Integration of autologous dendritic cell-based immunotherapy in the primary treatment for patients with newly diagnosed glioblastoma multiforme: a pilot study.
Despite resection, radiochemotherapy, and maintenance temozolomide chemotherapy (TMZm), the prognosis of patients with glioblastoma multiforme (GBM) remains poor. We integrated immunotherapy in the primary standard treatment for eight pilot adult patients (median age 50 years) with GBM, to assess clinical and immunological feasibility and toxicity in preparation of a phase I/II protocol HGG-2006. After maximum, safe resection, leukapheresis was performed before radiochemotherapy, and four weekly vaccinations with autologous GBM lysate-loaded monocyte-derived dendritic cells were given after radiochemotherapy. Boost vaccines with lysates were given during TMZm. During the course of vaccination, immunophenotyping showed a relative increase in CD8+CD25+ cells in six of the seven patients, complying with the prerequisites for implementation of immunotherapy in addition to postoperative radiochemotherapy. In five patients, a more than twofold increase in tumor antigen-reacting IFN-gamma-producing T cells on Elispot was seen at the fourth vaccination compared with before vaccination. In three of these five patients this more than twofold increase persisted after three cycles of TMZm. Quality of life during vaccination remained excellent. Progression-free survival at six months was 75%. Median overall survival for all patients was 24 months (range: 13-44 months). The only serious adverse event was an ischemic stroke eight months postoperatively. We conclude that tumor vaccination, fully integrated within the standard primary postoperative treatment for patients with newly diagnosed GBM, is feasible and well tolerated. The survival data were used to power a currently running phase I/II trial.


Demystifying Eukaryote Lateral Gene Transfer (Response to Martin 2017 DOI: 10.1002/bies.201700115).
In a recent BioEssays paper [W. F. Martin, BioEssays 2017, 39, 1700115], William Martin sharply criticizes evolutionary interpretations that involve lateral gene transfer (LGT) into eukaryotic genomes. Most published examples of LGTs in eukaryotes, he suggests, are in fact contaminants, ancestral genes that have been lost from other extant lineages, or the result of artefactual phylogenetic inferences. Martin argues that, except for transfers that occurred from endosymbiotic organelles, eukaryote LGT is insignificant. Here, in reviewing this field, we seek to correct some of the misconceptions presented therein with regard to the evidence for LGT in eukaryotes.


C4BP-IgM protein as a therapeutic approach to treat Neisseria gonorrhoeae infections.
Gonorrhea is a sexually transmitted infection with 87 million new cases per year globally. Increasing antibiotic resistance has severely limited treatment options. A mechanism that Neisseria gonorrhoeae uses to evade complement attack is binding of the complement inhibitor C4b-binding protein (C4BP). We screened 107 porin B1a (PorB1a) and 83 PorB1b clinical isolates randomly selected from a Swedish strain collection over the last 10 years and noted that 96/107 (89.7%) PorB1a and 16/83 (19.3%) PorB1b bound C4BP; C4BP binding substantially correlated with the ability to evade complement-dependent killing (r = 0.78). We designed 2 chimeric proteins that fused C4BP domains to the backbone of IgG or IgM (C4BP-IgG; C4BP-IgM) with the aim of enhancing complement activation and killing of gonococci. Both proteins bound gonococci (KD C4BP-IgM = 2.4 nM; KD C4BP-IgG 980.7 nM), but only hexameric C4BP-IgM efficiently outcompeted heptameric C4BP from the bacterial surface, resulting in enhanced complement deposition and bacterial killing. Furthermore, C4BP-IgM substantially attenuated the duration and burden of colonization of 2 C4BP-binding gonococcal isolates but not a non-C4BP-binding strain in a mouse vaginal colonization model using human factor H/C4BP-transgenic mice. Our preclinical data present C4BP-IgM as an adjunct to conventional antimicrobials for the treatment of gonorrhea.


Ketogenic diet attenuates cerebellar atrophy progression in a subject with a biallelic variant at the ATAD3A locus.
The ATPase AAA-domain protein 3 (ATAD3) is a ubiquitously expressed mitochondrial protein involved in mitochondrial dynamics, DNA-nucleoid structural organization, cholesterol transport and steroidogenesis. Mutations within the ancestral ATAD3A gene are strongly associated with neurological abnormalities due to alterations in the mitochondrial function and homeostasis. Here, we report the case of a subject diagnosed with developmental delay associated with ataxia and progressive atrophy of both cerebellar hemispheres and cerebellar vermis, despite exhibiting a normal biochemical profile. By whole exome sequencing, we identified two biallelic single nucleotide variants within the coding region of ATAD3A in the affected subject. Both variants were previously reported as monoallelic variants with uncertain clinical significance. Importantly, the variant ATAD3A c.251T>C leads to an amino acid change of a highly conserved residue across species and in silico analysis revealed structural alteration in the ATAD3A protein. Ketogenic diet was administered to the subject as a novel therapeutic approach. Notably, the treatment correlated with a reduction in cerebellum atrophy progression and the gradual enhancement of the subject's physical skills, vitality and personal interactions. Thus, we report the first subject with a homozygous status for the ATAD3A c.251T>C (p.Thr84Met) variant. We propose that this mutation led to an alteration of the mitochondrial function, causing the neurological symptoms observed in the subject. The symptoms were partially alleviated following ketogenic diet, improving the subject's quality of life.


Effects of a culturally grounded community-based diabetes prevention program for obese Latino adolescents.
The purpose of this study was to test the feasibility and preliminary effects of a culturally grounded, community-based diabetes prevention program among obese Latino adolescents. Fifteen obese Latino adolescents (body mass index [BMI] percentile = 96.3 ± 1.1, age = 15.0 ± 0.9 years) completed a 12-week intervention that included weekly lifestyle education classes delivered by bilingual/bicultural promotoras and three, 60-minute physical activity sessions per week. Participants were assessed for anthropometrics (height, weight, BMI, and waist circumference), cardiorespiratory fitness, physical activity/inactivity, nutrition behaviors, and insulin sensitivity and glucose tolerance by a 2-hour oral glucose tolerance test. The intervention resulted in significant decreases in BMI z score, BMI percentile, and waist circumference; increases in cardiorespiratory fitness; and decreases in physical inactivity and dietary fat consumption. In addition to these changes, the intervention led to significant improvements in insulin sensitivity and reductions in 2-hour glucose levels. These results support the feasibility and efficacy of a community-based diabetes prevention program for high-risk Latino youth. Translational approaches that are both culturally grounded and biologically meaningful represent a novel and innovative strategy for closing the obesity-related health disparities gap.


Cohort effects in children's delay of gratification.
In the 1960s at Stanford University's Bing Preschool, children were given the option of taking an immediate, smaller reward or receiving a delayed, larger reward by waiting until the experimenter returned. Since then, the "Marshmallow Test" has been used in numerous studies to assess delay of gratification. Yet, no prior study has compared the performance of children across the decades. Common wisdom suggests children today would wait less long, preferring immediate gratification. Study 1 confirmed this intuition in a survey of adults in the United States (N = 354; Mdn age = 34 years). To test the validity of this prediction, Study 2 analyzed the original data for average delay-of-gratification times (out of 10 min) of 840 typically developing U.S. children in three birth cohorts from similar middle-high socioeconomic backgrounds in the late 1960s, 1980s, and 2000s, matched on age (3 to 5 years) at the time of testing. In contrast to popular belief, results revealed a linear increase in delay over time (p < .0001, ηp2 = .047), such that children in the 2000s waited on average 2 min longer than children in the 1960s, and 1 min longer than children in the 1980s. This pattern was robust with respect to age, sex, geography and sampling effects. We posit that increases in symbolic thought, technology, preschool education, and public attention to executive function skills have contributed to this finding, but caution that more research in diverse populations is needed to examine the generality of the findings and to identify causal factors. (PsycINFO Database Record


Unusual entanglement transformation properties of the quantum radiation through one-dimensional random system containing left-handed-materials.
The quantum radiation through the multilayer structures containing the left-handed materials is investigated based on the Green-function approach to the quantization of the phenomenological Maxwell theory. Emphasis is placed on the effect of randomness on the generation and transmission of entangled-states. It is shown that some unusual properties appear for the present systems in comparison with those of the conventional dielectric structures. The quantum relative entropy is always enhanced with the increase of random degree due to the existence of nonlocalized mode in the present systems, while the maximal entanglement can be observed only at some certain randomness for the conventional dielectric structures. In contrast to exponential decrease in the conventional systems, the entanglement degrades slowly with the increase of disorder and thickness of the sample near the nonlocalized mode after transmission through the present systems. This will benefit the quantum communication for long distances.


Diethyl 1,8-diphenyl-11-oxatricyclo-[126.96.36.199(2,7)]undeca-2,4,6-triene-9,10-dicarboxyl-ate.
The title compound, C28H26O5, is the Diels-Alder adduct from 1,3-diphenyl-benzo[c]furan and diethyl maleate. The mol-ecule comprises of a fused tricyclic system containing two five-membered rings, which are in envelope conformations with the O atom at the flap, and a six-membered ring adopting a boat conformation. The dihedral angle between phenyl substituents in the 1,8-positions is 55.1 (1)°. The ethyl groups are disordered over two sets of sites, with occupancy ratios of 0.648 (9):0.352 (9) and 0.816 (1):0.184 (1). In the crystal, pairs of C-H⋯π inter-actions link the mol-ecules into inversion dimers.


Glial swelling during extracellular acidosis in vitro.
Intracellular and extracellular acidosis may determine the ultimate outcome for brain tissue in cerebral ischemia. An extracellular acidosis that occurs in the penumbra zone was investigated in vitro as to its role in the formation of cytotoxic cell swelling. For that purpose, C6 glioma cells or primary cultured astrocytes were suspended in normal isotonic medium in normoxia during acidification to a final pH of 6.2. The cell volume response was determined by flow cytometry using hydrodynamic focusing, which allows one to recognize changes in cell size of less than 1%. A threshold pH of 6.8 was found that had to be crossed to induce cell swelling by acidosis. Once pH fell below this threshold, the increase in cell size appeared to be an all-or-nothing phenomenon. The cells rapidly assumed a final cell size of 115% of normal in the case of C6 glioma or of 118% in the case of primary cultured astrocytes independent of the actual level of acidosis or the duration of exposure. Acidosis-induced glial swelling could be significantly attenuated by 1) addition of amiloride, 2) administration of acetazolamide, or 3) replacement of bicarbonate buffer against N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES). Replacement of extracellular Na+ by choline chloride led to complete prevention of the acidosis-induced cell swelling. Taken together, the findings strongly indicate a central involvement of Na+/H+ and Cl-/HCO3- exchange mechanisms in the development of cell swelling under these conditions. Activation of the Na+/H+ antiporter can be considered an attempt to maintain a normal intracellular pH at the expense of an abnormal cell volume.(ABSTRACT TRUNCATED AT 250 WORDS)


Nonstandard shift schedules and the risk of job-related injuries.
This study assessed the extent to which working various types of nonstandard shift schedules (eg, night and evening shifts) is associated with the risk of occupational injuries or illnesses. Multivariate analyses were conducted using data from 13 years (1987 to 2000) of the National Longitudinal Survey of Youth (NLSY) encompassing 110 236 job records and over 82 000 person-years of work experience. Cox proportional hazard regression techniques were used to derive hazard ratios comparing the relative risk of suffering a work-related injury among people working night, evening, rotating, split, and irregular shifts to the risks for those working conventional day shifts, after adjustment for age, gender, occupation, industry, and region. Incidence rates were normalized using a common denominator of 100 person-years of "at-risk time" to obtain valid comparisons. All of the nonstandard shift schedules, except split shifts, were found to have a higher risk for occupational injuries and illnesses than conventional day shifts. After control for the selected covariates, the calculated hazard ratios were 1.43 for evening shifts [95% confidence interval (95% CI) 1.26-1.62], 1.36 for rotating shifts (95% CI 1.17-1.58), 1.30 for night shifts (95% CI 1.12-1.52), 1.15 for irregular shifts (1.03-1.30), and 1.06 for split shifts (0.71-1.58). These findings suggest that nonstandard shifts are not more risky merely because of the concentration of hazardous jobs in those types of schedules or because of underlying differences in the characteristics of employees working nonstandard shifts. The results point to the need to extend targeted injury prevention programs not only to people working night shifts, but also to those who work evenings.


Compassion training alters altruism and neural responses to suffering.
Compassion is a key motivator of altruistic behavior, but little is known about individuals' capacity to cultivate compassion through training. We examined whether compassion may be systematically trained by testing whether (a) short-term compassion training increases altruistic behavior and (b) individual differences in altruism are associated with training-induced changes in neural responses to suffering. In healthy adults, we found that compassion training increased altruistic redistribution of funds to a victim encountered outside of the training context. Furthermore, increased altruistic behavior after compassion training was associated with altered activation in brain regions implicated in social cognition and emotion regulation, including the inferior parietal cortex and dorsolateral prefrontal cortex (DLPFC), and in DLPFC connectivity with the nucleus accumbens. These results suggest that compassion can be cultivated with training and that greater altruistic behavior may emerge from increased engagement of neural systems implicated in understanding the suffering of other people, executive and emotional control, and reward processing.


Activation and membrane binding of carboxypeptidase E.
Carboxypeptidase E (CPE) is a carboxypeptidase B-like enzyme that is thought to be involved in the processing of peptide hormones and neurotransmitters. Soluble and membrane-associated forms of CPE have been observed in purified secretory granules from various hormone-producing tissues. In this report, the influence of membrane association on CPE activity has been examined. A substantial amount of the membrane-associated CPE activity is solubilized upon extraction of bovine pituitary membranes with either 100 mM sodium acetate buffer (pH 5.6) containing 0.5% Triton X-100 and 1 M NaCl, or by extraction with high pH buffers (pH greater than 8). These treatments also lead to a two- to threefold increase in CPE activity. CPE extracted from membranes with either NaCl/Triton X-100 or high pH buffers hydrolyzes the dansyl-Phe-Ala-Arg substrate with a lower Km than the membrane-associated CPE. The Vmax of CPE present in extracts and membrane fractions after the NaCl/Triton X-100 treatment is twofold higher than in untreated membranes. Treatment of membranes with high pH buffers does not affect the Vmax of CPE in the soluble and particulate fractions. Pretreatment of membranes with bromoacetyl-D-arginine, an active site-directed irreversible inhibitor of CPE, blocks the activation by NaCl/Triton X-100 treatment. Thus the increase in CPE activity upon extraction from membranes is probably not because of the conversion of an inactive form to an active one, but is the result of changes in the conformation of the enzyme that effect the catalytic activity.


The potential therapeutic role of lymph node resection in epithelial ovarian cancer: a study of 13918 patients.
The aim of the study is to determine the role of lymphadenectomy in advanced epithelial ovarian cancer. The data were obtained from the Surveillance, Epidemiology and End Results (SEER) program reported between 1988 and 2001. Kaplan-Meier estimates and Cox proportional hazards regression models were used for analysis. Of 13 918 women with stage III-IV epithelial ovarian cancer (median age: 64 years), 87.9% were Caucasian, 5.6% African Americans, and 4.4% Asians. A total of 4260 (30.6%) underwent lymph node dissections with a median number of six nodes reported. For all patients, a more extensive lymph node dissection (0, 1, 2-5, 6-10, 11-20, and >20 nodes) was associated with an improved 5-year disease-specific survival of 26.1, 35.2, 42.6, 48.4, 47.5, and 47.8%, respectively (P<0.001). Of the stage IIIC patients with nodal metastases, the extent of nodal resection (1, 2-5, 6-10, 11-20, and >20 nodes) was associated with improved survivals of 36.9, 45.0, 47.8, 48.7, and 51.1%, respectively (P=0.023). On multivariate analysis, the extent of lymph node dissection and number of positive nodes were significant independent prognosticators after adjusting for age, year at diagnosis, stage, and grade of disease. The extent of lymphadenectomy is associated with an improved disease-specific survival of women with advanced epithelial ovarian cancer.


Exsolution of Catalytically Active Iridium Nanoparticles from Strontium Titanate.
The search for new functional materials that combine high stability and efficiency with reasonable cost and ease of synthesis is critical for their use in renewable energy applications. Specifically in catalysis, nanoparticles, with their high surface-to-volume ratio, can overcome the cost implications associated with otherwise having to use large amounts of noble metals. However, commercialized materials, that is, catalytic nanoparticles deposited on oxide supports, often suffer from loss of activity because of coarsening and carbon deposition during operation. Exsolution has proven to be an interesting strategy to overcome such issues. Here, the controlled emergence, or exsolution, of faceted iridium nanoparticles from a doped SrTiO3 perovskite is reported and their growth preliminary probed by in situ electron microscopy. Upon reduction of SrIr0.005Ti0.995O3, the generated nanoparticles show embedding into the oxide support, therefore preventing agglomeration and subsequent catalyst degradation. The advantages of this approach are the extremely low noble metal amount employed (∼0.5% weight) and the catalytic activity reported during CO oxidation tests, where the performance of the exsolved SrIr0.005Ti0.995O3 is compared to the activity of a commercial catalyst with 1% loading (1% Ir/Al2O3). The high activity obtained with such low doping shows the possibility of scaling up this new catalyst, reducing the high cost associated with iridium-based materials.


Thermal stress in North Western Australian iron ore mining staff.
Demand for Australian mined iron ore has increased employment within this sector, thus exposing increased numbers of workers to the harsh Australian climate. This study examined the influence of hot (>30°C wet bulb globe temperature) environmental temperatures, consistent with working in North Western Australia, on iron ore mining staff. Core temperature, hydration status, perceived exertion, mood, and fatigue state were measured in 77 participants at three time points (pre-, mid-, and post-shift) during a normal 12-h shift at an open-cut iron ore mining/processing site (n = 31; Site1) and an iron ore processing/shipping site (n = 46; Site2). A significant effect for time was observed for core temperature with greater mean core temperatures measured mid-shift (37.5±0.4°C) and post-shift (37.6±0.3°C) compared with pre-shift values (37.0±0.5°C). All mean core temperature measures were lower than ISO7933 thresholds (38°C) for thermal safety. Mean hydration measures [urine-specific gravity (USG)] were greater at Site1 (1.029±0.006) compared with those at Site2 (1.021±0.007). Furthermore, both pre- and post-shift measures from Site1 and the post-shift measures from Site2 were greater than the threshold for dehydration (USG = 1.020). No differences were observed for mood or perceived exertion over time; however, measures of fatigue state were greater post-shift compared with pre- and mid-shift values for both sites. Our findings indicate that the majority of mine workers in North Western Australia are able to regulate work rate in hot environments to maintain core temperatures below ISO safety guidelines; however, 22% of workers reached or exceeded the safety guidelines, warranting further investigation. Furthermore, hydration practices, especially when off-work, appear inadequate and could endanger health and safety.


Molecular Cytotoxic Mechanisms of 1-(3,4,5-Trihydroxyphenyl)-dodecylbenzoate in Human Leukemia Cell Lines.
Recent studies have shown that gallic acid and its alkylesters induce apoptosis in different cell lines. Since new compounds with biological activity and less cytotoxicity to normal cells are necessary for cancer therapy, the aim of this study was to evaluate the cytotoxic effect of 1-(3,4,5-trihydroxyphenyl)-dodecylbenzoate on human acute myeloid leukemia K562 cells and on human acute lymphoblastic leukemia Jurkat cells. The cell viability was determined by MTT method. The apoptosis induction was assessed by bromide and acridine orange staining and by Annexin V-FITC Apoptosis Detection kit. The cell cycle analysis was carried out by flow cytometry using propidium iodide. Cytometric analysis was also performed to evaluate the expression of the following proteins: AIF, p53, Bcl-2 and Bax. The mitochondrial potential was also assessed by flow cytometry using MitoView633 kit. The results showed that the compound significantly reduced the cell viability of K562 and Jurkat cells in a concentration and time dependent manner (IC50 of 30 μM). The compound induced cell cycle arrest in G0/G1phase and significantly increased the proportion of cells in the sub-G0/G1phase. Apoptosis was confirmed by the sight of morphological characteristics of apoptosis and by phosphatidylserine externalization (73.47±5.71% of cells expressing annexin). The results also showed that the compound promotes a modification in Bax:Bcl-2 ratio and increases p53 expression. Thus, it is possible to conclude that 1-(3,4,5-trihydroxyphenyl)-dodecylbenzoate induces apoptosis by inhibiting the antiapoptotic protein Bcl-2 and by increasing the release of AIF, Bax and p53. In addition, it blocks the cell cycle at G0/G1, stopping cell proliferation. So far, the results suggest that this compound may have a potential therapeutic effect against leukemia cells.


Waiting time information services: an evaluation of how well clearance time statistics can forecast a patient's wait.
Governments in some countries have created web-based information services so that patients requiring elective surgery can compare the waiting times of surgical units. This study investigated how accurately the waiting times of patients about to join a waiting list can be forecast by various clearance time statistics. It used 3 years of elective surgical activity data that covered 46 surgeons in 10 specialties within a public hospital. Six clearance time functions were tested, and the best function was compared with average waiting time statistics derived from census and throughput data. The forecast accuracy of the clearance time functions was found to be greatly affected by the characteristics and behaviour of a surgeon's waiting list. Although there was less difference in performance among the six functions, systematic differences between them were also found. The best of these performed better than the statistics derived from waiting time data, especially where waiting times exceeded 6 months. Yet, its accuracy was still poor. For each surgeon with an average waiting time of more than 6 months, at least 20% of patients waited more than 90 days beyond the clearance time forecast. Consequently, while waiting time information services should consider adopting the clearance time approach, they need to be explicit about its statistical limitations.


Percolating plasmonic networks for light emission control.
Optical nanoantennas have revolutionised the way we manipulate single photons emitted by individual light sources in a nanostructured photonic environment. Complex plasmonic architectures allow for multiscale light control by shortening or stretching the light wavelength for a fixed operating frequency, meeting the size of the emitter and that of propagating modes. Here, we study self-assembled semi-continuous gold films and lithographic gold networks characterised by large local density of optical state (LDOS) fluctuations around the electrical percolation threshold, a regime where the surface is characterised by large metal clusters with fractal topology. We study the formation of plasmonic networks and their effect on light emission from embedded fluorescent probes in these systems. Through fluorescence dynamics experiments we discuss the role of global long-range interactions linked to the degree of percolation and to the network fractality, as well as the local near-field contributions coming from the local electro-magnetic fields and the topology. Our experiments indicate that local properties dominate the fluorescence modification.


Aromatic hydrocarbon macrocycles for highly efficient organic light-emitting devices with single-layer architectures.
A modern electrophosphorescent organic light-emitting device (OLED) achieves quantitative electro-optical conversion by using multiple layers of molecular materials designed through role allotment for independent and specific functions. A unique, potentially innovative device architecture, i.e., a single-layer phosphorescent OLED, is currently being developed by designing multirole base materials via a structural combination of multiple functional components in single molecules. The multirole molecules, however, inevitably require multiple processes to synthesize their multiple components and, moreover, to assemble these components synthetically into one molecule. We herein show that the multirole base material for a highly efficient single-layer phosphorescent OLED can be designed and synthesized with a single, very simple aromatic hydrocarbon component of toluene merely through a one-pot macrocyclization. Without requiring the assembly tasks at the synthesis stage, the molecular design allows for a concise one-pot synthesis of, and a quantitative electro-optical conversion in, the single-layer device architecture with a single-component base material.


Shared control of gene expression in bacteria by transcription factors and global physiology of the cell.
Gene expression is controlled by the joint effect of (i) the global physiological state of the cell, in particular the activity of the gene expression machinery, and (ii) DNA-binding transcription factors and other specific regulators. We present a model-based approach to distinguish between these two effects using time-resolved measurements of promoter activities. We demonstrate the strength of the approach by analyzing a circuit involved in the regulation of carbon metabolism in E. coli. Our results show that the transcriptional response of the network is controlled by the physiological state of the cell and the signaling metabolite cyclic AMP (cAMP). The absence of a strong regulatory effect of transcription factors suggests that they are not the main coordinators of gene expression changes during growth transitions, but rather that they complement the effect of global physiological control mechanisms. This change of perspective has important consequences for the interpretation of transcriptome data and the design of biological networks in biotechnology and synthetic biology.


DSM-IV internal construct validity: when a taxonomy meets data.
The use of DSM-IV based questionnaires in child psychopathology is on the increase. The internal construct validity of a DSM-IV based model of ADHD, CD, ODD, Generalised Anxiety, and Depression was investigated in 11 samples by confirmatory factor analysis. The factorial structure of these syndrome dimensions was supported by the data. However, the model did not meet absolute standards of good model fit. Two sources of error are discussed in detail: multidimensionality of syndrome scales, and the presence of many symptoms that are diagnostically ambiguous with regard to the targeted syndrome dimension. It is argued that measurement precision may be increased by more careful operationalisation of the symptoms in the questionnaire. Additional approaches towards improved conceptualisation of DSM-IV are briefly discussed. A sharper DSM-IV model may improve the accuracy of inferences based on scale scores and provide more precise research findings with regard to relations with variables external to the taxonomy.


Amino acid loss during volume regulatory decrease in cultured chick heart cells.
Mechanisms of volume regulation in hyposomotically treated cultured chick heart cell preparations were studied using optical, biochemical, and nuclear magnetic resonance methods. This approach afforded the resolution of time-dependent responses that might ordinarily be obscured by the complex morphology of intact cardiac muscle preparations. In hyposmotic solutions, cells swelled to a peak volume within 3 min and slowly regulated toward original volume (regulatory volume decrease, RVD). Upon return of the cells to isosmotic solution following hyposmotic treatment, the cells shrank to a steady-state volume that was substantially less than the initial volume in control solution. A vigorous RVD could also be elicited by hyposmotic swelling under Cl(-)-free conditions. Measurement of both inorganic cation loss via atomic absorption spectroscopy and organic solute loss via 1H-nuclear magnetic resonance and high-pressure liquid chromatographic techniques revealed that the RVD observed following exposure to hyposomotic solutions was mediated in part by a substantial loss of taurine, glutamate, aspartate, and glycine as well as loss of inorganic ions (Na+,K+). The hyposmotically activated transport of amino acids was also associated with the production of glutamate and aspartate. The volume regulatory release and production of amino acids have significant implications for the metabolic and functional integrity of cardiac cells.


Resilience in family caregivers of patients diagnosed with advanced cancer - unravelling the process of bouncing back from difficult experiences, a hermeneutic review.
Despite the risk for developing mental disorders, most of advanced cancer patients' family caregivers undergo a resilient process throughout the caregiving period. Research on resilience in caregivers of advanced cancer patients is scarce and further hindered by the lack of a univocal definition and a theoretical framework. To provide clarity on the concept of resilience by proposing an integrative view that can support health care professionals and researchers in conducting and interpreting research on resilience. The review process was inspired by the hermeneutic methodology: a cyclic review process, consisting of repeated searching and analysing until data saturation is reached and focussed on achieving a deeper understanding of ill-defined concepts. The definitions from eighteen reviews on resilience and the theoretical frameworks from eight concept analyses were analysed. The composing elements of resilience were listed and compared. The American Psychological Association's definition of resilience and Bonanno's theoretical framework are suggested to guide further research on resilience. Moreover, four knowledge gaps were uncovered: (1) How do resilience resources interact? (2) What are the key predictors for a resilient trajectory? (3) How do the resilient trajectories evolve across the caregiving period? And (4) how does the patient's nearing death influence the caregiver's resilience? To address flaws in conceptualisation and the resulting gaps in knowledge, we suggest a definition and a theoretical framework that are suited to allow heterogeneity in the field, but enables the development of sound interventions, as well as facilitate the interpretation of intervention effectiveness.


Chronic Wound Dressings Based on Collagen-Mimetic Proteins.
Objective: Chronic wounds are projected to reach epidemic proportions due to the aging population and the increasing incidence of diabetes. There is a strong clinical need for an improved wound dressing that can balance wound moisture, promote cell migration and proliferation, and degrade at an appropriate rate to minimize the need for dressing changes. Approach: To this end, we have developed a bioactive, hydrogel microsphere wound dressing that incorporates a collagen-mimetic protein, Scl2GFPGER, to promote active wound healing. A redesigned Scl2GFPGER, engineered collagen (eColGFPGER), was created to reduce steric hindrance of integrin-binding motifs and increase overall stability of the triple helical backbone, thereby resulting in increased cell adhesion to substrates. Results: This study demonstrates the successful modification of the Scl2GFPGER protein to eColGFPGER, which displayed enhanced stability and integrin interactions. Fabrication of hydrogel microspheres provided a matrix with adaptive moisture technology, and degradation rates have potential for use in human wounds. Innovation: This collagen-mimetic wound dressing was designed to permit controlled modulation of cellular interactions and degradation rate without impact on other physical properties. Its fabrication into uniform hydrogel microspheres provides a bioactive dressing that can readily conform to irregular wounds. Conclusion: Overall, this new eColGFPGER shows strong promise in the generation of bioactive hydrogels for wound healing as well as a variety of tissue scaffolds.


Delayed Coronary Obstruction After Transcatheter Aortic Valve Replacement.
Delayed coronary obstruction (DCO) is an uncommon and barely reported complication following transcatheter aortic valve replacement (TAVR). The aim of this study was to describe the incidence and pathophysiological features of DCO after TAVR, obtained from a large international multicenter registry. Data were retrospectively collected from an international multicenter registry consisting of 18 centers between November 2005 and December 2016. During the study period, 38 DCO (incidence 0.22%) cases were identified from a total of 17,092 TAVR procedures. DCO occurred more commonly after valve-in-valve procedures (0.89% vs. 0.18%; p < 0.001) and if self-expandable valves were used during the index procedure (0.36% vs. 0.11% balloon expandable; p < 0.01). DCO was most likely to occur ≤24 h after the TAVR procedure (47.4%; n = 18); 6 (15.8%) cases occurred between 24 h and ≤7 days, with the remaining 14 (36.8%) at ≥60 days. The most frequent presentation was cardiac arrest (31.6%; n = 12), followed by ST-segment elevation myocardial infarction (23.7%; n = 9). The left coronary artery was obstructed in most cases (92.1%; n = 35). Percutaneous coronary intervention was attempted in the majority of cases (74.3% left main; 60% right coronary), and stent implantation was successful in 68.8%. The overall in-hospital death rate was 50% (n = 19), and was higher if DCO occurred ≤7 days from the index procedure (62.5% vs. 28.6%; p = 0.09). DCO following TAVR is a rare phenomenon that is associated with a high in-hospital mortality rate. Clinicians should be aware that coronary obstruction can occur after the original TAVR procedure and have a low threshold for performing coronary angiography when clinically suspected.


Contribution of prior semantic knowledge to new episodic learning in amnesia.
We evaluated whether prior semantic knowledge would enhance episodic learning in amnesia. Subjects studied prices that are either congruent or incongruent with prior price knowledge for grocery and household items and then performed a forced-choice recognition test for the studied prices. Consistent with a previous report, healthy controls' performance was enhanced by price knowledge congruency; however, only a subset of amnesic patients experienced the same benefit. Whereas patients with relatively intact semantic systems, as measured by an anatomical measure (i.e., lesion involvement of anterior and lateral temporal lobes), experienced a significant congruency benefit, patients with compromised semantic systems did not experience a congruency benefit. Our findings suggest that when prior knowledge structures are intact, they can support acquisition of new episodic information by providing frameworks into which such information can be incorporated.


Development of a Deep Learning Model for Dynamic Forecasting of Blood Glucose Level for Type 2 Diabetes Mellitus: Secondary Analysis of a Randomized Controlled Trial.
Type 2 diabetes mellitus (T2DM) is a major public health burden. Self-management of diabetes including maintaining a healthy lifestyle is essential for glycemic control and to prevent diabetes complications. Mobile-based health data can play an important role in the forecasting of blood glucose levels for lifestyle management and control of T2DM. The objective of this work was to dynamically forecast daily glucose levels in patients with T2DM based on their daily mobile health lifestyle data including diet, physical activity, weight, and glucose level from the day before. We used data from 10 T2DM patients who were overweight or obese in a behavioral lifestyle intervention using mobile tools for daily monitoring of diet, physical activity, weight, and blood glucose over 6 months. We developed a deep learning model based on long short-term memory-based recurrent neural networks to forecast the next-day glucose levels in individual patients. The neural network used several layers of computational nodes to model how mobile health data (food intake including consumed calories, fat, and carbohydrates; exercise; and weight) were progressing from one day to another from noisy data. The model was validated based on a data set of 10 patients who had been monitored daily for over 6 months. The proposed deep learning model demonstrated considerable accuracy in predicting the next day glucose level based on Clark Error Grid and ±10% range of the actual values. Using machine learning methodologies may leverage mobile health lifestyle data to develop effective individualized prediction plans for T2DM management. However, predicting future glucose levels is challenging as glucose level is determined by multiple factors. Future study with more rigorous study design is warranted to better predict future glucose levels for T2DM management.


Early healing events at the dentin-connective tissue interface. Light and transmission electron microscopy observations.
The objective of these studies was to follow early healing at the dentin-connective tissue interface. Small dentin blocks were surgically implanted in bone cavities under mucoperiosteal flaps in the edentulous alveolar ridges of five beagle dogs at various times. In two separate experiments, wound maturation on native dentin surfaces and on citric acid or heparin conditioned dentin surfaces was observed. Block specimens including bone, dentin, and surrounding soft tissues were obtained at 10 minutes, 1 and 6 hours, and 1, 3, and 7 days after flap closure and prepared for light and transmission electron microscopic examination of the interface. The very initial attachment to native dentin was mediated by a granular precipitate. At 1 and 6 hours, the intercellular matrix was more organized with fibrin formation around red blood cell aggregates and at the dentin surface. Polymorphonuclear leukocytes were observed throughout the interface. Red blood cells were undergoing degradation at day 1 and polymorphonuclear cells were prevalent at the dentin surface. The 3-day observation interval was characterized by further maturation of the fibrin clot. Macrophages were observed near the dentin surface and fibroblasts could be identified. The 7-day specimens exhibited areas of cell rich connective tissue attachment without inflammatory cells as well as areas showing the fibrin clot in various stages of decomposition. These observations suggest that connective tissue attachment to dentin surfaces is mediated by adsorption of plasma proteins to the surface and subsequent development and maturation of a fibrin clot. The sequence of healing events at dentin surfaces conditioned with citric acid or heparin was largely similar to healing at native dentin surfaces. However, at day 1 and later time points, clot adhesion to heparin-conditioned dentin appeared compromised, whereas the fibrin clot seemed to adhere to citric acid-conditioned dentin at all observation periods. These observations indicate that in the absence of mechanical trauma, epithelial proliferation, and infection, wound maturation at the dentin-connective tissue interface may not necessarily be affected by treatments that either enhance or inhibit clot adhesion to the dentin surface.


Electronic properties of molecules and surfaces with a self-consistent interatomic van der Waals density functional.
How strong is the effect of van der Waals (vdW) interactions on the electronic properties of molecules and extended systems? To answer this question, we derived a fully self-consistent implementation of the density-dependent interatomic vdW functional of Tkatchenko and Scheffler [Phys. Rev. Lett. 102, 073005 (2009)]. Not surprisingly, vdW self-consistency leads to tiny modifications of the structure, stability, and electronic properties of molecular dimers and crystals. However, unexpectedly large effects were found in the binding energies, distances, and electrostatic moments of highly polarizable alkali-metal dimers. Most importantly, vdW interactions induced complex and sizable electronic charge redistribution in the vicinity of metallic surfaces and at organic-metal interfaces. As a result, a substantial influence on the computed work functions was found, revealing a nontrivial connection between electrostatics and long-range electron correlation effects.


Stochastic calcium mechanisms cause dendritic calcium spike variability.
Bursts of dendritic calcium spikes play an important role in excitability and synaptic plasticity in many types of neurons. In single Purkinje cells, spontaneous and synaptically evoked dendritic calcium bursts come in a variety of shapes with a variable number of spikes. The mechanisms causing this variability have never been investigated thoroughly. In this study, a detailed computational model using novel simulation routines is applied to identify the roles that stochastic ion channels, spatial arrangements of ion channels, and stochastic intracellular calcium have toward producing calcium burst variability. Consistent with experimental recordings from rats, strong variability in the burst shape is observed in simulations. This variability persists in large model sizes in contrast to models containing only voltage-gated channels, where variability reduces quickly with increase of system size. Phase plane analysis of Hodgkin-Huxley spikes and of calcium bursts identifies fluctuation in phase space around probabilistic phase boundaries as the mechanism determining the dependence of variability on model size. Stochastic calcium dynamics are the main cause of calcium burst fluctuations, specifically the calcium activation of mslo/BK-type and SK2 channels. Local variability of calcium concentration has a significant effect at larger model sizes. Simulations of both spontaneous and synaptically evoked calcium bursts in a reconstructed dendrite show, in addition, strong spatial and temporal variability of voltage and calcium, depending on morphological properties of the dendrite. Our findings suggest that stochastic intracellular calcium mechanisms play a crucial role in dendritic calcium spike generation and are therefore an essential consideration in studies of neuronal excitability and plasticity.


Clinical characteristics and therapeutic procedure for four cases with 2019 novel coronavirus pneumonia receiving combined Chinese and Western medicine treatment.
Pneumonia associated with the 2019 novel coronavirus (2019-nCoV) is continuously and rapidly circulating at present. No effective antiviral treatment has been verified thus far. We report here the clinical characteristics and therapeutic procedure for four patients with mild or severe 2019-nCoV pneumonia admitted to Shanghai Public Health Clinical Center. All the patients were given antiviral treatment including lopinavir/ritonavir (Kaletra®), arbidol, and Shufeng Jiedu Capsule (SFJDC, a traditional Chinese medicine) and other necessary support care. After treatment, three patients gained significant improvement in pneumonia associated symptoms, two of whom were confirmed 2019-nCoV negative and discharged, and one of whom was virus negative at the first test. The remaining patient with severe pneumonia had shown signs of improvement by the cutoff date for data collection. Results obtained in the current study may provide clues for treatment of 2019-nCoV pneumonia. The efficacy of antiviral treatment including lopinavir/ritonavir, arbidol, and SFJDC warrants further verification in future study.


High-throughput mass-spectrometry monitoring for multisubstrate enzymes: determining the kinetic parameters and catalytic activities of glycosyltransferases.
A novel high-throughput screening (HTS) method with electrospray time-of-flight (ESI-TOF) mass spectrometry allows i) rapid and broad screening of multisubstrate enzyme catalytic activity towards a range of donor and acceptor substrates; ii) determination of full multisubstrate kinetic parameters and the binding order of substrates. Two representative glycosyltransferases (GTs, one common, one recently isolated, one O-glycosyltransferase (O-GT), one N-glycosyltransferase (N-GT)) have been used to validate this system: the widely used bovine beta-1,4-galactosyltransferase (EC 18.104.22.168), and the recently isolated Arabidopsis thaliana GT UGT72B1 (EC 2.4.1.-). The GAR (green/amber/red) broad-substrate-specificity screen, which is based on the mass ion abundance of product, provides a fast, high-throughput method for finding potential donors and acceptors from substrate libraries. This was evaluated by using six natural and non-natural donors (alpha-UDP-D-Glucose (UDPGlc), alpha-UDP-N-Acetyl-D-glucosamine (UDPGlcNAc), alpha-UDP-D-5-thioglucose (UDP5SGlc), alpha-GDP-L-fucose (GDPFuc), alpha-GDP-D-mannose (GDPMan), alpha,beta-UDP-D-mannose (UDPMan)) and 32 broad-ranging acceptors (sugars, plant hormones, antibiotics, flavonoids, coumarins, phenylpropanoids and benzoic acids). By using the fast-equilibrium assumption, KM, kcat and KIA were determined for representative substrates, and these values were used to determine substrate binding orders. These screening methods applied to the two very different enzymes revealed some unusual substrate specificities, thus highlighting the utility of broad-ranging substrate screening. For UGT72B1, it was shown that the donor specificity is determined largely by the nucleotide moiety. The method is therefore capable of identifying GT enzymes with usefully broad carbohydrate-transfer ability.


Diagnosis and treatment of hereditary angioedema with normal C1 inhibitor.
Until recently it was assumed that hereditary angioedema is a disease that results exclusively from a genetic deficiency of the C1 inhibitor. In 2000, families with hereditary angioedema, normal C1 inhibitor activity and protein in plasma were described. Since then numerous patients and families with that condition have been reported. Most of the patients by far were women. In many of the affected women, oral contraceptives, hormone replacement therapy containing estrogens, and pregnancies triggered the clinical symptoms. Recently, in some families mutations in the coagulation factor XII (Hageman factor) gene were detected in the affected persons.


Extrapulmonary tuberculosis in the European Union and European Economic Area, 2002 to 2011.
Tuberculosis (TB) is decreasing in the European Union/European Economic Area (EU/EEA), but remains a significant public health problem. Although pulmonary TB accounts for the majority of the cases and is the main transmissible form of the disease, extrapulmonary TB also contributes to the burden of disease and does not receive specific attention in international control strategies. We performed a descriptive analysis to assess the burden and trends of extrapulmonary TB in EU/EEA countries. During 2002–11, 167,652 cases of extrapulmonary TB were reported by the 30 Member States. Extrapulmonary TB accounted for 19.3% of all notified cases, ranging from 5.8% to 44.4% among the Member States. Overall, TB notification rates decreased in 2002–11 due to a decrease in pulmonary TB. Notification rates of extrapulmonary TB remained stable at 3.4 per 100,000 in 2002 and 3.2 per 100,000 in 2011. Thus the proportion of extrapulmonary TB increased from 16.4% in 2002 to 22.4% in 2011. Of all extrapulmonary TB cases reported during 2002–11, 37.9% were foreign-born or citizens of another country, 33.7% were culture-confirmed, and the overall treatment success was 81.4%. A significant percentage of notified TB cases are extrapulmonary, and in contrast to pulmonary TB, extrapulmonary TB rates are not decreasing.


Paeoniflorin attenuates schistosomiasis japonica-associated liver fibrosis through inhibiting alternative activation of macrophages.
Interleukin (IL)-13 and alternatively activated macrophages (AAMs) play an important role in liver granuloma and fibrosis of schistosomiasis. Paeoniflorin (PAE, C23H28O11) has been reported to have an anti-hepatic fibrosis effect in schistosomiasis; however, the mechanism has not been fully elucidated. In this study, we measured serum hyaluronic acid (HA) concentrations, liver granuloma diameter and volume density, fibrosis degree and expressions of IL-13, arginase-1 (ARG-1), nitric oxide synthase-2 (NOS-2), and phosphorylated signal transducer and activator of transcription 6 (p-STAT6) in mice liver of schistosomiasis. Then we detected expressions of specific biomarkers of AAMs and activity of Arg-1 in Kupffer cells (KCs) from infected and PAE-treated mice, or in KCs from uninfected mice, but exposed to rIL-13 in vitro. Finally, we observed expression of IL-13 signalling molecules in KCs and secretion of IL-13 from lymphocytes of infected and PAE-treated mice. Our results showed that during schistosomiasis, IL-13 expression and secretion increased with liver macrophages activated alternatively. PAE not only directly inhibited alternative activation of macrophages via reducing the phosphorylations of janus-activated kinase 2 (JAK2) and/or STAT6, leading to reduction of AAMs-related markers and Arg-1 activity, but also indirectly suppressed alternative activation of macrophages through decreasing secretion of IL-13. PAE might be a promising prophylactic agent for hepatic granuloma and fibrosis of schistosomiasis japonica.


Control over conflict during movement preparation: role of posterior parietal cortex.
Flexible behavior in humans often requires that rapid choices be made between conflicting action plans. Although much attention has focused on prefrontal regions, little is understood about the contribution of parietal cortex under situations of response conflict. Here we show that right parietal damage associated with spatial neglect leads to paradoxical facilitation (speeding) of rightward movements in the presence of conflicting leftward response plans. These findings indicate a critical role for parietal regions in action planning when there is response competition. In contrast, patients with prefrontal damage have an augmented cost of conflict for both leftward and rightward movements. The results suggest involvement of two independent systems in situations of response conflict, with right parietal cortex being a crucial site for automatic activation of competing motor plans and prefrontal regions acting independently to inhibit action plans irrelevant to current task goals.


Development and characterization of magnetic iron oxide nanoparticles with a cisplatin-bearing polymer coating for targeted drug delivery.
A highly selective and efficient cancer therapy can be achieved using magnetically directed superparamagnetic iron oxide nanoparticles (SPIONs) bearing a sufficient amount of the therapeutic agent. In this project, SPIONs with a dextran and cisplatin-bearing hyaluronic acid coating were successfully synthesized as a novel cisplatin drug delivery system. Transmission electron microscopy images as well as X-ray diffraction analysis showed that the individual magnetite particles were around 4.5 nm in size and monocrystalline. The small crystallite sizes led to the superparamagnetic behavior of the particles, which was exemplified in their magnetization curves, acquired using superconducting quantum interference device measurements. Hyaluronic acid was bound to the initially dextran-coated SPIONs by esterification. The resulting amide bond linkage was verified using Fourier transform infrared spectroscopy. The additional polymer layer increased the vehicle size from 22 nm to 56 nm, with a hyaluronic acid to dextran to magnetite weight ratio of 51:29:20. A maximum payload of 330 μg cisplatin/mL nanoparticle suspension was achieved, thus the particle size was further increased to around 77 nm with a zeta potential of -45 mV. No signs of particle precipitation were observed over a period of at least 8 weeks. Analysis of drug-release kinetics using the dialysis tube method revealed that these were driven by inverse ligand substitution and diffusion through the polymer shell as well as enzymatic degradation of hyaluronic acid. The biological activity of the particles was investigated in a nonadherent Jurkat cell line using flow cytometry. Further, cell viability and proliferation was examined in an adherent PC-3 cell line using xCELLigence analysis. Both tests demonstrated that particles without cisplatin were biocompatible with these cells, whereas particles with the drug induced apoptosis in a dose-dependent manner, with secondary necrosis after prolonged incubation. In conclusion, combination of dextran-coated SPIONs with hyaluronic acid and cisplatin represents a promising approach for magnetic drug targeting in the treatment of cancer.


Random forest Gini importance favours SNPs with large minor allele frequency: impact, sources and recommendations.
The use of random forests is increasingly common in genetic association studies. The variable importance measure (VIM) that is automatically calculated as a by-product of the algorithm is often used to rank polymorphisms with respect to their ability to predict the investigated phenotype. Here, we investigate a characteristic of this methodology that may be considered as an important pitfall, namely that common variants are systematically favoured by the widely used Gini VIM. As a consequence, researchers may overlook rare variants that contribute to the missing heritability. The goal of the present article is 3-fold: (i) to assess this effect quantitatively using simulation studies for different types of random forests (classical random forests and conditional inference forests, that employ unbiased variable selection criteria) as well as for different importance measures (Gini and permutation based); (ii) to explore the trees and to compare the behaviour of random forests and the standard logistic regression model in order to understand the statistical mechanisms behind the preference for common variants; and (iii) to summarize these results and previously investigated properties of random forest VIMs in the context of genetic association studies and to make practical recommendations regarding the choice of the random forest and variable importance type. All our analyses can be reproduced using R code available from the companion website: http://www.ibe.med.uni-muenchen.de/organisation/mitarbeiter/020_professuren/boulesteix/ginibias/.


The effects of dexketoprofen on duration of analgesia to a thermal stimulus when compared with a systemic control in a rat sciatic nerve block with levobupivacaine.
This study was designed to investigate whether dexketoprofen added to perineuraly or subcutaneously alters the effects of levobupivacaine in a rat model of sciatic nerve blockade. Thirty-six rats received unilateral sciatic nerve blocks along with a subcutaneous injection by a blinded investigator assigned at random. Combinations were as follows: Group 1 (sham) perineural and subcutaneous saline; Group 2, perineural levobupivacaine alone and subcutaneous saline; Group 3, perineural levobupivacaine plus dexketoprofen and subcutaneous saline; Group 4, perineural levobupivacaine and subcutaneous dexketoprofen; Group 5, perineural dexketoprofen and subcutaneous saline; and Group 6, perineural saline and subcutaneous dexketoprofen. The levobupivacaine concentration was fixed at 0.05%, and the dose of dexketoprofen was 1 mg kg(-1) . Sensory analgesia was assessed by paw withdrawal latency to a thermal stimulus every 30 min. The unblocked paw served as the control for the assessment of systemic, centrally mediated analgesia. Perineural and subcutaneous dexketoprofen coadministered with perineural levobupivacaine did not enhance the duration of sensory blockade when compared with levobupivacaine alone. There were significant differences between the operative and control paws for time points 30-90 min in the perineural levobupivacaine alone, levobupivacaine + dexketoprofen and subcutaneous dexketoprofen added levobupivacaine group. Significant differences were not determined between the levobupivacaine alone group and dexketoprofen added groups in operative paw. The effects of dexketoprofen are unknown for perineural administration. There is no significant difference between the analgesic effects of peripheral nerve blocks using levobupivacaine alone and plus subcutaneous or perineural dexketoprofen.


Effect of Continuing Olanzapine vs Placebo on Relapse Among Patients With Psychotic Depression in Remission: The STOP-PD II Randomized Clinical Trial.
Psychotic depression is a severely disabling and potentially lethal disorder. Little is known about the efficacy and tolerability of continuing antipsychotic medication for patients with psychotic depression in remission. To determine the clinical effects of continuing antipsychotic medication once an episode of psychotic depression has responded to combination treatment with an antidepressant and antipsychotic agent. Thirty-six week randomized clinical trial conducted at 4 academic medical centers. Patients aged 18 years or older had an episode of psychotic depression acutely treated with sertraline plus olanzapine for up to 12 weeks and met criteria for remission of psychosis and remission or near-remission of depressive symptoms for 8 weeks before entering the clinical trial. The study was conducted from November 2011 to June 2017, and the final date of follow-up was June 13, 2017. Participants were randomized either to continue olanzapine (n = 64) or switch from olanzapine to placebo (n = 62). All participants continued sertraline. The primary outcome was risk of relapse. Main secondary outcomes were change in weight, waist circumference, lipids, serum glucose, and hemoglobin A1c (HbA1c). Among 126 participants who were randomized (mean [SD] age, 55.3 years [14.9 years]; 78 women [61.9%]), 114 (90.5%) completed the trial. At the time of randomization, the median dosage of sertraline was 150 mg/d (interquartile range [IQR], 150-200 mg/d) and the median dosage of olanzapine was 15 mg/d (IQR, 10-20 mg/d). Thirteen participants (20.3%) randomized to olanzapine and 34 (54.8%) to placebo experienced a relapse (hazard ratio, 0.25; 95% CI, 0.13 to 0.48; P < .001). The effect of olanzapine on the daily rate of anthropometric and metabolic measures significantly differed from placebo for weight (0.13 lb; 95% CI, 0.11 to 0.15), waist circumference (0.009 inches; 95% CI, 0.004 to 0.014), and total cholesterol (0.29 mg/dL; 95% CI, 0.13 to 0.45) but was not significantly different for low-density lipoprotein cholesterol (0.04 mg/dL; 95% CI, -0.01 to 0.10), high-density lipoprotein cholesterol (-0.01 mg/dL; 95% CI, -0.03 to 0.01), triglyceride (-0.153 mg/dL; 95% CI, -0.306 to 0.004), glucose (-0.02 mg/dL; 95% CI, -0.12 to 0.08), or HbA1c levels (-0.0002 mg/dL; 95% CI, -0.0021 to 0.0016). Among patients with psychotic depression in remission, continuing sertraline plus olanzapine compared with sertraline plus placebo reduced the risk of relapse over 36 weeks. This benefit needs to be balanced against potential adverse effects of olanzapine, including weight gain. ClinicalTrials.gov Identifier: NCT01427608.


Impaired KCC2 Function Triggers Interictal-Like Activity Driven by Parvalbumin-Expressing Interneurons in the Isolated Subiculum In Vitro.
The decreased expression of the KCC2 membrane transporter in subicular neurons has been proposed to be a key epileptogenic event in temporal lobe epilepsy (TLE). Here, we have addressed this question in a reduced model in vitro and have studied the properties and mechanistic involvement of a major class of interneurons, that is, parvalbumin-expressing cells (PVs). When exposed to the KCC2 blocker VU0463271, mouse subicular slices generated hypersynchronous discharges that could be recorded electrophysiologically and visualized as clusters of co-active neurons with calcium imaging. The pharmacological profile of these events resembled interictal-like discharges in human epileptic tissue because of their dependence on GABAA and AMPA receptors. On average, PVs fired before pyramidal cells (PCs) and the area of co-active clusters was comparable to the individual axonal spread of PVs, suggesting their mechanistic involvement. Optogenetic experiments confirmed this hypothesis, as the flash-stimulation of PVs in the presence of VU0463271 initiated interictal-like discharges, whereas their optogenetic silencing suppressed network hyper-excitability. We conclude that reduced KCC2 activity in subicular networks in vitro is sufficient to induce interictal-like activity via altered GABAergic signaling from PVs without other epilepsy-related changes. This conclusion supports an epileptogenic role for impaired subicular KCC2 function during the progression of TLE.


A Novel Technique for Sterilization Using a Power Self-Regulated Single-Mode Microwave Cavity.
In this paper, a novel technique to achieve precise temperatures in food sterilization has been proposed. An accurate temperature profile is needed in order to reach a commitment between the total removal of pathogens inside the product and the preservation of nutritional and organoleptic characteristics. The minimal variation of the target temperature in the sample by means of a monitoring and control software platform, allowing temperature stabilization over 100 °C, is the main goal of this work. A cylindrical microwave oven, under pressure conditions and continuous control of the microwave supply power as function of the final temperature inside the sample, has been designed and developed with conditions of single-mode resonance. The uniform heating in the product is achieved by means of sample movement and the self-regulated power control using the measured temperature. Finally, for testing the sterilization of food with this technology, specific biological validation based on Bacillus cereus as a biosensor of heat inactivation has been incorporated as a distribution along the sample in the experimental process to measure the colony-forming units (CFUs) for different food samples (laboratory medium, soup, or fish-based animal by-products). The obtained results allow the validation of this new technology for food sterilization with precise control of the microwave system to ensure the uniform elimination of pathogens using high temperatures.


Patient barriers to cancer pain management: from the viewpoint of the cancer patients receiving analgesics in a teaching hospital of Taiwan.
The purpose of this study was to investigate the barriers to receiving analgesics for cancer pain in Taiwanese patients. The sample consisted of 128 hospitalized patients. All of the subjects were receiving analgesics. Three questionnaires entitled "Barriers Questionnaire-Taiwan Form (BQT)", "Brief Pain Inventory Short Form", and "Pain Management Index (PMI)" were used in this study. Data were analyzed using Student's t-test and Pearson correlation. The results showed that most of BQT subscales including disease progression, time interval, tolerance, injection, addiction, fatalism and side effects were approaching toward the moderate or high end of the scale. 42.1% (n = 54) of the patients had negative PMI scores indicating that they were using less than adequate analgesics for pain. There was a significant difference between those who had adequate medication and those who did not, in terms of disease progression score and the total BQT score. Overall the result revealed that pain management in these cancer patients was inadequate. Misconceptions on the part of patients still exist. Educational intervention could be an effective means for overcoming such barriers in Taiwanese patients who received analgesics for cancer pain.


Differential treatment response trajectories in individuals with subclinical and clinical PTSD.
Subclinical presentations of posttraumatic stress disorder (PTSD), wherein patients are one or two symptom criteria short of the full disorder, are prevalent and associated with levels of distress and impaired functioning approximating that of full PTSD. Nonetheless, research examining treatment efficacy for this group is in the nascent stage. The purpose of the present study was to examine whether the subclinical PTSD group would: (1) show a greater reduction in PTSD symptoms at pre and post treatment in response to an exposure based treatment and (2) show a greater rate of change over the course of treatment, when compared to the full criteria PTSD group. We also examined whether differences would emerge when examining PTSD symptom clusters. Consistent with predictions, the subclinical PTSD group demonstrated a greater reduction in PTSD symptoms at post-treatment (29%) than those with a PTSD diagnosis (14%). Further, the groups had different treatment trajectories, with the subclinical PTSD group showing a marginally greater rate of change during the course of treatment. Findings also varied by symptom cluster with the subclinical group showing a greater rate of change in the intrusions, hypervigilance, and avoidance symptom clusters. There was not a significant between group difference in the numbing symptom cluster. This study provides preliminary evidence that treating PTSD symptoms at the subclinical level may result in a larger, and more rapid symptom reduction, and thus has implications supporting treatment earlier in the developmental trajectory of the disorder.


What should we include in a cultural competence curriculum? An emerging formative evaluation process to foster curriculum development.
To identify, prioritize, and organize components of a cultural competence curriculum to address disparities in cardiovascular disease. In 2006, four separate nominal group technique sessions were conducted with medical students, residents, community physicians, and academic physicians to generate and prioritize a list of concepts (i.e., ideas) to include in a curriculum. Afterward, 45 educators and researchers organized and prioritized the concepts using a card-sorting exercise. Multidimensional scaling (MDS) and hierarchical cluster analysis produced homogeneous groupings of related concepts and generated a cognitive map. The main outcome measures were the number of cultural competence concepts, their relative ranks, and the cognitive map. Thirty participants generated 61 concepts; 29 were identified by at least two participants. The cognitive map organized concepts into four clusters, interpreted as (1) patient's cultural background (e.g., information on cultures, habits, values), (2) provider and health care (e.g., clinical skills, awareness of one's bias, patient centeredness, professionalism), communication skills (e.g., history, stereotype avoidance, health disparities epidemiology), (3) cross-culture (e.g., idiomatic expressions, examples of effective communication), and (4) resources to manage cultural diversity (e.g., translator guides, instructions, community resources). The MDS two-dimensional solution demonstrated a good fit (stress = 0.07; R² = 0.97). A novel, combined approach allowed stakeholders' inputs to identify and cognitively organize critical domains used to guide development of a cultural competence curriculum. Educators may use this approach to develop and organize educational content for their target audiences, especially in ill-defined areas like cultural competence.


Consilient research approaches in studying gene x environment interactions in alcohol research.
This review article discusses the importance of identifying gene-environment interactions for understanding the etiology and course of alcohol use disorders and related conditions. A number of critical challenges are discussed, including the fact that there is no organizing typology for classifying different types of environmental exposures, many key human environmental risk factors for alcohol dependence have no clear equivalents in other species, much of the genetic variance of alcohol dependence in human is not 'alcohol specific', and the potential range of gene-environment interactions that could be considered is so vast that maintaining statistical control of Type 1 errors is a daunting task. Despite these and other challenges, there appears to be a number of promising approaches that could be taken in order to achieve consilience and ecologically valid translation between human alcohol dependence and animal models. Foremost among these is to distinguish environmental exposures that are thought to have enduring effects on alcohol use motivation (and self-regulation) from situational environmental exposures that facilitate the expression of such motivations but do not, by themselves, have enduring effects. In order to enhance consilience, various domains of human approach motivation should be considered so that relevant environmental exposures can be sampled, as well as the appropriate species to study them in (i.e. where such motivations are ecologically relevant). Foremost among these are social environments, which are central to the initiation and escalation of human alcohol consumption. The value of twin studies, human laboratory studies and pharmacogenetic studies is also highlighted.


Major scientific advances with dairy foods in nutrition and health.
A large body of scientific evidence collected in recent decades demonstrates that an adequate intake of calcium and other nutrients from dairy foods reduces the risk of osteoporosis by increasing bone acquisition during growth, slowing age-related bone loss, and reducing osteoporotic fractures. These results have culminated in the new (2005) Dietary Guidelines for Americans that now recommend 3 servings of milk products per day to reduce the risk of low bone mass and contribute important amounts of many nutrients that may have additional health attributes beyond bone health. A number of animal, observational, and clinical studies have shown that dairy food consumption can help reduce the risk of hypertension. Clinical trials indicate that the consumption of recommended levels of dairy products, as part of a healthy diet, can contribute to lower blood pressure in individuals with normal and elevated blood pressure. Emerging data also indicate that specific peptides associated with casein and whey proteins can significantly lower blood pressure. In addition, a growing body of evidence has provided support for a beneficial effect of dairy foods on body weight and fat loss. Clinical studies have demonstrated that during caloric restriction, body weight and body fat loss occurs when adequate calcium is provided by supplements and that this effect is further augmented by an equivalent amount of calcium supplied from dairy foods. Several studies support a role for calcium, vitamin D, and dairy foods against colon cancer. Additionally, conjugated linoleic acid, a fatty acid found naturally in dairy fat, confers a wide range of anticarcinogenic benefits in experimental animal models and is especially consistent for protection against breast cancer.


Preceptorship and affirmation in the intergenerational world of nursing practice.
Research has shown that while preceptorship offers a reality-oriented learning environment and facilitates competence of students, there are inherent rewards and stressors associated with the experience. Students and preceptors can be from different generations, and as such, they may often come to the learning space with differing values and expectations. The nature of the preceptorship experience in this intergenerational context was explored in a recent phenomenological study with seven preceptors and seven nursing students in an undergraduate nursing program in Eastern Canada. Overall the experience was found to be inclusive of three main themes: being affirmed, being challenged, and being on a pedagogical journey. In this paper we explore the first of these themes, being affirmed. Highlighting the positive aspects of the preceptorship experience in the intergenerational context is necessary to promote a culture of openness and respect for generational differences within clinical nursing practice settings and to improving the overall quality of the educational experience.


p-Doping of graphene in hybrid materials with 3,10-diazapicenium dications.
N,N'-Didodecyl-substituted 3,10-diazapicenium salts featuring bromide and hexafluorophosphate counterions have been designed as novel dopants to realize individualized graphene sheets in a series of cutting edge experiments and to intrinsically stabilize them via p-doping. Importantly, electrochemical studies revealed two consecutive irreversible one-electron reductions of the N,N'-didodecyl-substituted 3,10-diazapicenium salts to yield the corresponding radical cation and neutral quinoidal species. Formation of both species was accompanied by characteristic changes in the absorption spectra. The 3,10-diazapicenium bromide was found to be a potent dopant to produce hybrid materials with exfoliated graphene. Microscopy based on AFM and TEM imaging and spectroscopy based on Raman probing corroborated that, upon drying, the hybrid material consists of few layer (5-8 layers) turbostratic graphene sheets that are p-doped. Our findings identify the newly synthesized N,N'-dialkylated 3,10-diazapicenium salts as highly promising candidates for the fabrication of functional graphene materials with tailored properties.


Venous and arterial endothelia: different dilator abilities in dog vessels.
It has been demonstrated by other investigators that endothelium-dependent vasodilators are more effective on arterial tissue than on venous tissue. The purpose of this study was to determine if this was due to a difference in the sensitivity of arterial and venous smooth muscle to the endothelial dilator (EDRF) or to a difference in the ability of arterial and venous endothelia to release EDRF. To differentiate between these two possibilities, an in vitro "sandwich" preparation was used in which the mechanical response to endothelium-dependent dilators of a de-endothelialized vessel was determined when "sandwiched" with an endothelialized vessel. Using dog femoral artery and saphenous vein, it was determined that acetylcholine (ACh), the ionophore A23187, and thrombin were endothelium-dependent dilators of the femoral artery, but their dilatory ability was significantly less in the saphenous vein. However, if the de-endothelialized saphenous vein was "sandwiched" with an endothelialized femoral artery, both ACh and A23187 significantly relaxed the vein. No relaxation of the de-endothelialized femoral artery occurred when it was "sandwiched" with an intact saphenous vein. Sodium nitroprusside, thought to act by a mechanism similar to EDRF, relaxed equally the saphenous vein and femoral artery. These observations suggest that the difference in responsiveness between femoral arteries and saphenous veins to endothelium-dependent dilators is due more to differences in the ability of their endothelia to release EDRF than to an inability of their smooth muscle to respond to EDRF.


Monoclonal antibodies that demonstrate specificity for several types of human lung cancer.
Monoclonal antibodies with selectivity for human lung cancer were produced by immunizing BALB/c mice with an established line of human small cell lung cancer (NCI-H69) and fusing the mouse spleen cells to mouse myeloma line X63-Ag8.653. The resulting hybrid cells were initially screened by immunoautoradiography for production of antibodies that would react with NCI-H69 and another small cell lung cancer line (NCI-H128) but not its autologous B-lymphoblastoid line (NCI-H128BL). Stable monoclonal antibody-producing lines were isolated by repeated cloning. Three independently derived monoclonal antibodies, designated 525A5, 534F8, and 538F12, were found to react with three of the major types of human lung cancer (small cell, adenocarcinoma, and squamous carcinoma). They did not react with bronchioloalveolar and large cell lung cancers, myeloma, lymphomas, leukemias, osteogeneic sarcoma, mesothelioma, hypernephroma, malignant melanoma, simian virus 40-transformed human fetal lung cells, skin fibroblast lines, human B-lymphoblastoid lines, human erythrocytes, and rodent cells. Interestingly, these antibodies also bound to three out of three human neuroblastomas and two out of three breast cancers but failed to react with mouse neuroblastoma and rat pheochromocytoma. The monoclonal antibodies reacted with human small cell lung cancer tumors obtained at autopsy, but had insignificant reactions with normal human lung, liver, spleen, and skeletal muscle. We conclude that monoclonal antibodies have been generated that react with common antigenic determinants expressed on several human lung cancer types, neuroblastoma, and some breast cancers, but are not detectable by our current assays on a variety of other human tumors or normal adult human tissues. Such antibodies are of potential clinical and biological importance.


[Not Available].
Obesity is increasing worldwide in both sexes and a challenge for health professionals and the health care system. Women have more subcutaneous fat and are more insulin sensitive while men have more visceral and liver fat and higher cardiovascular risk. Women more often show the metabolically healthy obese phenotype than males. However, with increasing BMI the risk for type 2 diabetes and cardiovascular diseases increases more dramatically in women compared to males. Obese women suffer more from weight-related problems, have a higher rate of depression and seek more often medical help to reduce weight. Both biological factors and psychosocial factors contribute to the disease and interact with each other. In this special edition of the journal sex and gender aspects in prevention, treatment and development of complications will be discussed, as proposed by the Austrian Obesity Association. Data available from the Austrian population will be included in the Austrian Gender Obesity Report.


Pharmacokinetics and antibacterial activity of daily gentamicin.
Twenty full term neonates with suspected bacterial infection were randomly assigned to a once daily or a twice daily dosage regimen with gentamicin (4 mg/kg/day). Concomitantly all patients were treated with ampicillin (200 mg/kg/day). The gentamicin concentration time curves were analysed by an open two compartment model under steady state conditions on day 4 of treatment. The mean theoretical maximum serum concentration in the group taking gentamicin once daily (10.9 micrograms/ml) was significantly higher than in the group taking it twice daily (7.4 micrograms/ml). Potentially toxic serum concentrations were never reached. Mean trough concentrations were comparable in both groups (once daily 0.8 micrograms/ml; twice daily 1.0 micrograms/ml). Urinary alanine aminopeptidase excretion increased during and even two days after end of treatment in both groups without any significant differences. The results of the dynamic in vitro model revealed that both dosage schedules showed comparable bactericidal effects on pathogens inhibited by low concentrations of gentamicin like Escherichia coli and Staphylococcus aureus. However the once daily regimen was significantly superior in isolates with high minimal inhibitory concentrations.


A Multicentre Study of 5-year Outcomes Following Focal Therapy in Treating Clinically Significant Nonmetastatic Prostate Cancer.
Clinically significant nonmetastatic prostate cancer (PCa) is currently treated using whole-gland therapy. This approach is effective but can have urinary, sexual, and rectal side effects. To report on 5-yr PCa control following focal high-intensity focused ultrasound (HIFU) therapy to treat individual areas of cancer within the prostate. This was a prospective study of 625 consecutive patients with nonmetastatic clinically significant PCa undergoing focal HIFU therapy (Sonablate) in secondary care centres between January 1, 2006 and December 31, 2015. A minimum of 6-mo follow-up was available for599 patients. Intermediate- or high-risk PCa was found in 505 patients (84%). Disease was localised using multiparametric magnetic resonance imaging (mpMRI) combined with targeted and systematic biopsies, or transperineal mapping biopsies. Areas of significant disease were treated. Follow-up included prostate-specific antigen (PSA) measurement, mpMRI, and biopsies. The primary endpoint, failure-free survival (FFS), was defined as freedom from radical or systemic therapy, metastases, and cancer-specific mortality. The median follow-up was 56 mo (interquartile range [IQR] 35-70). The median age was 65 yr (IQR 61-71) and median preoperative PSA was 7.2 ng/ml (IQR 5.2-10.0). FFS was 99% (95% confidence interval [CI] 98-100%) at 1 yr, 92% (95% CI 90-95%) at 3 yr, and 88% (95% 85-91%) at 5 yr. For the whole patient cohort, metastasis-free, cancer-specific, and overall survival at 5 yr was 98% (95% CI 97-99%), 100%, and 99% (95% CI 97-100%), respectively. Among patients who returned validated questionnaires, 241/247 (98%) achieved complete pad-free urinary continence and none required more than 1 pad/d. Limitations include the lack of long-term follow-up. Focal therapy for select patients with clinically significant nonmetastatic prostate cancer is effective in the medium term and has a low probability of side effects. In this multicentre study of 625 patients undergoing focal therapy using high-intensity focused ultrasound (HIFU), failure-free survival, metastasis-free survival, cancer-specific survival, and overall survival were 88%, 98%, 100%, and 99%, respectively. Urinary incontinence (any pad use) was 2%. Focal HIFU therapy for patients with clinically significant prostate cancer that has not spread has a low probability of side effects and is effective at 5 yr.


Comparative Genomic Analysis of Pseudomonas chlororaphis PCL1606 Reveals New Insight into Antifungal Compounds Involved in Biocontrol.
Pseudomonas chlororaphis PCL1606 is a rhizobacterium that has biocontrol activity against many soilborne phytopathogenic fungi. The whole genome sequence of this strain was obtained using the Illumina Hiseq 2000 sequencing platform and was assembled using SOAP denovo software. The resulting 6.66-Mb complete sequence of the PCL1606 genome was further analyzed. A comparative genomic analysis using 10 plant-associated strains within the fluorescent Pseudomonas group, including the complete genome of P. chlororaphis PCL1606, revealed a diverse spectrum of traits involved in multitrophic interactions with plants and microbes as well as biological control. Phylogenetic analysis of these strains using eight housekeeping genes clearly placed strain PCL1606 into the P. chlororaphis group. The genome sequence of P. chlororaphis PCL1606 revealed the presence of sequences that were homologous to biosynthetic genes for the antifungal compounds 2-hexyl, 5-propyl resorcinol (HPR), hydrogen cyanide, and pyrrolnitrin; this is the first report of pyrrolnitrin encoding genes in this P. chlororaphis strain. Single-, double-, and triple-insertional mutants in the biosynthetic genes of each antifungal compound were used to test their roles in the production of these antifungal compounds and in antagonism and biocontrol of two fungal pathogens. The results confirmed the function of HPR in the antagonistic phenotype and in the biocontrol activity of P. chlororaphis PCL1606.


Endovascular grafts for abdominal aortic aneurysm.
During the last two decades, endovascular technology has revolutionized the management of patients with abdominal aortic aneurysm (AAA). Today, endovascular aortic repair (EVAR) is the treatment of choice for the majority of patients with an AAA. Randomized controlled trials provide robust evidence for the indication of AAA repair and the rationale for the use of EVAR in selected patients. However, despite that, practice varies and several areas need further elucidation. Important future challenges and areas of research include the role of medical therapy in AAA, whether the indication for repair should be any different in women and in the elderly, and long-term follow-up of patients undergoing complex EVAR with adjuncts, both for elective treatment and for ruptured AAA. Continuous rapid technical and clinical development is to be expected. In this paper, we review the current practice and evidence of stenting in AAA.


Arterial wall lymphangiogenesis is increased in the human iliac atherosclerotic arteries: involvement of CCR7 receptor.
Twenty-six iliac artery segments were divided in two groups: atherosclerotic (A) and nonatherosclerotic (NA). Expression of LYVE-1, VEGF-C, VEGF-D, and CCR7 receptor were studied with immunohistochemistry (IHC) and Western blot (WB). IHC was performed on 26 samples of iliac arteries obtained from deceased 19 organ donors. The samples were divided into an atherosclerotic group (A) [subjects with history of cardiovascular disease (hypertension, ischemic heart disease) or/and diabetes] (n=16), and a nonatherosclerotic group (NA) [subjects without any known cardiovascular diseases or cardiovascular risk factors] (n=10). WB was performed on 19 iliac artery segments obtained from two groups, based on clinical data: an atherosclerotic group (A) [patients with atherosclerosis, who underwent surgery for lower limb ischemia] (n=10), and a nonatherosclerotic group (NA) [deceased organ donors without cardiovascular diseases/risk factors (n=9)]. Expression of LYVE-1, VEGF-C, VEGF-D, and CCR-7 was increased in atherosclerotic arteries. Positive correlations between LYVE-1 and VEGF-C expression in the intima-media complex assessed by IHC: (r=0.54; p=0.005) and WB: (r=0.47; p=0.005) were found. Positive correlations between expression of CCR-7 and other markers were observed. Lymphangiogenesis is enhanced within the atherosclerotic arterial wall. Our results confirm lymphatic system activation with increased lymphangiogenesis and lymphocyte/macrophage trafficking in atherosclerosis.


BIS2Analyzer: a server for co-evolution analysis of conserved protein families.
Along protein sequences, co-evolution analysis identifies residue pairs demonstrating either a specific co-adaptation, where changes in one of the residues are compensated by changes in the other during evolution or a less specific external force that affects the evolutionary rates of both residues in a similar magnitude. In both cases, independently of the underlying cause, co-evolutionary signatures within or between proteins serve as markers of physical interactions and/or functional relationships. Depending on the type of protein under study, the set of available homologous sequences may greatly differ in size and amino acid variability. BIS2Analyzer, openly accessible at http://www.lcqb.upmc.fr/BIS2Analyzer/, is a web server providing the online analysis of co-evolving amino-acid pairs in protein alignments, especially designed for vertebrate and viral protein families, which typically display a small number of highly similar sequences. It is based on BIS2, a re-implemented fast version of the co-evolution analysis tool Blocks in Sequences (BIS). BIS2Analyzer provides a rich and interactive graphical interface to ease biological interpretation of the results.


Regionalization of pediatric emergency care in Korea.
In order to care for an ill or injured child, it is crucial that every emergency department (ED) has a minimum set of personnel and resources because the majority of children are brought to the geographically nearest ED. In addition to adequate preparation for basic pediatric emergency care, a comprehensive, specialized healthcare system should be in place for a critically-ill or injured victim. Regionalization of healthcare means a system providing high-quality and cost-effective care for victims who present with alow frequency, but critical condition, such as multiple trauma or cardiac arrest. Within the pediatric field, neonatal intensive care and pediatric trauma care are good examples of regionalization. For successful regionalized pediatric emergency care, all aspects of a pediatric emergency system, from pre-hospital field to hospital care, should be categorized and coordinated. Efforts to set up the pediatric emergency care regionalization program based on a nationwide healthcare system are urgently needed in Korea.


Do environmental toxicants contribute to allergy and asthma?
The rates of asthma and allergy (Type 1 hypersensitivity disorders) have been increasing worldwide for the last few decades. Various theories have been proposed to account for this alarming trend. One of these is the impact of environmental toxicants. Epidemiological research has correlated exposure to environmental chemicals (such as pesticides, solvents, and air pollutants) with increasing rates of both asthma and allergies. Research has documented chemicals as causal agents capable of producing immune system imbalances characteristic of type 1 hypersensitivity. In vitro studies and in vivo animal models have demonstrated that many of the environmental chemicals and pollutants that have been epidemiologically associated with increased allergic tendency have been shown to enhance Type 2 helper T cell (Th2) dominance, which is consistent with the T-helper cell pattern found in asthma, allergic rhinitis, and other Type 1 hypersensitivity disorders. Depletion of glutathione is one possible mechanism for this T-helper cell imbalance. Preliminary evidence suggests the possibility that repletion of glutathione levels (with oral supplementation of N-acetylcysteine), and enhancement of glutathione transferase function (using sulforaphanes), might be therapeutic options for countering type 1 hypersensitivity disorders caused by environmental chemicals.


The long-term results of ankle arthrodesis.
Thirty-seven patients who had ankle arthrodesis carried out from 1-17 years previously were reviewed. The commonest indication in this series was post-traumatic osteoarthritis. Five different methods of fusion were used, the most common being the Charnley compression technique. The incidence of union, the fusion position, gait, subtalar stiffness and midtarsal hypermobility were recorded and analysed. Objective and subjective assessments were carried out. Poor results were recorded in 11 patients and these results are reported in more detail. The incidence of union was 78.4 per cent.


Investigation of adhesion and mechanical properties of human glioma cells by single cell force spectroscopy and atomic force microscopy.
Active cell migration and invasion is a peculiar feature of glioma that makes this tumor able to rapidly infiltrate into the surrounding brain tissue. In our recent work, we identified a novel class of glioma-associated-stem cells (defined as GASC for high-grade glioma--HG--and Gasc for low-grade glioma--LG) that, although not tumorigenic, act supporting the biological aggressiveness of glioma-initiating stem cells (defined as GSC for HG and Gsc for LG) favoring also their motility. Migrating cancer cells undergo considerable molecular and cellular changes by remodeling their cytoskeleton and cell interactions with surrounding environment. To get a better understanding about the role of the glioma-associated-stem cells in tumor progression, cell deformability and interactions between glioma-initiating stem cells and glioma-associated-stem cells were investigated. Adhesion of HG/LG-cancer cells on HG/LG-glioma-associated stem cells was studied by time-lapse microscopy, while cell deformability and cell-cell adhesion strengths were quantified by indentation measurements by atomic force microscopy and single cell force spectroscopy. Our results demonstrate that for both HG and LG glioma, cancer-initiating-stem cells are softer than glioma-associated-stem cells, in agreement with their neoplastic features. The adhesion strength of GSC on GASC appears to be significantly lower than that observed for Gsc on Gasc. Whereas, GSC spread and firmly adhere on Gasc with an adhesion strength increased as compared to that obtained on GASC. These findings highlight that the grade of glioma-associated-stem cells plays an important role in modulating cancer cell adhesion, which could affect glioma cell migration, invasion and thus cancer aggressiveness. Moreover this work provides evidence about the importance of investigating cell adhesion and elasticity for new developments in disease diagnostics and therapeutics.


Treating Multiple Myeloma Patients With Oral Therapies.
Recent advances have highlighted the importance of long-term, continuous treatment in multiple myeloma (MM) to improve survival. However, treatment burden continues to negatively impact the real-world duration of MM therapy, and strategies to limit the adverse impact of treatment on patient quality of life are therefore particularly important. Oral MM therapies include the immunomodulatory drugs lenalidomide, thalidomide, and pomalidomide; the alkylating agents melphalan and cyclophosphamide; the histone deacetylase inhibitor panobinostat; the corticosteroids prednisone and dexamethasone; and the proteasome inhibitor ixazomib. The most commonly reported adverse events with these treatments include hematologic events such as thrombocytopenia and neutropenia; the gastrointestinal events nausea, vomiting, and diarrhea; venous thrombotic events such as deep-vein thrombosis and pulmonary embolism; and events such as rash and peripheral neuropathy. It is important that patients receiving oral therapies at home report symptoms before they become difficult to manage. Appropriate management of these treatment-related adverse events, awareness of both food and drug interactions, and assisting patients with out-of-pocket costs are all important factors in providing efficacious, sustainable, and convenient MM therapy. We outline evidence-based recommendations to provide a practical guide for health care providers addressing the effective management of MM patients receiving oral therapy.


Nutritional manipulation for the primary prevention of gestational diabetes mellitus: a meta-analysis of randomised studies.
The rise in gestational diabetes (GDM), defined as first onset or diagnosis of diabetes in pregnancy, is a global problem. GDM is often associated with unhealthy diet and is a major contributor to adverse outcomes maternal and fetal outcomes. Manipulation of nutrition has the potential to prevent GDM. We assessed the effects of nutritional manipulation in pregnancy on GDM and relevant maternal and fetal outcomes by a systematic review of the literature. We searched MEDLINE, EMBASE, and Cochrane Database from inception to March 2014 without any language restrictions. Randomised controlled trials (RCT) of nutritional manipulation to prevent GDM were included. We summarised dichotomous data as relative risk (RR) and continuous data as standardised mean difference (SMD) with 95% confidence interval (CI). From 1761 citations, 20 RCTs (6,444 women) met the inclusion criteria. We identified the following interventions: diet-based (n = 6), mixed approach (diet and lifestyle) interventions (n = 13), and nutritional supplements (myo-inositol n = 1, diet with probiotics n = 1). Diet based interventions reduced the risk of GDM by 33% (RR 0.67; 95% CI 0.39, 1.15). Mixed approach interventions based on diet and lifestyle had no effect on GDM (RR 0.95; 95% CI 0.89, 1.22). Nutritional supplements probiotics combined with diet (RR 0.40; 95% CI 0.20, 0.78) and myo-inositol (RR 0.40; 95% CI 0.16, 0.99) were assessed in one trial each and showed a beneficial effect. We observed a significant interaction between the groups based on BMI for diet-based intervention. The risk of GDM was reduced in obese and overweight pregnant women for GDM (RR 0.40, 95% CI 0.18, 0.86). Nutritional manipulation in pregnancy based on diet or mixed approach do not appear to reduce the risk of GDM. Nutritional supplements show potential as agents for primary prevention of GDM.