a soluble form of hIGFIR and the Fc portion of hIgG1. The IGF-Trap has a high affinity for hIGFI and hIGFII but low affinity for insulin, as revealed by surface plasmon resonance. It efficiently blocked IGFIR signaling in several carcinoma cell types and inhibited tumor cell proliferation, migration, and invasion in vitro. In vivo, the IGF-Trap showed favorable pharmacokinetic properties and could suppress the growth of established breast carcinoma tumors when administered therapeutically into tumor-bearing mice, improving disease-free survival. Moreover, IGF-Trap treatment markedly reduced experimental liver metastasis of colon and lung carcinoma cells, increasing tumor cell apoptosis and reducing angiogenesis. Finally, when compared with an anti-IGFIR antibody or IGF-binding protein-1 that were used at similar or higher concentrations, the IGF-Trap showed superior therapeutic efficacy to both inhibitors. Taken together, we have developed a targeted therapeutic molecule with highly potent anticancer effects that could address limitations of current IGFIR-targeting agents.


Poly[μ2-aqua-μ4-[1-(4-chloro-phen-yl)-4,4,4-tri-fluoro-butane-1,3-dionato]-potassium].
In the title compound, [K(C10H5ClO2F3)(H2O)] n , the two independent K(+) ions are located on a twofold rotation axis. For each of the cations, the distorted cubic coordination environment is defined by two F and four O atoms of symmetry-related 1,4-chloro-phenyl-4,4,4-tri-fluoro-butane-1,3-dionate anions and by two O atoms of water mol-ecules. The μ4-bridging character of the anion and the μ2-bridging of the water mol-ecule lead to the formation of layers parallel to (100). The coordinating water mol-ecules are also involved in O-H⋯O hydrogen bonds that reinforce the mol-ecular cohesion within the layers, which are stacked along [100]. The β-diketonate anion is not planar, with an angle of 31.78 (10)° between the mean planes of the diketonate group and the chloro-phenyl ring.


A combined teamwork training and work standardisation intervention in operating theatres: controlled interrupted time series study.
Teamwork training and system standardisation have both been proposed to reduce error and harm in surgery. Since the approaches differ markedly, there is potential for synergy between them. Controlled interrupted time series with a 3 month intervention and observation phases before and after. Operating theatres conducting elective orthopaedic surgery in a single hospital system (UK Hospital Trust). Teamwork training based on crew resource management plus training and follow-up support in developing standardised operating procedures. Focus of subsequent standardisation efforts decided by theatre staff. Paired observers watched whole procedures together. We assessed non-technical skills using NOTECHS II, technical performance using glitch rate and compliance with WHO checklist using a simple quality tool. We measured complication and readmission rates and hospital stay using hospital administrative records. Before/after change was compared in the active and control groups using two-way ANOVA and regression models. 1121 patients were operated on before and 1100 after intervention. 44 operations were observed before and 50 afterwards. Non-technical skills (p=0.002) and WHO compliance (p<0.001) improved significantly after the intervention in the active versus the control group. Glitch count improved in both groups and there was no significant effect on clinical outcomes. Combined training in teamwork and system improvement causes marked improvements in team behaviour and WHO performance, but not technical performance or outcome. These findings are consistent with the synergistic hypothesis, but larger controlled studies with a strong implementation strategy are required to test potential outcome effects.


Compartmental Innervation of the Superior Oblique Muscle in Mammals.
Intramuscular innervation of mammalian horizontal rectus extraocular muscles (EOMs) is compartmental. We sought evidence of similar compartmental innervation of the superior oblique (SO) muscle. Three fresh bovine orbits and one human orbit were dissected to trace continuity of SO muscle and tendon fibers to the scleral insertions. Whole orbits were also obtained from four humans (two adults, a 17-month-old child, and a 33-week stillborn fetus), two rhesus monkeys, one rabbit, and one cow. Orbits were formalin fixed, embedded whole in paraffin, serially sectioned in the coronal plane at 10-μm thickness, and stained with Masson trichrome. Extraocular muscle fibers and branches of the trochlear nerve (CN4) were traced in serial sections and reconstructed in three dimensions. In the human, the lateral SO belly is in continuity with tendon fibers inserting more posteriorly on the sclera for infraducting mechanical advantage, while the medial belly is continuous with anteriorly inserting fibers having mechanical advantage for incycloduction. Fibers in the monkey superior SO insert more posteriorly on the sclera to favor infraduction, while the inferior portion inserts more anteriorly to favor incycloduction. In all species, CN4 bifurcates prior to penetrating the SO belly. Each branch innervates a nonoverlapping compartment of EOM fibers, consisting of medial and lateral compartments in humans and monkeys, and superior and inferior compartments in cows and rabbits. The SO muscle of humans and other mammals is compartmentally innervated in a manner that could permit separate CN4 branches to selectively influence vertical versus torsional action.


Always on guard: emotion regulation in women with borderline personality disorder compared to nonpatient controls and patients with cluster-C personality disorder.
Borderline personality disorder (BPD) is characterized by emotion dysregulation; however, it is unclear whether this is restricted to negative emotional stimuli or to what degree this is specific to BPD. We investigated neural correlates of hypothesized increased emotional sensitivity and impaired emotion regulation in patients with BPD. During fMRI scanning, patients with BPD, nonpatient controls and patients with cluster-C personality disorder completed an emotion regulation task, including negative, positive and erotic social pictures. We included 55 patients with BPD, 42 nonpatient controls and 24 patients with cluster-C personality disorder in our analyses. Passive viewing of negative stimuli resulted in greater activity in the anterior insula, temporoparietal junction and dorsolateral prefrontal cortex in patients with BPD than in nonpatient controls. The increased activity in the anterior insula and temporoparietal junction was also present when patients with BPD viewed positive stimuli. During regulation of negative stimuli compared with passive viewing, nonpatient controls showed greater activity in the dorsal anterior cingulate cortex, dorsolateral prefrontal cortex, middle temporal gyrus and bilateral inferior parietal lobule. Patients with BPD did not show this increase in activity. Findings cannot be generalized to men, and patients represented a heterogeneous group regarding comorbid diagnoses and medication. When looking at emotional stimuli, patients with BPD showed a unique pattern of activity, suggesting an increase in brain activity involved in emotion generation. In the case of negative stimuli this is accompanied by increased activity in regulation areas. In contrast, increase of regulation processes seems absent when patients with BPD are explicitly instructed to regulate. Results of diagnosis specificity support a dimensional rather than a dichotomous differentiation between BPD and cluster-C personality disorder regarding emotional sensitivity and emotional regulation of social stimuli.


Protective effects of polyamine depletion in mouse models of type 1 diabetes: implications for therapy.
The underlying pathophysiology of type 1 diabetes involves autoimmune-mediated islet inflammation, leading to dysfunction and death of insulin-secreting islet β cells. Recent studies have shown that polyamines, which are essential for mRNA translation, cellular replication, and the formation of the hypusine modification of eIF5A may play an important role in the progression of cellular inflammation. To test a role for polyamines in type 1 diabetes pathogenesis, we administered the ornithine decarboxylase inhibitor difluoromethylornithine to two mouse models--the low-dose streptozotocin model and the NOD model--to deplete intracellular polyamines, and administered streptozotocin to a third model, which was haploinsufficient for the gene encoding the hypusination enzyme deoxyhypusine synthase. Subsequent development of diabetes and/or glucose intolerance was monitored. In the low-dose streptozotocin mouse model, continuous difluoromethylornithine administration dose-dependently reduced the incidence of hyperglycemia and led to the preservation of β cell area, whereas in the NOD mouse model of autoimmune diabetes difluoromethylornithine reduced diabetes incidence by 50%, preserved β cell area and insulin secretion, led to reductions in both islet inflammation and potentially diabetogenic Th17 cells in pancreatic lymph nodes. Difluoromethylornithine treatment reduced hypusinated eIF5A levels in both immune cells and islets. Animals haploinsufficient for the gene encoding deoxyhypusine synthase were partially protected from hyperglycemia induced by streptozotocin. Collectively, these studies suggest that interventions that interfere with polyamine biosynthesis and/or eIF5A hypusination may represent viable approaches in the treatment of diabetes.


Reconstruction of complementary images in second harmonic generation microscopy.
Second harmonic generation microscopy(SHGM) has become widely used to image biological samples. Due to the complexity of biological samples, more and more effort has been put on polarization imaging in SHGM technology to uncover their structures. In this work, we put forward a novel stitching method based on careful mathematical calculation, and accomplish it by rotating laser polarization. We first show its validity in imaging a perfectly synthesized bio-origin polymer poly (3-hyroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx). Then, we test its power by getting a true image of fibrillar collagen structure of rat-tail tendon.


Development and validation of a prioritization rule for obtaining an immediate 12-lead electrocardiogram in the emergency department to identify ST-elevation myocardial infarction.
Current guidelines recommend an immediate (eg, <10 minutes) 12-lead electrocardiogram (ECG) to identify ST-elevation myocardial infarction (STEMI) among patients presenting to the emergency department (ED) with chest pain. Yet, one third of all patients with myocardial infarction do not have chest pain. Our objective was to develop a practical approach to identify patients, especially those without chest pain, who require an immediate ECG in the ED to identify STEMI. An ECG prioritization rule was derived and validated using classification and regression tree analysis among >3 million ED visits to 107 EDs from 2007 to 2008. The final study population included 3,575,178 ED patient visits; of these, 6,464 (0.18%) were diagnosed with STEMI. Overall, 1,413 (21.9%) of patients with STEMI did not present to the ED with chest pain. Major predictors of those requiring an immediate ECG in the ED included age ≥30 years with chest pain; age ≥50 years with shortness of breath, altered mental status, upper extremity pain, syncope, or generalized weakness; and those with age ≥80 years with abdominal pain or nausea/vomiting. When the ECG prioritization rule was applied to a validation sample, it had a sensitivity of 91.9% (95% CI 90.9%-92.8%) for STEMI and a negative predictive value 99.98% (95% CI 99.98%-99.98%). A simple ECG prioritization rule based on age and presenting symptoms in the ED can identify patients during triage who are at high risk for STEMI and therefore should receive an immediate 12-lead ECG, often before they are seen by a physician.


Pepsin A in Tracheal Secretions From Patients Receiving Mechanical Ventilation.
In patients in the intensive care unit (ICU) receiving mechanical ventilation, aspiration of gastric contents may lead to ventilator-associated events and other adverse outcomes. Pepsin in pulmonary secretions is a biomarker of microaspiration of gastric contents. To evaluate the association between tracheal pepsin A and clinical outcomes related to ventilator use. A subset of 297 patients from a larger clinical trial on aspiration of oral secretions in adults receiving mechanical ventilation consented to have pepsin A measured in their tracheal aspirate samples. A concentration ≥6.25 ng/mL indicated a positive result. Abundant microaspiration was defined as pepsin A in ≥30% of samples. Statistical analyses included analysis of variance, analysis of covariance, and χ2 tests. Most patients were White men, mean age 59.7 (SD, 18.8) years. Microaspiration was found in 43.8% of patients (n = 130), with abundant microaspiration detected in 17.5% (n = 52). After acuity was controlled for, patients with tracheal pepsin A had a longer mechanical ventilation duration (155 vs 104 hours, P < .001) and ICU stay (9.9 vs 8.2 days, P = .04), but not a longer hospital stay. Microaspiration of gastric contents occurred in nearly half of patients and was associated with a longer duration of mechanical ventilation and a longer stay in the ICU. Additional preventative interventions beyond backrest elevation, oropharyngeal suctioning, and management of endotracheal tube cuff pressure may be needed. Also, the timing of pepsin measurements to capture all microaspiration events requires additional exploration.


Umbilical cord blood transplantation in adults: results of the prospective Cord Blood Transplantation (COBLT).
The Cord Blood Transplantation study group conducted a prospective study of unrelated cord blood transplantation (CBT) to better define the role of this stem cell source for subjects requiring unrelated allogeneic transplantation. We report on 1 stratum of the study designated for adult subjects. The primary end point of the study was survival at 180 days. Secondary end points included engraftment, graft-versus-host disease, relapse, and long-term survival. Eligibility criteria for malignant and nonmalignant diseases were specified. Subjects with active central nervous system disease, Karnofsky performance status <70%, grade 3 or 4 or primary myelofibrosis, or suitable related donors were excluded. Enrollment required a single cord blood unit containing >10(7) nucleated cells per kilogram of recipient weight and matched at > or =4 HLA-A and -B (low or intermediate resolution) and -DRB1 (high resolution) types. Thirty-four subjects were entered, with a median age of 34.5 years (range, 18.2-55 years). Most subjects (n = 23) had a 4 of 6 match, 10 subjects had a 5 of 6 match, and 1 subject had a 6 of 6 match. Diagnoses at transplantation included acute myelogenous leukemia (n = 19), acute lymphoblastic leukemia (n = 9), chronic myelogenous leukemia (n = 3), myelodysplastic syndrome (n = 1), paroxysmal nocturnal hemoglobinuria (PNH) (n = 1), and non-Hodgkin lymphoma (n = 1); 94% were classified as poor risk according to National Marrow Donor Program criteria. Subjects received total body irradiation/cyclophosphamide (n = 27) or busulfan/melphalan (n = 7) conditioning regimens. Four subjects died before CBT and are described here but are not included in the main analysis. The cumulative incidence rates and median times to neutrophil (500/microL) and platelet (>20,000/microL) engraftment were 0.66 by day 42 (median, 31 days) and 0.35 by day 180 (median, 117 days). The cumulative incidence rate for grade II-IV GVHD was 0.34 by day 100. For the primary end point, survival at 180 days, Kaplan-Meier survival estimates were 0.30 (95% confidence interval, 0.14-0.46) by day 180 after transplantation. To date there are 2 survivors, and both are >36 months from enrollment. A retrospective analysis was performed by using high-resolution HLA-A and -B typing, which revealed that approximately one third of subjects had 1 or more additional HLA mismatches compared with results of low- or intermediate-resolution HLA typing. The findings of high treatment-related mortality and slow engraftment kinetics indicate that CBT should continue to be performed in specialized centers with a research focus on cord blood cells.


Recruitment of NIMA kinase shows that maturation of the S. pombe spindle-pole body occurs over consecutive cell cycles and reveals a role for NIMA in modulating SIN activity.
Mitotic exit in Saccharomyces cerevisiae and septation in Schizosaccharomyces pombe are regulated by a conserved signaling network called the mitotic exit and septum initiation networks (SIN), respectively. The network is active on one of the two anaphase B spindle-pole bodies (SPBs). Whereas the inherent asymmetry of growth by budding accounts for elements of the asymmetry in S. cerevisiae, it has been unclear how, or why, the pathway is asymmetric in S. pombe. We show that elements of SPB duplication in S. pombe are conservative, and that the SIN is active on the new SPB. SIN association with the new SPB persists after transient depolymerization of microtubules. The localization of the NIMA-related kinase, Fin1, reveals further complexity in SPB inheritance. Fin1 associates with the SPB bearing the older components in all cells and with the "new" SPB in half of the population. Fin1 only binds the new SPB when this new SPB has arisen from the duplication of an SPB that is two or more cycles old. Thus, each of the four SPBs generated over two consecutive cell cycles are different, because they have distinct fates in the next cell cycle. Fin1 binds the SPB once the SIN is active and the association requires the SIN inhibitors Byr4 and Cdc16. Fin1 physically associates with Byr4. Compromising Fin1 function leads to SIN activation on both anaphase B SPBs and promotes septation, indicating that Fin1 restrains SIN activity on the old SPB.


Trachealess (Trh) regulates all tracheal genes during Drosophila embryogenesis.
The Drosophila trachea is a branched tubular epithelia that transports oxygen and other gases. trachealess (trh), which encodes a bHLH-PAS transcription factor, is among the first genes to be expressed in the cells that will form the trachea. In the absence of trh, tracheal cells fail to invaginate to form tubes and remain on the embryo surface. Expression of many tracheal-specific genes depends on trh, but all of the known targets have relatively minor phenotypes compared to loss of trh, suggesting that there are additional targets. To identify uncharacterized transcriptional targets of Trh and to further understand the role of Trh in embryonic tracheal formation, we performed an in situ hybridization screen using a library of ~100 tracheal-expressed genes identified by the Berkeley Drosophila Genome Project (BDGP). Surprisingly, expression of every tracheal gene we tested was dependent on Trh, suggesting a major role for Trh in activation and maintenance of tracheal gene expression. A re-examination of the interdependence of the known early-expressed transcription factors, including trh, ventral veinless (vvl) and knirps/knirps-related (kni/knrl), suggests a new model for how gene expression is controlled in the trachea, with trh regulating expression of vvl and kni, but not vice versa. A pilot screen for the targets of Vvl and Kni/Knrl revealed that Vvl and Kni have only minor roles compared to Trh. Finally, genome-wide microarray experiments identified additional Trh targets and revealed that a variety of biological processes are affected by the loss of trh.


Emotional control, reappraised.
We are frequently challenged with situations requiring the control of our emotions, often under substantial time-pressure and rapidly changing contextual demands. Coping with those demands requires the ability to flexibly and rapidly switch between different emotional control strategies. However, this ability has been largely neglected by current neurocognitive models on emotional control. Drawing on the decision-making literature, we propose that rapid switching between alternative emotional control strategies requires the concurrent evaluation of unchosen (counterfactual) options. This model explains how an individual can adaptively change emotional control behavior to meet contextual demands and shifting goals. We propose that the neural implementation of this emotional control mechanism relies on the anterior prefrontal cortex (aPFC/lateral frontal pole), given its known role in monitoring alternative options during cognitive decision-making tasks. We reappraise meta-analytic evidence showing consistent aPFC involvement during emotional control when monitoring of alternative emotional control strategies is required, and when alternative emotional actions have high value. We conclude with emphasizing the clinical and evolutionary implications of this new framework on emotional control.


Psychiatric and psychosocial problems in adults with normal-intelligence autism spectrum disorders.
Individuals with autism spectrum disorders (ASDs) often display symptoms from other diagnostic categories. Studies of clinical and psychosocial outcome in adult patients with ASDs without concomitant intellectual disability are few. The objective of this paper is to describe the clinical psychiatric presentation and important outcome measures of a large group of normal-intelligence adult patients with ASDs. Autistic symptomatology according to the DSM-IV-criteria and the Gillberg & Gillberg research criteria, patterns of comorbid psychopathology and psychosocial outcome were assessed in 122 consecutively referred adults with normal intelligence ASDs. The subjects consisted of 5 patients with autistic disorder (AD), 67 with Asperger's disorder (AS) and 50 with pervasive developmental disorder not otherwise specified (PDD NOS). This study group consists of subjects pooled from two studies with highly similar protocols, all seen on an outpatient basis by one of three clinicians. Core autistic symptoms were highly prevalent in all ASD subgroups. Though AD subjects had the most pervasive problems, restrictions in non-verbal communication were common across all three subgroups and, contrary to current DSM criteria, so were verbal communication deficits. Lifetime psychiatric axis I comorbidity was very common, most notably mood and anxiety disorders, but also ADHD and psychotic disorders. The frequency of these diagnoses did not differ between the ASD subgroups or between males and females. Antisocial personality disorder and substance abuse were more common in the PDD NOS group. Of all subjects, few led an independent life and very few had ever had a long-term relationship. Female subjects more often reported having been bullied at school than male subjects. ASDs are clinical syndromes characterized by impaired social interaction and non-verbal communication in adulthood as well as in childhood. They also carry a high risk for co-existing mental health problems from a broad spectrum of disorders and for unfavourable psychosocial life circumstances. For the next revision of DSM, our findings especially stress the importance of careful examination of the exclusion criterion for adult patients with ASDs.


Enteric-coated mycophenolate sodium in psoriasis vulgaris: an open pilot study.
Mycophenolate mofetil is a well-known immunosuppressive agent in transplantation medicine. The efficacy of enteric-coated mycophenolate sodium (EC-MPS) was confirmed in other inflammatory skin diseases, including atopic dermatitis and SCLE. To investigate the efficacy and the tolerability/short-term safety of EC-MPS in patients with moderate to severe chronic plaque psoriasis. An open-label pilot study in which 20 patients with a PASI >10 received EC-MPS 720 mg twice daily for 6 weeks followed by 360 mg twice daily for another 6 weeks. Patients who completed 12 weeks of treatment were followed-up for an additional 12 weeks. Treatment outcomes were assessed with PASI50% and PASI75%. Eighteen men and two women (mean age 46 years) entered the study. Sixty-five percent (13/20) finished the treatment period. By week 6, no patient achieved PASI 75% and 8/20 patients achieved a PASI 50%. Compared to week 6, 4/13 showed a deterioration of their psoriasis at week 12. Twenty-five percent (2/8) achieved a PASI 75% in week 24. The most-reported adverse events were itching (30%), diarrhea (10%), and a reversible elevation of the triglycerides level. EC-MPS does not seem effective as monotherapy for moderate to severe psoriasis, but might be used at a dosage of 1440 mg daily in well-selected patients with treatment-resistant psoriasis.


Employers' Role in Employee Health: Why They Do What They Do.
Employers affect the health of employees and their families through work environments and employee benefits. We sought to understand employer decisions around those topics. Interviews with 21 executives from diverse, purposely-sampled, progressive companies with transcripts analyzed using inductive and deductive methods. Companies often viewed keeping employees healthy primarily as a means to profitability rather than an end in itself and rationalized stressful workplaces as necessary and non-changeable. Many possible actions including job redesign and changing benefits administrators were seen as infeasible. Even large, resource-rich organizations were strikingly non-agentic. Companies seem less committed to the goal of increasing employee health than they claim or than they should be, given the significant relationship between employee health and economic performance, and see external and internal barriers to improving health that are often self-created.


The IDEFICS community-oriented intervention programme: a new model for childhood obesity prevention in Europe?
The European Union-as well as other parts of the world-faces a major challenge of increasing incidence of overweight/obesity. In particular, the increase in childhood obesity gives rise to a strong imperative for immediate action. Yet, little is known about the effectiveness of community interventions, and further research in this field is needed. There is, however, a growing consensus that such research should start from the paradigm that the current living environments tend to counteract healthy lifestyles. Questioning these environments thoroughly can help to develop new pathways for sustainable health-promoting communities. Against this background, the IDEFICS (Identification and prevention of dietary- and lifestyle-induced health effects in children and infants) study developed and implemented innovative community-oriented intervention programmes for obesity prevention and healthy lifestyle primarily in children aged 2-10 years in eight European countries: Sweden, Estonia, Germany, Belgium, Hungary, Italy, Spain and Cyprus. The IDEFICS community-oriented intervention study mobilised an integrated set of interventional efforts at different levels of society, with the aim of facilitating the adoption of a healthy obesity-preventing lifestyle. The overall programme has been composed of 10 modules: three at community level, six at school level and one for parents. The main focus was on diet, physical activity and stress-coping capacity. The sphere of action encompassed both children and their (grand) parents, schools, local public authorities and influential stakeholders in the community. All materials for the interventions were centrally developed and culturally adapted. So far, the following has been achieved: focus group research, literature review and expert consultations were done in an early phase as a basis for the development of the intervention modules. The intervention mapping protocol was followed as guide for structuring the intervention research. The overall intervention programme's duration was 2 years, but a longer-term follow-up programme is under development. This large-scale European effort is expected to contribute significantly to the understanding of this major public health challenge.


Studying Independent Kcna6 Knock-out Mice Reveals Toxicity of Exogenous LacZ to Central Nociceptor Terminals and Differential Effects of Kv1.6 on Acute and Neuropathic Pain Sensation.
The potassium channel Kv1.6 has recently been implicated as a major modulatory channel subunit expressed in primary nociceptors. Furthermore, its expression at juxtaparanodes of myelinated primary afferents is induced following traumatic nerve injury as part of an endogenous mechanism to reduce hyperexcitability and pain-related hypersensitivity. In this study, we compared two mouse models of constitutive Kv1.6 knock-out (KO) achieved by different methods: traditional gene trap via homologous recombination and CRISPR-mediated excision. Both Kv1.6 KO mouse lines exhibited an unexpected reduction in sensitivity to noxious heat stimuli, to differing extents: the Kv1.6 mice produced via gene trap had a far more significant hyposensitivity. These mice (Kcna6lacZ ) expressed the bacterial reporter enzyme LacZ in place of Kv1.6 as a result of the gene trap mechanism, and we found that their central primary afferent presynaptic terminals developed a striking neurodegenerative phenotype involving accumulation of lipid species, development of "meganeurites," and impaired transmission to dorsal horn wide dynamic range neurons. The anatomic defects were absent in CRISPR-mediated Kv1.6 KO mice (Kcna6-/-) but were present in a third mouse model expressing exogenous LacZ in nociceptors under the control of a Nav1.8-promoted Cre recombinase. LacZ reporter enzymes are thus intrinsically neurotoxic to sensory neurons and may induce pathologic defects in transgenic mice, which has confounding implications for the interpretation of gene KOs using lacZ Nonetheless, in Kcna6-/- mice not affected by LacZ, we demonstrated a significant role for Kv1.6 regulating acute noxious thermal sensitivity, and both mechanical and thermal pain-related hypersensitivity after nerve injury.SIGNIFICANCE STATEMENT In recent decades, the expansion of technologies to experimentally manipulate the rodent genome has contributed significantly to the field of neuroscience. While introduction of enzymatic or fluorescent reporter proteins to label neuronal populations is now commonplace, often potential toxicity effects are not fully considered. We show a role of Kv1.6 in acute and neuropathic pain states through analysis of two mouse models lacking Kv1.6 potassium channels: one with additional expression of LacZ and one without. We show that LacZ reporter enzymes induce unintended defects in sensory neurons, with an impact on behavioral data outcomes. To summarize we highlight the importance of Kv1.6 in recovery of normal sensory function following nerve injury, and careful interpretation of data from LacZ reporter models.


Accuracy and continuity in discharge information for patients with eating difficulties after stroke.
To describe the accuracy and continuity of discharge information for patients with eating difficulties after stroke. Eating difficulties are prevalent and serious problems in patients with stroke. Screening for eating difficulties can predict undernutrition and subsequent care needs. For optimal care, information transferred between care settings has to be comprehensive and accurate. Prospective, descriptive. The study investigated a sample of 15 triads, each including one patient with stroke along with his patient record and discharge summary and two nursing staff in the municipal care to whom the patient was discharged. Data were collected by observations of patients' eating, record audits and interviews with nurses. Data were analysed using content analysis and descriptive statistics. Accuracy of recorded information on patients' eating difficulties and informational continuity were poor, as was accuracy in the transferred information according to nursing staff's perceptions. All patients were at risk of undernutrition and in too poor a state to receive rehabilitation. Nevertheless, patients' eating difficulties were described in a vague and unspecific language in the patient records. Co-ordinated care planning and management continuity related to eating difficulties were largely lacking in the documentation. Despite their important role in caring for patients with eating difficulties, little information on eating difficulties seemed to reach licensed practical nurses in the municipalities. Comprehensiveness in the documentation of eating difficulties and accuracy of transferred information were poor based on record audits and as perceived by the municipal nursing staff. Although all patients were at risk of undernutrition, had multiple eating difficulties and were in too poor a state for rehabilitation, explicit care plans for nutritional problems were lacking. Lack of accuracy and continuity in discharge information on eating difficulties may increase risk of undernutrition and related complications for patients in continuous stroke care. Therefore, the discharge process must be based on comprehensive and accurate documentation.


Advances in the treatment of superficial fungal infections: focus on onychomycosis and dry tinea pedis.
Onychomycosis is one of the most stubborn superficial mycoses. With few exceptions, oral antifungal therapy is needed to achieve resolution. Before oral itraconazole, fluconazole, and terbinafine hydrochloride became available, physicians had to rely on prolonged therapy with griseofulvin or oral ketoconazole. Of the newer oral agents, itraconazole appears to have the broadest spectrum of action, with therapeutic activity against dermatophytes, yeasts, and some nondermatophyte molds. Tissue pharmacokinetics accounts for significantly greater efficacy and much shorter treatment courses for fungal infections of the skin and nails. In general, oral itraconazole, fluconazole, and terbinafine are very well tolerated. The newer oral agents offer improved efficacy over griseofulvin and ketoconazole for onychomycosis and dry tinea pedis.


In vivo dynamics of nuclear pore complexes in yeast.
While much is known about the role of nuclear pore complexes (NPCs) in nucleocytoplasmic transport, the mechanism of NPC assembly into pores formed through the double lipid bilayer of the nuclear envelope is not well defined. To investigate the dynamics of NPCs, we developed a live-cell assay in the yeast Saccharomyces cerevisiae. The nucleoporin Nup49p was fused to the green fluorescent protein (GFP) of Aequorea victoria and expressed in nup49 null haploid yeast cells. When the GFP-Nup49p donor cell was mated with a recipient cell harboring only unlabeled Nup49p, the nuclei fused as a consequence of the normal mating process. By monitoring the distribution of the GFP-Nup49p, we could assess whether NPCs were able to move from the donor section of the nuclear envelope to that of the recipient nucleus. We observed that fluorescent NPCs moved and encircled the entire nucleus within 25 min after fusion. When assays were done in mutant kar1-1 strains, where nuclear fusion does not occur, GFP-Nup49p appearance in the recipient nucleus occurred at a very slow rate, presumably due to new NPC biogenesis or to exchange of GFP-Nup49p into existing recipient NPCs. Interestingly, in a number of existing mutant strains, NPCs are clustered together at permissive growth temperatures. This has been explained with two different hypotheses: by movement of NPCs through the double nuclear membranes with subsequent clustering at a central location; or, alternatively, by assembly of all NPCs at a central location (such as the spindle pole body) with NPCs in mutant cells unable to move away from this point. Using the GFP-Nup49p system with a mutant in the NPC-associated factor Gle2p that exhibits formation of NPC clusters only at 37 degrees C, it was possible to distinguish between these two models for NPC dynamics. GFP-Nup49p-labeled NPCs, assembled at 23 degrees C, moved into clusters when the cells were shifted to growth at 37 degrees C. These results indicate that NPCs can move through the double nuclear membranes and, moreover, can do so to form NPC clusters in mutant strains. Such clusters may result by releasing NPCs from a nuclear tether, or by disappearance of a protein that normally prevents pore aggregation. This system represents a novel approach for identifying regulators of NPC assembly and movement in the future.


DICCCOL: dense individualized and common connectivity-based cortical landmarks.
Is there a common structural and functional cortical architecture that can be quantitatively encoded and precisely reproduced across individuals and populations? This question is still largely unanswered due to the vast complexity, variability, and nonlinearity of the cerebral cortex. Here, we hypothesize that the common cortical architecture can be effectively represented by group-wise consistent structural fiber connections and take a novel data-driven approach to explore the cortical architecture. We report a dense and consistent map of 358 cortical landmarks, named Dense Individualized and Common Connectivity-based Cortical Landmarks (DICCCOLs). Each DICCCOL is defined by group-wise consistent white-matter fiber connection patterns derived from diffusion tensor imaging (DTI) data. Our results have shown that these 358 landmarks are remarkably reproducible over more than one hundred human brains and possess accurate intrinsically established structural and functional cross-subject correspondences validated by large-scale functional magnetic resonance imaging data. In particular, these 358 cortical landmarks can be accurately and efficiently predicted in a new single brain with DTI data. Thus, this set of 358 DICCCOL landmarks comprehensively encodes the common structural and functional cortical architectures, providing opportunities for many applications in brain science including mapping human brain connectomes, as demonstrated in this work.


The Path towards Endangered Species: Prehistoric Fisheries in Southeastern Brazil.
Brazilian shellmounds are archaeological sites with a high concentration of marine faunal remains. There are more than 2000 sites along the coast of Brazil that range in age from 8,720 to 985 cal BP. Here, we studied the ichthyoarchaeological remains (i.e., cranial/postcranial bones, otoliths, and teeth, among others) at 13 shellmounds on the southern coast of the state of Rio de Janeiro, which are located in coastal landscapes, including a sandy plain with coastal lagoons, rocky islands, islets and rocky bays. We identified patterns of similarity between shellmounds based on fish diversity, the ages of the assemblages, littoral geomorphology and prehistoric fisheries. Our new radiocarbon dating, based on otolith samples, was used for fishery characterization over time. A taxonomical study of the ichthyoarchaeological remains includes a diversity of 97 marine species, representing 37% of all modern species (i.e., 265 spp.) that have been documented along the coast of Rio de Janeiro state. This high fish diversity recovered from the shellmounds is clear evidence of well-developed prehistoric fishery activity that targeted sharks, rays and finfishes in a productive area influenced by coastal marine upwelling. The presence of adult and neonate shark, especially oceanic species, is here interpreted as evidence of prehistoric fisheries capacity for exploitation and possibly overexploitation in nursery areas. Various tools and strategies were used to capture finfish in seasonal fisheries, over rocky reef bottoms and in sandy littoral environments. Massive catches of whitemouth croaker, main target dermersal species of South Atlantic coast, show evidence of a reduction in body size of approximately 28% compared with modern fisheries. Fishery activity involving vulnerable species, especially in nursery areas, could mark the beginning of fish depletion along the southeastern Brazilian coast and the collapse of natural fish populations.


How far to the road not taken? The effect of psychological distance on counterfactual direction.
Upward and downward counterfactuals serve the distinct motivational functions of self-improvement and self-enhancement, respectively. Drawing on construal level theory, which contends that increasing psychological distance from an event leads people to focus on high-level, self-improvement versus low-level, self-enhancement goals, we propose that distance will alter counterfactual direction in a way that satisfies these distinct motives. We found that people generated more downward counterfactuals about recent versus distant past events, while they tended to generate more upward counterfactuals about distant versus recent past events (Experiment 1). Consistent results were obtained for social distance (Experiment 2). Experiment 3 demonstrated that distance affects the direction of open-ended counterfactual thoughts. Finally, Experiment 4 explored a potential mechanism, demonstrating that manipulating temporal distance produced changes in participants' self-improvement versus self-enhancement motivations when responding to negative events. Future directions and broader implications for self-control, social support, empathy, and learning are discussed.


Virtual learning collaboratives to improve urine culturing and antibiotic prescribing in long-term care: controlled before-and-after study.
Urine culturing practices are highly variable in long-term care and contribute to overprescribing of antibiotics for presumed urinary tract infections. The purpose of this study was to evaluate the use of virtual learning collaboratives to support long-term care homes in implementing a quality improvement programme focused on reducing unnecessary urine culturing and antibiotic overprescribing. Over a 4-month period (May 2018-August 2018), 45 long-term care homes were self-selected from five regions to participate in virtual learning collaborative sessions, which provided an orientation to a quality improvement programme and guidance for implementation. A process evaluation complemented the use of a controlled before-and-after study with a propensity score matched control group (n=127) and a difference-in-difference analysis. Primary outcomes included rates of urine cultures performed and urinary antibiotic prescriptions. Secondary outcomes included rates of emergency department visits, hospital admission and mortality. An 18-month baseline period was compared with a 16-month postimplementation period with the use of administrative data sources. Rates of urine culturing and urinary antibiotic prescriptions per 1000 resident days decreased significantly more among long-term care homes that participated in learning collaboratives compared with matched controls (differential reductions of 19% and 13%, respectively, p<0.0001). There was no statistically significant changes to rates of emergency department visits, hospital admissions or mortality. These outcomes were observed with moderate adherence to the programme model. Rates of urine culturing and urinary antibiotic prescriptions declined among long-term care homes that participated in a virtual learning collaborative to support implementation of a quality improvement programme. The results of this study have refined a model to scale this programme in long-term care.


Anorexia nervosa: long-term outcome in 50 female patients.
Fifty consecutively referred female patients with anorexia nervosa were followed-up to identify those completely healthy at a minimum of four years (mean eight years) since onset. As well as using Morgan's Outcome Measures, an independent psychiatrist elicited details of food/weight pre-occupation and psychiatric state. The outcome results, based on weight and menstruation, (36% 'good', 36% 'intermediate', and 26% 'poor' including 2% dead, and 2% not assessed) did not differ significantly from those of the three similar published studies on similar patients; 62% of patients continued to have some food/weight pre-occupation. DSM III criteria for a psychiatric disorder other than eating disorder were fulfilled by 50%; dysthymic disorder was common (34%), occurring exclusively in patients with continuing eating disorder symptoms, while only 20% of the sample were free of any physical or mental abnormality. Of 52 prognostic factors studied, only four were significantly related to the outcome measures. Length of illness at presentation was the only prognostic factor common to all four similarly conducted studies.


Network Analysis of Genome-Wide Selective Constraint Reveals a Gene Network Active in Early Fetal Brain Intolerant of Mutation.
Using robust, integrated analysis of multiple genomic datasets, we show that genes depleted for non-synonymous de novo mutations form a subnetwork of 72 members under strong selective constraint. We further show this subnetwork is preferentially expressed in the early development of the human hippocampus and is enriched for genes mutated in neurological Mendelian disorders. We thus conclude that carefully orchestrated developmental processes are under strong constraint in early brain development, and perturbations caused by mutation have adverse outcomes subject to strong purifying selection. Our findings demonstrate that selective forces can act on groups of genes involved in the same process, supporting the notion that purifying selection can act coordinately on multiple genes. Our approach provides a statistically robust, interpretable way to identify the tissues and developmental times where groups of disease genes are active.


Heterologous expression and molecular and cellular characterization of CaPUB1 encoding a hot pepper U-Box E3 ubiquitin ligase homolog.
The U-box motif is a conserved domain found in the diverse isoforms of E3 ubiquitin ligase in eukaryotes. From water-stressed hot pepper (Capsicum annuum L. cv Pukang) plants, we isolated C. annuum putative U-box protein 1 (CaPUB1), which encodes a protein containing a single U-box motif in its N-terminal region. In vitro ubiquitination and site-directed mutagenesis assays revealed that CaPUB1 possessed E3 ubiquitin ligase activity and that the U-box motif was indeed essential for its enzyme activity. RNA gel-blot analysis showed that CaPUB1 mRNA was induced rapidly by a broad spectrum of abiotic stresses, including drought, high salinity, cold temperature, and mechanical wounding, but not in response to ethylene, abscisic acid, or a bacterial pathogen, suggesting its role in the early events in the abiotic-related defense response. Because transgenic work was extremely difficult in hot pepper, in this study we overexpressed CaPUB1 in Arabidopsis (Arabidopsis thaliana) to provide cellular information on the function of this gene in the development and plant responses to abiotic stresses. Transgenic Arabidopsis plants that constitutively expressed the CaPUB1 gene under the control of the cauliflower mosaic virus 35S promoter had markedly longer hypocotyls and roots and grew more rapidly than the wild type, leading to an early bolting phenotype. Microscopic analysis showed that 35S::CaPUB1 roots had increased numbers of small-sized cells, resulting in disordered, highly populated cell layers in the cortex, endodermis, and stele. In addition, CaPUB1-overexpressing plants displayed increased sensitivity to water stress and mild salinity. These results indicate that CaPUB1 is functional in Arabidopsis cells, thereby effectively altering cell and tissue growth and also the response to abiotic stresses. Comparative proteomic analysis showed that the level of RPN6 protein, a non-ATPase subunit of the 26S proteasome complex, was significantly reduced in 35SCaPUB1 seedlings as compared to the wild type. Pull-down and ubiquitination assays demonstrated that RPN6 interacted physically with CaPUB1 and was ubiquitinated in a CaPUB1-dependent manner in vitro. Although the physiological function of CaPUB1 is not yet clear, there are several possibilities for its involvement in a subset of physiological responses to counteract dehydration and high-salinity stresses in transgenic Arabidopsis seedlings.


Telomere length variations in aging and age-related diseases.
Telomeres are gene sequences present at chromosomal ends and are responsible for maintaining genome integrity. Telomere length is maximum at birth and decreases progressively with advancing age and thus is considered as a biomarker of chronological aging. This age associated decrease in the length of telomere is linked to various ageing associated diseases like diabetes, hypertension, Alzheimer's disease, cancer etc. and their associated complications. Telomere length is a result of combined effect of oxidative stress, inflammation and repeated cell replication on it, and thus forming an association between telomere length and chronological aging and related diseases. Thus, decrease in telomere length was found to be important in determining both, the variations in longevity and age-related diseases in an individual. Ongoing and progressive research in the field of telomere length dynamics has proved that aging and age-related diseases apart from having a synergistic effect on telomere length were also found to effect telomere length independently also. Here a short description about telomere length variations and its association with human aging and age-related diseases is reviewed.


Discriminatory Indices of Typing Methods for Epidemiologic Analysis of Contemporary Staphylococcus aureus Strains.
Historically, a number of typing methods have been evaluated for Staphylococcus aureus strain characterization. The emergence of contemporary strains of community-associated S. aureus, and the ensuing epidemic with a predominant strain type (USA300), necessitates re-evaluation of the discriminatory power of these typing methods for discerning molecular epidemiology and transmission dynamics, essential to investigations of hospital and community outbreaks. We compared the discriminatory index of 5 typing methods for contemporary S. aureus strain characterization. Children presenting to St. Louis Children's Hospital and community pediatric practices in St. Louis, Missouri (MO), with community-associated S. aureus infections were enrolled. Repetitive sequence-based PCR (repPCR), pulsed-field gel electrophoresis (PFGE), multilocus sequence typing (MLST), staphylococcal protein A (spa), and staphylococcal cassette chromosome (SCC) mec typing were performed on 200 S. aureus isolates. The discriminatory index of each method was calculated using the standard formula for this metric, where a value of 1 is highly discriminatory and a value of 0 is not discriminatory. Overall, we identified 26 distinct strain types by repPCR, 17 strain types by PFGE, 30 strain types by MLST, 68 strain types by spa typing, and 5 strain types by SCCmec typing. RepPCR had the highest discriminatory index (D) of all methods (D = 0.88), followed by spa typing (D = 0.87), MLST (D = 0.84), PFGE (D = 0.76), and SCCmec typing (D = 0.60). The method with the highest D among MRSA isolates was repPCR (D = 0.64) followed by spa typing (D = 0.45) and MLST (D = 0.44). The method with the highest D among MSSA isolates was spa typing (D = 0.98), followed by MLST (D = 0.93), repPCR (D = 0.92), and PFGE (D = 0.89). Among isolates designated USA300 by PFGE, repPCR was most discriminatory, with 10 distinct strain types identified (D = 0.63). We identified 45 MRSA isolates which were classified as identical by PFGE, MLST, spa typing, and SCCmec typing (USA300, ST8, t008, SCCmec IV, respectively); within this collection, there were 5 distinct strain types identified by repPCR. The typing methods yielded comparable discriminatory power for S. aureus characterization overall; when discriminating among USA300 isolates, repPCR retained the highest discriminatory power. This property is advantageous for investigations conducted in the era of contemporary S. aureus infections.


Predicting daily physical activity in patients with chronic obstructive pulmonary disease.
Objectively measuring daily physical activity (PA) using an accelerometer is a relatively expensive and time-consuming undertaking. In routine clinical practice it would be useful to estimate PA in patients with chronic obstructive pulmonary disease (COPD) with more simple methods. To evaluate whether PA can be estimated by simple tests commonly used in clinical practice in patients with COPD. The average number of steps per day was measured for 7 days with a SenseWear Pro™ accelerometer and used as gold standard for PA. A physical activity level (PAL) of <1.4 was considered very inactive. Univariate and multivariate analyses were used to examine the relationship between the 6-minute walking distance (6MWD), the number of stands in the Sit-to-Stand Test (STST), hand-grip strength and the total energy expenditure as assessed by the Zutphen Physical Activity Questionnaire (TEE(ZPAQ)). ROC curve analysis was used to identify patients with an extremely inactive lifestyle (PAL<1.4). In 70 patients with COPD (21 females) with a mean [SD] FEV(1) of 43.0 [22.0] %predicted, PA was found to be significantly and independently associated with the 6MWD (r = 0.69, 95% CI 0.54 to 0.80, p<0.001), STST (r = 0.51, 95% CI 0.31 to 0.66, p = 0.001) and TEEZPAQ (r = 0.50, 95% CI 0.30 to 0.66, p<0.001) but not with hand-grip strength. However, ROC curve analysis demonstrated that these tests cannot be used to reliably identify patients with an extremely inactive lifestyle. In patients with COPD simple tests such as the 6-Minute Walk Test, the Sit-to-Stand Test and the Zutphen Physical Activity Questionnaire cannot be used to reliably predict physical inactivity.


Sustainable urban water management: understanding and fostering champions of change.
This paper highlights and discusses ten characteristic attributes of emergent leaders (also known as 'champions') who worked as influential change agents within publicly managed, Australian water agencies to encourage more sustainable forms of urban water management. These attributes relate to: the 'openness to experience' personality characteristic; career mobility and work history demographics; personal and position power; strategic social networks; the culture of their organisations; and five distinguishing leadership behaviours (e.g. persisting under adversity). Guided by the findings of an international literature review, the author conducted a multiple case study involving six water agencies. This research identified attributes of these leaders that were typically strong and/or distinguishing compared to relevant control groups, as well as influential contextual factors. While it is widely acknowledged that these leaders play a critical role in the delivery of sustainable urban water management, there has been a paucity of context-sensitive research involving them. The research project highlighted in this paper is a response to this situation and has led to the development of a suite of 39 practical, evidence-based strategies to build leadership capacity throughout water agencies. Such capacity is one of the elements needed to drive the transition to more 'water sensitive cities'.


Experimental learning in an optical perceptronlike neural network.
An optical perceptronlike neural network employing a delta learning rule and consisting of input units and a single output unit is constructed. Photorefractive crystals are used as holographic media for the interconnections between the input and the output layers. The learning rate for interconnection weight changes is optimally determined by setting the exposure time of the hologram. A learning experiment verifies the learning schedule's prediction that a fast, stable convergence of the learning process without oscillatory action can be obtained.


Change in objectively measured physical activity during the transition to adolescence.
Physical activity (PA) declines during adolescence but change in different PA intensities across population subgroups is rarely explored. We describe change in sedentary (SED) time, light (LPA), moderate (MPA) and vigorous PA (VPA) assessed at three time points over 4 years. Accelerometer-assessed PA (min) was obtained at baseline (N=2064), 1 and 4 years later among British children (baseline mean±SD 10.2±0.3-year-old; 42.5% male). Change in SED (<100 counts/min (cpm)), LPA (101-1999 cpm), MPA (2000-3999 cpm) and VPA (≥4000 cpm) was studied using three-level (age, individual and school) mixed-effects linear regression including participants with data at ≥2 time points (N=990). Differences in change by sex, home location and weight status were explored with interactions for SED, LPA and moderate and vigorous PA (MVPA). SED increased by 10.6 (95% CI 9.1 to 12.2) min/day/year. MPA and VPA decreased by 1.4 (1.0 to 1.8) and 1.5 (1.1 to 1.8) min/day/year, respectively. VPA decreased more than MPA as a percentage of the baseline value. MVPA declined more steeply among boys (3.9 (3.0 to 4.8)) versus girls (2.0 (1.2 to 2.7) min/day/year) despite lower MVPA among girls at all ages; rural (4.4 (3.5 to 5.2)) versus urban individuals (1.3 (0.4 to 2.3) min/day/year) and on weekends (6.7 (5.2 to 8.1)) versus weekdays (2.8 (1.9 to 3.7) min/day/year). MVPA was consistently lower among overweight/obese individuals (-17.5 (-3.9 to -2.5) min/day/year). PA decreases and is replaced by SED during early adolescence in British youth. Results indicate the urgency of PA promotion among all adolescents but especially girls and in rural areas. Increasing VPA and targeting PA promotion during weekends appear important.


Defective cholesterol metabolism in haematopoietic stem cells promotes monocyte-driven atherosclerosis in rheumatoid arthritis.
Rheumatoid arthritis (RA) is associated with an approximately two-fold elevated risk of cardiovascular (CV)-related mortality. Patients with RA present with systemic inflammation including raised circulating myeloid cells, but fail to display traditional CV risk-factors, particularly dyslipidaemia. We aimed to explore if increased circulating myeloid cells is associated with impaired atherosclerotic lesion regression or altered progression in RA. Using flow cytometry, we noted prominent monocytosis, neutrophilia, and thrombocytosis in two mouse models of RA. This was due to enhanced proliferation of the haematopoietic stem and progenitor cells (HSPCs) in the bone marrow and the spleen. HSPCs expansion was associated with an increase in the cholesterol content, due to a down-regulation of cholesterol efflux genes, Apoe, Abca1, and Abcg1. The HSPCs also had enhanced expression of key myeloid promoting growth factor receptors. Systemic inflammation was found to cause defective cellular cholesterol metabolism. Increased myeloid cells in mice with RA were associated with a significant impairment in lesion regression, even though cholesterol levels were equivalent to non-arthritic mice. Lesions from arthritic mice exhibited a less stable phenotype as demonstrated by increased immune cell infiltration, lipid accumulation, and decreased collagen formation. In a progression model, we noted monocytosis, enhanced monocytes recruitment to lesions, and increased plaque macrophages. This was reversed with administration of reconstituted high-density lipoprotein (rHDL). Furthermore, RA patients have expanded CD16+ monocyte subsets and a down-regulation of ABCA1 and ABCG1. Rheumatoid arthritis impairs atherosclerotic regression and alters progression, which is associated with an expansion of myeloid cells and disturbed cellular cholesterol handling, independent of plasma cholesterol levels. Infusion of rHDL prevented enhanced myelopoiesis and monocyte entry into lesions. Targeting cellular cholesterol defects in people with RA, even if plasma cholesterol is within the normal range, may limit vascular disease.


Biocompatibility and strength retention of biodegradable Mg-Ca-Zn alloy bone implants.
The biocompatibility and strength retention of a Mg-Ca-Zn alloy were studied to evaluate its efficacy for osteosynthesis applications. Mg-Ca-Zn alloy and self-reinforced poly l-lactide (SR-PLLA) bone screws were implanted into New Zealand rabbits for radiography analysis, micro computed tomography analysis, histomorphometry, hematology, serum biochemistry, histopathology, and inductively coupled plasma mass spectrometry analysis. Bending and torsion tests were performed on intact specimens to find the initial mechanical strength of these Mg-Ca-Zn alloy bone screws. Strength retention of the Mg-Ca-Zn alloy implants were calculated from in vivo degradation rates and initial mechanical strength. Based on the animal study, Mg-Ca-Zn alloy bone screw showed absence of subcutaneous gas pockets, characteristic surface erosion properties, faster degradation rate than SR-PLLA bone screw, normal reference range of hematology and serum biochemistry, better histopathological response than SR-PLLA bone screw, and stable concentrations of each constituent element in soft tissues surrounding the implants. The initial strength and strength retention of Mg-Ca-Zn alloy were compared with those of various biomaterials. The initial strength of Mg-Ca-Zn alloy was higher than those of biostable and biodegradable polymers. The strength retention of Mg-Ca-Zn alloy bone screws was similar to those of biodegradable polymer. Therefore, this Mg-Ca-Zn alloy represents an excellent biodegradable biomaterial candidate for osteosynthesis applications.


Stochastic blind motion deblurring.
Blind motion deblurring from a single image is a highly under-constrained problem with many degenerate solutions. A good approximation of the intrinsic image can, therefore, only be obtained with the help of prior information in the form of (often nonconvex) regularization terms for both the intrinsic image and the kernel. While the best choice of image priors is still a topic of ongoing investigation, this research is made more complicated by the fact that historically each new prior requires the development of a custom optimization method. In this paper, we develop a stochastic optimization method for blind deconvolution. Since this stochastic solver does not require the explicit computation of the gradient of the objective function and uses only efficient local evaluation of the objective, new priors can be implemented and tested very quickly. We demonstrate that this framework, in combination with different image priors produces results with Peak Signal-to-Noise Ratio (PSNR) values that match or exceed the results obtained by much more complex state-of-the-art blind motion deblurring algorithms.


Simulating the evolution of the human family: cooperative breeding increases in harsh environments.
Verbal and mathematical models that consider the costs and benefits of behavioral strategies have been useful in explaining animal behavior and are often used as the basis of evolutionary explanations of human behavior. In most cases, however, these models do not account for the effects that group structure and cultural traditions within a human population have on the costs and benefits of its members' decisions. Nor do they consider the likelihood that cultural as well as genetic traits will be subject to natural selection. In this paper, we present an agent-based model that incorporates some key aspects of human social structure and life history. We investigate the evolution of a population under conditions of different environmental harshness and in which selection can occur at the level of the group as well as the level of the individual. We focus on the evolution of a socially learned characteristic related to individuals' willingness to contribute to raising the offspring of others within their family group. We find that environmental harshness increases the frequency of individuals who make such contributions. However, under the conditions we stipulate, we also find that environmental variability can allow groups to survive with lower frequencies of helpers. The model presented here is inevitably a simplified representation of a human population, but it provides a basis for future modeling work toward evolutionary explanations of human behavior that consider the influence of both genetic and cultural transmission of behavior.


Cysteine cathepsin activity suppresses osteoclastogenesis of myeloid-derived suppressor cells in breast cancer.
Cysteine cathepsin proteases contribute to many normal cellular functions, and their aberrant activity within various cell types can contribute to many diseases, including breast cancer. It is now well accepted that cathepsin proteases have numerous cell-specific functions within the tumor microenvironment that function to promote tumor growth and invasion, such that they may be valid targets for anti-metastatic therapeutic approaches. Using activity-based probes, we have examined the activity and expression of cysteine cathepsins in a mouse model of breast cancer metastasis to bone. In mice bearing highly metastatic tumors, we detected abundant cysteine cathepsin expression and activity in myeloid-derived suppressor cells (MDSCs). These immature immune cells have known metastasis-promoting roles, including immunosuppression and osteoclastogenesis, and we assessed the contribution of cysteine cathepsins to these functions. Blocking cysteine cathepsin activity with multiple small-molecule inhibitors resulted in enhanced differentiation of multinucleated osteoclasts. This highlights a potential role for cysteine cathepsin activity in suppressing the fusion of osteoclast precursor cells. In support of this hypothesis, we found that expression and activity of key cysteine cathepsins were downregulated during MDSC-osteoclast differentiation. Another cysteine protease, legumain, also inhibits osteoclastogenesis, in part through modulation of cathepsin L activity. Together, these data suggest that cysteine protease inhibition is associated with enhanced osteoclastogenesis, a process that has been implicated in bone metastasis.


A reassuring presence: An evaluation of Bradford District Hospice at Home service.
Within the United Kingdom, a developing role for primary care services in cancer and palliative care has resulted in an increase in palliative home care teams. The provision of professional care in the home setting seeks to provide necessary services and enhanced choice for patients whose preference is to die at home.A mismatch between patient preference for home death and the actual number of people who died at home was identified within Bradford, the locality of this study. In response to this mismatch, and reflecting the policy environment of wishing to enhance community service provision, the four Primary Care Trusts (PCTs) in the city sought to offer support to patients who wished to remain in their own homes through the final stages of a terminal illness. To offer this support they set up a dedicated hospice at home team. This would provide services and support for patients in achieving a dignified, symptom free and peaceful death, allowing families to maximise time spent together. The aim of the study was to evaluate the Bradford hospice at home service from the perspective of carers, nurses and General Practitioners. Postal questionnaires were sent to carers (n = 289), district nurses (n = 508) and GP's (n = 444) using Bradford's hospice at home service. Resulting quantitative data was analysed using the Statical Package for Social Sciences (SPSS) and qualitative data was analysed using grounded theory techniques. The data from carers, district nurses and GPs provide general support for the Bradford hospice at home service. Carers valued highly the opportunity to 'fulfil a promise' to the individual who wished to be cared for at home. District nurses and GPs cited the positive impact of access to specialist expertise. This was a 'reassuring presence' for primary healthcare teams and offered 'relief of carer anxiety' by providing prompt, accessible and sensitive care. Carers and health professionals welcomed the increased possibility of patients being cared for at home. The study identified the need to focus on improving skill levels of staff and on ensuring continuity of care.


Three-dimensional analysis of retinal layer texture: identification of fluid-filled regions in SD-OCT of the macula.
Optical coherence tomography (OCT) is becoming one of the most important modalities for the noninvasive assessment of retinal eye diseases. As the number of acquired OCT volumes increases, automating the OCT image analysis is becoming increasingly relevant. In this paper, a method for automated characterization of the normal macular appearance in spectral domain OCT (SD-OCT) volumes is reported together with a general approach for local retinal abnormality detection. Ten intraretinal layers are first automatically segmented and the 3-D image dataset flattened to remove motion-based artifacts. From the flattened OCT data, 23 features are extracted in each layer locally to characterize texture and thickness properties across the macula. The normal ranges of layer-specific feature variations have been derived from 13 SD-OCT volumes depicting normal retinas. Abnormalities are then detected by classifying the local differences between the normal appearance and the retinal measures in question. This approach was applied to determine footprints of fluid-filled regions--SEADs (Symptomatic Exudate-Associated Derangements)--in 78 SD-OCT volumes from 23 repeatedly imaged patients with choroidal neovascularization (CNV), intra-, and sub-retinal fluid and pigment epithelial detachment. The automated SEAD footprint detection method was validated against an independent standard obtained using an interactive 3-D SEAD segmentation approach. An area under the receiver-operating characteristic curve of 0.961 +/- 0.012 was obtained for the classification of vertical, cross-layer, macular columns. A study performed on 12 pairs of OCT volumes obtained from the same eye on the same day shows that the repeatability of the automated method is comparable to that of the human experts. This work demonstrates that useful 3-D textural information can be extracted from SD-OCT scans and--together with an anatomical atlas of normal retinas--can be used for clinically important applications.


Land use and management effects on soil carbon in U.S. Lake States, with emphasis on forestry, fire, and reforestation.
There is growing need to quantify and communicate how land use and management activities influence soil organic carbon (SOC) at scales relevant to, and in the tangible control of landowners and forest managers. The continued proliferation of publications and growth of data sets, data synthesis and meta-analysis approaches allows the application of powerful tools to such questions at ever finer scales. In this analysis, we combined a literature review and effect-size meta-analysis with two large, independent, observational databases to assess how land use and management impact SOC stocks, primarily with regards to forest land uses. We performed this work for the (Great Lakes) U.S. Lake States, which comprise 6% of the land area, but 7% of the forest and 9% of the forest SOC in the United States, as the second in a series of ecoregional SOC assessments. Most importantly, our analysis indicates that natural factors, such as soil texture and parent material, exert more control over SOC stocks than land use or management. With that for context, our analysis also indicates which natural factors most influence management impacts on SOC storage. We report an overall trend of significantly diminished topsoil SOC stocks with harvesting, consistent across all three data sets, while also demonstrating how certain sites and soils diverge from this pattern, including some that show opposite trends. Impacts of fire grossly mirror those of harvesting, with declines near the top of the profile, but potential gains at depth and no net change when considering the whole profile. Land use changes showing significant SOC impacts are limited to reforestation on barren mining substrates (large and variable gains) and conversion of native forest to cultivation (losses). We describe patterns within the observational data that reveal the physical basis for preferential land use, e.g., cultivation of soils with the most favorable physical properties, and forest plantation establishment on the most marginal soils, and use these patterns to identify management opportunities and considerations. We also qualify our results with ratings of confidence, based on their degree of support across approaches, and offer concise, defensible tactics for adapting management operations to site-specific criteria and SOC vulnerability.


Severe metabolic alterations in liver cancer lead to ERK pathway activation and drug resistance.
The extracellular signal-regulated kinase (ERK) pathway regulates cell growth, and is hyper-activated and associated with drug resistance in hepatocellular carcinoma (HCC). Metabolic pathways are profoundly dysregulated in HCC. Whether an altered metabolic state is linked to activated ERK pathway and drug response in HCC is unaddressed. We deprived HCC cells of glutamine to induce metabolic alterations and performed various assays, including metabolomics (with 13C-glucose isotope tracing), microarray analysis, and cell proliferation assays. Glutamine-deprived cells were also treated with kinase inhibitors (e.g. Sorafenib, Erlotinib, U0126 amongst other MEK inhibitors). We performed bioinformatics analysis and stratification of HCC tumour microarrays to determine upregulated ERK gene signatures in patients. In a subset of HCC cells, the withdrawal of glutamine triggers a severe metabolic alteration and ERK phosphorylation (pERK). This is accompanied by resistance to the anti-proliferative effect of kinase inhibitors, despite pERK inhibition. High intracellular serine is a consistent feature of an altered metabolic state and contributes to pERK induction and the kinase inhibitor resistance. Blocking the ERK pathway facilitates cell proliferation by reprogramming metabolism, notably enhancing aerobic glycolysis. We have identified 24 highly expressed ERK gene signatures that their combined expression strongly indicates a dysregulated metabolic gene network in human HCC tissues. A severely compromised metabolism lead to ERK pathway induction, and primes some HCC cells to pro-survival phenotypes upon ERK pathway blockade. Our findings offer novel insights for understanding, predicting and overcoming drug resistance in liver cancer patients. FUND: DFG, BMBF and Sino-German Cooperation Project.