Heritability of Sleep EEG Topography in Adolescence: Results from a Longitudinal Twin Study.
The topographic distribution of sleep EEG power is a reflection of brain structure and function. The goal of this study was to examine the degree to which genes contribute to sleep EEG topography during adolescence, a period of brain restructuring and maturation. We recorded high-density sleep EEG in monozygotic (MZ; n = 28) and dizygotic (DZ; n = 22) adolescent twins (mean age = 13.2 ± 1.1 years) at two time points 6 months apart. The topographic distribution of normalized sleep EEG power was examined for the frequency bands delta (1-4.6 Hz) to gamma 2 (34.2-44 Hz) during NREM and REM sleep. We found highest heritability values in the beta band for NREM and REM sleep (0.44 ≤ h2 ≤ 0.57), while environmental factors shared amongst twin siblings accounted for the variance in the delta to sigma bands (0.59 ≤ c2 ≤ 0.83). Given that both genetic and environmental factors are reflected in sleep EEG topography, our results suggest that topography may provide a rich metric by which to understand brain function. Furthermore, the frequency specific parsing of the influence of genetic from environmental factors on topography suggests functionally distinct networks and reveals the mechanisms that shape these networks.


Microbial metagenome of urinary tract infection.
Urine culture and microscopy techniques are used to profile the bacterial species present in urinary tract infections. To gain insight into the urinary flora, we analyzed clinical laboratory features and the microbial metagenome of 121 clean-catch urine samples. 16S rDNA gene signatures were successfully obtained for 116 participants, while metagenome sequencing data was successfully generated for samples from 49 participants. Although 16S rDNA sequencing was more sensitive, metagenome sequencing allowed for a more comprehensive and unbiased representation of the microbial flora, including eukarya and viral pathogens, and of bacterial virulence factors. Urine samples positive by metagenome sequencing contained a plethora of bacterial (median 41 genera/sample), eukarya (median 2 species/sample) and viral sequences (median 3 viruses/sample). Genomic analyses suggested cases of infection with potential pathogens that are often missed during routine urine culture due to species specific growth requirements. While conventional microbiological methods are inadequate to identify a large diversity of microbial species that are present in urine, genomic approaches appear to more comprehensively and quantitatively describe the urinary microbiome.


Influence of surfactant concentration on counter-ion induced solubility of poly(pyridine-2,5-diyl).
Protonating the pyridine rings of poly(pyridine-2,5-diyl) with dodecybenzenesulfonic acid and camphorsulphonic acid produces polymer materials which can be dissolved in chloroform (in contrast to the unprotonated polymer, which can only be dissolved in strong acids such as formic acid) and allows mixing the protonated polymers with other chloroform soluble conjugated polymers for use in electronic devices. The protonating behavior of poly(pyridine-2,5-diyl) with two kinds of surfactants is different in some levels. Dodecybenzenesulfonic acid has higher protonating ability than camphorsulphonic acid.


Scene-specific pedestrian detection for static video surveillance.
The performance of a generic pedestrian detector may drop significantly when it is applied to a specific scene due to the mismatch between the source training set and samples from the target scene. We propose a new approach of automatically transferring a generic pedestrian detector to a scene-specific detector in static video surveillance without manually labeling samples from the target scene. The proposed transfer learning framework consists of four steps. 1) Through exploring the indegrees from target samples to source samples on a visual affinity graph, the source samples are weighted to match the distribution of target samples. 2) It explores a set of context cues to automatically select samples from the target scene, predicts their labels, and computes confidence scores to guide transfer learning. 3) The confidence scores propagate among target samples according to their underlying visual structures. 4) Target samples with higher confidence scores have larger influence on training scene-specific detectors. All these considerations are formulated under a single objective function called confidence-encoded SVM, which avoids hard thresholding on confidence scores. During test, only the appearance-based detector is used without context cues. The effectiveness is demonstrated through experiments on two video surveillance data sets. Compared with a generic detector, it improves the detection rates by 48 and 36 percent at one false positive per image (FPPI) on the two data sets, respectively. The training process converges after one or two iterations on the data sets in experiments.


An MHC-restricted CD8+ T-cell response is induced in cattle by foot-and-mouth disease virus (FMDV) infection and also following vaccination with inactivated FMDV.
Foot-and-mouth disease virus (FMDV) causes a highly contagious disease of cloven-hooved animals that carries enormous economic consequences. CD8(+) cytotoxic T lymphocytes play an important role in protection and disease outcome in viral infections but, to date, the role of the CD8(+) T-cell immune response to FMDV remains unclear. This study aimed to investigate major histocompatibility complex (MHC) class I-restricted CD8(+) T-cell responses to FMDV in vaccinated and in infected cattle. An in vitro assay was used to detect antigen-specific gamma interferon release by CD8(+) T cells in FMDV-infected cattle of known MHC class I genotypes. A significant MHC class I-restricted CD8(+) T-cell response was detected to both FMDV strain O1 BFS and a recombinant fowlpox virus expressing the structural proteins of FMDV. Antigen-specific MHC class I-restricted CD8(+) T-cell responses were also detected in cattle vaccinated with inactivated FMDV. These responses were shown to be directed, at least in part, to epitopes within the structural proteins (P12A region) of the virus. By using mouse cells expressing single cattle MHC class I alleles, it was possible to identify the restriction elements in each case. Identification of these epitopes will facilitate the quantitative and qualitative analysis of FMDV-specific memory CD8(+) T cells in cattle and help to ensure that potential vaccines induce a qualitatively appropriate CD8(+) T-cell response.


A study of the development of traits of entry-level occupational therapy students.
This study compared the personality traits of entry-level occupational therapy students before and after their participation in 2 years of academic and clinical education in order to examine the change of traits in their professional personality profile. Forty-nine occupational therapy students completed the 18 scales of the California Psychological Inventory during their first fall and second spring semesters. This time span included two Level I and one Level II fieldwork experiences. T tests were used to analyze the students' scales. Students' scores in the second test showed a statistically significant increase in 13 of the 18 scales as compared to their first test scores. Achievement via independence and psychological-mindedness emerged as the highest ranking personality traits of the students in their second test scores. The occupational therapy curriculum may have influenced the scores of the entry-level students, in both intellectual and psychosocial traits, in a positive direction.


Endothelial receptor-mediated binding of glucose-modified albumin is associated with increased monolayer permeability and modulation of cell surface coagulant properties.
Advanced glycosylation end products (AGE) of proteins accumulate in the vasculature with diabetes and aging, and are thought to be associated with vascular complications. This led us to examine the interaction of AGE-BSA as a prototype of this class of nonenzymatically glycosylated proteins subjected to further processing, with endothelium. Incubation of 125I-AGE-BSA with cultured bovine endothelium resulted in time-dependent, saturable binding that was half-maximal at a concentration of approximately 100 nM. Although unlabeled normal BSA was not a competitor, unlabeled AGE-BSA was an effective competitor of 125I-AGE-BSA-endothelial cell interaction. In addition, AGE modification of two alternative proteins, hemoglobin and ribonuclease, rendered them inhibitors of 125I-AGE-BSA binding to endothelium, although the native, unmodified forms of these proteins were not. At 37 degrees C, binding of 125I-AGE-BSA or gold-labeled AGE-BSA was followed by internalization and subsequent segregation either to a lysosomal compartment or to the endothelial-derived matrix after transcytosis. Exposure of endothelium to AGE-BSA led to perturbation of two important endothelial cell homeostatic properties, coagulant and barrier function. AGE-BSA downregulated the anticoagulant endothelial cofactor thrombomodulin, and induced synthesis and cell surface expression of the procoagulant cofactor tissue factor over the same range of concentrations that resulted in occupancy of cell surface AGE-BSA binding sites. In addition, AGE-BSA increased endothelial permeability, resulting in accelerated passage of an inert macromolecular tracer, [3H]inulin, across the monolayer. These results indicate that AGE derivatives of proteins, potentially important constituents of pathologic vascular tissue, bind to specific sites on the endothelial cell surface and modulate central endothelial cell functions. The interaction of AGE-modified proteins with endothelium may play an important role in the early stages of increased vascular permeability, as well as vessel wall-related abnormalities of the coagulation system, characteristic of diabetes and aging.


Enhancing mitophagy as a therapeutic approach for neurodegenerative diseases.
Neurodegenerative diseases are highly debilitating illnesses and a growing cause of morbidity and mortality worldwide. Mitochondrial dysfunction and impairment of mitochondrial-specific autophagy, namely mitophagy, have emerged as important components of the cellular processes underlying neurodegeneration. Defective mitophagy has been highlighted as the cause of the accumulation of damaged mitochondria, which consequently leads to cellular dysfunction and/or death in neurodegenerative diseases. Here, we highlight the recent advances in the molecular mechanisms of mitochondrial homeostasis and mitophagy in neurodegenerative diseases. In particular, we evaluate how mitophagy is altered in Alzheimer's, Parkinson's, and Huntington's diseases, as well as in amyotrophic lateral sclerosis, and the potential of restoring mitophagy as a therapeutic intervention. We also discuss the interlinked connections between mitophagy and innate immunity (e.g., the involvement of Parkin, interferons and TRIM21) as well as the opportunity these pathways provide to develop combinational therapeutic strategies targeting them and related molecular mechanisms in such neurodegenerative diseases.


The emerging relationship between regenerative medicine and physical therapeutics.
Dramatic changes in the health care landscape over the next few decades undoubtedly will affect rehabilitation specialists' practice. In the multidisciplinary field of regenerative medicine, cell, tissue, or organ substitutes are used to enhance the healing potential of the body. Given that the restoration of normal functioning of injured or diseased tissues is expected to be the ultimate goal of these therapies, the future of regenerative medicine is, undeniably, tightly intertwined with that of rehabilitation. Rehabilitation specialists not only must be aware of cutting-edge medical advances as they relate to regenerative medicine but also must work closely with basic scientists to guide the development of clinically relevant protocols. The purposes of this article are to provide a current perspective on biological approaches to the management of musculoskeletal disorders and to highlight the needed integration of physical therapeutics with regenerative medicine.


Molecular Techniques Complement Culture-Based Assessment of Bacteria Composition in Mixed Biofilms of Urinary Tract Catheter-Related Samples.
Urinary or ureteral catheter insertion remains one of the most common urological procedures, yet is considered a predisposing factor for urinary tract infection. Diverse bacterial consortia adhere to foreign body surfaces and create various difficult to treat biofilm structures. We analyzed 347 urinary catheter- and stent-related samples, treated with sonication, using both routine culture and broad-range 16S rDNA PCR followed by Denaturing Gradient Gel Electrophoresis and Sanger sequencing (PCR-DGGE-S). In 29 selected samples, 16S rRNA amplicon Illumina sequencing was performed. The results of all methods were compared. In 338 positive samples, from which 86.1% were polybacterial, 1,295 representatives of 153 unique OTUs were detected. Gram-positive microbes were found in 46.5 and 59.1% of catheter- and stent-related samples, respectively. PCR-DGGE-S was shown as a feasible method with higher overall specificity (95 vs. 85%, p < 0.01) though lower sensitivity (50 vs. 69%, p < 0.01) in comparison to standard culture. Molecular methods considerably widened a spectrum of microbes detected in biofilms, including the very prevalent emerging opportunistic pathogen Actinotignum schaalii. Using massive parallel sequencing as a reference method in selected specimens, culture combined with PCR-DGGE was shown to be an efficient and reliable tool for determining the composition of urinary catheter-related biofilms. This might be applicable particularly to immunocompromised patients, in whom catheter-colonizing bacteria may lead to severe infectious complications. For the first time, broad-range molecular detection sensitivity and specificity were evaluated in this setting. This study extends the knowledge of biofilm consortia composition by analyzing large urinary catheter and stent sample sets using both molecular and culture techniques, including the widest dataset of catheter-related samples characterized by 16S rRNA amplicon Illumina sequencing.


Frontiers in olefin polymerization: reinventing the world's most common synthetic polymers.
Synthetic polymers are vital to our society, affecting practically every aspect of modern life. The ubiquitous nature of these materials is a result of years of collaboration between basic and applied researchers across many disciplines, resulting in economic routes to materials that meet customer needs. These considerations are exemplified by recent developments in the synthesis of block copolymers from simple olefins. The practical application of creative chemistry has produced materials with a favorable balance of desirable polymer properties and process economics.


Exercise Self-Efficacy Scale: Validation of the Arabic Version Among Jordanians With Chronic Diseases.
This study assessed the psychometric properties of the Arabic version of Exercise Self-Efficacy scale (ESE-A) among Jordanian outpatients with a variety of chronic diseases using descriptive cross-sectional design. Participants' scores of ESE-A significantly correlated with their reported weekly exercise frequency ( r = .23, p< .001), duration ( r = .31, p< .001), and evaluation of their physical exercise ( r = .39, p< .001). The construct validity was tested using exploratory factor analysis, which retained all items, and the scree plot showed one meaningful factor with an eigenvalue of 10.38 and an explained variance of 57.7%. Furthermore, Cronbach's alpha was .89 and split-half coefficient was .83 indicating that the ESE-A is a reliable scale. The ESE-A was found to be a robust measure to evaluate exercise self-efficacy among Arabic patients with chronic diseases. Arabic researchers interested in exercise self-efficacy are invited to utilize the ESE-A in their studies to confirm its psychometric properties.


Relaxation dynamics of deeply supercooled confined water in L,L-diphenylalanine micro/nanotubes.
The temperature dependence (10-290 K) of the low-frequency (20-150 cm(-1)) Raman-active phonon modes of deeply supercooled confined water in L,L-diphenylalanine micro/nanotubes was analyzed. The isolated dynamics of a specific geometry of a water cluster (pentamer) in a supercooled confined regime was studied in detail. A fragile-to-strong transition at 204 K was observed and related to the crossing of the Widom line. Analysis of peptide vibrational modes coupled to water hydrogen bonds indicated that hydrogen bond fluctuations play an irrelevant role in this system. Our results are in agreement with the second critical point of water existence hypothesis.


Forgiveness and Reconciliation Processes in Dying Patients With Cancer.
This article studies forgiveness and reconciliation (F/R) in patients with cancer. It focuses on the end of life, when family conflicts resurface and unfinished business challenges patients and causes spiritual distress. Forgiveness and reconciliation may intensify patient-family relationships and facilitate peace of mind and peaceful death. Existing forgiveness models and interventions focus on coping in life, yet no study has examined F/R processes until death. Our mixed-method exploratory study hypothesized that F/R processes occur in phases, repeatedly, and are spurred by approaching death. Three interdisciplinary units at a major Swiss hospital observed 50 dying patients with cancer experiencing severe conflicts with relatives, themselves, and/or with fate/God. Participant observation was combined with interpretative phenomenological analysis and descriptive statistical analysis. A semi-structured observation protocol was developed based on a 5-phase model. The protocol included space for notes (emotions, interventions, effects on dying processes). It was assessed by 20 professionals for 1 year. Analysis was supported by international interdisciplinary experts. We found that conflicts were complex and involved relational, biographical, and spiritual layers. In 62% of patients, F/R processes occurred repeatedly. Many patients died after finding F/R (22 within 48 hours). Patients indicated that imminent death, a mediating third party, acceptance, and experiences of hope motivated them to seek F/R. Although deep relationships may support F/R processes, our limited data on near-death experience/spiritual experiences restrict interpretation. Forgiveness and reconciliation processes oscillate between 5 phases: denial, crisis, experience of hope, decision, and finding F/R. Understanding F/R processes, empathy, hope, and a neutral third party may support patients in seeking forgiveness.


Elemental Constituents of Particulate Matter and Newborn's Size in Eight European Cohorts.
The health effects of suspended particulate matter (PM) may depend on its chemical composition. Associations between maternal exposure to chemical constituents of PM and newborn's size have been little examined. We aimed to investigate the associations of exposure to elemental constituents of PM with term low birth weight (LBW; weight < 2,500 g among births after 37 weeks of gestation), mean birth weight, and head circumference, relying on standardized fine-scale exposure assessment and with extensive control for potential confounders. We pooled data from eight European cohorts comprising 34,923 singleton births in 1994-2008. Annual average concentrations of elemental constituents of PM ≤ 2.5 and ≤ 10 μm (PM2.5 and PM10) at maternal home addresses during pregnancy were estimated using land-use regression models. Adjusted associations between each birth measurement and concentrations of eight elements (copper, iron, potassium, nickel, sulfur, silicon, vanadium, and zinc) were calculated using random-effects regression on pooled data. A 200-ng/m3 increase in sulfur in PM2.5 was associated with an increased risk of LBW (adjusted odds ratio = 1.36; 95% confidence interval: 1.17, 1.58). Increased nickel and zinc in PM2.5 concentrations were also associated with an increased risk of LBW. Head circumference was reduced at higher exposure to all elements except potassium. All associations with sulfur were most robust to adjustment for PM2.5 mass concentration. All results were similar for PM10. Sulfur, reflecting secondary combustion particles in this study, may adversely affect LBW and head circumference, independently of particle mass. Pedersen M, Gehring U, Beelen R, Wang M, Giorgis-Allemand L, Andersen AM, Basagaña X, Bernard C, Cirach M, Forastiere F, de Hoogh K, Gražulevičienė R, Gruzieva O, Hoek G, Jedynska A, Klümper C, Kooter IM, Krämer U, Kukkonen J, Porta D, Postma DS, Raaschou-Nielsen O, van Rossem L, Sunyer J, Sørensen M, Tsai MY, Vrijkotte TG, Wilhelm M, Nieuwenhuijsen MJ, Pershagen G, Brunekreef B, Kogevinas M, Slama R. 2016. Elemental constituents of particulate matter and newborn's size in eight European cohorts. Environ Health Perspect 124:141-150; http://dx.doi.org/10.1289/ehp.1409546.


The relationship between fatty acid profiles in milk identified by Fourier transform infrared spectroscopy and onset of luteal activity in Norwegian dairy cattle.
To investigate the feasibility of milk fatty acids as predictors of onset of luteal activity (OLA), 87 lactations taken from 73 healthy Norwegian Red cattle were surveyed over 2 winter housing seasons. The feasibility of using frozen milk samples for dry-film Fourier transform infrared (FTIR) determination of milk samples was also tested. Morning milk samples were collected thrice weekly (Monday, Wednesday, Friday) for the first 10 wk in milk (WIM). These samples had bronopol (2-bromo-2-nitropropane-1,3-diol) added to them before being frozen at -20°C, thawed, and analyzed by ELISA to determine progesterone concentration and the concentrations of the milk fatty acids C4:0, C14:0, C16:0, C18:0, and cis-9 C18:1 as a proportion of total milk fatty acid content using dry-film FTIR, and averaged by WIM. Onset of luteal activity was defined as the first day that milk progesterone concentrations were >3 ng/mL for 2 successive measurements; the study population was categorized as early (n=47) or late (n=40) OLA, using the median value of 21 DIM as the cutoff. Further milk samples were collected 6 times weekly, from morning and afternoon milkings, these were pooled by WIM, and one proportional sample was analyzed fresh for fat, protein, and lactose content by the dairy company Tine SA, using traditional FTIR spectrography in the wet phase of milk. Daily energy-balance calculations were performed in 42 lactations and averaged by WIM. Animals experiencing late OLA had a more negative energy balance in WIM 1, 3, 4, and 5, with the greatest differences been seen in WIM 3 and 4. A higher proportion of the fatty acids were medium chained, C14:0 and C16:0, in the early than in the late OLA group from WIM 1. In WIM 4, the proportion of total fatty acid content that was C16:0 predicted late OLA, with 74% sensitivity and 80% specificity. The long-chain proportion of the fatty acids C18:0 and cis-9 C18:1 were lower in the early than in the late OLA group. Differences were greatest in WIM 4 and 5. Differences in concentrations of cis-9 C18:1 were seen between the groups from WIM 1. No relationship was seen between OLA and milk concentrations of either protein or fat, or between OLA and the milk fat:protein ratio. The differences in milk fatty acid proportions between the 2 groups are most likely related to differences in energy balance. The study shows that frozen milk samples can be tested for fatty acids by FTIR spectroscopy and that FTIR spectroscopy of milk can be used to provide real-time information about cow reproductive function.


Self-healing properties of recycled asphalt mixtures containing metal waste: An approach through microwave radiation heating.
The concept of self-healing asphalt mixtures by bitumen temperature increase has been used by researchers to create an asphalt mixture with crack-healing properties by microwave or induction heating. Metals, normally steel wool fibers (SWF), are added to asphalt mixtures prepared with virgin materials to absorb and conduct thermal energy. Metal shavings, a waste material from the metal industry, could be used to replace SWF. In addition, reclaimed asphalt pavement (RAP) could be added to these mixtures to make a more sustainable road material. This research aimed to evaluate the effect of adding metal shavings and RAP on the properties of asphalt mixtures with crack-healing capabilities by microwave heating. The research indicates that metal shavings have an irregular shape with widths larger than typical SWF used with asphalt self-healing purposes. The general effect of adding metal shavings was an improvement in the crack-healing of asphalt mixtures, while adding RAP to mixtures with metal shavings reduced the healing. The average surface temperature of the asphalt samples after microwave heating was higher than temperatures obtained by induction heating, indicating that shavings are more efficient when mixtures are heated by microwave radiation. CT scan analysis showed that shavings uniformly distribute in the mixture, and the addition of metal shavings increases the air voids. Overall, it is concluded that asphalt mixtures with RAP and waste metal shavings have the potential of being crack-healed by microwave heating.


Alu element mutation spectra: molecular clocks and the effect of DNA methylation.
In primate genomes more than 40% of CpG islands are found within repetitive elements. With more than one million copies in the human genome, the Alu family of retrotransposons represents the most successful short interspersed element (SINE) in primates and CpG dinucleotides make up about 20% of Alu sequences. It is generally thought that CpG dinucleotides mutate approximately ten times faster than other dinucleotides due to cytosine methylation and the subsequent deamination and conversion of C-->T. However, the disparity of Alu subfamily age estimations based upon CpG or non-CpG substitution density indicates a more complex relationship between CpG and non-CpG substitutions within the Alu elements. Here we report an analysis of the mutation patterns for 5296 Alu elements comprising 20 subfamilies. Our results indicate a relatively constant CpG versus non-CpG substitution ratio of approximately 6 for the young (AluY) and intermediate (AluS) Alu subfamilies. However, a more complex non-linear relationship between CpG and non-CpG substitutions was observed when old (AluJ) subfamilies were included in the analysis. These patterns may be the result of the slowdown of the neutral mutation rate during primate evolution and/or an increase in the CpG mutation rate as the consequence of increased DNA methylation in response to a burst of retrotransposition activity approximately 35 million years ago.


Validation of the RIDASCREEN® Peanut for Determination of Peanut Protein in Cookies, Milk Chocolate, Ice Cream, Trail Mix, Puffed Rice Cereals, and Granola Bar: AOAC Performance Tested MethodSM 112102.
Regulations in many countries worldwide prescribe that peanut must be listed on food labels as a cause of food allergies. Re-evaluated voluntary incidental trace allergen labelling (VITAL) values for peanut revealed the eliciting dose (ED01) value-at which 99% of all peanut-allergic individuals will not react-is 0.2 mg peanut protein. Validation of a sandwich ELISA based on monoclonal antibodies to detect peanut proteins. Non-processed and processed samples are extracted by an easy procedure at 60°C within 10 min. The measurement range is between 0.75 and 6 mg/kg peanut using a national institute of standards and technology (NIST) reference material as calibrator. The system shows no cross-reactivity against 91 different food commodities. The LOD was 0.15 mg/kg for food matrixes such as cookies, milk chocolate, ice cream, trail mix, puffed rice cereal, and granola bar. LOQ was verified at a level of 0.75 mg/kg. Recovery studies with incurred milk chocolate and ice cream revealed consistent recoveries between 67 and 85%. Mean recoveries for incurred cookies depend on the baking temperature and time and ranged from 60 to 109%. Repeatability was between 5.2 and 12.3%, whereas relative intermediate precision was between 6.4 and 13.0%. The results for incurred cookies and milk chocolate in the independent laboratory study showed mean recoveries between 99 and 104% with RSDs between 3.56 and 19.5% under repeatability conditions. The results from the in-house validation study and the independent lab confirmed that the method is accurate and in accordance with requirements laid down in Standard Method Performance Requirement 2017.020. RIDASCREEN® Peanut quantifies proteins from peanut in a wide range of food categories.


Failure to comply with NCCN guidelines for the management of pancreatic cancer compromises outcomes.
There are little data available regarding compliance with the National Comprehensive Cancer Network (NCCN) guidelines. We investigated variation in the management of pancreatic cancer (PC) among large hospitals in California, USA, specifically to evaluate whether compliance with NCCN guidelines correlates with patient outcomes. The California Cancer Registry was used to identify patients treated for PC from 2001 to 2006. Only hospitals with ≥ 400 beds were included to limit evaluation to centres possessing resources to provide multimodality care (n= 50). Risk-adjusted multivariable models evaluated predictors of adherence to stage-specific NCCN guidelines for PC and mortality. In all, 3706 patients were treated for PC in large hospitals during the study period. Compliance with NCCN guidelines was only 34.5%. Patients were less likely to get recommended therapy with advanced age and low socioeconomic status (SES). Using multilevel analysis, controlling for patient factors (including demographics and comorbidities), hospital factors (e.g. size, academic affiliation and case volume), compliance with NCCN guidelines was associated with a reduced risk of mortality [odds ratio (OR) for death 0.64 (0.53-0.77, P < 0.0001)]. There is relatively poor overall compliance with the NCCN PC guidelines in California's large hospitals. Higher compliance rates are correlated with improved survival. Compliance is an important potential measure of the quality of care.


Urea modulation of beta-amyloid fibril growth: experimental studies and kinetic models.
Aggregation of beta-amyloid (Abeta) into fibrillar deposits is widely believed to initiate a cascade of adverse biological responses associated with Alzheimer's disease. Although it was once assumed that the mature fibril was the toxic form of Abeta, recent evidence supports the hypothesis that Abeta oligomers, intermediates in the fibrillogenic pathway, are the dominant toxic species. In this work we used urea to reduce the driving force for Abeta aggregation, in an effort to isolate stable intermediate species. The effect of urea on secondary structure, size distribution, aggregation kinetics, and aggregate morphology was examined. With increasing urea concentration, beta-sheet content and the fraction of aggregated peptide decreased, the average size of aggregates was reduced, and the morphology of aggregates changed from linear to a globular/linear mixture and then to globular. The data were analyzed using a previously published model of Abeta aggregation kinetics. The model and data were consistent with the hypothesis that the globular aggregates were intermediates in the amyloidogenesis pathway rather than alternatively aggregated species. Increasing the urea concentration from 0.4 M to 2 M decreased the rate of filament initiation the most; between 2 M and 4 M urea the largest change was in partitioning between the nonamyloid and amyloid pathways, and between 4 M and 6 M urea, the most significant change was a reduction in the rate of filament elongation.


Adipocyte fatty acid-binding protein, aP2, alters late atherosclerotic lesion formation in severe hypercholesterolemia.
The adipocyte fatty acid-binding protein, aP2, has important effects on insulin resistance, lipid metabolism, and atherosclerosis. Its expression in macrophages enhances early foam cell formation and atherosclerosis in vivo. This study was designed to determine whether aP2 deficiency has a similar effect in the setting of advanced atherosclerosis and severe hypercholesterolemia. Mice deficient in aP2 and apolipoprotein E (aP2(-/-)apoE(-/-) mice) and apolipoprotein E-deficient control mice (apoE(-/-) mice) were fed a Western diet for 14 weeks. No significant differences in fasting serum levels of cholesterol, triglycerides, or free fatty acids were found between groups for each sex. Compared with apoE(-/-) control mice, male and female aP2(-/-)apoE(-/-) mice had significant reductions in mean atherosclerotic lesion size in the proximal aorta, en face aorta, and innominate/right carotid artery. Feeding the Western diet in the apoE-deficient background did not cause a significant reduction in insulin sensitivity in vivo, as determined by steady-state serum glucose levels and insulin tolerance testing. These data demonstrate an important role for aP2 expression in the advanced stages of atherosclerotic lesion formation. Thus, aP2 provides an important physiological link between different features of the metabolic syndrome and is a potential target for therapy of atherosclerosis.


The Effects of Transcranial Direct Current Stimulation (tDCS) on Balance Control in Older Adults: A Systematic Review and Meta-Analysis.
Background: Recently, considerable research has been conducted to study the effects of transcranial direct current stimulation (tDCS) on balance control in older adults. We completed a comprehensive systematic review and meta-analysis to assess the efficacy of tDCS on balance control in this population. Methods: A search strategy based on the PICOS principle was used to find the literatures in the databases of PubMed, EMBASE, EBSCO, Web of Science. The quality and risk of bias in the studies were independently assessed by two researchers. Results: Ten studies were included in the systematic review. A meta-analysis was completed on six of these ten, with a total of 280 participants. As compared to sham (i.e., control), tDCS induced significant improvement with low heterogeneity in balance control in older adults. Specifically, tDCS induced large effects on the performance of the timed-up-and-go test, the Berg balance scale, and standing postural sway (e.g., sway area) and gait (e.g., walking speed) in dual task conditions (standardized mean differences (SMDs) = -0.99~3.41 95% confidence limits (CL): -1.52~4.50, p < 0.006, I 2 < 52%). Moderate-to-large effects of tDCS were also observed in the standing posture on a static or movable platform (SMDs = 0.37~1.12 95%CL: -0.09~1.62, p < 0.03, I 2 < 62%). Conclusion: Our analysis indicates that tDCS holds promise to promote balance in older adults. These results warrant future studies of larger sample size and rigorous study design and results report, as well as specific research to establish the relationship between the parameter of tDCS and the extent of tDCS-induced improvement in balance control in older adults.


Sequential analysis of an interactive peer support group.
A therapeutic matrix for women who had survived breast cancer was designed by combining the principle of interactive peer support with the exploratory approach of group therapy. An observation instrument was designed and applied to the recorded therapeutic sessions, thereby enabling the multidimensional coding of the interactive support process. Lag sequential analysis was then applied to the data. The analysis revealed patterns of interactive peer support which were conditioned by the therapist's communicative behaviour and by other derived behaviours. The significant associations correspond to strategies that serve to facilitate the therapeutic factors. The therapist's behaviour is the fundamental axis around which the corrective process unfolds, and it is this process that facilitates the mobilization of therapeutic factors. The levels of interactive support shown by the group members acquire greater discursive complexity and interpersonal sensitivity as the group sessions progress.


Dentin phosphoprotein gene locus is not associated with dentinogenesis imperfecta types II and III.
Dentinogenesis imperfecta (DGI) is an autosomal dominant inherited dental disease which affects dentin production and mineralization. Genetic linkage studies have been performed on several multigeneration informative kindreds. These studies determined linkage between DGI type II and III and group-specific component (vitamin D-binding protein). This gene locus has been localized to the long arm of human chromosome 4 in the region 4q11-q21. Although this disease has been mapped to chromosome 4, the defective gene product is yet to be determined. Biochemical studies have suggested abnormal levels of dentin phosphoprotein (DPP) associated with DGI type II. This highly acidic protein is the major noncollagenous component of dentin, being solely expressed by the ectomesenchymal derived odontoblast cells of the tooth. The purpose of the present study was to establish whether DPP is associated with DGI types II and III, by using molecular biology techniques. The strategy was to use a synthetic degenerative DPP oligonucleotide probe to map this sequence to the long arm of human chromosome 4, 4q13-q21, by using somatic cell hybrids. Our results indicated that DPP is not localized to any region of human chromosome 4, thus suggesting that the DPP gene is not directly associated with DGI type II or DGI type III. Our data do not exclude the possibility that other proteins associated with DPP posttranslational modifications might be responsible for this genetic disease.


Pleurodesis for malignant pleural effusions.
Approximately half of all patients with metastatic cancer develop a malignant pleural effusion which is likely to lead to a significant reduction in quality of life secondary to symptoms such as dyspnoea and cough. The aim of pleurodesis in these patients is to prevent re-accumulation of the effusion and thereby of symptoms, and avoid the need for repeated hospitalization for thoracocentesis. Numerous clinical studies have been performed to try to determine the optimal pleurodesis strategy, and synthesis of the available evidence should facilitate this. The aims of this review were to ascertain the optimal technique of pleurodesis in cases of malignant pleural effusion; to confirm the need for a sclerosant; and to clarify which, if any, of the sclerosants is the most effective. The Cochrane Central Register of Controlled Trials was searched for studies on 'pleurodesis'. Studies for inclusion were also identified from MEDLINE (1980 to June 2002) and EMBASE (1980 to May 2002). No language restriction was applied. RCTs of adults subjects undergoing pleurodesis for pleural effusion in the context of metastatic malignancy (or a malignant process leading to pleural effusion) were included. Two reviewers independently selected studies for inclusion in the review, and extracted data using a standard data collection form. Primary outcome measures sought were effectiveness of pleurodesis as defined by freedom from recurrence of effusions, and mortality after pleurodesis. Secondary outcomes were adverse events due to pleurodesis. Dichotomous data were meta-analysed using a fixed effect model and expressed as relative risk. The number-needed-to-treat (NNT) was calculated for pleurodesis efficacy. In addition, for adverse events, the overall percentage of patients across studies exhibiting a particular adverse effect such as fever, pain, or gastrointestinal symptoms was calculated. A total of 36 RCTs with 1499 subjects were eligible for meta-analysis. The use of sclerosants (mitozantrone, talc and tetracycline combined)compared with control (instillation of isotonic saline or equivalent pH isotonic saline or tube drainage alone) was associated with an increased efficacy of pleurodesis. The relative risk (RR) of non-recurrence of an effusion is 1.20 (95% CI 1.04 to 1.38) in favour of the use of sclerosants based on five studies with a total 228 subjects. Comparing different sclerosants, talc was found to be the most efficacious. The RR of effusion non-recurrence was 1.34 (95% CI 1.16 to 1.55) in favour of talc compared with bleomycin, tetracycline, mustine or tube drainage alone based on 10 studies comprising 308 subjects. This was not associated with increased mortality post pleurodesis. The RR of death was 1.19 (95% CI 0.08 to 1.77) for talc compared to bleomycin, tetracycline, mustine and tube drainage alone based on six studies of 186 subjects. Death was not reported in all studies and, when reported, was attributed to underlying disease, only one death being reported as procedure-related. In the comparison of thoracoscopic versus medical pleurodesis, thoracoscopic pleurodesis was found to be more effective. The RR of non-recurrence of effusion is 1.19 (95% CI 1.04 to 1.36) in favour of thoracoscopic pleurodesis compared with tube thoracostamy pleurodesis utilizing talc as sclerosant based on two studies with 112 subjects. Comparing thoracoscopic versus bedside instillation (with different sized chest tubes) of various sclerosants (tetracycline, bleomycin, talc or mustine) the RR of non-recurrence of effusion is 1.68 (95% CI 1.35 to 2.10) based on five studies with a total of 145 participants.Adverse events were not reported adequately to enable meta-analysis. The available evidence supports the need for chemical sclerosants for successful pleurodesis, the use of talc as the sclerosant of choice, and thoracoscopic pleurodesis as the preferred technique for pleurodesis based on efficacy. There was no evidence for an increase in mortality following talc pleurodesis.


Vaccination against helminth parasites--the ultimate challenge for vaccinologists?
Helminths are multicellular pathogens which infect vast numbers of human and animal hosts, causing widespread chronic disease and morbidity. Vaccination against these parasites requires more than identification of effective target antigens, because without understanding the immunology of the host-parasite relationship, ineffective immune mechanisms may be invoked, and there is a danger of amplifying immunopathogenic responses. The fundamental features of the immune response to helminths are therefore summarised in the context of vaccines to helminth parasites. The contention between type-1 and type-2 responses is a central issue in helminth infections, which bias the immune system strongly to the type-2 pathway. Evidence from both human and experimental animal infections indicates that both lineages contribute to immunity in differing circumstances, and that a balanced response leads to the most favourable outcome. A diversity of immune mechanisms can be brought to bear on various helminth species, ranging from antibody-independent macrophages, antibody-dependent granulocyte killing, and nonlymphoid actions, particularly in the gut. This diversity is highlighted by analysis of rodent infections, particularly in comparisons of cytokine-depleted and gene-targeted animals. This knowledge of protective mechanisms needs to be combined with a careful choice of parasite antigens for vaccines. Many existing candidates have been selected with host antibodies, rather than T-cell responses, and include a preponderance of highly conserved proteins with similarities to mammalian or invertebrate antigens. Advantage has yet to be taken of parasite genome projects, or of directed searches for novel, parasite-specific antigens and targets expressed only by infective stages and not mature forms which may generate immunopathology. With advances under way in parasite genomics and new vaccine delivery systems offering more rapid assessment and development, there are now excellent opportunities for new antihelminth vaccines.


Development of a predictive model for estimating the probability of treatment success one year after total shoulder replacement - cohort study.
To Estimate the probability of treatment success 1 year after a total shoulder arthroplasty by developing a model based on preoperative clinical factors. Between June 2003 and December 2006, 140 patients undergoing shoulder operations were assessed for age, gender, current rheumatoid arthritis, Short Form (SF) 36 physical and mental sum scores, previous shoulder operations, the Disabilities of Arm, Shoulder and Hand (DASH) symptom and function scores, the Shoulder Pain and Disability Index (SPADI), and insurance status. One year after the operation a Constant score of 80 or more out of 100 indicated successful treatment. Patient variables were analyzed with a logistic regression model augmented in a stepwise manner and bootstrapped 100 times. Variables selected at least 33 times were incorporated into a final model and the Area under the Receiver Operating Characteristics Curve (aROC) was calculated. There were 47/140 (33.6%) successful treatments. The probability of success was reduced in patients with previous shoulder operations (Odds Ratio [O.R.] 0.17, 95% Confidence Interval (95%CI) 0.04-0.85; P=0.03) and older than 75 years (O.R. 0.21, 95%CI 0.05-0.77; P=0.02). The probability of success increased in patients with a higher SF 36 mental sum score (O.R. 1.03, 95%CI 0.96-1.09, P=0.42) and a higher DASH function score (O.R. 1.05, 95%CI 1.02-1.07, P=0.001). The aROC was 0.79 (0.70-0.88) indicating that the model has a high predictive capacity. Once validated this model based on four preoperative clinical factors offers a prediction of whether a patient will respond to treatment 1 year after total shoulder arthroplasty.


Western diet induces dysbiosis with increased E coli in CEABAC10 mice, alters host barrier function favouring AIEC colonisation.
Western diet is a risk factor for Crohn's disease (CD). Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is abnormally expressed in CD patients. This allows adherent-invasive Escherichia coli (AIEC) to colonise the gut mucosa and leads to inflammation. We assessed the effects of a high fat/high sugar (HF/HS) Western diet on gut microbiota composition, barrier integrity and susceptibility to infection in transgenic CEABAC10 mice expressing human CEACAMs. Colonic microbiota composition and susceptibility of CEABAC10 mice to AIEC LF82 bacteria infection were determined in mice fed a conventional or HF/HS diet. Barrier function and inflammatory response were assessed by studying intestinal permeability, tight junction protein and mucin expression and localisation, and by determining histological score and levels of cytokine release. HF/HS diet led to dysbiosis in WT and transgenic CEABAC10 mice, with a particular increase in E coli population in HF/HS-fed CEABAC10 mice. These mice showed decreased mucus layer thickness, increased intestinal permeability, induction of Nod2 and Tlr5 gene transcription, and increased TNFα secretion. These modifications led to a higher ability of AIEC bacteria to colonise the gut mucosa and to induce inflammation. Western diet induces changes in gut microbiota composition, alters host homeostasis and promotes AIEC gut colonisation in genetically susceptible mice. These results support the multifactorial aetiology of CD and highlight the importance of diet in CD pathogenesis.


Characterizing social media metrics of scholarly papers: the effect of document properties and collaboration patterns.
A number of new metrics based on social media platforms--grouped under the term "altmetrics"--have recently been introduced as potential indicators of research impact. Despite their current popularity, there is a lack of information regarding the determinants of these metrics. Using publication and citation data from 1.3 million papers published in 2012 and covered in Thomson Reuters' Web of Science as well as social media counts from Altmetric.com, this paper analyses the main patterns of five social media metrics as a function of document characteristics (i.e., discipline, document type, title length, number of pages and references) and collaborative practices and compares them to patterns known for citations. Results show that the presence of papers on social media is low, with 21.5% of papers receiving at least one tweet, 4.7% being shared on Facebook, 1.9% mentioned on blogs, 0.8% found on Google+ and 0.7% discussed in mainstream media. By contrast, 66.8% of papers have received at least one citation. Our findings show that both citations and social media metrics increase with the extent of collaboration and the length of the references list. On the other hand, while editorials and news items are seldom cited, it is these types of document that are the most popular on Twitter. Similarly, while longer papers typically attract more citations, an opposite trend is seen on social media platforms. Finally, contrary to what is observed for citations, it is papers in the Social Sciences and humanities that are the most often found on social media platforms. On the whole, these findings suggest that factors driving social media and citations are different. Therefore, social media metrics cannot actually be seen as alternatives to citations; at most, they may function as complements to other type of indicators.


An advanced case of indium lung disease with progressive emphysema.
To report the occurrence of an advanced case of indium lung disease with severely progressive emphysema in an indium-exposed worker. A healthy 42-year-old male smoker was employed to primarily grind indium-tin oxide (ITO) target plates, exposing him to indium for 9 years (1998-2008). In 2004, an epidemiological study was conducted on indium-exposed workers at the factory in which he worked. The subject's serum indium concentration (In-S) was 99.7 μg/l, while his serum Krebs von den Lungen-6 level was 2,350 U/ml. Pulmonary function tests showed forced vital capacity (FVC) of 4.17 l (91.5% of the JRS predicted value), forced expiratory volume in 1 s (FEV1) of 3.19 l (80.8% of predicted), and an FEV1-to-FVC ratio of 76.5%. A high-resolution chest computed tomography (HRCT) scan showed mild interlobular septal thickening and mild emphysematous changes. In 2008, he was transferred from the ITO grinding workplace to an inspection work section, where indium concentrations in total dusts had a range of 0.001-0.002 mg/m3. In 2009, the subject's In-S had increased to 132.1 μg/l, and pulmonary function tests revealed obstructive changes. In addition, HRCT scan showed clear evidence of progressive lung destruction with accompanying severe centrilobular emphysema and interlobular septal thickening in both lung fields. The subject's condition gradually worsened, and in 2015, he was registered with the Japan Organ Transplant Network for lung transplantation (LTx). Heavy indium exposure is a risk factor for emphysema, which can lead to a severity level that requires LTx as the final therapeutic option.


Pharmacokinetics of oral morphine sulfate in dogs: a comparison of sustained release and conventional formulations.
The pharmacokinetics and bioavailability (F) of single dose sustained release morphine sulfate (OSRMS) and nonsustained release morphine sulfate (NSRMS) were compared to each other and to a bolus injection of morphine sulfate (MS) intravenously (i.v.) in dogs. Beagles (n = 6) were randomly assigned to 3 treatment groups: namely, OSRMS 15 mg orally, NSRMS 15 mg orally, and 15 mg i.v. Serum samples were drawn at intervals up to 480 min following oral and 420 min following i.v. administration. Serum was analysed for morphine concentration using a radioimmunoassay. Data were analysed using non-compartmental pharmacokinetics. The only statistically significant difference between OSRMS and NSRMS was maximum serum concentration (Cmax). There were trends toward longer time to maximum serum concentration (Tmax) and longer mean absorption time (MAT) for OSRMS when compared to NSRMS, but the differences were not statistically significant (P < 0.05). Pharmacokinetic parameters for both oral formulations exhibited large variability in the rate of absorption of MS from the gastrointestinal tract. Bioavailability of both OSRMS and NSRMS was low (15%-17%). As expected, the area under the concentration vs time curve (AUC) and Cmax for the i.v. data was significantly greater than for both oral groups, and Tmax and mean residence time (MRT) were significantly less following i.v. administration. There were no statistically significant differences among the 3 treatment groups for apparent volume of distribution at steady state (Vdss) or elimination parameters. The OSRMS formulation used in this study provided equivalent bioavailability to NSRMS in dogs, accompanied by large individual variability in drug absorption. It also did not appear that the sustained release formulation provided sufficiently prolonged release of morphine sulfate from the tablet matrix in dogs to allow prolonged dosing intervals compared to NSRMS.


Epigenetic Switch Driven by DNA Inversions Dictates Phase Variation in Streptococcus pneumoniae.
DNA methylation is an important epigenetic mechanism for phenotypic diversification in all forms of life. We previously described remarkable cell-to-cell heterogeneity in epigenetic pattern within a clonal population of Streptococcus pneumoniae, a leading human pathogen. We here report that the epigenetic diversity is caused by extensive DNA inversions among hsdSA, hsdSB, and hsdSC, three methyltransferase hsdS genes in the Spn556II type-I restriction modification (R-M) locus. Because hsdSA encodes the sequence recognition subunit of this type-I R-M DNA methyltransferase, these site-specific recombinations generate pneumococcal cells with variable HsdSA alleles and thereby diverse genome methylation patterns. Most importantly, the DNA methylation pattern specified by the HsdSA1 allele leads to the formation of opaque colonies, whereas the pneumococci lacking HsdSA1 produce transparent colonies. Furthermore, this HsdSA1-dependent phase variation requires intact DNA methylase activity encoded by hsdM in the Spn556II (renamed colony opacity determinant or cod) locus. Thus, the DNA inversion-driven ON/OFF switch of the hsdSA1 allele in the cod locus and resulting epigenetic switch dictate the phase variation between the opaque and transparent phenotypes. Phase variation has been well documented for its importance in pneumococcal carriage and invasive infection, but its molecular basis remains unclear. Our work has discovered a novel epigenetic cause for this significant pathobiology phenomenon in S. pneumoniae. Lastly, our findings broadly represents a significant advancement in our understanding of bacterial R-M systems and their potential in shaping epigenetic and phenotypic diversity of the prokaryotic organisms because similar site-specific recombination systems widely exist in many archaeal and bacterial species.


Replacement of two amino acids of 9R-dioxygenase-allene oxide synthase of Aspergillus niger inverts the chirality of the hydroperoxide and the allene oxide.
The genome of Aspergillus niger codes for a fusion protein (EHA25900), which can be aligned with ~50% sequence identity to 9S-dioxygenase (DOX)-allene oxide synthase (AOS) of Fusarium oxysporum, homologues of the Fusarium and Colletotrichum complexes and with over 62% sequence identity to homologues of Aspergilli, including (DOX)-9R-AOS of Aspergillus terreus. The aims were to characterize the enzymatic activities of EHA25900 and to identify crucial amino acids for the stereospecificity. Recombinant EHA25900 oxidized 18:2n-6 sequentially to 9R-hydroperoxy-10(E),12(Z)-octadecadienoic acid (9R-HPODE) and to a 9R(10)-allene oxide. 9S- and 9R-DOX-AOS catalyze abstraction of the pro-R hydrogen at C-11, but the direction of oxygen insertion differs. A comparison between twelve 9-DOX domains of 9S- and 9R-DOX-AOS revealed conserved amino acid differences, which could contribute to the chirality of products. The Gly616Ile replacement of 9R-DOX-AOS (A. niger) increased the biosynthesis of 9S-HPODE and the 9S(10)-allene oxide, whereas the Phe627Leu replacement led to biosynthesis of 9S-HPODE and the 9S(10)-allene oxide as main products. The double mutant (Gly616Ile, Phe627Leu) formed over 90% of the 9S stereoisomer of HPODE. 9S-HPODE was formed by antarafacial hydrogen abstraction and oxygen insertion, i.e., the original H-abstraction was retained but the product chirality was altered. We conclude that 9R-DOX-AOS can be altered to 9S-DOX-AOS by replacement of two amino acids (Gly616Ile, Phe627Leu) in the DOX domain.


Prescribing antiepileptics for the elderly: differences between guideline recommendations and clinical practice.
The incidence of epilepsy in patients aged >60 years is higher than in any other period of life. Yet, until recently, what was known about the treatment of older patients with epilepsy has been inferred from studies in younger patients. A growing body of clinical evidence focused exclusively on the elderly suggests that, while some issues are similar for older and younger adults, older patients with epilepsy may require even more attention regarding antiepileptic drug (AED) selection than younger patients. This article reviews published guidelines and recommendations to identify explicit recommendations for use of specific AEDs in the elderly, and assesses the extent to which those recommendations have been adopted in clinical practice. We found that while one systematically derived guideline stated that lamotrigine may be a good choice for older patients because of its favourable adverse effect profile, only clinical recommendations based on expert opinion explicitly identified AEDs that are more and less appropriate for use in the elderly. Examination of published studies describing recent AED-prescribing patterns suggests that clinical recommendations have been, at best, slowly adopted. This observation is exemplified by the fact that older patients newly diagnosed with epilepsy are still prescribed phenobarbital--a drug identified as suboptimal in 1985. In order to better understand the delay in adopting clinical recommendations, we examine these findings in light of diffusion of innovations theory, a theory that has been used to understand dissemination of other new medical technologies. According to this theory, while it is too early to suggest that use of second-generation AEDs in the elderly has been delayed, the continued use of phenobarbital in older patients newly diagnosed with epilepsy represents a serious delay in adoption of recent guidelines. Delays may be related to lack of knowledge by primary care clinicians and emergency room physicians (who frequently treat older patients with epilepsy), lack of 'opinion leaders' in primary care and perhaps general neurology, clinicians' focus on seizure control as the primary endpoint in treating patients with epilepsy, and difficulties in changing long-standing prescribing patterns. Research targeting barriers to more appropriate prescribing is needed to determine appropriate strategies for changing AED prescribing practices in the elderly.


Anomalous response of supported few-layer hexagonal boron nitride to DC electric fields: a confined water effect?
We use electric force microscopy (EFM) to study the response of supported few-layer hexagonal boron nitride (h-BN) to an electric field applied by the EFM tip. Our results show an anomalous behavior in the dielectric response of h-BN atop Si oxide for different bias polarities: for a positive bias applied to the tip, h-BN layers respond with a larger dielectric constant than the dielectric constant of the substrate, while for a negative bias, the h-BN dielectric constant appears to be smaller. Based on ab initio calculations, we propose that this behavior is due to a water layer confined between the Si oxide substrate and h-BN layers. This hypothesis was experimentally confirmed by sample annealing and also by a comparative analysis with h-BN on a non-polar substrate.


Imatinib in combination with hydroxyurea versus hydroxyurea alone as oral therapy in patients with progressive pretreated glioblastoma resistant to standard dose temozolomide.
A randomized, multicenter, open-label, phase 3 study of patients with progressive, recurrent glioblastoma multiforme (GBM) for whom front-line therapy had failed was conducted. This study was designed to determine whether combination therapy with imatinib and hydroxyurea (HU) has superior antitumor activity compared with HU monotherapy in the treatment of recurrent GBM. The target population consisted of patients with confirmed recurrent GBM and an Eastern Cooperative Oncology Group performance status of 0-2 who had completed previous treatment comprising surgical resection, irradiation therapy, and first-line chemotherapy (preferably temozolomide (TMZ) containing regimen) and who have progressed despite treatment. If first-line chemotherapy did not contain TMZ, a second completed chemotherapy was acceptable. The primary efficacy parameter was progression-free survival (PFS). The primary comparison of combination therapy versus monotherapy for PFS was not significant (adjusted P = 0.56). The hazard ratio (HR) (adjusted HR = 0.93) was not clinically relevant. The median PFS for the combination arm was low at 6 weeks and similar to the median PFS in the monotherapy arm (6 weeks). The 6-month PFS for the two treatment groups was very similar (5% in the combination arm vs. 7% in the monotherapy arm). No clinically meaningful differences were found between the two treatment arms, and the primary study end point was not met. Among the patients receiving imatinib, no adverse events were reported that were either previously unknown or unexpected as a consequence of the disease.


Recombination in eukaryotic single stranded DNA viruses.
Although single stranded (ss) DNA viruses that infect humans and their domesticated animals do not generally cause major diseases, the arthropod borne ssDNA viruses of plants do, and as a result seriously constrain food production in most temperate regions of the world. Besides the well known plant and animal-infecting ssDNA viruses, it has recently become apparent through metagenomic surveys of ssDNA molecules that there also exist large numbers of other diverse ssDNA viruses within almost all terrestrial and aquatic environments. The host ranges of these viruses probably span the tree of life and they are likely to be important components of global ecosystems. Various lines of evidence suggest that a pivotal evolutionary process during the generation of this global ssDNA virus diversity has probably been genetic recombination. High rates of homologous recombination, non-homologous recombination and genome component reassortment are known to occur within and between various different ssDNA virus species and we look here at the various roles that these different types of recombination may play, both in the day-to-day biology, and in the longer term evolution, of these viruses. We specifically focus on the ecological, biochemical and selective factors underlying patterns of genetic exchange detectable amongst the ssDNA viruses and discuss how these should all be considered when assessing the adaptive value of recombination during ssDNA virus evolution.


The MSOAC approach to developing performance outcomes to measure and monitor multiple sclerosis disability.
The Multiple Sclerosis Outcome Assessments Consortium (MSOAC) was formed by the National MS Society to develop improved measures of multiple sclerosis (MS)-related disability. (1) To assess the current literature and available data on functional performance outcome measures (PerfOs) and (2) to determine suitability of using PerfOs to quantify MS disability in MS clinical trials. (1) Identify disability dimensions common in MS; (2) conduct a comprehensive literature review of measures for those dimensions; (3) develop an MS Clinical Data Interchange Standards Consortium (CDISC) data standard; (4) create a database of standardized, pooled clinical trial data; (5) analyze the pooled data to assess psychometric properties of candidate measures; and (6) work with regulatory agencies to use the measures as primary or secondary outcomes in MS clinical trials. Considerable data exist supporting measures of the functional domains ambulation, manual dexterity, vision, and cognition. A CDISC standard for MS ( http://www.cdisc.org/therapeutic#MS ) was published, allowing pooling of clinical trial data. MSOAC member organizations contributed clinical data from 16 trials, including 14,370 subjects. Data from placebo-arm subjects are available to qualified researchers. This integrated, standardized dataset is being analyzed to support qualification of disability endpoints by regulatory agencies.


Recommendations for including multiple symptoms as endpoints in cancer clinical trials: a report from the ASCPRO (Assessing the Symptoms of Cancer Using Patient-Reported Outcomes) Multisymptom Task Force.
The multiple symptoms arising from cancer and its treatment impose significant distress for patients. However, in clinical research, there is no agreed-upon way of assessing and presenting the effects of treatment on multiple symptoms, as either individual scores or a composite score. The ASCPRO (Assessing the Symptoms of Cancer Using Patient-Reported Outcomes) Multisymptom Task Force was established to make recommendations about measuring multiple symptoms as outcomes in cancer clinical trials. The Multisymptom Task Force addressed how to choose the symptoms to be assessed and how multiple individual symptom scores or composite scores of several symptoms might be used as clinical trial outcomes. Consensus was reached on a definition of a multisymptom outcome, the problem of source attribution, and the need for a hypothesis-driven conceptual framework to measure multisymptom outcomes. Validated single-item and multi-item measures currently available or that can be easily generated for oncology use were deemed sufficient for measuring multiple symptoms. The relative value of a composite score versus a set of individual symptom scores was discussed, along with issues in developing and deploying such a composite measure. The results indicated that more research on combining scores of different symptoms is needed. Symptom data should be a required component of cancer clinical trials. Patient-reported symptoms provide a unique patient perspective on treatment benefit and risk that goes beyond clinician-reported adverse events. A representation of changes in multiple symptoms would clarify the impact of treatment and enhance the interpretation of cancer clinical trials for clinicians, patients, and those who make health care policy.


Unexpected photolysis of the sunscreen octinoxate in the presence of the sunscreen avobenzone.
A major concern raised about photostability studies of sunscreen products is that the photodegradation of sunscreens does not readily translate into changes in product performance. This study examines the correlation between photochemical degradation of sunscreen agents and changes in protection provided by sunscreen films. Films of a commercial sunscreen product containing avobenzone, oxybenzone and octinoxate were irradiated using a fluorescent UV-A phototherapy lamp with additional UV-B blocking filter. Periodically, during irradiation the transmittances of the films were measured and samples collected for chemical analysis of the sunscreen agents using high-performance liquid chromatography techniques. The results show that UV-induced changes in UV transmittance of sunscreen films correlate with changes in concentration of sunscreen agents. In a parallel experiment, we also irradiated a thin film of the same product in the cavity of an electron spin resonance (ESR) spectrometer. We report the concomitant photolysis of avobenzone and octinoxate that predominates over expected E/Z photoisomerization and that irradiation of a film of this product produced free radicals detected by ESR spectroscopy that persisted even after exposure had ended.


Ximelagatran: direct thrombin inhibitor.
Warfarin sodium is an effective oral anticoagulant drug. However, warfarin has a narrow therapeutic window with significant risks of hemorrhage at therapeutic concentrations. Dosing is difficult and requires frequent monitoring. New oral anticoagulant agents are required to improve current anticoagulant therapy. Furthermore, while warfarin is effective in venous disease, it does not provide more than 60% risk reduction compared with placebo in venous thrombosis prophylaxis and considerably lower risk reduction in terms of arterial thrombosis. Ximelagatran is an oral pro-drug of melagatran, a synthetic small peptidomimetic with direct thrombin inhibitory actions and anticoagulant activity. As an oral agent, ximelagatran has a number of desirable properties including a rapid onset of action, fixed dosing, stable absorption, apparent low potential for medication interactions, and no requirement for monitoring of drug levels or dose adjustment. It has a short plasma elimination half-life of about 4 hours in cases of unexpected hemorrhage or need for reversal. Its main toxicity relates to the development of abnormal liver biochemistry and/or liver dysfunction with "long-term" use of the drug. This usually occurs within the first 6 months of commencing therapy, with a small percentage of patients developing jaundice. The biochemical abnormality usually resolves despite continuation of the drug. The cause of this toxicity remains unknown. Clinical studies to date have shown that ximelagatran is noninferior to warfarin in stroke prevention in patients with nonvalvular atrial fibrillation, noninferior to standard therapy as acute and extended therapy of deep vein thrombosis (DVT), and superior to warfarin for the prevention of venous thromboembolism post-major orthopedic surgery. It has also been shown to be more effective than aspirin alone for prevention of recurrent major cardiovascular events in patients with recent myocardial infarction.


Metabolic bone disease among in-patients with rheumatoid arthritis.
Twenty-five consecutive in-patients who had suffered from rheumatoid arthritis for at least five years were investigated radiologically, histologically and biochemically for evidence of metabolic bone disease. Dietary intake of vitamin D was universally well below recommended levels. Serum 25-hydroxycholecalciferol (25-OHD) concentrations did not correlate with dietary intake of vitamin D but correlated significantly with a sunlight exposure score (p less than 0.01). Despite seven patients having 25-OHD levels below the normal reference range, no cases of osteomalacia were found. Pathological fractures, often initially unrecognized, had occurred in the lower limb bones of seven patients in the previous five years. Those with fractures of the leg bones had evidence of more pronounced osteoporosis of the axial skeleton radiologically and histologically and five of the seven had been taking oral corticosteroids. There was close agreement between qualitative histological assessment of osteoporosis and radiographic evidence of vertebral collapse and those with the severest osteoporosis had lower serum levels of 25-OHD than the rest (p less than 0.02). Ten subjects had reduced xylose absorption tests, although frank malabsorption was not found, and in five patients studied the jejunal mucosa was normal.


Colonic pseudo-obstruction: a new complication of jejunoileal bypass.
Five female patients ranging in age from 25 to 44 years are reported in whom jejunoileal bypass (three end-to-side and two end-to end), performed for morbid obesity, was complicated 1 1/2 to three years later by symptoms of colonic pseudo-obstruction. In each size, the colon was markedly elongated, dilated, and atonic but with no demonstrate organic obstruction. The cause of this complication is not known. Full thickness rectal biopsy in one case showed normal intrinsic nervous plexuses and ganglia. Serum electrolytes were normal. Functional and defunctionalized small bowel were not involved. Symptoms varied from complete colonic paralysis to incapacitating crampy abdominal pain and distention. In the three patients with end-to-side bypass, dilatation affected the entire colon, while, in the two patients with end-to-end bypass, the dilatation was localized to colon distal to the anastomosis with the defunctionalized small bowel. Resection of the affected portion of colon in one case resulted in recurrence distal to the new site of drainage of defunctioned bowel. Treatment with anti-anaerobe antibiotics in two cases produced dramatic but temporary relief of symptoms.


Kinetics of in vitro lysozyme deposition on silicone hydrogel, PMMA, and FDA groups I, II, and IV contact lens materials.
We sought to compare the kinetics of in vitro lysozyme deposition on silicone hydrogel (SH), polymethyl methacrylate (PMMA), and FDA groups I, II, and IV contact lenses. Lenses were incubated in 125I-labeled lysozyme for time periods ranging from 1 hr to 28 days, and radioactive counts were determined. SH lenses and PMMA deposited less lysozyme than conventional hydrogel lenses (p < 0.05). Lysozyme accumulation on group IV lenses reached a maximum on the seventh day and then plateaued, whereas on groups I, II, and SH lenses, deposition continued to increase across all time periods, reiterating that kinetics of lysozyme deposition is highly material dependent.


Biomolecule storage on non-modified thermoplastic microfluidic chip by ink-jet printing of ionogels.
This paper reports an innovative technique for reagents storage in microfluidic devices by means of a one-step UV-photoprintable ionogel-based microarray on non-modified polymeric substrates. Although the ionogel and the ink-jet printing technology are well published, this is the first study where both are used for long-term reagent storage in lab-on-a-chip devices. This technology for reagent storage is perfectly compatible with mass production fabrication processes since pre-treatment of the device substrate is not necessary and inkjet printing allows for an efficient reagent deposition process. The functionality of this microarray is demonstrated by testing the release of biotin-647 after being stored for 1 month at room temperature. Analysis of the fluorescence of the ionogel-based microarray that contains biotin-647 demonstrated that 90% of the biotin-647 present was released from the ionogel-based microarray after pumping PBS 0.1% Tween at 37 °C. Moreover, the activity of biotin-647 after being released from the ionogel-based microarray was investigated trough the binding capability of this biotin to a microcontact printed chip surface with avidin. These findings pave the way for a novel, one-step, cheap and mass production on-chip reagents storage method applicable to other reagents such as antibodies and proteins and enzymes.


Objective tests of analgesic drugs in ponies.
An equine model, subjected to three kinds of pain (superficial, deep, and visceral) was used to test effects of analgesic drugs. Two groups of ponies were used. In the first group of six ponies, six drugs (fentanyl, meperidine, methadone, oxymorphone, pentazocine, and xylazine) were given according to a Latin square experimental design, and tests were made at 30-minute intervals for 4 hours. Mean values (control) for the three kinds of pain were obtained before and after the tests and were compared with the mean values (drugs) obtained over 2- and 4-hour intervals (four and eight measurements per interval, respectively). Xylazine was significantly more effective in obtunding deep pain (P less than 0.05) at 2- and 4-hour intervals than were the other drugs. Significant differences were not found between values for controls and values for drugs tested for relief of superficial and visceral pain at 2- and 4-hour intervals. In the second group of four ponies, the drug (xylazine) determined most effective in group 1 ponies was given alone or in combination with the next most effective drugs (fentanyl, meperidine, and oxymorphone). Data were obtained in the same manner as for the first group. Mean values were calculated for 2- and 4-hour intervals, and the variance was analyzed. Xylazine and fentanyl combined had the best 2- and 4-hour performance for the relief of visceral pain in the second group (P less than 0.1). Neither xylazine nor a combination of drugs differed markedly from control values for 2- and 4-hour intervals for relief of superficial and deep pain.


Low-cost HIV-1 diagnosis and quantification in dried blood spots by real time PCR.
Rapid and cost-effective methods for HIV-1 diagnosis and viral load monitoring would greatly enhance the clinical management of HIV-1 infected adults and children in limited-resource settings. Recent recommendations to treat perinatally infected infants within the first year of life are feasible only if early diagnosis is routinely available. Dried blood spots (DBS) on filter paper are an easy and convenient way to collect and transport blood samples. A rapid and cost effective method to diagnose and quantify HIV-1 from DBS is urgently needed to facilitate early diagnosis of HIV-1 infection and monitoring of antiretroviral therapy. We have developed a real-time LightCycler (rtLC) PCR assay to detect and quantify HIV-1 from DBS. HIV-1 RNA extracted from DBS was amplified in a one-step, single-tube system using primers specific for long-terminal repeat sequences that are conserved across all HIV-1 clades. SYBR Green dye was used to quantify PCR amplicons and HIV-1 RNA copy numbers were determined from a standard curve generated using serially diluted known copies of HIV-1 RNA. This assay detected samples across clades, has a dynamic range of 5 log(10), and %CV <8% up to 4 log(10) dilution. Plasma HIV-1 RNA copy numbers obtained using this method correlated well with the Roche Ultrasensitive (r = 0.91) and branched DNA (r = 0.89) assays. The lower limit of detection (95%) was estimated to be 136 copies. The rtLC DBS assay was 2.5 fold rapid as well as 40-fold cheaper when compared to commercial assays. Adaptation of the assay into other real-time systems demonstrated similar performance. The accuracy, reliability, genotype inclusivity and affordability, along with the small volumes of blood required for the assay suggest that the rtLC DBS assay will be useful for early diagnosis and monitoring of pediatric HIV-1 infection in resource-limited settings.


The externality of the inside: body images of pregnancy.
This paper draws on literature, empirical data and a range of theoretical perspectives on the maternal body to examine understandings of the relationship between a pregnant woman and her foetus, with a particular focus on the body images used by women to represent this relationship. Psychoanalytic and nursing accounts of the relationship between mother and foetus have often described a symbiotic 'oneness' or unity during pregnancy. Such accounts, however, stress the temporary nature of this unity and identify a series of 'stages' of separation or 'polarisation' between mother and foetus during pregnancy. In contrast, many of the 25 women who participated in our interview study of new motherhood described a confusion of the boundary between self and foetus. For many women the experience of pregnancy and the relationship with the unborn baby was ambiguous and uncertain. Importantly, none of these women described her relationship with the foetus as a series of developmental stages, but rather saw it as fluctuating throughout pregnancy. These findings are more consistent with the work of feminist theorists who describe pregnancy as a dynamic and fluid merging of the inside and the outside of the body/self.


Valvular heart disease associated with systemic lupus erythematosus - the Tygerberg Hospital experience.
BACKGROUND: Valvular heart disease is the most important cardiac manifestation of systemic lupus erythematosus (SLE). We performed a study to determine the presence of valvular heart disease in our patients with SLE. METHODS: We performed clinical, electrocardiographic, transthoracic echocardiographic and laboratory evaluations in 24 patients with SLE. The echocardiographic findings were compared with those of 10 age- and sex-matched volunteers. RESULTS: None of the 24 patients had obvious symptoms of cardiac origin. Valvular abnormalities were common. Valvular thickening was the most predominant finding (more than 50%), followed by mitral valvular regurgitation (12.5%) and pericardial effusions (12.5%). Valvular abnormalities were uncommon in the control group. CONCLUSION: Valvular heart disease is common in our patient population with SLE, although haemodynamically significant valvular dysfunction is rare.


Mapping a complete neural population in the retina.
Recording simultaneously from essentially all of the relevant neurons in a local circuit is crucial to understand how they collectively represent information. Here we show that the combination of a large, dense multielectrode array and a novel, mostly automated spike-sorting algorithm allowed us to record simultaneously from a highly overlapping population of >200 ganglion cells in the salamander retina. By combining these methods with labeling and imaging, we showed that up to 95% of the ganglion cells over the area of the array were recorded. By measuring the coverage of visual space by the receptive fields of the recorded cells, we concluded that our technique captured a neural population that forms an essentially complete representation of a region of visual space. This completeness allowed us to determine the spatial layout of different cell types as well as identify a novel group of ganglion cells that responded reliably to a set of naturalistic and artificial stimuli but had no measurable receptive field. Thus, our method allows unprecedented access to the complete neural representation of visual information, a crucial step for the understanding of population coding in sensory systems.


Slow potentials, event-related potentials, "gamma-band" activity, and motor responses during aversive conditioning in humans.
We examined slow potentials, transient event-related potentials, and oscillatory-like responses in the electroencephalogram during aversive conditioning in humans, in order to determine what is happening in the neocortex when behavioral adaptations are learned. Pictures of an angry and a happy human face served as reinforced (CS+) and unreinforced (CS-) conditioned stimuli, respectively, in one group, and either the reversed condition or two discriminably different neutral faces in two other groups (total n = 48 subjects). The unconditioned stimulus (US) was intracutaneous shock delivered to the left hand 5 s after CS+ onset. The electroencephalographic (EEG) activity was recorded from Fz, Cz, Pz, C3, and C4, electromyographic (EMG) activity from bilateral forearm and corrugator muscles, and skin conductance from the right hand. During acquisition a negative slow potential developed after CS+ (not CS-), which was more pronounced when a neutral face served as CS+. Early (iCNV, initial contingent negative variation) and late (tCNV, terminal contingent negative variation) components of the slow-potential response were positively related to the magnitude of conditioned EMG responses. Differentiation of tCNV was larger when neutral faces signaled the US; iCNV persisted during extinction when a happy face served as CS+. Late-occurring event-related potentials (ERPs) elicited by the US diminished over conditioning, whereas short-latency US components and ERPs elicited by CS events did not. Fourier analysis revealed oscillatory ("gamma-band") activity between 30 and 40 Hz, which persisted up to 3 s after US delivery and diminished as conditioning progressed. Our findings indicate that learning is expressed in neocortical structures at the earliest stages of conditioning. The functional roles of the three types of EEG response in learning are discussed.


Changes in Body Mass Index Following HAART Initiation among HIV-Infected Women in the Women's Interagency HIV Study.
Examine changes in, and factors associated with changing body mass index (BMI) in women following highly active antiretroviral therapy (HAART) initiation. 1177 HIV-infected Women's Interagency HIV Study participants who contributed 10,754 years of follow-up following HAART initiation were studied. Changes in median BMI up to 15 years following HAART initiation, and the highest and lowest BMI reached following HAART initiation were summarized by pre-HAART BMI category (<18.5 [underweight], 18.5-<25.0 [normal weight], 25.0-<30.0 [overweight], 30.0-<40.0 [obese], and ≥ 40.0 [morbidly obese]). Multivariate mixed effects ordinal logistic regression estimated the degree of association of each exposure of interest with post-HAART BMI. Before HAART, 39% percent of women had normal BMI, 31% were overweight, 23% were obese, and 5% were morbidly obese. Following HAART initiation, median BMI change (per 5 years) was 0.21 kg/m2 (90% confidence interval [CI]: -1.33, 0.42) for those with normal pre-HAART BMI, 0.39 kg/m2 (90% CI: 0.15,0.66) for overweight, 0.31 kg/m2 (90% CI: -1.18,0.67) for obese, and -0.36kg/m2 for morbidly obese women. After initiating HAART, 40% with normal pre-HAART BMI became overweight at some point; of those overweight, 46% remained overweight and 47% became obese; 71% of obese women remained obese and 27% became morbidly obese. Each year of nucleoside analog reverse transcriptase inhibitor use was associated with a 3% decreased odds of reaching a higher BMI category (OR 0.97, 95% CI: 0.95, 0.99), while each year of protease inhibitor or non-nucleoside analog reverse transcriptase inhibitor use were associated with a 6% (OR 1.06, 95% CI: 1.04, 1.08) and 5%(OR 1.05, 95% CI: 1.01, 1.08) increased odds of having a higher BMI category, respectively. Although overweight and obesity are highly prevalent in this large cohort of HIV-infected, minority women, HAART use was associated with only a modest increase in BMI over time.


A feasibility study of implementing a patient-centered outcome set for pregnancy and childbirth.
Patient-reported outcome and experience measures (PROM and PREM) can facilitate shared decision making and hold potential to improve healthcare quality. However, their adoption in perinatal care is still limited. The International Consortium for Health Outcomes Measurement (ICHOM) developed a Pregnancy and Childbirth (PCB) outcome set, including PROM and PREM questionnaires. We studied the feasibility to use these PROMs/PREMs in Dutch perinatal care, addressing both women's and professionals' perspective. Patients and professionals in primary and hospital care participated. Women under care at one of five timepoints for PROM/PREM collection of the PCB set (2 during pregnancy, 3 postpartum) were e-mailed a questionnaire and discussed their answers with their obstetric professional the next regular visit. Compliance was recorded. After discussing the PROMs/PREMs, usability and experience were assessed with separate surveys amongst women and professionals. Of 26 women approached, 21 completed and discussed their PROM/PREM questionnaire. Mean questionnaire completion rate was 97%. Average reported time completing the questionnaires was 10 minutes; most women (90%) stated this was acceptable. Women preferred completing questionnaires digitally and discuss their answers with an obstetric professional rather than other care professionals, also 6 months postpartum. Over half of women agreed PROMs/PREMs supported shared decision making (58%), ability to raise issues (60%), and patient-clinician relationship (52%). Six professionals participated: two obstetricians, two clinical midwives, and two community midwives. Most professionals experienced sufficient time to discuss the responses, except at 6 months postpartum. They knew what items to discuss but did not always feel responsible to act upon them. Professionals agreed PROMs/PREMs supported symptom detection and personalized care. Patients and obstetric professionals consider the PCB set a feasible instrument for PROM/PREM assessment, with good compliance, acceptability and usability. Important determinants of successful implementation are a well-equipped ICT-tool, agreements regarding professionals' responsibilities and how outcomes are discussed or acted upon.


The first water coordination sphere of lanthanide(iii) motexafins (Ln-Motex2+, Ln = La, Gd, Lu) and its effects on structures, reduction potentials and UV-vis absorption spectra. Theoretical studies.
Density functional calculations have been performed to study selected hydrated lanthanide(iii) motexafins (Ln-Motex2+, Ln = La, Gd, Lu) by using energy-consistent 4f-in-core lanthanide pseudopotentials to include the major relativistic effects due to the heavy metals. The maximum number (n) of water molecules bound strongly to [Ln-Motex]2+ (Ln = La, Gd, Lu) was determined to be 6 by calculating the change of the Gibbs energies for the reactions [Ln-Motex(H2O)n]2+ + H2O → [Ln-Motex(H2O)n+1]2+. The number of water molecules coordinated directly to Ln3+ was found to be 3 for La, and 2 for Gd and Lu. The explicit treatment of the tightly bound water molecules in [Ln-Motex(H2O)6]2+ in combination with the COSMO solvation model yielded calculated reduction potentials and UV-vis absorption spectra in good agreement with available experimental data.


Fluvastatin inhibits hypoxic proliferation and p38 MAPK activity in pulmonary artery fibroblasts.
The earliest structural change in hypoxia-induced pulmonary hypertension is increased proliferation of adventitial fibroblasts. This fibroproliferative response occurs in acute and chronic hypoxic models, is dependent on p38 mitogen-activated protein (MAP) kinase activation, is selective for the pulmonary circulation, and would seem an important therapeutic target. Simvastatin attenuates pulmonary vascular remodeling in animal models, but additional information regarding mechanisms of action, differential antiproliferative effects and dose responses of available statins is required for appropriate clinical trial design. Our objectives were to determine the effects of statins on acute hypoxia-induced proliferation and p38 MAP kinase activation in pulmonary and systemic artery fibroblasts, to assess the effects of cholesterol intermediates, prenyltransferase and related inhibitors, and to determine the statin's mechanism of action. Atorvastatin, fluvastatin, and simvastatin inhibited adventitial fibroblast proliferation. At low doses (1 microM), this effect was selective for hypoxic (versus serum-induced) proliferation and was also selective for pulmonary (versus systemic) fibroblasts. Complete inhibition of hypoxia-induced p38 MAP kinase activity was achieved at this 1-microM dose. The lipophilic statins exhibited similar potency. The statin effect was reversed by geranylgeranyl pyrophosphate and mimicked by geranylgeranyl transferase and Rac1 inhibitors. Hypoxia-induced p38 MAP kinase activation and proliferation in pulmonary adventitial fibroblasts is dependent on a geranylgeranylated signaling protein, probably Rac1. One micromolar of fluvastatin exhibits a circulation- and stimulus-selective antiproliferative effect on pulmonary artery fibroblasts. The pharmacokinetics of fluvastatin would suggest that its antiproliferative effects may be useful in pulmonary hypertension associated with hypoxia.


The Drosophila dead ringer gene is required for early embryonic patterning through regulation of argos and buttonhead expression.
The dead ringer (dri) gene of Drosophila melanogaster is a member of the recently discovered ARID-box family of eukaryotic genes that encode proteins with a conserved DNA binding domain. dri itself is highly conserved, with specific orthologs in the human, mouse, zebrafish and C. elegans genomes. We have generated dri mutant alleles to show that dri is essential for anterior-posterior patterning and for muscle development in the embryo. Consistent with the mutant phenotype and the sequence-specific DNA-binding properties of its product, dri was found to be essential for the normal early embryonic expression pattern of several key regulatory genes. In dri mutant embryos, expression of argos in the terminal domains was severely reduced, accounting for the dri mutant head phenotype. Conversely, buttonhead expression was found to be deregulated in the trunk region, accounting for the appearance of ectopic cephalic furrows. Curiously, dri was found also to be required for maintenance of expression of the ventrolateral region of even-skipped stripe four. This study establishes dri as an essential co-factor in the regulated expression of specific patterning genes during early embryogenesis.


CD40 inhibits B cell apoptosis by upregulating bcl-xL expression and blocking oxidant accumulation.
Signaling through the CD40 receptor on human and murine B lymphocytes is necessary for germinal center formation and immunoglobulin class switching in vivo and rescues B cells from apoptosis triggered by cross-linking of surface immunoglobulin M in vitro. Ligation of CD40 on the immature mouse B cell line WEHI-231 with recombinant CD40 ligand (CD40L) was found to protect cells from apoptosis after gamma irradiation, as well as that following treatment with the sphingomyelin ceramide or compounds that deplete intracellular glutathione. CD40 signaling led to a rapid increase in the expression of the apoptosis inhibitory protein Bcl-xL. In addition, the apoptosis-induced accumulation of intracellular oxidants in WEHI-231 B cells was rapidly diminished by CD40 crosslinking. This antioxidant response was observed within 1 h and coincided with a preservation of intracellular thiols. These findings indicate that CD40 signaling induces a generalized cellular resistance to apoptosis characterized by an upregulation of Bcl-xL and changes in the intracellular redox potential.


The timeline of epigenetic drug discovery: from reality to dreams.
The flexibility of the epigenome has generated an enticing argument to explore its reversion through pharmacological treatments as a strategy to ameliorate disease phenotypes. All three families of epigenetic proteins-readers, writers, and erasers-are druggable targets that can be addressed through small-molecule inhibitors. At present, a few drugs targeting epigenetic enzymes as well as analogues of epigenetic modifications have been introduced into the clinic use (e.g. to treat haematological malignancies), and a wide range of epigenetic-based drugs are undergoing clinical trials. Here, we describe the timeline of epigenetic drug discovery and development beginning with the early design based solely on phenotypic observations to the state-of-the-art rational epigenetic drug discovery using validated targets. Finally, we will highlight some of the major aspects that need further research and discuss the challenges that need to be overcome to implement epigenetic drug discovery into clinical management of human disorders. To turn into reality, researchers from various disciplines (chemists, biologists, clinicians) need to work together to optimise the drug engineering, read-out assays, and clinical trial design.


General methods for generating phase-shifting interferometry algorithms.
Two completely independent systematic approaches for designing algorithms are presented. One approach uses recursion rules to generate a new algorithm from an old one, only with an insensitivity to more error sources. The other approach uses a least-squares method to optimize the noise performance of an algorithm while constraining it to a desired set of properties. These properties might include insensitivity to detector nonlinearities as high as a certain power, insensitivity to linearly varying laser power, and insensitivity to some order to the piezoelectric transducer voltage ramp with the wrong slope. A noise figure of merit that is valid for any algorithm is also derived. This is crucial for evaluating algorithms and is what is maximized in the least-squares method. This noise figure of merit is a certain average over the phase because in general the noise sensitivity depends on it. It is valid for both quantization noise and photon noise. The equations that must be satisfied for an algorithm to be insensitive to various error sources are derived. A multivariate Taylor-series expansion in the distortions is used, and the time-varying background and signal amplitudes are expanded in Taylor series in time. Many new algorithms and families of algorithms are derived.


Nucleotide sequence analysis of genome segment A of infectious bursal disease virus.
The nucleotide sequence of genome segment A cDNA of the STC strain of infectious bursal disease virus (IBDV) was determined and compared with sequences of the homologous genome segment of the 002-73 strain of IBDV and the Jasper strain of infectious pancreatic necrosis virus (IPNV). The STC-IBDV genome segment A was determined to be 3262 base pairs (bp), which is close to the estimated total length of 3300 bp for genome segment A in IBDV, although there is no proof that it is the real length of this genome segment. The STC-IBDV genome segment A contains two major overlapping open reading frames (ORFs). The large ORF of 3036 bp predicts a polyprotein of Mr 109,358, whereas the small ORF is 435 bp and predicts a protein of Mr 16,550 in STC-IBDV. STC-IBDV and 002-73-IBDV polyproteins are closely related (97.4% amino acid homology). Most of the amino acid mismatches are in VP2 sequences, mainly within the area of the conformation-dependent epitope. Comparison with the Jasper-IPNV polyprotein reveals levels of amino acid sequence homology of about 40% in VP2, 32% in VP3 and 21% in VP4. Within the VP2 molecule the conformation-dependent epitope area is again the least homologous, but the heterogeneity is more conspicuous than between the two IBDV strains, which is not surprising since IBDV and IPNV are serologically unrelated. The small ORF proteins have about 88% amino acid sequence homology between STC-IBDV and 002-73-IBDV, and 30% between each IBDV strain and Jasper-IPNV. There is no homology at all in the non-coding regions of IBDV and IPNV. These comparative sequence data will be useful for subgrouping the Birnaviridae family.