In-silico Design and ADMET Studies of Natural Compounds as Inhibitors of Xanthine Oxidase (XO) Enzyme.
Xanthine oxidase a ubiquitous enzyme has been found to be involved in various pathological disorders including gout, hyperuricemia, inflammation, oxidative stress and cardiovascular diseases. Inhibitors of xanthine oxidase thus find a crucial role in the therapeutic treatment of these deadly diseases. Considering the side effects of today's treatment regimen here we choose nature based compounds to act as xanthine oxidase inhibitors. In the present work, we performed in-silico docking of natural compounds to reveal the underlying mechanism of inhibition of xanthine oxidase. Further filtration of screened compounds with ADMET studies has been performed. An in-house library of natural compounds screened through ADMET profile for the drug likeliness property was approached for docking studies using Schrödinger suite. Calculation of docking score was done by glide module and free binding energy calculations were performed through MM/GBSA software. Natural leads having better pharmacokinetic profile and mechanism of inhibition were obtained. Docking score, binding energy and different forces involved in interaction were calculated for the top-ranked molecules and good comparison with the standard drugs was achieved Conclusion: Compounds having potential therapeutic activity with low systematic toxicity has been identified against xanthine oxidase which could serve as pharmacophore for the design and synthesis of new drug-like molecules.


How and when do students use flashcards?
Previous survey research has documented students' use of self-regulated study strategies, with a particular interest in self-testing. These surveys indicate that students frequently use flashcards to self-test and that self-testing is primarily used as a way to monitor learning. Whereas previous surveys provide information about whether and why students self-test, they provide minimal information about how and when students choose to self-test. Accordingly, the primary purpose of the current survey was to explore how and when students engage in self-testing. We surveyed 374 undergraduates about the amount of practice and the timing of practice, two factors that strongly affect the efficacy of self-testing. Results indicate that students understand the benefits of practising to higher criterion levels (amount of practice) but do not typically implement or understand the benefits of practising with longer lags (timing of practice). We discuss practical implications for supporting more successful student learning.


Impact of foot-and-mouth disease on fertility performance in a large dairy herd in Kenya.
This was a retrospective cohort study using data collected from a large-scale dairy herd in Kenya (n = 328 female animals), to investigate the effects of foot-and-mouth disease (FMD) on herd fertility performance following a confirmed outbreak in a regularly vaccinated herd. Kaplan-Meier graphs were used to depict differences in survival functions between exposure groups and Cox regression models were used to calculate hazard ratios (HR) for associations between being clinical FMD cases and the following fertility outcomes: age at first calving; fertility failure related culling (not in calf); time to first service; time to conception. Potential confounding variables investigated and controlled for were age, breed, parity, stage of lactation/gestation and eligibility for service. A case control study was nested within the cohort to investigate the effects of disease on conception HR following calving by comparing animals susceptible to fertility suppression at the time of the outbreak (cases) to animals that had conceived prior to the outbreak (controls). The median age of first calving in clinically affected young-stock was 2.7 months higher than non-clinical cases (adjusted HR = 0.37, 95%CI 0.21-0.67, P = 0.01). There was no evidence of a difference in fertility related culling and times to first service and conception. Animals susceptible to fertility suppression at the time of the outbreak had a lower hazard of conception compared to animals served prior to the outbreak (HR = 0.56, 95%CI 0.41-0.75, P = 0.01). Within the herd, the odds of being a case decreased with parity and age likely related to the lifetime number of vaccination doses received which may reduce the impact among older animals in the herd. Moreover, one would expect the impact to be higher in a non-vaccinating herd to be higher. Notwithstanding these limitations, the results of this study provide evidence that FMD outbreaks in endemic settings impact herd fertility performance. An increased age at first calving is likely to increase rearing costs and reduce an animal's lifetime productivity while poorer conception rates will likely extend calving intervals. Impaired herd fertility and production will incur higher costs to the farmer and society as animals are less productive which for FMD can extend beyond the outbreak period where economic studies tend to focus. These impacts of FMD on herd fertility should be considered when conducting benefit-cost analyses of FMD control to inform resource allocation.


Patient-controlled benzodiazepine dose reduction in a community mental health service.
Abstact Objectives: We report a patient-controlled benzodiazepine discontinuation programme in a generic multidisciplinary community mental health service. A prescribing audit identified suboptimal benzodiazepine use which stimulated a discontinuation programme [prescribing policy, psychoeducation, anxiety management] to encourage benzodiazepine cessation. Benzodiazepine status was re-assessed at 12 and 24 month follow-ups. 158 patients were receiving benzodiazepines at study onset. At 12 month follow-up, 68 of these were still receiving benodiazepines. This was due to discontinuation (n = 32), dose reduction (n = 26) and service dropout (n = 71). Benzodiazepine status at follow-up was predicted by attendance at anxiety management sessions (p = 0.01) and shorter duration of benzodiazepine use (p = 0.005). Patients attending anxiety management sessions were 2.5 times more likely to reduce use. Discontinuation followed four patterns: (a) rapid and complete discontinuation (n = 19); (b) total discontinuation in a gradual manner (n = 13); (c) partial dose reduction without total discontinuation (n = 18) and (d) almost total discontinuation with continued low-dose use (n = 8). The patients that achieved total discontinuation were younger (p = 0.01) and in receipt of benzodiazepine agents for a shorter duration (p = 0.009). At 24 month follow-up only three patients had relapsed into benzodiazepine use and a further 13 had achieved total discontinuation. Many chronic benzodiazepine users can achieve lasting discontinuation with patient-controlled dose tapering. Patient refusal and service dropout are common during discontinuation programmes. Anxiety management is a valuable adjunct to discontinuation.


Diabetes education programs and the endocrinologist.
In the past, control of diabetes was considered important, but studies had not substantiated the effect of high-quality care on the outcome for patients with diabetes. Recently, however, published results of the Diabetes Control and Complications Trial indicated that optimal control of diabetes minimized the associated complications. As a consequence, educational efforts have focused on informing and encouraging patients with diabetes to help achieve and maintain the best possible medical care. This situation has created a market for products and services to assist patients with diabetes, and many nonphysicians have promoted their products without actual participation in a team effort to improve outcomes for patients with diabetes. Clinical endocrinologists, who are experts in the management of diabetes, should assume a leadership role on the diabetes-care team and should not relinquish this responsibility to those who are less qualified to provide care for the growing number of patients with diabetes who seek optimally effective treatment.


Unraveling the Synergy of Chemical Hydroxylation and the Physical Heterointerface upon Improving the Hydrogen Evolution Kinetics.
Efficient transition metal oxide electrocatalysts for the alkaline hydrogen evolution reaction (HER) have received intensive attention to energy conversion but are limited by their sluggish water dissociation and unfavorable hydrogen migration and coupling. Herein, systematic density functional theory (DFT) predicts that on representative NiO, the hydroxylation (OH-) and heterointerface coupled with metallic Cu can respectively reduce the energy barrier of water dissociation and facilitate hydrogen spillover. Motivated by theoretical predictions, we subtly designed a delicate strategy to realize the electrochemical OH- modification in KOH with moderate concentration (HOM-NiO) and to channel rapid hydrogen spillover at the heterointerface of HOM-NiO and Cu, ensuring an enhanced HER kinetic. This HOM-NiO/Cu is systematically investigated by in situ XAS and electrochemical simulations, verifying its extraordinary merits for HER including the enhanced water dissociation, alleviated oxophilicity that is advantageous for consecutive adsorptions of water, and accelerated hydrogen spillover, thereby exhibiting superb HER activity with 33 and 310 mV overpotentials at the current densities of 10 and 1000 mA cm-2 in 1.0 M KOH, outperforming the Pt/C. This study might provide a reasonable strategy for the functionalized design of superior electrocatalysts.


Lack of association between receipt of conjugate haemophilus influenzae type B vaccine (HbOC) in infancy and risk of type 1 (juvenile onset) diabetes: long term follow-up of the HbOC efficacy trial cohort.
We evaluated the effect of infant vaccination with HbOC Haemophilus influenzae type b (Hib) conjugate vaccine on the risk of onset of type 1 juvenile diabetes later in life by examining data from a large controlled prospective Phase III clinical efficacy trial conducted within Northern California Kaiser Permanente between 1988 and 1990. The overall study population included children who were offered the Hib conjugate vaccine (acceptors and refusers) as well as a cohort of children who were systemically excluded from the trial on the basis of their birth date. These children are now 10 to 12 years of age. We found no evidence that vaccination with Hib conjugate vaccine in infancy is associated with risk of diabetes later in life.


Repeated divergence of amphibians and reptiles across an elevational gradient in northern Madagascar.
How environmental factors shape patterns of biotic diversity in tropical ecosystems is an active field of research, but studies examining the possibility of ecological speciation in terrestrial tropical ecosystems are scarce. We use the isolated rainforest herpetofauna on the Montagne d'Ambre (Amber Mountain) massif in northern Madagascar as a model to explore elevational divergence at the level of populations and communities. Based on intensive sampling and DNA barcoding of amphibians and reptiles along a transect ranging from ca. 470-1470 m above sea level (a.s.l.), we assessed a main peak in species richness at an elevation of ca. 1000 m a.s.l. with 41 species. The proportion of local endemics was highest (about 1/3) at elevations >1100 m a.s.l. Two species of chameleons (Brookesia tuberculata, Calumma linotum) and two species of frogs (Mantidactylus bellyi, M. ambony) studied in depth by newly developed microsatellite markers showed genetic divergence up the slope of the mountain, some quite strong, others very weak, but in each case with genetic breaks between 1100 and 1270 m a.s.l. Genetic clusters were found in transect sections significantly differing in bioclimate and herpetological community composition. A decrease in body size was detected in several species with increasing elevation. The studied rainforest amphibians and reptiles show concordant population genetic differentiation across elevation along with morphological and niche differentiation. Whether this parapatric or microallopatric differentiation will suffice for the completion of speciation is, however, unclear, and available phylogeographic evidence rather suggests that a complex interplay between ecological and allopatric divergence processes is involved in generating the extraordinary species diversity of Madagascar's biota. Our study reveals concordant patterns of diversification among main elevational bands, but suggests that these adaptational processes are only part of the complex of processes leading to species formation, among which geographical isolation is probably also important.


[Synthesis and antibacterial activity of imidazothiadiazoles and heterocyclic-amine Mannich-base hydrochloride].
To optimize the synthetic method and antibacterial activity of fused heterocyclic thiadiazole compounds, cyclocondensation of 2-(4-methoxyphenyl)-5-amino-1,3,4-thiadiazole (2) with alpha-chloro-4-chloro acetophenone (3) resulted in a key intermediate (4), 6 -(4-chlorophenyl)-2-(4-methoxyphenyl)-imidazo-[2,1-b][1,3,4]thiadiazole, which was carried out an nucleophilic substitution with substituted piperazine to give the corresponding free bases of piperazine (5a-5c), then followed by Mannich reaction with heterocyclicamines and formaldehyde to yield the corresponding Mannich bases, (1a-11) as respective hydrochloride salts. The structures were confirmed by IR, 1H NMR, MS and elemental analysis and the antibacterial activities in vitro of fifteen newly synthesized compounds were also tested against Gram positive bacteria and Gram negative bacteria with the standard 2-fold agar dilution method. The antibacterial results showed that the introduction of a polar group resulted in the enhancement of antibacterial activity in vitro. Thus, the structures of these fused compounds could further be investigated.


Exendin-4 agonist and exendin(9-39)amide antagonist of the GLP-1(7-36)amide effects in liver and muscle.
The GLP-1 structurally related peptides exendin-4 and exendin(9-39)amide were found to act, in rat liver and skeletal muscle, as agonist and antagonist, respectively, of the GLP-1(7-36)amide effects on glucose metabolism. Thus, like GLP-1(7-36)amide, exendin-4 increased glycogen synthase a activity and glucose incorporation into glycogen in both tissues and also stimulated exogenous D-glucose utilization and oxidation in muscle. These effects of GLP-1(7-36)amide and exendin-4 were inhibited by exendin(9-39)amide. Our findings provide further support to the proposed use of GLP-1, or exendin-4, as a tool in the treatment of diabetes mellitus. Thus, in addition to the well-known insulinotropic action of the peptides, they act both in liver and in muscle in a manner most suitable for restoration of glucose homeostasis, with emphasis on their positive effects upon glycogen synthesis in the two tissues and on the stimulation of exogenous glucose catabolism in muscle.


Older, vulnerable patient view: a pilot and feasibility study of the patient measure of safety (PMOS) with patients in Australia.
The UK-developed patient measure of safety (PMOS) is a validated tool which captures patient perceptions of safety in hospitals. We aimed (1) to investigate the extent to which the PMOS is appropriate for use with stroke, acute myocardial infarction (AMI) and hip fracture patients in Australian hospitals and (2) to pilot the PMOS for use in a large-scale, national study 'Deepening our Understanding of Quality in Australia' (DUQuA). Stroke, AMI and hip fracture patients (n=34) receiving care in 3 wards in 1 large hospital. 2 phases were conducted. First, a 'think aloud' study was used to determine the validity of PMOS with this population in an international setting, and to make amendments based on patient feedback. The second phase tested the revised measure to establish the internal consistency reliability of the revised subscales, and piloted the recruitment and administration processes to ensure feasibility of the PMOS for use in DUQuA. Of the 43 questions in the PMOS, 13 (30%) were amended based on issues patients highlighted for improvement in phase 1. In phase 2, a total of 34 patients were approached and 29 included, with a mean age of 71.3 years (SD=16.39). Internal consistency reliability was established using interitem correlation and Cronbach's α for all but 1 subscale. The most and least favourably rated aspects of safety differed between the 3 wards. A study log was categorised into 10 key feasibility factors, including liaising with wards to understand operational procedures and identify patterns of patient discharge. Capturing patient perceptions of care is crucial in improving patient safety. The revised PMOS is appropriate for use with vulnerable older adult groups. The findings from this study have informed key decisions made for the deployment of this measure as part of the DUQuA study.


Psychological factors selectively upregulate rectal pain perception in hypersensitive patients with irritable bowel syndrome.
Visceral hypersensitivity and psychological symptoms are frequent features in irritable bowel syndrome (IBS). Exploring mechanistic pathways leading to visceral hypersensitivity is of importance to direct future studies and treatment options. In this study, we evaluated the contribution of psychological factors to the perception of painful and non-painful rectal sensations in hyper- vs normosensitive IBS patients. We included 138 IBS patients (Rome II criteria) who underwent an ascending method of limited rectal balloon distension paradigm. At the end of each distension step, subjects rated the perceived intensity of non-painful ('unpleasantness') and painful rectal sensations on visual analog scales. Sensitivity status was determined based on pain thresholds. Anxiety, depression and somatization were assessed by questionnaires. Mixed models were used to test the relationship between sensitivity status, psychological variables, and pain & unpleasantness ratings upon increasing distension. Hypersensitive IBS patients had lower sensory thresholds for pain, first perception, urge to defecate, and discomfort (p < 0.0001). Upon increasing distension, they rated both painful and non-painful sensations as more intense than normosensitive patients (p < 0.0001). Psychological factors were associated with higher pain ratings during distension in hypersensitive (p < 0.006-0.0001), but not in normosensitive patients. Anxiety, but not depression or somatization, was associated with increased intensity ratings of non-painful sensations (p < 0.001), independent of sensitivity status. Hypersensitive IBS patients are characterized by increased perception of pain, but also of non-painful sensations. Psychological factors increase the perception of painful sensations in hypersensitive patients only, whereas non-painful visceral sensations were exaggerated in anxious patients regardless of the sensitivity status.


Impact of neighbourhood-level social determinants of health on healthcare utilisation and perinatal outcomes in pregnant women with NAFLD cirrhosis: a population-based study in Ontario, Canada.
Cirrhosis is rising in North America, driven partly by the epidemic of non-alcoholic fatty liver disease (NAFLD), most in women of reproductive age. Little is known about factors that impact perinatal outcomes and healthcare utilisation in pregnant women with NAFLD cirrhosis. We investigated the association between population-level social determinants, health outcomes and healthcare utilisation. We retrospectively analysed healthcare utilisation and perinatal outcomes in a cohort of pregnant women with NAFLD cirrhosis from Ontario, Canada from 2000 to 2016 and followed for 90 days postdelivery. We compared utilisation and health outcomes according to income, residential instability, material deprivation, dependency and ethnic diversity. A Cochran-Armitage test for trend was done to assess whether utilisation patterns were linear across quintiles. 3320 pregnant women with NAFLD cirrhosis formed the study cohort. Decreasing income quintile associated with a higher proportion of women with at least one emergency department (ED) visit. Increasing residential instability, material deprivation and dependency were associated with a higher frequency of ED visitation, with no compelling differences in the rates of perinatal complications or adverse outcomes in pregnant women with NAFLD cirrhosis. Using multiple population-level proxies for social determinants of health, this study demonstrates an association between marginalisation and increased ED visitation. As the incidence rate of pregnancies among women with NAFLD cirrhosis continues to rise, understanding how this population uses healthcare services will help coordinate care for these patients.


[Incidence of childhood leukemia in the Lublin region of Poland in 1988-2000].
Purpose of the work was the analysis of the number and structure of leukemia in children living in the Lublin Region of Poland. The study included the population of children aged 0-17 in the years 1988-2000. Among leukemias, according to the International Classification of Childhood Cancers, were counted: lymphoid leukemia, acute non-lymphocytic leukemia, chronic myeloid leukemia, other specified and unspecified leukemias. Number of cases and incidence for the whole group as well as sex, age and descending (rural and urban) distribution of leukemias were calculated. 244 cases of leukemia were reported (152 boys--62.3% and 92 girls--37.7%). The most of children were from urban regions (139-57%). The mean morbidity rate was 29.9 per million (among boys--36.4/mln, girls--23.1/min). The highest morbidity was observed in years 1989-1990. After 1992 year vehemently decrease of morbidity was noted. Incidence fall with the age, the higher was found in the 0-4 years group (58.7/mln). The decreasing incidence was noted in following years of observation only among the youngest children, while the incidence in children 5-17 years was stable. The higher morbidity was observed among children living in urban regions than in rural ones (35.7/mln vs 24.6/mln) and the incidence in urban region decreased. In the Lublin Region lower percentage of leukemia was observed compared to the values determined for the country. Incidence of leukemia was falling, but the analysis in age-groups proved, that it was caused by the decreasing incidence in children under 5 year. The higher morbidity was noted in urban children than in rural ones.


[Evaluation of effective jaw position and body posture for oral appliance of patients with obstructive sleep apnea syndrome].
The aim of this study was to evaluate whether substantial airflow changes occur by changing both jaw position and body posture in normal subjects and patients with obstructive sleep apnea syndrome (OSAS). Fifteen normal controls (9 males and 6 females) and 15 male OSAS patients participated in this study. For all subjects their maximum forced inspiratory flow (FIF(25-75)) curve was measured in seven positions as follows: a) 0% jaw forward-upright position, b) 0% jaw forward-supine position, c) 50% jaw forward-supine position, d) 75% jaw forward-supine position, e) 0% jaw forward-lateral position, f) 50% jaw forward-lateral position, and g) 75% jaw forward-lateral position. Although FIF(25-75) was increased by changing the body posture from supine to lateral in normal subjects, it was not increased by increasing the jaw forward position of them. On the other hand, the more forward the jaw position, the more FIF(25-75) increased in OSAS patients. However, it was not increased by changing the body posture of them. There were no significant differences between the 50% forward and 75% forward jaw positions in both groups. In normal subjects, change of jaw position was more effective than that of body posture for FIF(25-75). However, in OSAS patients, change of body posture was more effective than that of jaw position for FIF(25-75). It was suggested that the treatment effect in the 50% forward position was similar to that in the 75% forward position.


Ru-porphyrin protein scaffolds for sensing O2.
Hemoprotein-based scaffolds containing phosphorescent ruthenium(II) CO mesoporphyrin IX (RuMP) are reported here for oxygen (O(2)) sensing in biological contexts. RuMP was incorporated into the protein scaffolds during protein expression utilizing a novel method that we have described previously. A high-resolution (2.00 A) crystal structure revealed that the unnatural porphyrin binds to the proteins in a manner similar to the native heme and does not perturb the protein fold. The protein scaffolds were found to provide unique coordination environments for RuMP and modulate the porphyrin emission properties. Emission lifetime measurements demonstrate a linear O(2) response within the physiological range and precision comparable to commercial O(2) sensors. The RuMP proteins are robust, readily modifiable platforms and display promising O(2) sensing properties for future in vivo applications.


[A case of superficial primary malignant melanoma of the esophagus].
A 71-year-old man who was being followed-up for esophagus melanosis in the middle thoracic esophagus for 2 years was found to have a black semipedunculated tumor at the same site. Radical subtotal esophagectomy with 2-field lymph node dissection was performed. Histopathological examination indicated a malignant melanoma (pT1b [SM1], N0, Stage I). Adjuvant chemotherapy with DAC-tam (dacarbazine, nimustine, cisplatin, and tamoxifen) was administrated for a diagnosis of primary cutaneous malignant melanoma. After 2 courses of chemotherapy, no recurrence was observed for 10 months. Combined radical surgery with lymph node dissection and systemic chemotherapy is recommended for primary malignant melanoma of the esophagus with submucosal tumor invasion. This treatment is necessary because of the risk of high local recurrence and distant metastasis based on the malignant potential predicted by histopathological examination.


First report of Epicoccum nigrum causing leaf spots on Campomanesia guazumifolia (Camb.) Berg in Brazil.
Campomanesia guazumifolia is a native tree that produces fruit that can be consumed fresh or used by industry (Donadio et al., 2002). In February 2022, in the experimental area of the Universidade Tecnológica Federal do Paraná - Brazil, disease was observed in 22 trees, with 50% to 80% severity in crown leaves. Symptoms were small, irregular, or circular-shaped, dark-brown lesions with yellow halos (Figure S1). As the disease progressed, the lesions increased in size, without distinction between mature and young tissues, causing complete leaf wilting. Twenty symptomatic leaves from 11 trees grown in the same orchard line were collected. For fungal isolation, the leaf surfaces were disinfected with 0.5% NaOCl solution for 1 min, rinsed in sterile distilled water, and dried on sterile filter paper. Five fragments of diseased leaf tissue were placed on a potato dextrose agar medium. The morphological characteristics of the colony, such as filamentous mycelium and golden yellow on the upper part, with the presence of circular to ovoid and multicellular conidia (mean 21.00 µm x 24.45 µm, n = 30) of the nine isolates, coincided with the description of the fungus of the genus Epicoccum (Valenzuela-Lopez et al., 2018). Further identification of one of these nine isolates was confirmed by amplifying and sequencing three loci (ITS, β-tubulin, and RPB2) using the ITS1/ITS4, Bt2a/Bt2b, and 5F2/7cR primer pairs, respectively (White et al., 1990, Glass and Donaldson, 1995, O'Donnell et al., 2007). A single representative isolate (Cgen01) was analyzed and submitted to GenBank (OR020968, OR079879, and OR079878). The Bayesian Inference was used to reconstruct the phylogenetic trees (Figure S2), starting from random trees for 5,000,000 generations, using MrBayes v. 3.2.1 (Ronquist et al., 2012). The isolate clustered together with the isolate of Epicoccum nigrum (Chen et al., 2017) with a high posterior probability (0.98). For the pathogenicity tests, four young, healthy branches containing 20 leaves were spray-inoculated with 1.5 mL of conidia suspension of Cgen01 (106 conidia mL-1), covered with perforated transparent plastic bags, and moistened with distilled water in the orchard. The air temperature ranged from 14ºC to 25ºC. Sterile distilled water was used as a control. Three replicates (pathogen and control) on different trees were evaluated. After five days, the fungus was re-isolated from the symptomatic lesion, showing morphological characteristics similar to those of Cgen01. Control branches did not show fungal growth. The inoculation test was conducted twice and similar symptoms were observed. This is the first report of leaf spots caused by E. nigrum on C. guazumifolia in Brazil. E. nigrum, an endophytic fungus described as a mycoparasite, showed phytopathogenic behavior in this study, causing spots and loss of leaves in C. guazumifolia, drastically reducing the production of photoassimilates and affecting the quality of the fruits.


Effect of antitumor drugs in low concentrationson the biological, immunophenotypic and cytogenetic characteristics of human colon cancer cells in vitro.
To estimate the impact of the low-dose anticancer drugs (ACD) with the different mechanisms of action and human interferon (IFN) alpha 2b on the biological properties, immunophenotypic and cytogenetic characteristics of colon cancer cells in vitro. The study was performed on human colon cancer cell lines COLO 205, HT-29 and 3C-P treated with ACD and IFN in subtoxic concentrations. Expression of CD44, N-cadherin, vimentin, β-catenin, ERCC1 and Slug was assessed by immunocytochemical method. Using cytogenetic analysis, the numbers of mitoses, cells with micronuclei, apoptotic cells and cells with nuclear protrusions were studied. The prolonged exposure (up to 30 days) of colon cancer cells to low-dose ACD (0.2-0.5 µg/ml cisplatin and 0.1-0.2 µg/ml irinotecan) in combination with IFN (500-1000 IU/ml) led to 37-fold decreased colony-forming activity of these cell and 10-fold reduction of the number of cells expressing mesenchymal protein markers (N-cadherin, vimentin). Also, in COLO 205 cells treated with ACD and IFN the number of SLUG- and CD44-positive cells decreased by 92 and by 85%, respectively. Long-term cultivation of HT-29 cells in the presence of cisplatin and IFN resulted in 5-fold suppression of ERCC1 expression. The cytogenetic analysis has shown that the ACD, IFN and their combinations in subtoxic concentrations caused significant genotoxic effect, suppression of cell proliferation and accumulation of cells with micronuclei. The sensitivity of colon cancer cells to ACD in standard cytotoxic concentrations did not change after prolonged low-dose exposure. The data showed that the prolonged action of the low doses of ACD on human colon cancer cells resulted in the suppression of cell proliferation, colony-forming activity in soft agar, expression of epithelial-mesenchymal transition-associated markers and significant cytogenetic changes.


Evaluation of chiral separation based on bovine serum albumin-conjugated carbon nanotubes as stationary phase in capillary electrochromatography.
In this work, we utilized adsorbed BSA and multiwalled carbon nanoparticles (BSA/MWCNTs) as a stationary phase in open tubular (OT) capillary for separation of chiral drugs. (3-Aminopropyl)triethoxysilane was used to assist fabrication of BSA/MWCNTs-coated OT column by covalent bonding. Incorporation of MWCNTs nanomaterials into a polymer matrix could increase the phase ratio and take advantage of the easy preparation of an open tubular CEC column. SEM was carried out to characterize the BSA/MWCNTs OT columns. The electrochromatographic performance of the OT columns was evaluated by separation of ketoprofen, ibuprofen, uniconazole, and hesperidin. The effects of MWCNTs concentration, background solution pH and concentration, and applied voltage on separation were investigated. Chiral separations of ketoprofen, ibuprofen, uniconazole, and hesperidin were achieved using the BSA/MWCNTs-coated OT column with resolutions of 24.20, 12.81, 1.50, and 1.85, respectively. Their optimas were found in the 30 mM phosphate buffers at pH 5.0, 6.5, 7.0, and 6.5, respectively. In addition, the columns demonstrated good repeatability and stability with the run-to-run, day-to-day, and batch-to-batch RSDs of migration times less than 3.5%.


High-resolution structures of two complexes between thrombin and thrombin-binding aptamer shed light on the role of cations in the aptamer inhibitory activity.
The G-quadruplex architecture is a peculiar structure adopted by guanine-rich oligonucleotidic sequences, and, in particular, by several aptamers, including the thrombin-binding aptamer (TBA) that has the highest inhibitory activity against human α-thrombin. A crucial role in determining structure, stability and biological properties of G-quadruplexes is played by ions. In the case of TBA, K(+) ions cause an enhancement of the aptamer clotting inhibitory activity. A detailed picture of the interactions of TBA with the protein and with the ions is still lacking, despite the importance of this aptamer in biomedical field for detection and inhibition of α-thrombin. Here, we fill this gap by presenting a high-resolution crystallographic structural characterization of the thrombin-TBA complex formed in the presence of Na(+) or K(+) and a circular dichroism study of the structural stability of the aptamer both free and complexed with α-thrombin, in the presence of the two ionic species. The results indicate that the different effects exerted by Na(+) and K(+) on the inhibitory activity of TBA are related to a subtle perturbation of a few key interactions at the protein-aptamer interface. The present data, in combination with those previously obtained on the complex between α-thrombin and a modified aptamer, may allow the design of new TBA variants with a pharmacological performance enhancement.


Separation anxiety: at the neurobiological crossroads of adaptation and illness.
Physiological and adaptive separation anxiety (SA) is intimately connected with the evolutionary emergence of new brain structures specific of paleomammalians, the growth of neomammalian--and later hominid--brain and skull size, and the appearance of bipedalism. All these evolutionary milestones have contributed to expanding the behavioral repertoire and plasticity of prehuman and human beings, at the cost of more prolonged dependency of the infant and of the child on parental care. Separation anxiety disorder (SAD) can be seen as an exaggerated/inappropriate manifestation of SA that constitutes a gateway to poorer mental and physical health. By blending epidemiological, genetic-epidemiological, endophenotypic, and animal laboratory approaches, it is possible to delineate some of the mechanisms that link childhood-adolescence SA and SAD to health problems later in life. Causal mechanisms include gene-environment interplays and likely differential regulation of genes and functional net-works that simultaneously affect multiple behavioral and physical phenotypes after exposure to early-life adversity, including parental separation/loss.


Nucleic Acid-Gated Covalent Organic Frameworks for Cancer-Specific Imaging and Drug Release.
Developing nanoplatforms that simultaneously integrate diagnostic imaging and therapy functions has been a promising but challenging task for cancer theranostics. Herein, we report the rational design of a smart nucleic acid-gated covalent organic framework (COF) nanosystem for cancer-specific imaging and microenvironment-responsive drug release. Cy5 dye-labeled single-stranded DNA (ssDNA) for mRNA recognition was adsorbed on the surface of doxorubicin (Dox)-loaded COF nanoparticles (NPs). Dox loaded in the pores of COF NPs could strengthen the interactions between ssDNA and COF and enhance the fluorescence quenching effect toward Cy5, while the densely coated ssDNA could prevent the leakage of Dox from COF NPs. The obtained nanosystem exhibited low fluorescence signal and Dox release in normal cells; however, the ssDNA could be released by the overexpressed TK1 mRNA in cancer cells to recover the intense fluorescence signal of Cy5, and the loaded Dox could be further released for chemotherapy. Therefore, cancer cell-specific diagnostic imaging and drug release were realized with the rationally developed nanosystem. This work offers a universal nanoplatform for cancer theranostics and a promising strategy for regulating the interaction between COFs and biomolecules.


The word "bioethics": the struggle over its earliest meanings.
An article by Warren Reich in the December 1994 issue of this journal concludes that the word "bioethics" and the field of study it names experienced a "bilocated birth" in 1970/1971 under Van Rensselaer Potter, at the University of Wisconsin, and André Hellegers, at Georgetown University. Further historical inquiry confirms (1) that there were, from the start, some major differences -- even clashes -- between the Potter and the Hellegers/Georgetown understandings of bioethics; and (2) that the Hellegers/Georgetown approach came to be the more widely accepted meaning of the term, while Potter's idea of bioethics remained largely marginalized. However, this inquiry also results in a third, unanticipated, conclusion: that Hellegers (in contrast to the dominant model offered by the Georgetown scholars) actually proposed a global approach to bioethics, bringing his vision much closer to Potter's evolving view than previously has been acknowledged.


Kondo effect in electromigrated gold break junctions.
We present gate-dependent transport measurements of Kondo impurities in bare gold break junctions, generated with high yield using an electromigration process that is actively controlled. Thirty percent of measured devices show zero-bias conductance peaks. Temperature dependence suggests Kondo temperatures approximately 7 K. The peak splitting in magnetic field is consistent with theoretical predictions for g = 2, though in many devices the splitting is offset from 2g mu(B)B by a fixed energy. The Kondo resonances observed here may be due to atomic-scale metallic grains formed during electromigration.


Passive kinematics and laxity of prosthetic knees and intact knees as measured by a novel computer-assisted system.
A system was developed for recording and analyzing passive kinematics and laxity of intact and operated knees using contemporary infrared surgical navigation hardware with custom-written data analysis software. Initial results are presented, suggesting that intra- and interobserver laxity assessment and kinematic behavior with the knee intact vs arthrotomy performed are repeatable. Normal and diseased knees have distinct kinematic and laxity behaviors, but, because of the laxity of the quadriceps in this study, additional data are needed before generalizations can be made.


Patient-Reported Treatment Experience with Oral Rivaroxaban: Results from the Noninterventional XALIA Study of Deep-Vein Thrombosis.
For venous thromboembolism (VTE) treatment, patient satisfaction was shown to improve with rivaroxaban versus standard anticoagulation in the phase III EINSTEIN DVT and EINSTEIN PE trials. This substudy of the prospective, noninterventional XALIA study of rivaroxaban for deep-vein thrombosis treatment assessed if this was also observed in routine clinical practice. Patients enrolled in XALIA who received rivaroxaban or standard anticoagulation treatment were eligible for inclusion in this substudy. Treatment decisions were at the physician's discretion. Patients completed the 17-item Anti-Clot Treatment Scale (ACTS, comprising a 12-item Burdens subscale, a 3-item Benefits subscale and one global item per subscale) during follow-up. The propensity score-matched set (PMS) was used for the main analysis; the adjusted safety analysis (ASAF) set was used for confirmatory purposes. Analyses by follow-up visit and subgroup, including age, sex, and previous VTE, were also conducted. The PMS-ACTS analysis included 458 rivaroxaban-treated and 434 standard anticoagulation-treated patients. Baseline demographic and clinical characteristics were generally similar across treatment arms. ACTS Burdens scores significantly improved with rivaroxaban versus standard anticoagulation (least-squares mean difference of 2.4 ± 0.4 points; p < 0.0001); ACTS Benefits scores were numerically higher with rivaroxaban (least-squares mean difference of 0.2 ± 0.1 points; p = 0.2). Similar findings occurred across follow-up visits and subgroups. Results were confirmed in the ASAF-ACTS analysis. Consistent with phase III analyses, rivaroxaban was associated with improved ACTS Burdens scores; ACTS Benefits scores numerically favored rivaroxaban, although without reaching statistical significance.


Transformation of sensory organ identity by ectopic expression of Cut in Drosophila.
The loss of cut activity results in a change in neural identity in the peripheral nervous system so that the neurons and support cells of external sensory (es) organs are transformed into those of internal chordotonal (ch) organs, cut encodes a large nuclear homeo domain protein (Cut) that is expressed in the differentiated cells of es organs and their precursors but not in the cells of ch organs. We now analyze the effects of ectopic Cut expression in transformant lines of flies containing the Cut-coding sequences under inducible regulatory control. We demonstrate that ubiquitous Cut expression in embryos results specifically in the morphologic and antigenic transformation of ch organs into es organs. This effect appears to involve positive autoregulation of Cut expression. We conclude that Cut is not only necessary but sufficient for the specification of es organ identify in sensory organ precursor cells and their progeny. The specificity of Cut function to sensory organ cells involves the proneural loci daughterless and the achaete-scute complex.


Imaging mass spectrometry demonstrates age-related decline in human adipose plasticity.
Quantification of stable isotope tracers has revealed the dynamic state of living tissues. A new form of imaging mass spectrometry quantifies isotope ratios in domains much smaller than a cubic micron, enabling measurement of cell turnover and metabolism with stable isotope tracers at the single-cell level with a methodology we refer to as multi-isotope imaging mass spectrometry. In a first-in-human study, we utilize stable isotope tracers of DNA synthesis and de novo lipogenesis to prospectively measure cell birth and adipocyte lipid turnover. In a study of healthy adults, we elucidate an age-dependent decline in new adipocyte generation and adipocyte lipid turnover. A linear regression model suggests that the aging effect could be mediated by a decline in insulin-like growth factor-1 (IGF-1). This study therefore establishes a method for measurement of cell turnover and metabolism in humans with subcellular resolution while implicating the growth hormone/IGF-1 axis in adipose tissue aging.


Effect of parameter mismatch on the synchronization of chaotic semiconductor lasers with electro-optical feedback.
We investigate the detrimental effects of parameter mismatch on the synchronization of semiconductor lasers with electro-optical feedback, whose intensity dynamics can display a hyperchaotic behavior. Analytical techniques are developed to study the statistical properties of the synchronization error as a function of the various types of mismatches. The multiple mismatch case, which is of high experimental interest, is also studied and some compensation conditions allowing the improvement of the synchronization are derived. The analytical predictions are confirmed by numerical simulations and by some experimental measurements.


The Indirect Effect of Perceived Criticism on Suicide Ideation and Attempts.
The effect of perceived criticism from others is one potentially important risk factor for suicide that has received scant attention, despite decades of research on the role of criticism in the treatment and course of mental illnesses such as schizophrenia and mood disorders. This study analyzed the effect of perceived criticism's association with suicidal ideation and attempts as well as its connection with the suicide related constructs thwarted belongingness and perceived burdensomeness as described in the Interpersonal Theory of Suicide. Fifty participants (66% female, MAge = 18.7), 18 of whom had previously made one or more suicide attempts, completed a battery of self-report assessments as well as two in-person, structured clinical interviews. Analyses demonstrated that perceived parental criticism is a significant indicator of suicide ideation (β = .297, p = .003) and attempts (β = .373, p < .001) and that perceived criticism from close friends is a significant indicator of suicide attempts (β = .297, p = .006). Perceived criticism has a strong indirect effect on suicide ideation and attempts through its effect on thwarted belongingness, but not perceived burdensomeness, while controlling for mental illnesses. Some limitations of this study include the cross-sectional design and the use of a relatively small, restricted age sample. Treatment designed to mitigate perceived criticism and thwarted belongingness may be an important component in combatting suicidal ideation and attempts, particularly among young adults.


Genetic association analysis highlights new loci that modulate hematological trait variation in Caucasians and African Americans.
Red blood cell, white blood cell, and platelet measures, including their count, sub-type and volume, are important diagnostic and prognostic clinical parameters for several human diseases. To identify novel loci associated with hematological traits, and compare the architecture of these phenotypes between ethnic groups, the CARe Project genotyped 49,094 single nucleotide polymorphisms (SNPs) that capture variation in ~2,100 candidate genes in DNA of 23,439 Caucasians and 7,112 African Americans from five population-based cohorts. We found strong novel associations between erythrocyte phenotypes and the glucose-6 phosphate dehydrogenase (G6PD) A-allele in African Americans (rs1050828, P<2.0×10(-13), T-allele associated with lower red blood cell count, hemoglobin, and hematocrit, and higher mean corpuscular volume), and between platelet count and a SNP at the tropomyosin-4 (TPM4) locus (rs8109288, P=3.0×10(-7) in Caucasians; P=3.0×10(-7) in African Americans, T-allele associated with lower platelet count). We strongly replicated many genetic associations to blood cell phenotypes previously established in Caucasians. A common variant of the α-globin (HBA2-HBA1) locus was associated with red blood cell traits in African Americans, but not in Caucasians (rs1211375, P<7×10(-8), A-allele associated with lower hemoglobin, mean corpuscular hemoglobin, and mean corpuscular volume). Our results show similarities but also differences in the genetic regulation of hematological traits in European- and African-derived populations, and highlight the role of natural selection in shaping these differences.


Effects of dietary oxidized oil on laying performance, lipid metabolism, and apolipoprotein gene expression in laying hens.
We studied the effects of dietary oxidized oils on serum lipid metabolic indices, estradiol level, and the gene expression of apolipoprotein B-100 and apolipoprotein VLDL-II in laying hens. Hy-Line Grey hens (280 ± 10 d old; average egg production, 90.0 ± 2.5%) were allotted to 1 of 4 dietary treatments, which were supplemented with 0 (control group), 1% (low oxidized group), 2% (moderately oxidized group), or 4% (highly oxidized group) thermally oxidized soybean oil. Each treatment contained 6 replicates, with 12 birds each. The feeding trial lasted for 30 d. Laying performance data were recorded weekly. Other indices were measured on d 0, 2, 6, 14, and 30 of the feeding trial. Hens in the moderately and highly oxidized groups had significantly lowered feed conversion ratios (P < 0.05). Those in the highly oxidized group also had decreased concentrations of serum very low density lipoprotein cholesterol on d 30 (P < 0.05) compared with the very low density lipoprotein cholesterol of hens in the moderately oxidized group. Hens in the moderately oxidized group had significantly increased expression of apolipoprotein B-100 (P < 0.05) from d 6 to 30. Consequently, hepatic triglyceride increased in this group on d 30 (P < 0.05). Serum triglyceride decreased in the moderately oxidized group on d 30 (P < 0.05), which may have been caused by the activation of peroxisome proliferator-activating receptor α. Serum estradiol levels were not significantly affected by oxidized oils at any time of measurement, but were significantly different between d 0 and 30 within the moderately oxidized group. This fact indicated that the effect of oxidized oils on apolipoprotein B-100 might partially be a cumulative result of the increasing secretion of estradiol. The results suggested that oxidized oil may affect the performance of laying hens through the regulation of apolipoproteins and estradiol.


The soft agar colony formation assay.
Anchorage-independent growth is the ability of transformed cells to grow independently of a solid surface, and is a hallmark of carcinogenesis. The soft agar colony formation assay is a well-established method for characterizing this capability in vitro and is considered to be one of the most stringent tests for malignant transformation in cells. This assay also allows for semi-quantitative evaluation of this capability in response to various treatment conditions. Here, we will demonstrate the soft agar colony formation assay using a murine lung carcinoma cell line, CMT167, to demonstrate the tumor suppressive effects of two members of the Wnt signaling pathway, Wnt7A and Frizzled-9 (Fzd-9). Concurrent overexpression of Wnt7a and Fzd-9 caused an inhibition of colony formation in CMT167 cells. This shows that expression of Wnt7a ligand and its Frizzled-9 receptor is sufficient to suppress tumor growth in a murine lung carcinoma model.


Molecular dissection of hippocampal theta-burst pairing potentiation.
Long-term potentiation (LTP) of synaptic efficacy in the hippocampus is frequently induced by tetanic stimulation of presynaptic afferents or by pairing low frequency stimulation with postsynaptic depolarization. Adult (P42) GluR-A(-/-) mice largely lack these forms of LTP. LTP in wt mice can also be induced by coincident pre- and postsynaptic action potentials, where an initial rapid component is expressed but a substantial fraction of the potentiation develops with a delayed time course. We report here that this stimulation protocol, delivered at theta frequency (5 Hz), induces LTP in GluR-A(-/-) mice in which the initial component is substantially reduced. The remaining GluR-A independent component differs from the initial component in that its expression develops over time after induction and its induction is differentially dependent on postsynaptic intracellular Ca(2+) buffering. Thus, in adult mice, theta-burst pairing evokes two forms of synaptic potentiation that are induced simultaneously but whose expression levels vary inversely with time. The two components of synaptic potentiation could be relevant for different forms of information storage that are dependent on hippocampal synaptic transmission such as spatial reference and working memory.


No-reference panoramic image quality assessment based on multi-region adjacent pixels correlation.
The distortion measurement plays an important role in panoramic image processing. Most measurement algorithms judge the panoramic image quality by means of weighting the quality of the local areas. However, such a calculation fails to globally reflect the quality of the panoramic image. Therefore, the multi-region adjacent pixels correlation (MRAPC) is proposed as the efficient feature for no-reference panoramic images quality assessment in this paper. Specifically, from the perspective of the statistical characteristics, the differences of the adjacent pixels in panoramic image are proved to be highly related to the degree of distortion and independent of image content. Besides, the difference map has limited pixel value range, which can improve the efficiency of quality assessment. Based on these advantages, the proposed MRAPC feature collaborates with the support vector regression to globally predict the quality of panoramic images. Extensive experimental results show that the proposed no-reference panoramic image quality assessment algorithm achieves higher evaluation performance than the existing algorithms.


Serum levels of neopterin in patients with lichen planus.
Lichen planus (LP) is a chronic dermatosis whose clinical features include mildly erythematous to violaceous flat-topped, polygonal papules. The etiology of lichen planus is unknown, but it has been postulated that immune mechanism is important. Although it is of importance to monitor the course of immune-mediated diseases, there is a limited number of reliable biomarkers which can be used for lichen planus. Neopterin (NP), a 2-amino-4-hydroxy-(1'2'3'-trihydroxypropyl)-pteridine, is secreted by monocytes and macrophages, mainly as a response to INF-gamma secretion by activated T-lymphocytes. Therefore NP may be a sensitive marker of T-cell mediated immunity. The aim of the presented study was to assess the serum levels of neopterin in patients with lichen planus and to investigate whether serum neopterin levels reflect extensive lesions and progression of this disease. We studied 66 patients with lichen planus who were classified into one of two diagnostic groups: Group I comprised 33 patients with generalized lesions; group II comprised 33 patients with circumscribed lesions. The control group consisted of 30 healthy sex- and age-matched individuals. The serum neopterin concentrations were measured with a commercially available enzyme-linked immunosorbent assay kit. The results of our study are summarized in Table 1. In our study, the serum neopterin levels in the patients with lichen planus classified to group I (9.12 +/- 4.39 ng/mL) and group II (3.80 +/- 0.68 ng/mL) as well as in the whole collection of patients (group I and group II; 6.55 +/- 2.30 ng/mL) were significantly higher than those of the control subjects (2.55 +/- 0.34 ng/mL). Our findings confirm a role for enhanced cellular immunity as well as macrophages activation observed in lichen planus. It seems to us that evaluation of serum neopterin levels, despite the relatively low specificity, reflects extensive lesions and lichen planus progression.


Extreme resilience in cochleate nanoparticles.
Cochleates, prospective nanoscale drug delivery vehicles, are rolls of negatively charged phospholipid membrane layers. The membrane layers are held together by calcium ions; however, neither the magnitude of membrane interaction forces nor the overall mechanical properties of cochleates have been known. Here, we manipulated individual nanoparticles with atomic force microscopy to characterize their nanomechanical behavior. Their stiffness (4.2-12.5 N/m) and membrane-rupture forces (45.3-278 nN) are orders of magnitude greater than those of the tough viral nanoshells. Even though the fundamental building material of cochleates is a fluid membrane, the combination of supramolecular geometry, the cross-linking action of calcium, and the tight packing of the ions apparently lead to extreme mechanical resilience. The supramolecular design of cochleates may provide efficient protection for encapsulated materials and give clues to understanding biomolecular structures of similar design, such as the myelinated axon.


Tinzaparin: new indication. Easier treatment of less severe pulmonary embolism.
(1) The standard first-line antithrombotic treatment for pulmonary embolism in patients without cardiovascular shock or marked hypotension is intravenous infusion of unfractionated heparin for a few days, followed by several months of oral anticoagulation. (2) In France, tinzaparin is the first low-molecular-weight heparin (LMWH) to be licensed specifically for treating pulmonary embolism (one subcutaneous injection daily). (3) The clinical file mainly comprises data from a comparative unblinded trial versus unfractionated heparin in 612 patients, which shows tinzaparin to have no advantage in terms of overall mortality or the incidence of bleeding. A trial comparing unfractionated heparin with another LMWH, reviparin, gave similar results. (4) In practice, tinzaparin offers the advantage over unfractionated heparin of not requiring intravenous administration. For the least severely ill patients, tinzaparin is an advance. Close laboratory monitoring of clotting factors is warranted for elderly and obese patients, and those with renal impairment. For other patients, intravenous infusion of unfractionated heparin remains the standard treatment for pulmonary embolism.


A single particle model to simulate the dynamics of entangled polymer melts.
We present a computer simulation model of polymer melts representing each chain as one single particle. Besides the position coordinate of each particle, we introduce a parameter n(ij) for each pair of particles i and j within a specified distance from each other. These numbers, called entanglement numbers, describe the deviation of the system of ignored coordinates from its equilibrium state for the given configuration of the centers of mass of the polymers. The deviations of the entanglement numbers from their equilibrium values give rise to transient forces, which, together with the conservative forces derived from the potential of mean force, govern the displacements of the particles. We have applied our model to a melt of C(800)H(1602) chains at 450 K and have found good agreement with experiments and more detailed simulations. Properties addressed in this paper are radial distribution functions, dynamic structure factors, and linear as well as nonlinear rheological properties.


Value-of-information analysis to reduce decision uncertainty associated with the choice of thromboprophylaxis after total hip replacement in the Irish healthcare setting.
The National Centre for Pharmacoeconomics, in collaboration with the Health Services Executive, considers the cost effectiveness of all new medicines introduced into Ireland. Health Technology Assessments (HTAs) are conducted in accordance with the existing agreed Irish HTA guidelines. These guidelines do not specify a formal analysis of value of information (VOI). The aim of this study was to demonstrate the benefits of using VOI analysis in decreasing decision uncertainty and to examine the viability of applying these techniques as part of the formal HTA process for reimbursement purposes within the Irish healthcare system. The evaluation was conducted from the Irish health payer perspective. A lifetime model evaluated the cost effectiveness of rivaroxaban, dabigatran etexilate and enoxaparin sodium for the prophylaxis of venous thromboembolism after total hip replacement. The expected value of perfect information (EVPI) was determined directly from the probabilistic analysis (PSA). Population-level EVPI (PEVPI) was determined by scaling up the EVPI according to the decision incidence. The expected value of perfect parameter information (EVPPI) was calculated for the three model parameter subsets: probabilities, preference weights and direct medical costs. In the base-case analysis, rivaroxaban dominated both dabigatran etexilate and enoxaparin sodium. PSA indicated that rivaroxaban had the highest probability of being the most cost-effective strategy over a threshold range of &U20AC;0-&U20AC;100 000 per QALY. At a threshold of &U20AC;45 000 per QALY, the probability that rivaroxaban was the most cost-effective strategy was 67%. At a threshold of &U20AC;45 000 per QALY, assuming a 10-year decision time horizon, the PEVPI was &U20AC;11.96 million and the direct medical costs subset had the highest EVPPI value (&U20AC;9.00 million at a population level). In order to decrease uncertainty, a more detailed costing study was undertaken. In the subsequent analysis, rivaroxaban continued to dominate both comparators. In the PSA, rivaroxaban continued to have the highest probability of being optimal over the threshold range &U20AC;0-&U20AC;100 000 per QALY. At &U20AC;45 000 per QALY, the probability that rivaroxaban was the most cost-effective strategy increased to 80%. At &U20AC;45 000 per QALY, the 10-year PEVPI decreased to &U20AC;3.58 million and the population value associated with the direct medical costs fell to &U20AC;1.72 million. This increase in probability of cost effectiveness, coupled with a substantially reduced potential opportunity loss could influence a decision maker's confidence in making a reimbursement decision. On discussions with the decision maker we now intend to incorporate the use of VOI into our HTA process.


Augmentation of NK cell activity by a circulating peptide isolated from the plasma of trauma patients.
Natural killer cell (NK) activity was assessed in patients with nonthermal injury. NK activity was assessed employing a standard 4-hour 51Cr release. Peripheral mononuclear cells from healthy human donors and trauma ward patients served as effector cells at three effector/target ratios. Labeled K562 erythroleukemia cells were used as targets. Multiple dilutions of crude and purified proteolysis inducing factor (PIF), isolated from three septic patients, were evaluated in comparison with other adjuvants. Greater augmentation of anti-K562 activity was obtained in long-term pretreatment of effector cells with adjuvants present as opposed to immediate NK assay. Untreated effectors from trauma patients demonstrated the least amount of baseline NK activity; however, a combination of PIF and interferon showed the greatest cytotoxicity. Untreated healthy cells exhibited a significant (p less than 0.001), twofold greater amount of cytotoxicity than untreated trauma cells. PIF enhances NK activity and may be key to mobilization of host defense in trauma.


From cellular to chemical approach for acute neural and alternative options for age-induced functional diseases.
Endogenous "stem cell niche" (SCN) accompanying vessels contains immune system components which in vivo determine differentiation of multi potent stem cells toward proper cell types in given tissue. Combinations of sex steroids may represent novel chemical approach for neuronal areas of regenerative medicine, since they cause transformation of vascular smooth muscle stem cells into differentiating neuronal cells. Circulating sex steroids are present during pregnancy and can be utilized where needed, when various embryonic/fetal tissues develop from their stem cells. Utilization of induced regeneration of tissues (regenerative medicine) is expected being more effective in sudden failures of younger individuals carrying intact SCN, as compared to established chronic disorders caused by SCN alteration. An essential component of SCN are monocyte-derived cells exhibiting tissue-specific "stop effect" (SE) preventing, for instance, an aging of neuronal cells. Its alteration causes that implantation of neuronal stem cells will also result in their differentiation toward aging cells. When we repair the SE by supply of circulating mononuclear cells from young healthy individuals, we may be able to provide novel regenerative treatments of age-induced neural diseases by sex steroid combinations. Questions regarding some age-induced body alterations are also addressed.


Driver sleepiness and risk of serious injury to car occupants: population based case control study.
To estimate the contribution of driver sleepiness to the causes of car crash injuries. Population based case control study. Auckland region of New Zealand, April 1998 to July 1999. 571 car drivers involved in crashes where at least one occupant was admitted to hospital or killed ("injury crash"); 588 car drivers recruited while driving on public roads (controls), representative of all time spent driving in the study region during the study period. Relative risk for injury crash associated with driver characteristics related to sleep, and the population attributable risk for driver sleepiness. There was a strong association between measures of acute sleepiness and the risk of an injury crash. After adjustment for major confounders significantly increased risk was associated with drivers who identified themselves as sleepy (Stanford sleepiness score 4-7 v 1-3; odds ratio 8.2, 95% confidence interval 3.4 to 19.7); with drivers who reported five hours or less of sleep in the previous 24 hours compared with more than five hours (2.7, 1.4 to 5.4); and with driving between 2 am and 5 am compared with other times of day (5.6, 1.4 to 22.7). No increase in risk was associated with measures of chronic sleepiness. The population attributable risk for driving with one or more of the acute sleepiness risk factors was 19% (15% to 25%). Acute sleepiness in car drivers significantly increases the risk of a crash in which a car occupant is injured or killed. Reductions in road traffic injuries may be achieved if fewer people drive when they are sleepy or have been deprived of sleep or drive between 2 am and 5 am.


Protein Labeling Facilitates the Understanding of Protein Corona Formation via Fluorescence Resonance Energy Transfer and Fluorescence Correlation Spectroscopy.
Once nanoparticles enter into the biological milieu, nanoparticle-biomacromolecule complexes, especially the protein corona, swiftly form, which cause obvious effects on the physicochemical properties of both nanoparticles and proteins. Here, the thermodynamic parameters of the interactions between water-soluble GSH-CdSe/ZnS core/shell quantum dots (GSH-QDs) and human serum albumin (HSA) were investigated with the aid of labeling fluorescence of HSA. It was proved that the labeling fluorescence originating from a fluorophore (BDP-CN for instance) could be used to investigate the interactions between QDs and HSA. Gel electrophoresis displayed that the binding ratio between HSA and QDs was ∼2:1 by direct visualization. Fluorescence resonance energy transfer (FRET) results indicated that the distance between the QDs and the fluorophore BDP-CN in HSA was 7.2 nm, which indicated that the distance from the fluorophore to the surface of the QDs was ∼4.8 nm. Fluorescence correlation spectroscopy (FCS) results showed that HSA formed a monolayer of a protein corona with a thickness of 5.5 nm. According to the spatial structure of HSA, we could speculate that the binding site of QDs was located at the side edge (not the triangular plane) of HSA with an equilateral triangular prism. The elaboration of the thermodynamic parameters, binding ratio, and interaction orientation will highly improve the fundamental understanding of the formation of protein corona. This work has guiding significance for the exploration of the interactions between proteins and nanomaterials.


Bioaerosol exposure by farm type in Korea.
Bioaerosols exist in almost every environment and are known to be risk factors for a variety of diseases. Agricultural work involves high exposure to bioaerosols and its workplace concentrations affect the surrounding areas. The study evaluates bioaerosol concentrations in agricultural workplaces and residential areas according to farm type. In 2013-2015, a total of 381 samples were collected for endotoxin and microbial testing from three farm types: open field, greenhouse, and livestock facilities. Endotoxins were measured using a 37-mm glass fire filter connected to an air pump calibrated to 2 LPM. Microorganisms were measured using a gelatin filter and impaction (single-stage Andersen sampler). The concentration of endotoxins and microorganisms at the livestock facilities was significantly higher than in the open fields and greenhouses (p<0.05). Among the livestock farms, the concentrations of endotoxins and gram-negative bacteria were highest at hog farms, and the concentrations of total bacteria and fungi were the highest in poultry houses. In both greenhouses and livestock facilities, the concentrations of bioaerosols were higher in the workplace than in a nearby residential area, and the difference in concentration was significantly greater in the case of livestock facilities. The concentrations of bioaerosols in agricultural workplaces and nearby residential areas were higher than in the control and general areas. Therefore, measures should be taken to prevent exposure to bioaerosols at agricultural workplaces and their vicinities.


Recent Developments in Metal-Catalyzed Bio-orthogonal Reactions for Biomolecule Tagging.
With the rapid advances in single-molecule and live-cell imaging studies to investigate biological problems, the role of chemical probes to monitor reactions in a live cell has considerably increased. However, selective labeling of a target protein or a specific residue is highly challenging due to the high complexity of the biological system. In particular, biological macromolecules (such as proteins, DNA, or RNA) share many functional groups that potentially cross-react with exogenous chemical probes. Thus, there are high demands for perfect biocompatible reactions utilizing biologically unavailable chemistry. Metal-catalyzed reactions have been extensively investigated as synthetic methodology studies, including initial attempts in applying the chemistry in aqueous solutions in vitro or even in biological conditions. Herein, the latest developments and progress in metal-catalyzed bio-orthogonal reactions for biomolecule labeling are summarized.


An approach to the characterization of mononuclear phagocytes involved in pathological processes.
Cells participating in an inflammatory response are derived from the bone marrow (i.e. granulocytes and monocytes) or lymphoid organes (i.e. T and B lymphocytes), or of mesenchymal origin (i.e. fibroblast, reticulum cells). The identification of these different kinds of cell in the inflammatory exudate is often difficult, because the morphological characteristics are not specific enough. For example, in the morphological description of pathological processes often terms such as round-cell infiltration and mononuclear cells are used, which is confusing. For the clear understanding of the course of an inflammatory reaction and the effect of anti-inflammatory drugs it is necessary, however, to define exactly the participating cells. Such an identification can be performed on the basis of morphological, cytochemical and immunological characteristics of the cells, together with their kinetic parameters. These characteristics have been established for murine mononuclear phagocytes. Recently these characteristics have also been studied in human promonocytes, monocytes and skin macrophages. The results show that human mononuclear phagocytes are in many respects similar to those of mice. On this basis an outline for the participation of mononuclear phagocytes in pathological processes (i.e. inflammatory processes, neoplastic processes, and storage disorders) has been made.


Occupational exposure to glycol ethers: implications for occupational health nurses.
1. Evaluation of workplace exposure to reproductive hazards is difficult and is often confounded by occupational exposure to multiple agents and exposure to non-occupational factors. 2. A growing body of evidence from animal and human study data supports a causal association between occupational exposure to certain glycol ethers and adverse reproductive outcomes. 3. Occupational health nurses providing services to employees exposed to glycol ethers should remain knowledgeable about the results of epidemiologic studies and current trends in the regulation of glycol ethers in industry. 4. Occupational health nurses are in a key position to reduce exposure to reproductive hazards by monitoring trends in group data and by implementing training and education programs to employees exposed to reproductive hazards.


Successful endovascular therapy of a penetrating zone III jugular bulb injury. A case report.
Penetrating venous injuries via Zone III of the neck extended over jugular bulb are rare. The optimal strategies for these venous injuries are currently unknown because many of the vital structures in this region are poorly accessible to the surgeon and therefore it is difficult to control bleeding. A 76-year-old man got drunk and fell down onto a paper door. The wooden framework of the paper door was broken and got stuck deep in the right side of his neck. Enhanced computed tomography showed the wood stick had penetrated through the right jugular foramen and injured the jugular bulb. We successfully performed right sigmoid and jugular vein occlusion via an endovascular approach using Guglielmi detachable coils at first and then to draw out the wood stick in order to avoid venous bleeding. To our best knowledge, these venous injuries have reported in only four cases. Only one case was performed by endovascular approach using n-butyl cyanoacrylate (NBCA). Coil embolization is much better than NBCA in the light of reducing complications due to adhesion to the inserted wood stick and embolization of unintended vessels. Venous occlusion using coil embolization is the best way to treat a penetrating jugular bulb injury via zone III because of reducing the hemorrhage and air embolism.


Arginine-containing toothpastes for dentin hypersensitivity: systematic review and meta-analysis.
Arginine-containing toothpastes are a promising new treatment for dentin hypersensitivity (DH), which afflicts a considerable number of patients. However, there have to date been only individual studies. We aim to present an overview of the clinical evidence in order to determine trends and establish firmer conclusions regarding the use of arginine-containing toothpastes for management of DH. A protocol was developed based on the Cochrane Handbook for Systematic Reviews of Interventions (version 5.1.0), including: search strategy, selection criteria, data extraction, and risk of bias assessment. We searched electronic databases (up to October 2012) without language limitation, and reference lists of relevant papers for randomized controlled trials that assessed the efficacy of arginine-containing toothpastes for DH treatment. Data extraction and domain-based risk of bias assessment were independently performed by two reviewers. The meta-analysis was performed in STATA (version 12.0). The GRADE analysis was conducted in GRADE profiler (version 3.6). Fourteen randomized controlled studies with different risk of bias were included in the meta-analysis, all evaluated by tactile and air blast assessment. The mean differences and standard deviations for each treatment group were pooled for analysis using a random-effect model. We found that arginine-containing toothpastes had better overall effects in comparison with placebo toothpastes (P < .05), potassium salt-containing toothpastes (P < .05), and strontium-containing toothpastes (P < .05). The GRADE analysis showed that quality of the evidence was moderate when arginine-containing toothpastes were compared to placebo and potassium salt-containing toothpastes, and quality of the evidence was low with comparison to strontium-containing toothpastes. Current available clinical evidence suggests that arginine-containing toothpastes are associated with the reduction of DH compared to both placebo and positive control toothpastes. However, there are limitations to the current studies, and more well-designed trials are needed to confirm the efficacy.


Effects of irradiation intensity and pH on nutrients release and solids destruction of waste activated sludge using the microwave-enhanced advanced oxidation process.
Using the microwave-enhanced advanced oxidation process (MW/H2O2-AOP), the pH and irradiation intensity on waste activated sludge samples were investigated to provide insight to the athermal effects on nutrients release, solids destruction, particle size distribution and dewaterability, and to demonstrate their interrelationships. Carbonaceous matters and nutrients released into solution depended on the irradiation intensity and time. Higher irradiation levels tended to be more effective in the solubilization of nutrients and had more pronounced effects in the dewaterability of sludge. In terms of particle size distribution, detectable particles increased in size for treatments in acidic conditions, while the dewaterability of treated sludge was improved. In treatments under neutral and alkaline conditions, the particle size range increased, with more small particles formed, thereby significantly deteriorating the dewaterability of sludge treated in alkaline conditions. The best results for the solubilization of nutrients were in alkaline conditions with high irradiation power, but dewaterability of the sludge was compromised. Sludge treatment with the MW/H2O2-AOP in acidic conditions with high irradiation power yielded the best dewaterable sludge and significant nutrient solubilization; therefore, it is the recommended treatment condition for activated sludge.


Malleus osteotomy: improving access to the anterior tympanum.
Access to the anterior tympanic cavity is often restricted by the handle of the malleus. The aim of this paper is to describe a surgical malleus osteotomy that allows the malleus handle to swing superiorly. The authors have found few problems related to this technique, especially with regard to restoration of normal post-operative hearing.


Development of bacterial plaque in the oral cavity.
Dental plaque may be defined as bacterial aggregations upon the teeth and other solid structures inserted in the oral cavity. It is formed by oral microorganisms which attach to the teeth in sheltered areas along the gingival margin, on the approximal surfaces, and in pits and fissures on the masticatory surfaces. The plaque increases in quantity either by multiplication of already attached organisms, or by continuous addition to the deposits of bacteria from the saliva. Structural analyses indicate that the organisms are held together in an exracellular matrix partly produced by the organisms and partly derived from saliva. The microflora of plaque is complex and shows great individual variation. There are also characteristic differences in plaque from different sites on the teeth. Thus dento-gingival plaque is qualitatively different from that of the occlusal fissures. Furthermore, the relative proportion of different types of microorganisms may vary with the age of the deposit. Such information must be taken in consideration when attempts are made to develop chemical agents for the purpose of inhibiting plaque formation in order to prevent periodontal disease and caries.


ISSR molecular markers and anatomical structures can assist in rapid and directional screening of cold-tolerant seedling mutants of medicinal and ornamental plant in Plumbago indica L.
Plumbago indica L. is a perennial herb with ornamental and anticancer medicinal functions widely distributed in the tropics. It is affected by temperature and cannot bloom normally in colder subtropical regions, which seriously affects its ornamental value. To create low-temperature resistance mutants and enrich new germplasm resources, this study used tissue culture and chemical reagent (0.5 mmol/L NaN3) and low-temperature stress (0°C, full darkness for 48h) induction to target and screen for cold-resistance mutants. The results showed that the ISSR band polymorphism ratio of the 24 suspected mutant materials was 87.5%. The DNA profiles of the 9 mutants initially identified were altered. The content of plumbagin in the stems and leaves of the mutants was examined, and it was found that the accumulation in the leaves of the mutant SA24 could be as high as 3.84 times that of the control, which was 0.5991%. There were significant differences in the anatomical structures of roots, stems and leaves. The mutants mostly exhibited reduced root diameter (only 0.17-0.69 times that of CK), increased stem diameter (up to 2.19 times that of CK), enlarged mesophyll cells, increased thickness (up to 1.83 times that of CK) and high specificity, which are thought to be important for the different cold resistance obtained by the mutants. In the cold resistance experiment, four cold-tolerant mutants were successfully screened according to their morphological characteristics and physiological indexes, and the mutagenesis efficiency could be as high as 2.22% and did not affect the accumulation of plumbagin in their stems and leaves, even higher than CK. The responses of the screened mutants SA15, SA19, SA23 and SA24 to low temperature showed slower leaf wilting, higher light energy conversion efficiency, less accumulation of MDA content, increased enzymatic activities of antioxidant enzymes (SOD, CAT, POD) and more accumulation of soluble sugars and proline content. These characteristics are consistent with the response of cold-resistance plants to low temperatures. The cold- resistance mutants cultivated in soil were observed of agronomic and ornamental traits for one year, mainly manifested as delayed flowering and delayed entry into the senescence stage. This study provides a more rapid and accurate technique for identifying and screening cold-tolerant mutants, and lays the foundation for future experiments on the creation of new cold-resistant varieties.


Effect of glicentin-related peptides upon the secretion of insulin and glucagon in the canine pancreas.
In order to clarify responses of the endocrine pancreas to glicentin, four glicentin-related peptides were investigated in a local circulation preparation of the canine pancreas. These peptides were administered in a dosage of 200 pmole for 10 min into the pancreaticoduodenal artery under the continuous infusion of 0.5% arginine solution. In a group of six dogs, the administration of glicentin-related pancreatic peptide (GRPP) and glicentin 1-16 resulted in an increase in plasma insulin (IRI) and a decrease in plasma glucagon (IRG). In the other group of six dogs, the administration of glicentin 62-69 induced an increase in plasma IRI and a decrease in plasma IRG. Following the successive infusion of oxyntomodulin, both plasma IRI and IRG increased slightly. Porcine glucagon administered at the end of each experiment exerted a rise in blood glucose and plasma IRI in addition to an increase in plasma IRG. In comparison of the maximal responses of plasma IRI and IRG to these glicentin-related peptides, the administration of glicentin 1-16, 62-69 or GRPP elicited an increase in plasma IRI and a decrease in plasma IRG. In contrast, oxyntomodulin and glucagon increased both plasma IRI and IRG. The present study indicates that glicentin-related peptides, both the N- and C-terminal portions, affect the endocrine function of the pancreas and suggests that glicentin released by nutrient ingestion plays an important role in the enteroinsular axis.


Predicting adolescent smoking.
Two hundred and ninety-seven seventh grade students (143 males and 154 females) participated in a prospective study to predict adolescent cigarette smoking behavior one year later. Predictor variables included 10 survey items assessing the smoking behavior of students' friends and family, students' school behavior and beliefs about smoking and students' intentions to smoke in the future. The one-year follow-up survey was administered under "bogus pipeline" conditions to enhance the validity of self-reported smoking status by including the collection of saliva thiocyanate samples. Univariate analyses indicated that smokers differed from nonsmokers on a number of measures and that there were few sex differences on either the survey variables or on smoking status. Stepwise discriminant function analyses revealed that it was possible to accurately predict the onset of adolescent cigarette smoking by combining the survey variables. The three variables that consistently accounted for the greatest proportion of te variance were number of friends who smoke, intentions to smoke in the future and percent of older siblings who smoke. The implications of this work for programs intended to prevent adolescent smoking are discussed.


Hepatitis C virus-related proteins in kidney tissue from hepatitis C virus-infected patients with cryoglobulinemic membranoproliferative glomerulonephritis.
Membranoproliferative glomerulonephritis (MPGN) may be a component of a generalized vasculitis as well as a component of the clinical expression of type-II mixed cryoglobulinemia (MC). Several studies have established a striking association between hepatitis C virus (HCV) infection and MC. The potential role of HCV in the pathogenesis of MPGN, which occurs in almost half of the cases of MC patients, has not been fully investigated, and the demonstration of HCV proteins as the antigenic constituent of the glomerular immune deposits has remained elusive. Kidney biopsy specimens were obtained from 12 HCV RNA, antibody to HCV (anti-HCV)-positive patients with MPGN and type-II MC, and from 8 controls (3 HCV RNA, anti-HCV-negative patients with MPGN and MC and 5 with noncryoglobulinemic "idiopathic" MPGN). Murine monoclonal antibodies developed against c22-3, E2/NS1, c33c, c100-3, and NS5 proteins were used to detect HCV-related antigens by indirect immunohistochemistry. Acid electroelution of tissue sections was performed to enhance the sensitivity of the immunohistochemical method. Specific HCV-related proteins were detected in glomerular and tubulo-interstitial vascular structures in 8 (66.7%) HCV-positive MC patients and in none of the HCV RNA, anti-HCV-negative controls. HCV immunoreactive deposits displayed the following two major patterns: 1) a linear, homogeneous deposition along glomerular capillary walls, including endothelial cells and sub-endothelial spaces; and 2) a granular bead-like appearance with distinct deposits in mesangial and paramesangial cells. Immunoglobulin G (IgG) and M (IgM) and C3 fraction deposition in adjacent kidney sections displayed features comparable with those found for HCV deposits. Patients with granular deposits showed more pronounced renal impairment and severe proteinuria. These findings indicate that in MC patients with HCV-associated MPGN, kidney deposits consist of HCV-containing immune complexes that are likely to play a direct pathogenetic role in the renal damage.


Quality of life in patients with leg ulcers: results from CHALLENGE, a double-blind randomised controlled trial.
We recently showed the superiority of a matrix metalloproteinase (MMP) modulating dressing (foam impregnated with NOSF, nano-oligosaccharide factor) compared with a lipidocolloid matrix (TLC) control dressing in median wound area reduction (WAR). Here we report the results from the same study assessing the performance and safety of TLC-NOSF in the local management of venous leg ulcers (VLUs) or mixed leg ulcers and determining its impact on the patient's health-related quality of life (HRQoL). A superiority randomised double-blind controlled trial was conducted on patients presenting with a non-infected leg ulcer (VLUs or mixed leg ulcers) of predominantly venous origin (ABPI >0.8), with a surface area ranging from 5 to 50cm2 and a duration of 6 to 36 months. Patients were randomly allocated to either the TLC-NOSF matrix foam (UrgoStart) dressing group or to the neutral TLC foam dressing group (UrgoTul Absorb). All received appropriate compression therapy and the wounds were assessed blindly (clinical examination, wound area tracing and photographic record) every 2 weeks for a period of 8 weeks, or until complete closure. A secondary endpoint, described here, was the patient's HRQoL, documented by the patient, through the EuroQol 5D tool (EQ-5D) questionnaire and visual analogue scale (VAS). In total, 187 patients were randomised to either the TLC-NOSF group (n=94) or the control dressing group (n=93). The two groups were well balanced at baseline with regard to wound and patient characteristics. In the HRQoL questionnaire (EQ-5D), the pain/discomfort and anxiety/depression dimensions were significantly improved in the TLC-NOSF group versus the control one (pain/discomfort: 1.53±0.53 versus 1.74±0.65; p=0.022, and anxiety/depression: 1.35±0.53 versus 1.54±0.60, p=0.037). The VAS score was better in the test group compared with the control group (72.1±17.5 versus 67.3±18.7, respectively), without reaching significance (p=0.072). Acceptability and tolerance of the two products were similar in both groups. The double-blind clinical trial has demonstrated that the TLC-NOSF matrix dressing promotes faster healing of VLUs and mixed leg ulcers and significantly reduces the pain/discomfort and anxiety/depression experienced by the patients. These results suggest that acceleration of VLU healing could improve the HRQoL of the patients and reduced the emotional and social burden of these chronic wounds.


Bidirectional associative plasticity of unitary CA3-CA1 EPSPs in the rat hippocampus in vitro.
Associative long-term potentiation (LTP) and depression of compound and unitary CA3-CA excitatory postsynaptic potentials (EPSPs) were investigated in rat hippocampal slice cultures. The induction of LTP with synchronous pairing of synaptic activation and postsynaptic depolarization resulted in an increase in the amplitude of EPSPs to the same absolute level, regardless of whether the input was naive or had been previously depressed by asynchronous pairing of pre- and postsynaptic activity. Saturated LTP of compound and unitary EPSPs was reversed by asynchronous pairing and could be reinduced by synchronous pairing. The likelihood that an action potential in a presynaptic CA3 cell failed to trigger an unitary EPSP in a postsynaptic CA1 cell decreased after induction of associative potentiation and increased after induction of associative depotentiation. These changes in the rate of transmission failures were accompanied by large changes in the amplitude of nonfailure EPSPs. We conclude that the same CA3-CA1 synapses can alternatively undergo associative potentiation and depression, perhaps through opposite changes in a single expression mechanism.


Hyperfunction of the entero-PP axis in non-insulin dependent diabetes mellitus.
In a previous study we have found that the plasma pancreatic polypeptide (PP) response to oral glucose loading is exaggerated in diabetic patients compared with normal subjects. We have investigated, therefore, the effects of a protein-rich meal or meat extract ingestion on plasma PP secretion and examined also the effects of intravenous arginine administration on PP levels in normal subjects and in patients with noninsulin-dependent diabetes mellitus (NIDDM). Following a 600 Kcal meal ingestion, plasma PP levels increased immediately and showed biphasic secretion in normal subjects and in NIDDM, but the response was exaggerated in NIDDM. A 50 g meat extract administration also produced an exaggerated PP response in NIDDM compared with normal subjects. In NIDDM and normal subjects, plasma PP levels did not change significantly during an arginine infusion (30 g for 45 min) but after the end of the infusion PP levels increased significantly compared with basal levels. In normal subjects, plasma PP rose abruptly after a bolus arginine injection (4 g for 2 min) and then remained at significantly high levels even 30 min after the injection. In NIDDM, however, plasma PP levels tended to increase, but not significantly, after the bolus arginine injection. Since in NIDDM the protein-rich meal and meat extract ingestion produced an exaggerated rise in plasma PP while the PP responses to the intravenous arginine administration were rather impaired compared with normal subjects, we suggest that the entero-PP axis is overactive in NIDDM.


An eight residue fragment of an acyl carrier protein suffices for post-translational introduction of fluorescent pantetheinyl arms in protein modification in vitro and in vivo.
Genetically encoded tags for tracking a given protein continue to be of great interest in a multitude of in vitro and in vivo contexts. Acyl carrier proteins, both free-standing and as embedded 80-100 residue domains, contain a specific serine side chain that undergoes post-translational pantetheinylation from CoASH as donor substrate. We have previously used phage display methods to select a 12 residue fragment that retains recognition for modification by the Escherichia coli phosphopantetheinyltransferase (PPTase) AcpS. In this work, we have used (15)N-HSQC based NMR titration experiments of a 12-residue peptide substrate with AcpS to identify six specifically interacting residues (S3, L4, D5, M6, W9, and L11) without the formation of any notable secondary structure. Synthesis of a corresponding octapeptide containing 5 of the 6 interacting residues generated a minimal fragment capable of efficient post-translational phosphopantetheinylation. Genetic insertion of this eight residue coding sequence into the proteins sonic hedgehog and transferrin receptor enabled good in vitro and in vivo PPTase-mediated modification by a series of fluorescent CoAs, leading to a set of fluorescent proteins with a peptide tag minimally perturbant to protein folds.


Platelet HMGB1 is required for efficient bacterial clearance in intra-abdominal bacterial sepsis in mice.
Thrombocytopenia impairs host defense and hemostasis in sepsis. However, the mechanisms of how platelets regulate host defense are not fully understood. High-mobility group box 1 (HMGB1), a danger-associated molecular pattern protein, is released during infection and contributes to the pathogenesis of sepsis. Platelets express HMGB1, which is released on activation and has been shown to play a critical role in thrombosis, monocyte recruitment, and neutrophil extracellular trap (NET) production. However, the contribution of platelet HMGB1 to host defense is unknown. To determine the role of platelet HMGB1 in polymicrobial sepsis, platelet-specific HMGB1 knockout (HMGB1 platelet factor 4 [PF4]) mice were generated and were subjected to cecal ligation and puncture (CLP), a clinically relevant intra-abdominal sepsis model. Compared with HMGB1 Flox mice and wild-type (WT) mice, HMGB1 PF4 mice showed significantly higher bacterial loads in the peritoneum and blood, an exaggerated systemic inflammation response, and significantly greater mortality after CLP. Deletion of HMGB1 in platelets was associated with lower platelet-derived chemokines (PF4 and RANTES) in the peritoneal cavity, and a decrease of platelet-neutrophil interaction in the lung after CLP. In vitro, neutrophils cocultured with activated HMGB1 knockout platelets showed fewer platelet-neutrophil aggregates, reduced reactive oxygen species (ROS) burst as compared with control. Taken together, these data reveal an unrecognized role of platelet HMGB1 in the regulation of neutrophil recruitment and activation via modulation of platelet activation during sepsis.


Influence of route of administration on physiological availability of levodopa in dogs.
The physiological basis for the reduced levodopa bioavailability following oral administration was investigated. Four dogs received single 25-mg/kg doses of 14C-levodopa on three separate occasions in a crossover fashion via hepatoportal catheter, intravenous, and oral administrations. Plasma and urine specimens were analyzed for intact levodopa and total radioactivity. The ratios of areas under the plasma concentration-time curves following hepatoportal and intravenous adminstrations were close to unity, and the shapes of the curves were virtually identical. Following oral administration, however, significant reductions in the areas under the plasma concentration-time curves were observed. These data indicate that the physiologically impaired bioavailability of orally administered levodopa occurs almost exclusively as a result of metabolic degradation within the GI lumen and/or gut wall.


Validation of the 24-item recovery assessment scale-revised (RAS-R) in the Norwegian language and context: a multi-centre study.
The Recovery Assessment Scale-revised (RAS-R) is a self-report instrument measuring mental health recovery. The purpose of the present study was to translate and adapt the RAS-R into the Norwegian language and to investigate its psychometric properties in terms of factor structure, convergent and discriminant validity and reliability in the Norwegian context. The present study is a cross-sectional multi-centre study. After a pilot test, the Norwegian version of the RAS-R was distributed to 231 service users in mental health specialist and community services. The factor structure of the instrument was investigated by a confirmatory factor analysis (CFA), and internal consistency was assessed by Cronbach's alpha. The RAS-R was found to be acceptable and feasible for service users. The original five-factor structure was confirmed. All model fit indices, including the standardised root mean square residual (SRMR), which is independent of the χ2-test, met the criteria for an acceptable model fit. Internal consistencies within sub-scales as measured by Cronbach's alpha ranged from 0.65 to 0.85. Cronbach's alpha for the total scale was 0.90. As expected, some redundancy between factors existed (in particular among the factors Personal confidence and hope, Goal and success orientation and Not dominated by symptoms). The Norwegian RAS-R showed acceptable psychometric properties in terms of convergent validity and reliability, and fit indices from the CFA confirmed the original factor structure. We recommend the Norwegian RAS-R as a tool in service users' and health professionals' collaborative work towards the service users' recovery goals and as an outcome measure in larger evaluations.