Molecular cloning and DNA sequence analysis of the 37-kilodalton endoflagellar sheath protein gene of Treponema pallidum.
We have used a combination of nucleotide and N-terminal-amino-acid-sequence analyses to determine the primary structure of the 37-kilodalton (kDa) endoflagellar outer layer, or sheath, protein. Initially, a lambda gt11 clone (designated lambda A34) expressing a portion of the 37-kDa protein was selected from a Treponema pallidum genomic library with a murine monoclonal antibody (H9-2) directed against an epitope of the 37-kDa protein. The insert from lambda A34 provided a probe with which a chimeric plasmid (pR14) encoding all but the nine N-terminal amino acids of the entire protein was selected from a T. pallidum(pBR322) genomic library. The nine N-terminal amino acids determined by amino acid sequencing were combined with the DNA sequence encoded by pR14 to determine the primary structure of the entire 37-kDa protein; the combined sequence made up a polypeptide with a calculated molecular mass of 36,948 Da. Approximately one-third of the deduced sequence was confirmed by N-terminal amino acid analysis of tryptic peptides from the purified 37-kDa protein. Repeated attempts to clone upstream portions of the gene (flaA) by using a variety of strategies were unsuccessful, suggesting that unregulated expression of the intact sheath protein or of its most amino-terminal portions is toxic in Escherichia coli. These studies should provide the basis for further molecular investigations of the endoflagellar apparatus and of treponemal motility.


Cinnamate-4-hydroxylase expression in Arabidopsis. Regulation in response to development and the environment.
Cinnamate-4-hydroxylase (C4H) is the first Cyt P450-dependent monooxygenase of the phenylpropanoid pathway. To study the expression of this gene in Arabidopsis thaliana, a C4H cDNA clone from the Arabidopsis expressed sequence tag database was identified and used to isolate its corresponding genomic clone. The entire C4H coding sequence plus 2.9 kb of its promoter were isolated on a 5.4-kb HindIII fragment of this cosmid. Inspection of the promoter sequence revealed the presence of a number of putative regulatory motifs previously identified in the promoters of other phenylpropanoid pathway genes. The expression of C4H was analyzed by RNA blot hybridization analysis and in transgenic Arabidopsis carrying a C4H-beta-glucuronidase transcriptional fusion. C4H message accumulation was light-dependent, but was detectable even in dark-grown seedlings. Consistent with these data, C4H mRNA was accumulated to light-grown levels in etiolated det1-1 mutant seedlings. C4H is widely expressed in various Arabidopsis tissues, particularly in roots and cells undergoing lignification. The C4H-driven beta-glucuronidase expression accurately reflected the tissue-specificity and wound-inducibility of the C4H promoter indicated by RNA blot hybridization analysis. A modest increase in C4H expression was observed in the tt8 mutant of Arabidopsis.


Signal diffusion along connectome gradients and inter-hub routing differentially contribute to dynamic human brain function.
Human cognition is dynamic, alternating over time between externally-focused states and more abstract, often self-generated, patterns of thought. Although cognitive neuroscience has documented how networks anchor particular modes of brain function, mechanisms that describe transitions between distinct functional states remain poorly understood. Here, we examined how time-varying changes in brain function emerge within the constraints imposed by macroscale structural network organization. Studying a large cohort of healthy adults (n = 326), we capitalized on manifold learning techniques that identify low dimensional representations of structural connectome organization and we decomposed neurophysiological activity into distinct functional states and their transition patterns using Hidden Markov Models. Structural connectome organization predicted dynamic transitions anchored in sensorimotor systems and those between sensorimotor and transmodal states. Connectome topology analyses revealed that transitions involving sensorimotor states traversed short and intermediary distances and adhered strongly to communication mechanisms of network diffusion. Conversely, transitions between transmodal states involved spatially distributed hubs and increasingly engaged long-range routing. These findings establish that the structure of the cortex is optimized to allow neural states the freedom to vary between distinct modes of processing, and so provides a key insight into the neural mechanisms that give rise to the flexibility of human cognition.


Loss of the neuroprotective factor Sphingosine 1-phosphate early in Alzheimer's disease pathogenesis.
The greatest genetic risk factor for late-onset Alzheimer's disease (AD) is the ϵ4 allele of Apolipoprotein E (ApoE). ApoE regulates secretion of the potent neuroprotective signaling lipid Sphingosine 1-phosphate (S1P). S1P is derived by phosphorylation of sphingosine, catalysed by sphingosine kinases 1 and 2 (SphK1 and 2), and SphK1 positively regulates glutamate secretion and synaptic strength in hippocampal neurons. S1P and its receptor family have been subject to intense pharmacological interest in recent years, following approval of the immunomodulatory drug Fingolimod, an S1P mimetic, for relapsing multiple sclerosis. We quantified S1P levels in six brain regions that are differentially affected by AD pathology, in a cohort of 34 post-mortem brains, divided into four groups based on Braak neurofibrillary tangle staging. S1P declined with increasing Braak stage, and this was most pronounced in brain regions most heavily affected by AD pathology. The S1P/sphingosine ratio was 66% and 64% lower in Braak stage III/IV hippocampus (p = 0.010) and inferior temporal cortex (p = 0.014), respectively, compared to controls. In accordance with this change, both SphK1 and SphK2 activity declined with increasing Braak pathology in the hippocampus (p = 0.032 and 0.047, respectively). S1P/sphingosine ratio was 2.5-fold higher in hippocampus of ApoE2 carriers compared to ApoE4 carriers, and multivariate regression showed a significant association between APOE genotype and hippocampal S1P/sphingosine (p = 0.0495), suggesting a new link between APOE genotype and pre-disposition to AD. This study demonstrates loss of S1P and sphingosine kinase activity early in AD pathogenesis, and prior to AD diagnosis. Our findings establish a rationale for further exploring S1P receptor pharmacology in the context of AD therapy.


Sea lice infestations on farmed Atlantic salmon in Scotland and the use of ectoparasitic treatments.
A recently compiled national database on sea lice infestations on farmed Atlantic salmon, contains detailed records for the period 1996 to 2000 from over 30 commercial sites on the west coast of Scotland. The data indicate that the two prevalent species of lice, Lepeophtheirus salmonis and Caligus elongatus, have different trends in abundance and distinctive seasonal patterns of infestation on farmed salmon. For the economically important species L salmonis, its abundance on fish varies with the time of the production cycle, the time of year and the particular year. Weekly fluctuations in sea lice counts indicate that treatment can be very effective in controlling infestations but that the counts recover rapidly and regular treatments are necessary to ensure control. A comparison of sites using medium or large numbers of treatments suggests that they do not reduce sea lice infestations to the same levels. There is also evidence that sites using treatments based on different chemical constituents had significantly different levels of infestation.


Monitoring ATPase induced pH changes in single proteoliposomes with the lipid-coupled fluorophore Oregon Green 488.
Monitoring the proton pumping activity of proteins such as ATPases in reconstituted single proteoliposomes is key to quantify the function of proteins as well as potential proton pump inhibitors. However, most pH-detecting assays available are either not quantitative, require well-adapted reconstitution protocols or are not appropriate for single vesicle studies. Here, we describe the quantitative and time-resolved detection of F-type ATPase-induced pH changes across vesicular membranes doped with the commercially available pH sensitive fluorophore Oregon Green 488 DHPE. This dye is shown to be well suited to monitor acidification of lipid vesicles not only in bulk but also at the single vesicle level. The pKa value of Oregon Green 488 DHPE embedded in a lipid environment was determined to be 6.1 making the fluorophore well suited for a variety of physiologically relevant proton pumps. The TFOF1-ATPase from a thermophilic bacterium was reconstituted into large unilamellar vesicles and the bulk acidification assay clearly reveals the overall activity of the F-type ATPase in the vesicle ensemble with an average pH change of 0.45. However, monitoring the pH changes in individual vesicles attached to a substrate demonstrates that the fraction of vesicles with a significant observable pH change is only about 5%, a number that cannot be gathered from bulk experiments and which is considerably lower than expected.


Thermal stress impacts reproductive development and grain yield in rice.
Rice is highly sensitive to temperature stress (cold and heat), particularly during the reproductive and grain-filling stages. In this review, we discuss the effects of low- and high-temperature sensitivity in rice at various reproductive stages (from meiosis to grain development) and propose strategies for improving the tolerance of rice to terminal thermal stress. Cold stress impacts reproductive development through (i) delayed heading, due to its effect on anther respiration, which increases sucrose accumulation, protein denaturation and asparagine levels, and decreases proline accumulation, (ii) pollen sterility owing to tapetal hypertrophy and related nutrient imbalances, (iii) reduced activity of cell wall bound invertase in the tapetum of rice anthers, (iv) impaired fertilization due to inhibited anther dehiscence, stigma receptivity and ability of the pollen tube to germinate through the style towards the ovary, and (v) floret sterility, which increases grain abortion, restricts grain size, and thus reduces grain yield. Heat stress affects grain formation and development through (i) poor anther dehiscence due to restricted closure of the locules, leading to reduced pollen dispersal and fewer pollen on the stigma, (ii) changes in pollen proteins resulting in significant reductions in pollen viability and pollen tube growth, leading to spikelet sterility, (iii) delay in heading, (iv) reduced starch biosynthesis in developing grain, which reduces starch accumulation, (v) increased chalkiness of grain with irregular and round-shaped starch granules, and (vi) a shortened grain-filling period resulting in low grain weight. However, physiological and biotechnological tools, along with integrated management and adaptation options, as well as conventional breeding, can help to develop new rice genotypes possessing better grain yield under thermal stress during reproductive and grain-filling phases.


Adolescent diet and subsequent serum hormones, breast density, and bone mineral density in young women: results of the Dietary Intervention Study in Children follow-up study.
Adolescent diet is hypothesized to influence breast cancer risk. We evaluated the long-term effects of an intervention to lower fat intake among adolescent girls on biomarkers that are related to breast cancer risk in adults. A follow-up study was conducted on 230 girls who participated in the Dietary Intervention Study in Children (DISC), in which healthy, prepubertal, 8 to 10 year olds were randomly assigned to usual care or to a behavioral intervention that promoted a reduced fat diet. Participants were 25 to 29 years old at follow-up visits. All tests of statistical significance are two-sided. In analyses that did not take account of diet at the time of the follow-up visit, the only statistically significant treatment group difference was higher bone mineral content in intervention group participants compared with usual care group participants; their mean bone mineral contents were 2,444 and 2,377 g, respectively. After adjustment for current diet, the intervention group also had statistically significantly higher bone mineral density and luteal phase serum estradiol concentrations. Serum progesterone concentrations and breast density did not differ by treatment group in unadjusted or adjusted analyses. Results do not support the hypothesis that consumption of a lower fat diet during adolescence reduces breast cancer risk via effects on subsequent serum estradiol and progesterone levels, breast density, or bone mineral density. It remains unclear, however, if the results are specific to the DISC intervention or are more broadly applicable. Modest reductions in fat intake during adolescence are unlikely to lower later breast cancer risk via long-term effects on the biomarkers measured.


Does Simulation Improve Recognition and Management of Pediatric Septic Shock, and If One Simulation Is Good, Is More Simulation Better?
Determine whether serial simulation training sessions improve resident recognition and initial septic shock management in a critically ill simulated septic shock patient, and to determine whether serial simulations further improve resident task performance when compared with a single simulation session. Prospective observational cohort study with a live expert review of trainee simulation performance. Expert reviewers blinded to prior trainee performance. A PICU room in a quaternary-care children's hospital, featuring a hi-fidelity pediatric patient simulator. Postgraduate year-2 and postgraduate year-3 pediatric residents who rotate through the PICU. Postgraduate year-3 residents as the control cohort, completing one simulation near the start of their third residency year. Postgraduate year-2 residents as the intervention cohort, completing two simulations during their second residency year and one near the start of their third residency year. Resident objective performance was measured using a validated 27-item checklist (graded 0/1) related to monitoring, data gathering, and interventions in the diagnosis and management of pediatric septic shock. The intervention cohort had a higher mean performance percentage score during their third simulation than the control cohort completing their single simulation (87% vs 77%; p < 0.001). Septic shock was correctly diagnosed more often in the intervention cohort at the time of their third simulation (100% vs 78%; p < 0.001). Appropriate broad-spectrum antibiotics were administered correctly more often in the intervention cohort (83% vs 50%; p < 0.001). Simulations significantly improved resident performance scores in the management of septic shock with repetitive simulation showing significant ongoing improvements. Further studies are needed to determine long-term impact on knowledge and skill retention and whether results attained in a simulation environment are translatable into clinical practice in improving bedside care.


Contrasting patterns in genetic diversity following multiple invasions of fresh and brackish waters.
Biological invasions may combine the genetic effects of population bottlenecks and selection and thus provide valuable insight into the role of such processes during novel environmental colonizations. However, these processes are also influenced by multiple invasions, the number of individuals introduced and the degree of similarity between source and receiving habitats. The amphipod Gammarus tigrinus provides a useful model to assess these factors, as its invasion history has involved major environmental transitions. This species is native to the northwest Atlantic Ocean, although it invaded both brackish and freshwater habitats in the British Isles after introduction more than 65 years ago. It has also spread to similar habitats in Western Europe and, most recently, to Eastern Europe, the Baltic Sea, and the Laurentian Great Lakes. To examine sources of invasion and patterns of genetic change, we sampled populations from 13 native estuaries and 19 invaded sites and sequenced 542 bp of the mitochondrial COI gene. Strong native phylogeographical structure allowed us to unambiguously identify three allopatrically evolved clades (2.3-3.1% divergent) in invading populations, indicative of multiple introductions. The most divergent clades occurred in the British Isles and mainland Europe and were sourced from the St Lawrence and Chesapeake/Delaware Bay estuaries. A third clade was found in the Great Lakes and sourced to the Hudson River estuary. Despite extensive sampling, G. tigrinus did not occur in freshwater at putative source sites. Some European populations showed reduced genetic diversity consistent with bottlenecks, although selection effects cannot be excluded. The habitat distribution of clades in Europe was congruent with the known invasion history of secondary spread from the British Isles. Differences in salinity tolerance among lineages were suggested by patterns of habitat colonization by different native COI clades. Populations consisting of admixtures of the two invading clades were found principally at recently invaded fresh and brackish water sites in Eastern Europe, and were characterized by higher genetic diversity than putative source populations. Further studies are required to determine if these represent novel genotypes. Our results confirm that biological invasions need not result in diminished genetic diversity, particularly if multiple source populations, each with distinctive genetic composition, contribute to the founding populations.


Molecular AND and INHIBIT gates based on control of porphyrin fluorescence by photochromes.
A molecular triad consisting of a porphyrin (P) covalently linked to two photochromes-one from the dihydroindolizine family (DHI) and one from the dihydropyrene family (DHP)-has been synthesized and found to act as either a molecular AND logic gate or an INHIBIT gate, depending on the inputs and initial state of the photochromes. The basis of these functions is quenching of porphyrin fluorescence (output of the gates) by the photochromes. The spiro form of DHI does not quench porphyrin fluorescence, whereas its betaine isomer strongly quenches by photoinduced electron transfer. DHP also quenches porphyrin fluorescence, but its cyclophanediene isomer does not. The triad has been designed using suitable energetics and electronic interactions, so that although these quenching phenomena may be observed, independent isomerization of the attached photochromes still occurs. This makes it possible to switch porphyrin fluorescence on or off by isomerization of the photochromes using various combinations of inputs such as UV light, red light, and heat.


Novel, emerging and provisional renal entities: The Genitourinary Pathology Society (GUPS) update on renal neoplasia.
The Genitourinary Pathology Society (GUPS) undertook a critical review of the recent advances in renal neoplasia, particularly focusing on the newly accumulated evidence post-2016 World Health Organization (WHO) classification. In the era of evolving histo-molecular classification of renal neoplasia, morphology is still key. However, entities (or groups of entities) are increasingly characterized by specific molecular features, often associated either with recognizable, specific morphologies or constellations of morphologies and corresponding immunohistochemical profiles. The correct diagnosis has clinical implications leading to better prognosis, potential clinical management with targeted therapies, may identify hereditary or syndromic associations, which may necessitate appropriate genetic testing. We hope that this undertaking will further facilitate the identification of these entities in practice. We also hope that this update will bring more clarity regarding the evolving classification of renal neoplasia and will further reduce the category of "unclassifiable renal carcinomas/tumors". We propose three categories of novel entities: (1) "Novel entity", validated by multiple independent studies; (2) "Emerging entity", good compelling data available from at least two or more independent studies, but additional validation is needed; and (3) "Provisional entity", limited data available from one or two studies, with more work required to validate them. For some entities initially described using different names, we propose new terminologies, to facilitate their recognition and to avoid further diagnostic dilemmas. Following these criteria, we propose as novel entities: eosinophilic solid and cystic renal cell carcinoma (ESC RCC), renal cell carcinoma with fibromyomatous stroma (RCC FMS) (formerly RCC with leiomyomatous or smooth muscle stroma), and anaplastic lymphoma kinase rearrangement-associated renal cell carcinoma (ALK-RCC). Emerging entities include: eosinophilic vacuolated tumor (EVT) and thyroid-like follicular renal cell carcinoma (TLFRCC). Finally, as provisional entities, we propose low-grade oncocytic tumor (LOT), atrophic kidney-like lesion (AKLL), and biphasic hyalinizing psammomatous renal cell carcinoma (BHP RCC).


C. elegans positive olfactory associative memory is a molecularly conserved behavioral paradigm.
While it is thought that short-term memory arises from changes in protein dynamics that increase the strength of synaptic signaling, many of the underlying fundamental molecular mechanisms remain unknown.Our lab developed a Caenorhabditis elegans assay of positive olfactory short-term associative memory (STAM), in which worms learn to associate food with an odor and can remember this association for over 1h. Here we use this massed olfactory associative assay to identify regulators of C. elegans short-term and intermediate-term associative memory (ITAM) processes. We show that there are unique molecular characteristics for different temporal phases of STAM, which include: learning, which is tested immediately after training, short-term memory, tested 30min after training, intermediate-term memory, tested 1h after training, and forgetting, tested 2h after training. We find that, as in higher organisms, C. elegans STAM requires calcium and cAMP signaling, and ITAM requires protein translation. Additionally, we found that STAM and ITAM are distinct from olfactory adaptation, an associative paradigm in which worms learn to disregard an inherently attractive odor after starvation in the presence of that odor. Adaptation mutants show variable responses to short-term associative memory training. Our data distinguish between shorter forms of a positive associative memory in C. elegans that require canonical memory pathways. Study of STAM and ITAM in C. elegans could lead to a more general understanding of the distinctions between these important processes and also to the discovery of novel conserved memory regulators.


Plasmodium infection alters Anopheles gambiae detoxification gene expression.
Anopheles gambiae has been shown to change its global gene expression patterns upon Plasmodium infection. While many alterations are directly related to the mosquito's innate immune response, parasite invasion is also expected to generate toxic by-products such as free radicals. The current study aimed at identifying which loci coding for detoxification enzymes are differentially expressed as a function of Plasmodium berghei infection in midgut and fat body tissues. Using a custom-made DNA microarray, transcript levels of 254 loci primarily belonging to three major detoxification enzyme families (glutathione S-transferases, cytochrome P450 monooxygenases and esterases) were compared in infected and uninfected mosquitoes both during ookinete invasion and the release of sporozoites into the hemocoel. The greatest changes in gene expression were observed in the midgut in response to ookinete invasion. Interestingly, many detoxification genes including a large number of P450s were down-regulated at this stage. In the fat body, while less dramatic, gene expression alterations were also observed and occurred during the ookinete invasion and during the release of sporozoites into the hemocoel. While most gene expression changes were tissue-related, CYP6M2, a CYP previously associated with insecticide resistance, was over-expressed both in the midgut and fat body during ookinete invasion. Most toxicity-related reactions occur in the midgut shortly after the ingestion of an infected blood meal. Strong up-regulation of CYP6M2 in the midgut and the fat body as well as its previous association with insecticide resistance shows its broad role in metabolic detoxification.


A randomized controlled trial of an intervention delivered by mobile phone text message to increase the acceptability of effective contraception among young women in Palestine.
Research has shown that mobile phone contraceptive behavioral interventions can increase knowledge and use of contraception, but other studies have failed to demonstrate a beneficial effect. The objective of this trial was to estimate the effect of a contraceptive behavioral intervention delivered by mobile phone text message on young Palestinian women's attitudes towards effective contraception. We conducted a randomized controlled trial among women aged 18-24 years living in the West Bank, who were not using an effective method of contraception. The intervention group received zero to three messages per day (113 messages for female-not married and 120 messages for female-married) for 120 days. The control group received 16 messages over 120 days about trial participation. The primary outcome was acceptability of at least one method of effective contraception at 4 months. Secondary outcomes were use of effective contraception at 4 months and any use during the study, acceptability of individual methods, service uptake, unintended pregnancy and abortion. Process outcomes included knowledge, perceived norms, personal agency and intention. All outcomes were self-reported. We analyzed the outcomes using logistic and linear regression. A total of 578 participants were enrolled and 464 (80%) completed follow up at 4 months. Intervention group participants were more likely to find at least one method of effective contraception acceptable (31% in the intervention group versus 17% in the control group, adjusted OR 2.34, 95% CI 1.48-3.68, p < 0.001). They had a higher mean knowledge score, were more likely to find the intrauterine device, injection, implant and patch acceptable, to agree that their friends would use an effective method and to intend to use an effective method, compared to participants in the control group. While in the direction of intervention benefit, there were no differences between the groups in the use of effective contraception at 4 months and any use during the study, pill acceptability, service uptake, unintended pregnancy and induced abortion. The intervention can improve attitudes, knowledge-perceived norms and intention to use effective contraception among young women in Palestine. Research is needed to evaluate the efficacy of the intervention for contraceptive behavioral outcomes in Palestine. ClinicalTrials.gov, NCT02905461 . Registered on 14 September 2016. World Health Organization Trial Registration Data Set: http://apps.who.int/trialsearch/Trial2.aspx?TrialID=NCT02905461.


Degree of conversion and leached monomers of urethane dimethacrylate-hydroxypropyl methacrylate-based dental resin systems.
The degree of conversion (DC) and monomer leaching of three experimental urethane dimethacrylate (UEDMA)-hydroxypropyl methacrylate (HPMA)-based resin systems were studied. Three experimental resins (E1: 70.6 wt% UEDMA + 27.4 wt% HPMA, E2: 80.6 wt% UEDMA + 17.4 wt% HPMA, E3: 90.6 wt% UEDMA + 7.4 wt% HPMA) and one control resin [C: 70.6 wt% bis-phenol A glycidyl methacrylate (bis-GMA) + 27.4 wt% methyl methacrylate (MMA)] were prepared. For the DC test, cylindrical specimens [1.5 mm (h) × 6 mm (d)] were scanned with an ATR-FTIR instrument before and after light-curing (n = 5). For the monomer leaching test, block-shaped specimens [5.67 mm (l) × 2.00 mm (w) × 2.00 mm (h)] were light-cured (n = 6), stored in a 75% ethanol:water solution for 3 days, and then analyzed with HPLC. The UEDMA-HPMA-based experimental groups showed higher DC (62-78%) than the bis-GMA-MMA-based control group (58-66%), and the DC decreased as the UEDMA content increased (P < 0.05). Amongst the four groups, E3 exhibited the lowest leaching of both mono methacrylate (0.1% HPMA) and dimethacrylate (<0.043% UEDMA) monomers after 30 or 40 s of curing. The UEDMA-HPMA-based resins, therefore, exhibited higher DC and less monomer leaching compared to the bis-GMA-MMA-based resin. (J Oral Sci 58, 15-22, 2016).


The Use of Modified Mindfulness-Based Stress Reduction and Mindfulness-Based Cognitive Therapy Program for Family Caregivers of People Living with Dementia: A Feasibility Study.
The aim of this study was to investigate the feasibility and preliminary efficacy of a modified mindfulness-based stress reduction (MBSR) program and mindfulness-based cognitive therapy (MBCT) program for reducing the stress, depressive symptoms, and subjective burden of family caregivers of people with dementia (PWD). A prospective, parallel-group, randomized controlled trial design was adopted. Fifty-seven participants were recruited from the community and randomized into either the modified MBSR group (n = 27) or modified MBCT group (n = 26), receiving seven face-to-face intervention sessions for more than 16 weeks. Various psychological outcomes were measured at baseline (T0), immediately after intervention (T1), and at the 3-month follow-up (T2). Both interventions were found to be feasible in view of the high attendance (more than 70.0%) and low attrition (3.8%) rates. The mixed analysis of variance (ANOVA) results showed positive within-group effects on perceived stress (p = .030, Cohen's d = 0.54), depressive symptoms (p = .002, Cohen's d = 0.77), and subjective caregiver burden (p < .001, Cohen's d = 1.12) in both interventions across the time points, whereas the modified MBCT had a larger effect on stress reduction, compared with the modified MBSR (p = .019). Both the modified MBSR and MBCT are acceptable to family caregivers of PWD. Their preliminary effects were improvements in stress, depressive symptoms, and subjective burden. The modified MBCT may be more suitable for caregivers of PWD than the MBSR. A future clinical trial is needed to confirm their effectiveness in improving the psychological well-being of caregivers of PWD.


Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of moderately emetogenic chemotherapy or anthracycline and cyclophosphamide regimens in patients with cancer: a randomised, active-controlled, double-blind, phase 3 trial.
Chemotherapy-induced nausea and vomiting is a common side-effect of many antineoplastic regimens and can occur for several days after treatment. We aimed to assess the neurokinin-1 receptor antagonist rolapitant, in combination with a serotonin (5-HT3) receptor antagonist and dexamethasone, for the prevention of chemotherapy-induced nausea and vomiting in patients with cancer after administration of moderately emetogenic chemotherapy or regimens containing an anthracycline and cyclophosphamide. We conducted a global, randomised, double-blind, active-controlled, phase 3 study at 170 cancer centres in 23 countries. We included patients with cancer aged 18 years or older, who had not received moderately or highly emetogenic chemotherapy before, with a Karnofsky performance score of 60 or higher, and a predicted life expectancy of 4 months or longer. We used an interactive web-based randomisation system to randomly allocate patients to receive either oral rolapitant (one 180 mg dose; rolapitant group) or a placebo that was identical in appearance (active control group) 1-2 h before administration of moderately emetogenic chemotherapy. Patients were stratified by sex. All patients also received granisetron (2 mg orally) and dexamethasone (20 mg orally) on day 1 (except for patients receiving taxanes as part of moderately emetogenic chemotherapy, who received dexamethasone according to the package insert) and granisetron (2 mg orally) on days 2-3. Every cycle was a minimum of 14 days. In up to five subsequent cycles, patients received the same study drug they were assigned in cycle 1, unless they chose to leave the study or were removed at the treating clinician's discretion. Efficacy analysis was done in the modified intention-to-treat population (comprising all patients who received at least one dose of study drug at a study site compliant with Good Clinical Practice [GCP]). The primary endpoint was the proportion of patients achieving a complete response (defined as no emesis or use of rescue medication) in the delayed phase (>24-120 h after initiation of chemotherapy) in cycle 1. This study is registered with ClinicalTrials.gov, number NCT01500226. The study has been completed. Between March 5, 2012, and Sept 6, 2013, 1369 patients were randomised to receive either rolapitant (n=684) or active control (n=685). 666 patients in each group received at least one dose of study drug at a GCP-compliant site and were included in the modified intention-to-treat population. A significantly greater proportion of patients receiving rolapitant had complete responses in the delayed phase than did those receiving active control (475 [71%] vs 410 [62%]; odds ratio 1·6, 95% CI 1·2-2·0; p=0·0002). The incidence of adverse events was similar in the rolapitant and control groups, with the most frequently reported treatment-related treatment-emergent adverse events being fatigue, constipation, and headache. For cycle 1, the most common grade 3-4 adverse event in the rolapitant versus active control groups was neutropenia (32 [5%] vs 23 [3%] patients). No serious adverse event was treatment-related, and no treatment-related treatment-emergent adverse event resulted in death. Rolapitant in combination with a 5-HT3 receptor antagonist and dexamethasone is well tolerated and shows superiority over active control for the prevention of chemotherapy-induced nausea and vomiting during the 5-day (0-120 h) at-risk period after administration of moderately emetogenic chemotherapy or regimens containing an anthracycline and cyclophosphamide. TESARO, Inc.


Mucosal adenosine deaminase activity and gastritis histology: a comparative study of partially resected and intact stomachs.
Adenosine deaminase is an enzyme which is postulated to have a role in the generation of gastric mucosal inflammation. The aim of our study was to determine and compare adenosine deaminase activity in the gastric mucosa of patients with chronic gastritis developed in partially resected and intact stomachs. 182 patients were studied, 102 non-operated and 80 after distal gastric resection. Biopsy specimens were taken endoscopically from the gastric mucosa 2 cm proximal to the stoma or corresponding upper third of the intact stomach. Gastritis was classified according to the Sydney system. The activity of adenosine deaminase in the mucosal homogenates was measured by determination of ammonia liberated from the substrate and expressed in nmol NH3/mg protein/min. Adenosine deaminase activity was lower in partially resected than in intact stomachs, regardless of Helicobacter pylori infection. While no difference was found in adenosine deaminase activity between Billroth I and Billroth II procedures in subjects without H. pylori infection, the activity was lower in those with Billroth II procedure in the presence of H. pylori infection. As the severity of gastritis increased, enzyme activity decreased in the mucosa of the intact stomach, but was not significantly altered in the mucosa of the gastric remnant. Adenosine deaminase activity differs in intact and partially resected stomachs, but it does not appear to be a factor promoting chronic gastritis.


Changes in retinoblastoma cell adhesion associated with optic nerve invasion.
In the 1970s, several human retinoblastoma cell lines were developed from cultures of primary tumors. As the human retinoblastoma cell lines were established in culture, growth properties and changes in cell adhesion were described. Those changes correlated with the ability of the human retinoblastoma cell lines to invade the optic nerve and metastasize in orthotopic xenograft studies. However, the mechanisms that underlie these changes were not determined. We used the recently developed knockout mouse models of retinoblastoma to begin to characterize the molecular, cellular, and genetic changes associated with retinoblastoma tumor progression and optic nerve invasion. Here we report the isolation and characterization of the first mouse retinoblastoma cell lines with targeted deletions of the Rb family. Our detailed analysis of these cells as they were propagated in culture from the primary tumor shows that changes in cadherin-mediated cell adhesion are associated with retinoblastoma invasion of the optic nerve prior to metastasis. In addition, the same changes in cadherin-mediated cell adhesion correlate with the invasive properties of the human retinoblastoma cell lines isolated decades ago, providing a molecular mechanism for these earlier observations. Most importantly, our studies are in agreement with genetic studies on human retinoblastomas, suggesting that changes in this pathway are involved in tumor progression.


Associations of Urinary Uromodulin with Clinical Characteristics and Markers of Tubular Function in the General Population.
Allelic variants in UMOD, the gene coding for uromodulin, are associated with rare tubulointerstitial kidney disorders and risk of CKD and hypertension in the general population. The factors associated with uromodulin excretion in the normal population remain largely unknown, and were therefore explored in this study. Urinary uromodulin excretion was measured using a validated ELISA in two population-based cohorts that included more than 6500 individuals. The Swiss Kidney Project on Genes in Hypertension study (SKIPOGH) included 817 adults (mean age±SD, 45±17 years) who underwent renal ultrasonography and performed a 24-hour urine collection. The Cohorte Lausannoise study included 5706 adults (mean age, 53±11 years) with fresh spot morning urine samples. We calculated eGFRs using the CKD-Epidemiology Collaboration formula and by 24-hour creatinine clearance. In both studies, positive associations were found between uromodulin and urinary sodium, chloride, and potassium excretion and osmolality. In SKIPOGH, 24-hour uromodulin excretion (median, 41 [interquartile range, 29-57] mg/24 h) was positively associated with kidney length and volume and with creatinine excretion and urine volume. It was negatively associated with age and diabetes. Both spot uromodulin concentration and 24-hour uromodulin excretion were linearly and positively associated (multivariate analyses) with eGFR<90 ml/min per 1.73 m(2). Age, creatinine excretion, diabetes, and urinary volume are independent clinical correlates of urinary uromodulin excretion. The associations of uromodulin excretion with markers of tubular functions and kidney dimensions suggest that it may reflect tubule activity in the general population.


The C-terminal domain of glutamate receptor subunit 1 is a target for calpain-mediated proteolysis.
The AMPA receptors are glutamate-gated ion channels mediating synaptic transmission at the majority of excitatory synapses in the mammalian CNS. They are composed of four subunits (GluR1-4) which exist in two alternatively spliced variants (flip and flop) and are generally considered to form pentameric receptors. The transmembrane structure of the receptors remains a matter of controversy as some data suggest a transmembrane topology consisting of five, four, or three membrane spanning regions. Some receptor properties have been shown to be regulated by phosphorylation processes as well as by the phospholipid environment. More recently, we have shown that calcium treatment of thin (10 microns) frozen-thawed brain sections resulted in profound modifications of the immunochemical properties of the AMPA receptors. More specifically, immunolabelling of the AMPA receptors with antibodies directed against the C-terminal domain of GluR1 and GluR2/3 was markedly decreased in dendritic fields following such treatment at 35 degrees C. This effect was temperature-dependent and completely blocked by inhibitors of the calcium-dependent proteases calpains, and we suggested that calpains are involved in the regulation of AMPA receptor properties. The results of the present study demonstrate that calpain activation produces a partial proteolysis in the C-terminal domain of the receptors and generates a new receptor species with an apparent molecular weight of 103,000 mol. wt. Sequence analysis of the GluR1 C-terminal domain suggests a couple of cleavage sites for calpains. These results are of particular interest considering the body of evidence implicating calpains and changes in excitatory amino acid receptors in mechanisms of synaptic plasticity as well as in neurodegenerative processes.


The role of NF-κB and AhR transcription factors in lead-induced lung toxicity in human lung cancer A549 cells.
Lead (Pb) is recognized as the first heavy metal of the top six toxic air pollutants threatening human health and the second hazardous substance. Pb exposure is associated with lung impairment and high incidences of lung cancer. Nuclear factor kappa B (NF-κB) and aryl hydrocarbon receptor (AhR) signaling pathways are known to be expressed and play an important role in the lung. However, the link between Pb lung toxicity and NF-κB and/or AhR pathways remains unclear. This study was established to explore the role of NF-κB and AhR modulation in Pb-induced lung toxicity in human lung cancer A549 cells. In the current study, treatment of A549 cells with Pb significantly induced cell apoptosis as evidenced by increasing a) the percentage of cells underwent apoptosis determined by flow cytometry and b) p53 mRNA level. Pb treatment induced oxidative stress by a) increasing the formation of reactive oxygen species and b) decreasing GSTA1 mRNA levels. The toxic effects of Pb on the lung was associated with significant increases in NF-κB and AhR levels which was accompanied with increases in downstream targets genes, iNOS and CYP1A1, respectively. Inhibition of NF-κB or AhR either chemically using resveratrol or genetically using small interfering RNA (siRNA) significantly rescued A549 cells from Pb-mediated lung toxicity. The results clearly indicate that Pb-mediated lung toxicities are NF-κB and AhR-dependent mechanism.


Histone Purification from Saccharomyces cerevisiae.
The nucleosome structure consists of a histone octamer made by a tetramer of H3-H4 histones and two dimers of H2A-H2B. Nucleosomes undergo extensive posttranslational modifications that regulate nucleosome interactions, position, and stability.We describe a protocol allowing the robust purification of histones from the yeast Saccharomyces cerevisiae. This method appears to be suitable to quantitatively analyze specific posttranslational histone modifications.


The intertwined relationship between depression and marital distress: elements of marital therapy conductive to effective treatment outcome.
Within the framework of the interpersonal view of depression, this article examines the linkage between depression and four aspects of marital relationship: stress, support, role expectations, and interactional dynamics. Acknowledging the intertwined relationship between depression and marital adjustment, existing models of martial therapy for married depressed patients are examined for the extent to which they address these four aspects. The empirical evidence for the efficacy of these models is also reviewed, suggesting elements of marital therapy that are conducive to effective treatment outcome.


Long-term survival with open-chest cardiac massage after ineffective closed-chest compression in a canine preparation.
The ultimate goal of cardiopulmonary resuscitation (CPR) is long-term, neurologically intact survival. This study examined whether open-chest cardiac massage could improve 7 day survival and neurologic function when instituted after the failure of standard closed-chest compression CPR. Twenty-nine mongrel dogs were anesthetized and then instrumented with catheters to monitor right atrial and ascending aortic pressures. Ventricular fibrillation was induced and after 3 min standard CPR was begun. Standard CPR was performed with a Thumper programmed for 2 inch chest compressions at 60/min with a 50% duty cycle. External defibrillation was attempted twice after 15 min of ventricular fibrillation. Unsuccessfully defibrillated animals were randomly assigned to either an additional 2 min of continued closed-chest compressions, or 2 min of open-chest cardiac massage. All animals underwent a period of advanced cardiac life support and were followed until they were resuscitated or died. Follow-up care, including scoring of neurologic deficit, was performed for 7 days. In dogs receiving open-chest cardiac massage there was significantly more immediate resuscitation success (14/14 vs 5/14; p less than .005), 24 hr survival (12/14 vs 4/14; p less than .005), and 7 day survival (11/14 vs 4/14; p less than .02) than in those receiving continued closed-chest compression. Open-chest cardiac massage significantly improved long-term outcome when instituted after 15 min of ineffective closed-chest compression.


Spiritual needs of Taiwan's older patients with terminal cancer.
To explore the core constitutive patterns from the perspective of the older patient with terminal cancer, the major foci of spiritual needs, and professional actions that manifest tangibly as spiritual care. Hermeneutic inquiry. Two leading teaching hospitals in Taiwan. 35 older patients with terminal cancer with a life expectancy of three months. Participatory observation and in-depth interviews were the major data collection strategies. Hermeneutic inquiry was used to disclose, document, and interpret participants' lived experiences. The perceptions of older Taiwanese patients with terminal cancer and their particular healthcare needs across various transition stages. Two constitutive patterns, "caring for the mortal body" and "transcending the worldly being," each with three themes and a related transformational process emerged from the data analysis. Two foci of spiritual needs were discovering patients' concerns about their dying bodies and their worldly being and facilitating the transcendence of the spiritual being from the physical realm. Caring for older Taiwanese patients with terminal cancer and helping them transcend the fear of the unknown when they give up worldly being can produce insights into patients' primary concerns, perceptions, and spiritual needs to help them achieve a "good" death. The knowledge gained in this study and the six major spiritual care actions identified may empower oncology nurse educators to develop culturally valid spiritual care courses. Research-based guidance for nurse clinicians who are taking care of older Taiwanese patients with terminal cancer will be provided.


Implementing a telehealth service: nurses' perceptions and experiences.
Telehealth is defined as the remote surveillance of a patient's health to aid early diagnosis and timely intervention. Understanding how the stakeholders perceive telehealth can influence its acceptability and diffusion. A primary care trust (PCT) in south London has been providing telehealth services for chronic obstructive pulmonary disease (COPD) and heart-failure patients for the past 22 months. The aim of this study was to elicit practice nurses' perceptions of the telehealth service provided by this PCT. A descriptive qualitative design was chosen to elicit practice nurses' perceptions. A semi-structured email interview was used to investigate their experiences of the service to date and their views about the future of the service. Seven nurses, working on telehealth for an average of 15 months and providing the service to 34 patients, were interviewed. Overall, the nurses described their experience with telehealth to be positive. Lack of resources, organisational support, patient selection criteria and technical support were identified as barriers to effective implementation of telehealth. Additional team members, more input and training, and expanded patient selection criteria were suggested by the nurses to enhance and ensure the success of telehealth. The challenges and barriers to the implementation of telehealth identified by the practice nurses need to be addressed by health services to ensure its continuity and success.


Tight junction regulation through vesicle trafficking: bringing cells together.
Epithelial layers are integral for many physiological processes and are maintained by intercellular adhesive structures. During disease, these structures can disassemble, leading to breakdown of epithelia. TJs (tight junctions) are one type of intercellular adhesion. Loss of TJs has been linked to the pathogenesis of many diseases. The present review focuses on the role of vesicle trafficking in regulation of TJs, in particular trafficking of the TJ protein occludin. We examine how endocytosis and endosomal recycling modulate occludin localization under steady-state conditions and during stimulated TJ disassembly.


Immunophenotype and cytogenetic characteristics in the relationship between birth weight and childhood leukemia.
High birth weight increases the risk of childhood acute lymphoid leukemia (ALL) through unknown mechanisms. Whether this risk is specific to ALL subtypes is unknown, and low case numbers have prevented investigation of the rarer leukemias. Here we address these associations using a large population-based dataset. Using the National Registry of Childhood Tumors, birth weights of 7,826 leukemia cases, defined by immunophenotype and cytogenetic subgroup, were compared with those of 10,785 controls born in England and Wales between 1980 and 2007. The risk for overall leukemia increases 7% with each 0.5 kg increase in birth weight (OR 1.07, 95%CI 1.04-1.10). This risk is limited to the lymphoid leukemias (OR 1.08, 95%CI 1.05-1.12) diagnosed between 1 and 9 years of age. Analysis by cytogenetic feature reveals that there appears to be association with specific chromosomal abnormality: the risk of tumors with high hyperdiploid karyotypes increases 12% per 0.5 kg increase in birth weight (OR 1.12, 95%CI 1.05-1.20), and t(1;19) tumors show an increased risk of 41% per 0.5 kg increase (OR 1.41, 95%CI 1.09-1.84). The risk of acute myeloid leukemia is elevated in high and low birth weight babies. There is no significant risk relationship to other leukemias or myeloproliferative diseases. Birth weight is a risk factor for ALL and AML. Other subtypes of the disease are not significantly affected. There appears to be association with specific chromosomal abnormality, which may aid our understanding of the development of childhood leukemia in utero.


Recent evolution of surgical treatment for gastric cancer in Korea.
Gastric cancer is the most common malignancy and the incidence is steadily increasing in Korea. The principal treatment modality for gastric cancer is surgical extirpation of tumor along with draining lymph nodes. Gastrectomy with D2 lymph node dissection has been well established as a standard of surgery and improved the survival of gastric cancer patients. Recently, technological advances are drastically reshaping the landscape of surgical treatment of gastric cancer. One of the most notable trends is that minimal access surgery becomes dominating the treatment of early stage diseases. For advanced diseases, the standard access surgery is considered a reference treatment. Although there is a pilot study underway to evaluate the feasibility of the application of minimal access surgery to advanced gastric cancer (AGC), the evidence for oncological safety is not yet provided sufficiently. Based on the recent randomized controlled trials, the extent of surgery for AGC has re-defined as para-aortic lymph node dissection dose not add any survival benefit while increasing surgery-related morbidities. In addition, it is now accepted as a standard operation omitting unnecessary procedures such as splenectomy and/or distal pancreatectomy for prophylactic lymph node dissection. Conceptual and technical innovation has contributed to decreasing morbidity and mortality without impairing oncological safety. All these recent advances in the field of gastric cancer surgery would be concluded in maximizing therapeutic index for gastric cancer while improving quality of life.


Spatially disaggregated population estimates in the absence of national population and housing census data.
Population numbers at local levels are fundamental data for many applications, including the delivery and planning of services, election preparation, and response to disasters. In resource-poor settings, recent and reliable demographic data at subnational scales can often be lacking. National population and housing census data can be outdated, inaccurate, or missing key groups or areas, while registry data are generally lacking or incomplete. Moreover, at local scales accurate boundary data are often limited, and high rates of migration and urban growth make existing data quickly outdated. Here we review past and ongoing work aimed at producing spatially disaggregated local-scale population estimates, and discuss how new technologies are now enabling robust and cost-effective solutions. Recent advances in the availability of detailed satellite imagery, geopositioning tools for field surveys, statistical methods, and computational power are enabling the development and application of approaches that can estimate population distributions at fine spatial scales across entire countries in the absence of census data. We outline the potential of such approaches as well as their limitations, emphasizing the political and operational hurdles for acceptance and sustainable implementation of new approaches, and the continued importance of traditional sources of national statistical data.


A new model of temporary focal neocortical ischemia in the rat.
We describe a new rat model of temporary focal ischemia that produces neocortical ischemia without the need for prolonged anesthesia. Temporary focal cerebral ischemia was initiated during halothane anesthesia, maintained for varying periods without anesthesia, and reversed by clip removal requiring brief anesthesia. Tandem carotid and middle cerebral artery occlusion for 1-4 hours and permanent occlusion were used to determine the duration and extent of ischemia necessary to produce predictable volumes of neocortical infarction in Wistar and spontaneously hypertensive rats. In Wistar rats, occlusion of the right middle cerebral and both common carotid arteries resulted in cerebral blood flow reductions to approximately 8% of baseline. One hour of transient ischemia with 23 hours of reperfusion did not result in infarction. Three hours of ischemia followed by 21 hours of reperfusion resulted in infarction comparable to that caused by 24 hours of permanent ischemia. In spontaneously hypertensive rats, unilateral right middle cerebral and common carotid artery occlusion reduced cerebral blood flow to approximately 11% of baseline. Minimal damage was seen with 1 hour of reversible ischemia, but intervals of 2 and subsequently 3 hours followed by 22-21 hours of reperfusion produced progressively larger infarcts. Damage indistinguishable from that seen with 24 hours of permanent ischemia was seen with 3 or 4 hours of transient ischemia followed by 21 or 20 hours of reperfusion. For unanesthetized normothermic rats, cerebral blood flow reductions to 10-20% of baseline resulted in maximal infarction once ischemic durations exceeded 2-3 hours. To be effective, experimental therapies aimed at lessening infarct size or restoring blood flow must be initiated within this critical time interval.


Increased T Cell Differentiation and Cytolytic Function in Bangladeshi Compared to American Children.
During the first 5 years of life, children are especially vulnerable to infection-related morbidity and mortality. Conversely, the Hygiene Hypothesis suggests that a lack of exposure to infectious agents early in life could explain the increasing incidence of allergies and autoimmunity in high-income countries. Understanding these phenomena, however, is hampered by a lack of comprehensive, direct immune monitoring in children with differing degrees of microbial exposure. Using mass cytometry, we provide an in-depth profile of the peripheral blood mononuclear cells (PBMCs) of children in regions at the extremes of exposure: the San Francisco Bay Area, USA and an economically poor district of Dhaka, Bangladesh. Despite variability in clinical health, functional characteristics of PBMCs were similar in Bangladeshi and American children at 1 year of age. However, by 2-3 years of age, Bangladeshi children's immune cells often demonstrated altered activation and cytokine production profiles upon stimulation with PMA-ionomycin, with an overall immune trajectory more in line with American adults. Conversely, immune responses in children from the US remained steady. Using principal component analysis, donor location, ethnic background, and cytomegalovirus infection status were found to account for some of the variation identified among samples. Within Bangladeshi 1-year-olds, stunting (as measured by height-for-age z-scores) was found to be associated with IL-8 and TGFβ expression in PMA-ionomycin stimulated samples. Combined, these findings provide important insights into the immune systems of children in high vs. low microbial exposure environments and suggest an important role for IL-8 and TGFβ in mitigating the microbial challenges faced by the Bangladeshi children.


TMPRSS2-ERG status is not prognostic following prostate cancer radiotherapy: implications for fusion status and DSB repair.
Preclinical data suggest that TMPRSS2-ERG gene fusions, present in about 50% of prostate cancers, may be a surrogate for DNA repair status and therefore a biomarker for DNA-damaging agents. To test this hypothesis, we examined whether TMPRSS2-ERG status was associated with biochemical failure after clinical induction of DNA damage following image-guided radiotherapy (IGRT). Pretreatment biopsies from two cohorts of patients with intermediate-risk prostate cancer [T1/T2, Gleason score (GS) < 8, prostate-specific antigen (PSA) < 20 ng/mL; >7 years follow-up] were analyzed: (i) 126 patients [comparative genomic hybridization (CGH) cohort] with DNA samples assayed by array CGH (aCGH) for the TMPRSS2-ERG fusion; and (ii) 118 patients [immunohistochemical (IHC) cohort] whose biopsy samples were scored within a defined tissue microarray (TMA) immunostained for ERG overexpression (known surrogate for TMPRSS2-ERG fusion). Patients were treated with IGRT with a median dose of 76 Gy. The potential role of TMPRSS2-ERG status as a prognostic factor for biochemical relapse-free rate (bRFR; nadir + 2 ng/mL) was evaluated in the context of clinical prognostic factors in multivariate analyses using a Cox proportional hazards model. TMPRSS2-ERG fusion by aCGH was identified in 27 (21%) of the cases in the CGH cohort, and ERG overexpression was found in 59 (50%) patients in the IHC cohort. In both cohorts, TMPRSS2-ERG status was not associated with bRFR on univariate or multivariate analysis. In two similarly treated IGRT cohorts, TMPRSS2-ERG status was not prognostic for bRFR, in disagreement with the hypothesis that these prostate cancers have DNA repair defects that render them clinically more radiosensitive. TMPRSS2-ERG is therefore unlikely to be a predictive factor for IGRT response.


Secondary Caries in situ Models: A Systematic Review.
In situ caries research serves as a bridge between clinical research and laboratory studies. In this kind of research, volunteers wear a removable intraoral splint or prosthesis containing research samples. Many different in situ models exist to investigate secondary caries. This systematic review compared currently existing secondary caries models and their lesion progression per day values. Three databases (Medline, Embase, and Cochrane) were searched for relevant literature. Bias risk was assessed and model parameters and caries-related outcomes were extracted by 2 independent researchers. Where possible, caries-related outcomes were normalized by estimating lesion progression per day by dividing lesion depth extracted from microradiographic or microhardness data by the number of days the study lasted. The literature search identified 335 articles. After eliminating duplicates and selection, 31 articles were included. The models differed greatly on factors such as sample location, presence of fluoride in the model, and analysis methods. Three main groups could be identified by sample placement; 68% of models placed samples palatally in the upper jaw, and the lower jaw model could be divided into the buccal (26%) and approximal (6%) areas. Average lesion progression in enamel next to composite was 4.3 ± 2.8 µm (range1.1-8.8 µm/day). Studies conducted with palatal models showed caries progression rates 2-5 times higher than the estimated clinical progression rates. Lesion progression per day could be a useful tool for future comparison of models and establishing a standardized model.


Defining Lineage Potential and Fate Behavior of Precursors during Pancreas Development.
Pancreas development involves a coordinated process in which an early phase of cell segregation is followed by a longer phase of lineage restriction, expansion, and tissue remodeling. By combining clonal tracing and whole-mount reconstruction with proliferation kinetics and single-cell transcriptional profiling, we define the functional basis of pancreas morphogenesis. We show that the large-scale organization of mouse pancreas can be traced to the activity of self-renewing precursors positioned at the termini of growing ducts, which act collectively to drive serial rounds of stochastic ductal bifurcation balanced by termination. During this phase of branching morphogenesis, multipotent precursors become progressively fate-restricted, giving rise to self-renewing acinar-committed precursors that are conveyed with growing ducts, as well as ductal progenitors that expand the trailing ducts and give rise to delaminating endocrine cells. These findings define quantitatively how the functional behavior and lineage progression of precursor pools determine the large-scale patterning of pancreatic sub-compartments.


HapCol: accurate and memory-efficient haplotype assembly from long reads.
Haplotype assembly is the computational problem of reconstructing haplotypes in diploid organisms and is of fundamental importance for characterizing the effects of single-nucleotide polymorphisms on the expression of phenotypic traits. Haplotype assembly highly benefits from the advent of 'future-generation' sequencing technologies and their capability to produce long reads at increasing coverage. Existing methods are not able to deal with such data in a fully satisfactory way, either because accuracy or performances degrade as read length and sequencing coverage increase or because they are based on restrictive assumptions. By exploiting a feature of future-generation technologies-the uniform distribution of sequencing errors-we designed an exact algorithm, called HapCol, that is exponential in the maximum number of corrections for each single-nucleotide polymorphism position and that minimizes the overall error-correction score. We performed an experimental analysis, comparing HapCol with the current state-of-the-art combinatorial methods both on real and simulated data. On a standard benchmark of real data, we show that HapCol is competitive with state-of-the-art methods, improving the accuracy and the number of phased positions. Furthermore, experiments on realistically simulated datasets revealed that HapCol requires significantly less computing resources, especially memory. Thanks to its computational efficiency, HapCol can overcome the limits of previous approaches, allowing to phase datasets with higher coverage and without the traditional all-heterozygous assumption. Our source code is available under the terms of the GNU General Public License at http://hapcol.algolab.eu/ firstname.lastname@example.com Supplementary data are available at Bioinformatics online.


Establishing a Collaboration Contract to Facilitate Team Performance.
Effective collaboration is essential for team projects whether related to research, evidence-based practice, or quality improvement efforts and is especially relevant to the doctor of nursing practice (DNP)-prepared nurse (American Association of Colleges of Nursing [AACN], 2006). High-quality projects are accomplished through planning and organization and cannot be left to chance (Yonge, Skillen, & Henderson, 1996). A collaboration contract negates the "left to chance" philosophy by promoting clarity of roles, responsibilities, and team processes. Seven "Cs" of collaboration (contribution, communication, commitment, compatibility, consensus, credit, and cohesion) provide a guiding format for essential components of a contract (Govoni & Pierce, 1997; Lancaster, 1985). This article describes these components and the process for establishing a collaboration contract. An example of a contract is provided that can serve as a template for team projects. Approaches to adapting the contract for use with teams of varied composition are shared. A collaborative contract, along with professional conduct standards, supports achievement of the team goal.


The response to prolonged fasting in hypothalamic serotonin transporter availability is blunted in obesity.
Serotonergic and dopaminergic systems in the brain are essential for homeostatic and reward-associated regulation of food intake and systemic energy metabolism. It is largely unknown how fasting influences these systems or if such effects are altered in humans with obesity. We therefore aimed to evaluate the effects of fasting on hypothalamic/thalamic serotonin transporter (SERT) and striatal dopamine transporter (DAT) availability in lean subjects and subjects with obesity. In this randomized controlled cross-over trial, we assessed the effects of 12 vs 24 h of fasting on SERT and DAT availability in the hypothalamus/thalamus and striatum, respectively, using SPECT imaging in 10 lean men and 10 men with obesity. As compared with the 12-h fast, a 24-h fast increased hypothalamic SERT availability in lean men, but not in men with obesity. We observed high inter-individual variation in the effects of fasting on thalamic SERT and striatal DAT, with no differences between lean men and those with obesity. In all subjects, fasting-induced increases in circulating free fatty acid (FFA) concentrations were associated with an increase in hypothalamic SERT availability and a decrease in striatal DAT availability. Multiple regression analysis showed that changes in plasma insulin and FFAs together accounted for 44% of the observed variation in striatal DAT availability. Lean men respond to prolonged fasting by increasing hypothalamic SERT availability, whereas this response is absent in men with obesity. Inter-individual differences in the adaptations of the cerebral serotonergic and dopaminergic systems to fasting may, in part, be explained by changes in peripheral metabolic signals of fasting, including FFAs and insulin.


Natural remedies for Herpes simplex.
Herpes simplex is a common viral infection of the skin or mucous membranes. The lesions caused by this infection are often painful, burning, or pruritic, and tend to recur in most patients. Short-term treatment with acyclovir can accelerate the healing of an acute outbreak, and continuous acyclovir therapy is often prescribed for people with frequent recurrences. While this drug can reduce the recurrence rate by 60-90 percent, it can also cause a wide array of side effects, including renal failure, hepatitis, and anaphylaxis. Safe and effective alternatives are therefore needed. There is evidence that certain dietary modifications and natural substances may be useful for treating active Herpes simplex lesions or preventing recurrences. Treatments discussed include lysine, vitamin C, zinc, vitamin E, adenosine monophosphate, and lemon balm (Melissa officinalis).


Cytokines and mechanisms of action of glucocorticoids and aminosalicylates in the treatment of ulcerative colitis and Crohn's disease.
Medical therapy of ulcerative colitis and Crohn's disease involves the control of active inflammation to obtain clinical remission and then maintaining that remission. Corticosteroids and 5-aminosalicylic acid are the mainstay of such management. Both have a wide range of properties and are able to inhibit many effector mechanisms which are potentially involved in mucosal inflammation. In in vitro assays, both are able to inhibit the release of a wide variety of pro-inflammatory and immunoregulatory cytokines. In vivo, such effects would limit tissue damage, prevent further amplification of the immune response and restore epithelial function.


Preparation of well-defined ibuprofen prodrug micelles by RAFT polymerization.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to treat acute pain, fever, and inflammation and are being explored in a new indication in cancer. Side effects associated with long-term use of NSAIDs such as gastrointestinal damage and elevated risk of stroke, however, can limit their use and exploration in new indications. Here we report a facile method to prepare well-defined amphiphilic diblock copolymer NSAID prodrugs by direct reversible addition-fragmentation transfer (RAFT) polymerization of the acrylamide derivative of ibuprofen (IBU), a widely used NSAID. The synthesis and self-assembling behavior of amphiphilic diblock copolymers (PEG-PIBU) having a hydrophilic poly(ethylene glycol) block and a hydrophobic IBU-bearing prodrug block were investigated. Release profiles of IBU from the micelles by hydrolysis were evaluated. Furthermore, the antiproliferative action of the IBU-containing micelles in human cervical carcinoma (HeLa) and murine melanoma (B16-F10) cells was assessed.


[Effect of puerarin on hypoxic pulmonary hypertension and accompanying pulmonary fibrosi].
To investigate the effect and regulatory mechanism of puerarin on pulmonary arterial hypertension due to hypoxia and the possible accompanying pulmonary fibrosis, The rat model of hypoxic pulmonary hypertension and the rat model of hypoxia were established. Totally 18 clean-grade SD rats were fed and randomly divided into normal control group, model group and hypoxia+medicine group. Each group received intraperitoneal injection 30 min before modeling every day; hypoxia+medicine group was injected with 20 mg·kg⁻¹ puerarin. Normal control group and model group were injected with the equal volume of 0.9% NaCl solution. Normal control group was cultured under normal conditions in the laboratory, while model group and hypoxia+medicine group were cultured in ahypoxia environment for 21 days to observe rat hypoxic characteristics and make the preliminary judgment about modeling. Afterwards, small animal echocardiography, right cardiac catheterization, HE dyeing and other experiments were used to verify the successful modeling, and puerarin has a therapeutic effect in pulmonary hypertension caused by hypoxia in SD rats. Fluorescence quantitative PCR, Western blot and immunofluorescence method were used to detect the changes caused by hypoxia pulmonary fibrosis-associated protein. It was found that puerarin could be given in anoxia to promote the expressions of CD31, VE-cadherin, inhibit the expressions of α-SMA, vimentin and fibronection, namely the inhibition of vascular wall thickening. Puerarin has the therapeutic effect on the pulmonary hypertension and accompanying pulmonary fibrosis in rats induced by hypoxia.


Excessive sugar intake alters binding to dopamine and mu-opioid receptors in the brain.
Palatable food stimulates neural systems implicated in drug dependence; thus sugar might have effects like a drug of abuse. Rats were given 25% glucose solution with chow for 12 h followed by 12 h of food deprivation each day. They doubled their glucose intake in 10 days and developed a pattern of excessive intake in the first hour of daily access. After 30 days, receptor binding was compared to chow-fed controls. Dopamine D-1 receptor binding increased significantly in the accumbens core and shell. In contrast, D-2 binding decreased in the dorsal striatum. Binding to dopamine transporter increased in the midbrain. Opioid mu-1 receptor binding increased significantly in the cingulate cortex, hippocampus, locus coeruleus and accumbens shell. Thus, intermittent, excessive sugar intake sensitized D-1 and mu-1 receptors much like some drugs of abuse.


Microvascular filtration is increased in the forearms of patients with breast cancer-related lymphedema.
Breast cancer-related lymphedema (BCRL) is a frequent and debilitating complication of breast cancer treatment. The pathophysiology is complex and remains poorly understood; however, data suggest that changes in the peripheral circulation may contribute to edema formation. In 13 volunteers with unilateral BCRL, the following aspects of upper extremity peripheral circulation were examined: muscle relative microvascular volume; capillary filtration coefficient; central and local sympathetic vascular reflexes; skin blood flow; and forearm blood flow. These were studied via real-time, contrast-enhanced ultrasound; venous occlusion strain-gauge plethysmography; lower-body negative pressure; noninvasive blood pressure measurements; and skin (99m)Tc-pertechnetate clearance technique. Measurements were performed bilaterally and simultaneously in the forearms, enabling use of the nonedematous forearm as a control. Capillary filtration coefficients were additionally measured in healthy, age-matched controls. The capillary filtration coefficient was 7.98 ± 2.52 μl·100 ml(-1)·mmHg(-1)·min(-1) (mean ± SD) in edematous forearms and 6.09 ± 1.83 μl·100ml·(-1)·mmHg(-1)·min(-1) in nonedematous forearms in the patient group (P < 0.001). The capillary filtration coefficient was 3.32 ± 1.17 μl·100ml(-1)·mmHg(-1)·min(-1) in the forearms of healthy controls; significantly less than the both the edematous and nonedematous forearms of the patient group (P < 0.001). No significant differences were found in muscle relative microvascular volume, forearm blood flow, skin blood flow, or central or local sympathetic vascular reflexes. Forearm microvascular filtration is increased in patients with BCRL, and more so in the edematous arm. The vascular sympathetic control mechanisms seem to be preserved. We propose that the increased capillary permeability may be due to low-grade inflammation promoted by reduced clearance of inflammatory mediators.


Recommendations for Accurate Resolution of Gene and Isoform Allele-Specific Expression in RNA-Seq Data.
Genetic variation modulates gene expression transcriptionally or post-transcriptionally, and can profoundly alter an individual's phenotype. Measuring allelic differential expression at heterozygous loci within an individual, a phenomenon called allele-specific expression (ASE), can assist in identifying such factors. Massively parallel DNA and RNA sequencing and advances in bioinformatic methodologies provide an outstanding opportunity to measure ASE genome-wide. In this study, matched DNA and RNA sequencing, genotyping arrays and computationally phased haplotypes were integrated to comprehensively and conservatively quantify ASE in a single human brain and liver tissue sample. We describe a methodological evaluation and assessment of common bioinformatic steps for ASE quantification, and recommend a robust approach to accurately measure SNP, gene and isoform ASE through the use of personalized haplotype genome alignment, strict alignment quality control and intragenic SNP aggregation. Our results indicate that accurate ASE quantification requires careful bioinformatic analyses and is adversely affected by sample specific alignment confounders and random sampling even at moderate sequence depths. We identified multiple known and several novel ASE genes in liver, including WDR72, DSP and UBD, as well as genes that contained ASE SNPs with imbalance direction discordant with haplotype phase, explainable by annotated transcript structure, suggesting isoform derived ASE. The methods evaluated in this study will be of use to researchers performing highly conservative quantification of ASE, and the genes and isoforms identified as ASE of interest to researchers studying those loci.


Mutations in the D-loop region and increased copy number of mitochondrial DNA in human laryngeal squamous cell carcinoma.
The effects of D-loop mutations and the mtDNA copy number alterations in LSCC are poorly understood. Herein, we investigated the features and roles of somatic mutations of the D-loop region and copy number alterations in mtDNA of LSCC. Using direct sequencing and real-time quantitative PCR, we examined D-loop mutations and mtDNA copy number in LSCC tissues, paracancerous normal tissues and peripheral vein blood samples from 40 LSCC patients. A student's t test, ANOVA test and χ(2) test were used to analyze association among mutations, mtDNA copy number alterations with clinicopathologic parameters. The results revealed that 21 tumors (52.5 %) had somatic mtDNA D-loop mutations with a total of 34 mutations. Among them, 28 (82.4 %) and 6 (17.6 %) were located in HVII and HVI, respectively. D-loop mutations correlated with tumor differentiation and p53 mutation (P < 0.05), and increased mtDNA copy number. In addition, mtDNA copy number in tumor tissues and paracancerous normal tissues were all significantly higher than in peripheral blood (P < 0.05). The copy number of mtDNA in the cases which carried D-loop mutation was significantly higher than that of the negative cases (P < 0.05). These results suggest that the mtDNA D-loop in LSCC is an unstable region with a high frequency of somatic mutation and polymorphisms. Together with the increase in mtDNA copy number, these factors may play a role in carcinogenesis of the larynx.


Hybrid quantum logic and a test of Bell's inequality using two different atomic isotopes.
Entanglement is one of the most fundamental properties of quantum mechanics, and is the key resource for quantum information processing (QIP). Bipartite entangled states of identical particles have been generated and studied in several experiments, and post-selected or heralded entangled states involving pairs of photons, single photons and single atoms, or different nuclei in the solid state, have also been produced. Here we use a deterministic quantum logic gate to generate a 'hybrid' entangled state of two trapped-ion qubits held in different isotopes of calcium, perform full tomography of the state produced, and make a test of Bell's inequality with non-identical atoms. We use a laser-driven two-qubit gate, whose mechanism is insensitive to the qubits' energy splittings, to produce a maximally entangled state of one (40)Ca(+) qubit and one (43)Ca(+) qubit, held 3.5 micrometres apart in the same ion trap, with 99.8 ± 0.6 per cent fidelity. We test the CHSH (Clauser-Horne-Shimony-Holt) version of Bell's inequality for this novel entangled state and find that it is violated by 15 standard deviations; in this test, we close the detection loophole but not the locality loophole. Mixed-species quantum logic is a powerful technique for the construction of a quantum computer based on trapped ions, as it allows protection of memory qubits while other qubits undergo logic operations or are used as photonic interfaces to other processing units. The entangling gate mechanism used here can also be applied to qubits stored in different atomic elements; this would allow both memory and logic gate errors caused by photon scattering to be reduced below the levels required for fault-tolerant quantum error correction, which is an essential prerequisite for general-purpose quantum computing.


Efficacy and safety of abatacept in lupus nephritis: a twelve-month, randomized, double-blind study.
To compare the efficacy and safety of intravenous (IV) abatacept, a selective T cell costimulation modulator, versus placebo for the treatment of active class III or IV lupus nephritis, when used on a background of mycophenolate mofetil and glucocorticoids. This was a 12-month, randomized, phase II/III, multicenter, international, double-blind study. A total of 298 patients were treated in 1 of 3 IV treatment arms: placebo, abatacept at the standard weight-tiered dose (approximating 10 mg/kg), or abatacept at 30 mg/kg for 3 months, followed by the standard weight-tiered dose (abatacept 30/10). The primary end point, time to confirmed complete response, was a composite measure that required maintenance of glomerular filtration rate, minimal proteinuria, and inactive urinary sediment over the 52-week treatment period. There were no differences among treatment arms in the time to confirmed complete response or in the proportion of subjects with confirmed complete response following 52 weeks of treatment. Treatment with abatacept was associated with greater improvements from baseline in anti-double-stranded DNA antibody, C3, and C4 levels. Among 122 patients with nephrotic-range proteinuria, treatment with abatacept resulted in an ∼20-30% greater reduction in mean urinary protein-to-creatinine ratio compared with placebo. Abatacept was well tolerated; rates of deaths, serious adverse events, and serious infections were similar across treatment arms. Gastroenteritis and herpes zoster occurred more frequently with abatacept treatment. Although the primary end point was not met, abatacept showed evidence of biologic activity and was well tolerated in patients with active class III or IV lupus nephritis.


Development and validation of a field microphone-in-real-ear approach for measuring hearing protector attenuation.
Numerous studies have shown that the reliability of using laboratory measurements to predict individual or even group hearing protector attenuation for occupationally exposed workers is quite poor. This makes it difficult to properly assign hearing protectors when one wishes to closely match attenuation to actual exposure. An alternative is the use of field-measurement methods, a number of which have been proposed and are beginning to be implemented. We examine one of those methods, namely the field microphone-in-real-ear (F-MIRE) approach in which a dual-element microphone probe is used to measure noise reduction by quickly sampling the difference in noise levels outside and under an earplug, with appropriate adjustments to predict real-ear attenuation at threshold (REAT). We report on experiments that validate the ability of one commercially available F-MIRE device to predict the REAT of an earplug fitted identically for two tests. Results are reported on a representative roll-down foam earplug, stemmed-style pod plug, and pre-molded earplug, demonstrating that the 95% confidence level of the Personal Attenuation Rating (PAR) as a function of the number of fits varies from ± 4.4 dB to ± 6.3 dB, depending on the plug type, which can be reduced to ± 3.1 dB to ± 4.5 dB with a single repeat measurement. The added measurement improves precision substantially. However, the largest portion of the error is due to the user's fitting variability and not the uncertainty of the measurement system. Further we evaluated the inherent uncertainty of F-MIRE vs. the putative "gold standard" REAT procedures finding, that F-MIRE measurement uncertainty is less than one-half that of REAT at most test frequencies. An American National Standards Institute (ANSI) working group (S12/WG11) is currently involved in developing methods similar to those in this paper so that procedures for evaluating and reporting uncertainty on all types of field attenuation measurement systems can be standardized. We conclude that the hearing conservationist now has available a portable, convenient, quick, and easy-to-use system that can improve training and motivation of employees, assign hearing protection devices based on noise exposures, and address other management and compliance issues.


Climatic variability, plasticity, and dispersal: A case study from Lake Tana, Ethiopia.
The numerous dispersal events that have occurred during the prehistory of hominin lineages are the subject of longstanding and increasingly active debate in evolutionary anthropology. As well as research into the dating and geographic extent of such dispersals, there is an increasing focus on the factors that may have been responsible for dispersal. The growing body of detailed regional palaeoclimatic data is invaluable in demonstrating the often close relationship between changes in prehistoric environments and the movements of hominin populations. The scenarios constructed from such data are often overly simplistic, however, concentrating on the dynamics of cyclical contraction and expansion during severe and ameliorated conditions respectively. This contribution proposes a two-stage hypothesis of hominin dispersal in which populations (1) accumulate high levels of climatic tolerance during highly variable climatic phases, and (2) express such heightened tolerance via dispersal in subsequent low-variability phases. Likely dispersal phases are thus proposed to occur during stable climatic phases that immediately follow phases of high climatic variability. Employing high resolution palaeoclimatic data from Lake Tana, Ethiopia, the hypothesis is examined in relation to the early dispersal of Homo sapiens out of East Africa and into the Levant. A dispersal phase is identified in the Lake Tana record between c. 112,550 and c. 96,975 years ago, a date bracket that accords well with the dating evidence for H. sapiens occupation at the sites of Qafzeh and Skhul. Results are discussed in relation to the complex pattern of H. sapiens dispersal out of East Africa, with particular attention paid to the implications of recent genetic chronologies for the origin of non-African modern humans.


Neurodevelopment, nutrition, and growth until 12 mo of age in infants fed a low-energy, low-protein formula supplemented with bovine milk fat globule membranes: a randomized controlled trial.
Observational studies have indicated that differences in the composition of human milk and infant formula yield benefits in cognitive development and early growth for breastfed infants. The objective was to test the hypothesis that feeding an infant formula with reduced energy and protein densities and supplemented with bovine milk fat globule membrane (MFGM) reduces differences in cognitive development and early growth between formula-fed and breastfed infants. In a prospective, double-blind, randomized controlled trial, 160 infants <2 mo of age were randomly assigned to be fed an MFGM-supplemented, low-energy, low-protein experimental formula (EF) or a standard formula (SF) until 6 mo of age. The energy and protein contents of the EF and SF were 60 and 66 kcal/100 mL and 1.20 and 1.27 g/100 mL, respectively. A breastfed reference (BFR) group consisted of 80 infants. At 12 mo of age, the cognitive score (mean ± SD) on testing with the Bayley Scales of Infant and Toddler Development, Third Edition, was significantly higher in the EF group than in the SF group (105.8 ± 9.2 compared with 101.8 ± 8.0; P = 0.008) but was not significantly different from that in the BFR group (106.4 ± 9.5; P = 0.73). The EF group ingested larger volumes of formula than did the SF group (864 ± 174 compared with 797 ± 165 mL/d; P = 0.022), fully compensating for the lower energy density. No significant differences in linear growth, weight gain, body mass index, percentage body fat, or head circumference were found between the EF and SF groups. MFGM supplementation to infant formula narrows the gap in cognitive development between breastfed and formula-fed infants. Between 2 and 6 mo of age, formula-fed term infants have the capacity to upregulate their ingested volumes when the energy density of formula is reduced from 66 to 60 kcal/100 mL.


Neurabin-I is phosphorylated by Cdk5: implications for neuronal morphogenesis and cortical migration.
The correct morphology and migration of neurons, which is essential for the normal development of the nervous system, is enabled by the regulation of their cytoskeletal elements. We reveal that Neurabin-I, a neuronal-specific F-actin-binding protein, has an essential function in the developing forebrain. We show that gain and loss of Neurabin-I expression affect neuronal morphology, neurite outgrowth, and radial migration of differentiating cortical and hippocampal neurons, suggesting that tight regulation of Neurabin-I function is required for normal forebrain development. Importantly, loss of Neurabin-I prevents pyramidal neurons from migrating into the cerebral cortex, indicating its essential role during early stages of corticogenesis. We demonstrate that in neurons Rac1 activation is affected by the expression levels of Neurabin-I. Furthermore, the Cdk5 kinase, a key regulator of neuronal migration and morphology, directly phosphorylates Neurabin-I and controls its association with F-actin. Mutation of the Cdk5 phosphorylation site reduces the phenotypic consequences of Neurabin-I overexpression both in vitro and in vivo, suggesting that Neurabin-I function depends, at least in part, on its phosphorylation status. Together our findings provide new insight into the signaling pathways responsible for controlled changes of the F-actin cytoskeleton that are required for normal development of the forebrain.


Effect of the doping level on the biological stability of hydrogenated boron doped diamond electrodes.
Fouling of electrode surfaces by electrode reaction products or by biological spectator species is known to inactivate electrochemical sensors and thus limit their use in biological conditions. Here we present an investigation on the stability of boron doped diamond (BDD) electrodes with different levels of doping. Three different doping levels were used (0.1, 1 and 5% in the carbon phase). The highly doped (5%) BDD is of particular interest as it is here used for the first time for biological applications. Three different redox reactions were examined based on their electrode reaction characteristics: ruthenium(III) hexaammine (outer sphere), ferrocyanide (surface dependent), dopamine (adsorption mediated). The effect of albumin at blood concentration was studied. All results were compared with glassy carbon. There were no significant differences for the outer sphere electrochemistry, but all the BDDs showed improved resistance to fouling for the ferrocyanide oxidation. The electrocatalytic activity of BBD towards dopamine oxidation increased with increased boron content. However, this appears to be due to a larger number of defect sites which also increases the vulnerability to fouling by albumin and by electrode reaction products and the 5% BDD had similar properties to glassy carbon in this regard. These results suggest that it is possible to optimise the BDD performance for specific applications and that the large potential window for BDD may be due, at least in part, to its relatively poor electrocatalytic activity.


Living in danger: previous violence, socioeconomic position, and mortality risk among women over a 10-year period.
Violence against women has many negative consequences. In this short report the authors investigate patterns of mortality among women experiencing violence leading to inpatient care from 1992 to 2006. Do women who are victims of severe violence have an increased mortality risk (a) in general? (b) by violence? (c) by suicide? Does socioeconomic position have any bearing on the mortality risk? The study was based on Swedish national registers, where 6,085 women exposed to violence resulting in inpatient care were compared with a nonexposed population sample of 55,016 women. Women of all social strata previously exposed to severe violence and treated in hospital had a highly increased risk of premature death from all-cause mortality, violence, or suicide. Women previously exposed to severe violence continue to live a life in danger. There is need for a societal response to support and protect these women against further violence after discharge from hospital.


Argo: an integrative, interactive, text mining-based workbench supporting curation.
Curation of biomedical literature is often supported by the automatic analysis of textual content that generally involves a sequence of individual processing components. Text mining (TM) has been used to enhance the process of manual biocuration, but has been focused on specific databases and tasks rather than an environment integrating TM tools into the curation pipeline, catering for a variety of tasks, types of information and applications. Processing components usually come from different sources and often lack interoperability. The well established Unstructured Information Management Architecture is a framework that addresses interoperability by defining common data structures and interfaces. However, most of the efforts are targeted towards software developers and are not suitable for curators, or are otherwise inconvenient to use on a higher level of abstraction. To overcome these issues we introduce Argo, an interoperable, integrative, interactive and collaborative system for text analysis with a convenient graphic user interface to ease the development of processing workflows and boost productivity in labour-intensive manual curation. Robust, scalable text analytics follow a modular approach, adopting component modules for distinct levels of text analysis. The user interface is available entirely through a web browser that saves the user from going through often complicated and platform-dependent installation procedures. Argo comes with a predefined set of processing components commonly used in text analysis, while giving the users the ability to deposit their own components. The system accommodates various areas and levels of user expertise, from TM and computational linguistics to ontology-based curation. One of the key functionalities of Argo is its ability to seamlessly incorporate user-interactive components, such as manual annotation editors, into otherwise completely automatic pipelines. As a use case, we demonstrate the functionality of an in-built manual annotation editor that is well suited for in-text corpus annotation tasks. DATABASE URL: http://www.nactem.ac.uk/Argo.


Fatty acids, α-tocopherol, β-carotene, and lutein contents in forage legumes, forbs, and a grass-clover mixture.
Fresh forages are an important natural source of vitamins and fatty acids in ruminant diets, and their concentrations in forage species are important for the quality of animal-derived foods such as dairy and meat products. The aims of this study were to obtain novel information on vitamins and fatty acids (FA) in a variety of forage legumes and non-legume forb species compared to a grass-clover mixture and to explore implications for animal-derived products. Seven dicotyledons [four forbs (salad burnet ( Sanguisorba minor ), caraway ( Carum carvi ), chicory ( Cichorium intybus ), and ribwort plantain ( Plantago lanceolata )) and three legume species (yellow sweet clover ( Melilotus officinalis ), lucerne ( Medicago sativa ), and birdsfoot trefoil ( Lotus corniculatus ))] and a perennial ryegrass-white clover mixture were investigated in a cutting trial with four harvests (May-October) during 2009 and 2010. The experimental design was a randomized complete block, and analyses of variance were performed. In addition, three other forbs were grown: borage ( Borago officinalis ), viper's bugloss ( Echium vulgare ), and chervil ( Anthriscus cerefolium ). Lucerne and yellow sweet clover had the lowest α-tocopherol concentrations (21-23 mg kg(-1) DM) and salad burnet and ribwort plantain the highest (77-85 mg kg(-1) DM); β-carotene concentrations were lowest in lucerne, salad burnet, and yellow sweet clover (26-33 mg kg(-1) DM) and highest in caraway, birdsfoot trefoil, and ribwort plantain (56-61 mg kg(-1) DM). Total FA concentrations were lowest in lucerne, ribwort plantain, chicory, and yellow sweet clover (15.9-19.3 g kg(-1) DM) and highest in caraway and birdsfoot trefoil (24.5-27.0 g kg(-1) DM). Birdsfoot trefoil had the highest (53.6 g 100 g(-1) FA) and caraway and lucerne the lowest (33.7-35.7 g 100 g(-1) FA) proportions of n-3 FA. This study demonstrated higher vitamin concentrations in some forbs compared with major forages such as lucerne and grass-clover, more total FA in salad burnet, caraway, and birdsfoot trefoil than in lucerne, and higher n-3 FA concentrations in all forbs than in lucerne. Opportunities are discussed to develop novel biodiverse pastures for particular product quality characteristics.