The prion protein is not required for peripheral nerve de- and remyelination after crush injury.
The cellular prion protein (PrP) is essential to the long-term maintenance of myelin sheaths in peripheral nerves. PrP activates the adhesion G-protein coupled receptor Adgrg6 on Schwann cells and initiates a pro-myelination cascade of molecular signals. Because Adgrg6 is crucial for peripheral myelin development and regeneration after nerve injury, we investigated the role of PrP in peripheral nerve repair. We performed experimental sciatic nerve crush injuries in co-isogenic wild-type and PrP-deficient mice, and examined peripheral nerve repair processes. Generation of repair Schwann cells, macrophage recruitment and remyelination were similar in PrP-deficient and wild-type mice. We conclude that PrP is dispensable for sciatic nerve de- and remyelination after crush injury. Adgrg6 may sustain its function in peripheral nerve repair independently of its activation by PrP.


Peptide Retention in Hydrophilic Strong Anion Exchange Chromatography Is Driven by Charged and Aromatic Residues.
Hydrophilic strong anion exchange chromatography (hSAX) is becoming a popular method for the prefractionation of proteomic samples. However, the use and further development of this approach is affected by the limited understanding of its retention mechanism and the absence of elution time prediction. Using a set of 59 297 confidentially identified peptides, we performed an explorative analysis and built a predictive deep learning model. As expected, charged residues are the major contributors to the retention time through electrostatic interactions. Aspartic acid and glutamic acid have a strong retaining effect and lysine and arginine have a strong repulsion effect. In addition, we also find the involvement of aromatic amino acids. This suggests a substantial contribution of cation-π interactions to the retention mechanism. The deep learning approach was validated using 5-fold cross-validation (CV) yielding a mean prediction accuracy of 70% during CV and 68% on a hold-out validation set. The results of this study emphasize that not only electrostatic interactions but rather diverse types of interactions must be integrated to build a reliable hSAX retention time predictor.


Leucocyte sodium pump activity after meals or insulin in normal and obese subjects: cause for increased energetic efficiency in obesity?
As cellular sodium pumping is an energy consuming process and differences in the obese may account for their energetic efficiency, leucocyte sodium-22 efflux was studied in obese and normal volunteers both in the fasting state and after a test meal or infusion of glucose and insulin intravenously. The 22Na ouabain sensitive efflux rate constant was significantly higher in obese subjects than normal (mean (1 SD) 2.69 (0.40)/h v 2.35 (0.49)/h). Two hours after a 4.2 MJ (1000 kcal) meal there was an increase in the efflux rate constant from its fasting value in normal weight subjects (2.39 (0.33)/h to 2.71 (0.40)/h) but not in obese subjects (2.65 (0.54)/h to 2.61 (0.58)/h). The rise in ouabain sensitive efflux rates was significantly higher in normal than obese subjects. Both groups showed a rise in intracellular sodium concentrations. The euglycaemic clamp produced similar results. Feeding or infusion of insulin increases sodium pump activity more in normal than obese subjects. This difference may contribute to any defective dietary thermogenesis in obesity, which may lead to energetic efficiency and a tendency to gain weight.


The prevalence of and risk factors for hypertension in adults living in Istanbul.
The prevalence of and risk factors for hypertension were determined among habitants in the European side of Istanbul who are 25 years and older. Eight administrative districts were selected with the method of simple random sampling. The participants were selected through systematic calling from address lists. Between 17 and 22 June 2002, the questionnaires were applied to the participants in a face-to-face interview; then arterial blood pressures, body weights and heights of the participants were measured. Of 423 adults participating in the study, 35.5% were hypertensive; 35.9% were obese, 27.9% were overweight and 2.1% were underweight. Risk factors for hypertension such as age, gender, educational status, social security, family history of hypertension and cardiovascular disease, medical history of diabetes and congestive heart failure, smoking and alcohol use, and body mass index in the hypertensive and non-hypertensive groups were investigated by means of logistic regression analysis. Age [odds ratio (OR): 5.20, 95% confidence interval (CI): 2.18-12.40], body mass index (OR: 2.22, 95% CI: 1.57-3.16) and smoking (OR: 0.72, 95% CI: 0.55-0.95) were found to be correlated with hypertension. The results showed that the prevalence of hypertension was high in Istanbul, and obesity, being overweight and advanced age were the risk factors for hypertension.


Role-Play Assessment of Therapist Adherence and Skill in Implementation of Trauma-Focused Cognitive-Behavioral Therapy.
Numerous efforts are underway to train clinicians in evidence-based practices. Unfortunately, the field has few practical measures of therapist adherence and skill with which to judge the success of these training and implementation efforts. One possible assessment method is using behavioral rehearsal, or role-play, as an analogue for therapist in-session behavior. The current study describes aspects of reliability, validity and utility of a behavioral role-play assessment developed to evaluate therapist adherence and skill in implementing Trauma-Focused Cognitive-Behavioral Therapy (TF-CBT). TF-CBT role-play assessments were conducted with a sample of 43 therapists as part of a larger training study. The TF-CBT role-play assessments were independently coded for TF-CBT adherence and skill by a certified TF-CBT trainer and three clinical psychology doctoral students. Findings indicated good interrater reliability for the individual items (ICC: M = .71, SD = .15). Regarding utility, 67.19% (n = 43/64) of contacted therapists completed the role-play assessment, which took an average of 30 min (M = 31.42, SD = 5.65) to complete and 60 min (M = 62.84, SD = 11.31) to code. Therapists with a master's degree were more likely to complete the role-play assessment than those with other degrees but no other differences in demographic variables, practice characteristics, or TF-CBT knowledge or training were found between participants and nonparticipants. Role-play assessments may offer an alternative to observational coding for assessing therapist adherence and skill, particularly in contexts where session recordings are not feasible.


Patients' smoking status: the family practice physician's view.
Smoking rates have decreased in western countries as well as in Israel during the past 20 years. To estimate current rates of smoking and smoking cessation, and to assess factors associated with smoking and smoking cessation in family practice. Prospective face-to-face interviews were conducted with 1,094 subjects, aged 16 years or older, registered in a family practice. Of all subjects studied, 746 (68.2%) were nonsmokers, 237 (21.7%) were current smokers, and 111 (10.1%) had stopped smoking. Overall, 31.8% of the males and 13.8% of the females were current smokers, and 20.1% males and 2.4% females had stopped smoking. Current smoking and smoking cessation rates were significantly and inversely associated with age among males and females. Smoking rates were higher among males and females who were married, had 10-12 years of education, and among males of North African origin and females of Israeli origin. The number of cigarettes smoked per day was associated with smoking and smoking cessation in males, but not in females. The highest rate of quitting occurred among males who smoked > or = 25 cigarettes per day. In a multiple regression analysis, gender and the number of cigarettes smoked per day were the most significant factors that predicted smoking cessation. The most common reason for stopping was the appearance of new signs of illness or the development of a new chronic disease, followed by a physician's recommendation to quit smoking. Female smokers and male smokers who smoke less than 25 cigarettes per day are the least likely to quit smoking. Future programs should be designed for and targeted at these groups of patients.


Analysis of expressed sequence tags generated from full-length enriched cDNA libraries of melon.
Melon (Cucumis melo), an economically important vegetable crop, belongs to the Cucurbitaceae family which includes several other important crops such as watermelon, cucumber, and pumpkin. It has served as a model system for sex determination and vascular biology studies. However, genomic resources currently available for melon are limited. We constructed eleven full-length enriched and four standard cDNA libraries from fruits, flowers, leaves, roots, cotyledons, and calluses of four different melon genotypes, and generated 71,577 and 22,179 ESTs from full-length enriched and standard cDNA libraries, respectively. These ESTs, together with ~35,000 ESTs available in public domains, were assembled into 24,444 unigenes, which were extensively annotated by comparing their sequences to different protein and functional domain databases, assigning them Gene Ontology (GO) terms, and mapping them onto metabolic pathways. Comparative analysis of melon unigenes and other plant genomes revealed that 75% to 85% of melon unigenes had homologs in other dicot plants, while approximately 70% had homologs in monocot plants. The analysis also identified 6,972 gene families that were conserved across dicot and monocot plants, and 181, 1,192, and 220 gene families specific to fleshy fruit-bearing plants, the Cucurbitaceae family, and melon, respectively. Digital expression analysis identified a total of 175 tissue-specific genes, which provides a valuable gene sequence resource for future genomics and functional studies. Furthermore, we identified 4,068 simple sequence repeats (SSRs) and 3,073 single nucleotide polymorphisms (SNPs) in the melon EST collection. Finally, we obtained a total of 1,382 melon full-length transcripts through the analysis of full-length enriched cDNA clones that were sequenced from both ends. Analysis of these full-length transcripts indicated that sizes of melon 5' and 3' UTRs were similar to those of tomato, but longer than many other dicot plants. Codon usages of melon full-length transcripts were largely similar to those of Arabidopsis coding sequences. The collection of melon ESTs generated from full-length enriched and standard cDNA libraries is expected to play significant roles in annotating the melon genome. The ESTs and associated analysis results will be useful resources for gene discovery, functional analysis, marker-assisted breeding of melon and closely related species, comparative genomic studies and for gaining insights into gene expression patterns.


Ectopic expression of an endoparasitic wasp venom protein in Drosophila melanogaster affects immune function, larval development and oviposition.
Endoparasitic hymenoptera inject maternal factors into the host, along with their eggs, to subvert the host immune system. The venom protein, Vn50, previously characterized from the wasp Cotesia rubecula inhibits prophenoloxidase activation in its host Pieris rapae and in another lepidopteran, Manduca sexta. We generated a stable line in the model insect, Drosophila melanogaster, which ectopically expresses Vn50. Results indicated that Vn50 expression accelerates larval development, increases oviposition and reduces melanization in the haemolymph of the transgenic flies. Since melanization is known to be an important facet of the insect immune response, we examined the impact of Vn50 expression on susceptibility to pathogens. Transgenic Vn50 flies challenged with the fungus Beauveria bassiana had increased mortality compared with control flies, but there was no significant change in survival in flies challenged with the pathogenic bacteria, Serratia marcescens. Interestingly, mortality induced by the natural pathogen Drosophila C virus was significantly delayed in Vn50 expressing flies. This indicates a wider range of potential hosts that may be affected by Vn50 and its potential for manipulation of immune system in insects.


Genetic structures at the origin of acquisition and expression of the carbapenem-hydrolyzing oxacillinase gene blaOXA-58 in Acinetobacter baumannii.
Genetic structures surrounding the carbapenem-hydrolyzing oxacillinase gene blaOXA-58 were characterized in a series of OXA-58-positive Acinetobacter baumannii strains isolated from different countries. We showed that in most of the cases, acquisitions of the blaOXA-58-containing overall structure, including insertion sequence elements, may be likely the results of recombination events. In type strain A. baumannii MAD, the genetic structure surrounding the blaOXA-58 gene was bracketed by two 27-bp repeated sequences. The isolation of a clonally related OXA-58-negative A. baumannii isolate that possessed the same plasmid backbone as A. baumannii MAD but lacked this genetic structure indicated that the mechanism of acquisition could be reversible. Parts of the structure identified in A. baumannii MAD were conserved in other blaOXA-58-positive isolates from various European countries. Primer extension experiments showed that blaOXA-58 expression was related to promoter sequences brought by different insertion sequence elements, such as an ISAba3-like element, ISAba1, ISAba2, and IS18. This work identified novel structures at the origin of acquisition and expression of a carbapenem-hydrolyzing beta-lactamase identified in non-clonally related A. baumannii isolates.


Streptomycin resistance and lineage-specific polymorphisms in Mycobacterium tuberculosis gidB gene.
Mutations related to streptomycin resistance in the rpsL and rrs genes are well known and can explain about 70% of this phenotypic resistance. Recently, the gidB gene was found to be associated with low-level streptomycin resistance in Mycobacterium tuberculosis. Mutations in gidB have been reported with high frequency, and this gene appears to be very polymorphic, with frameshift and point mutations occurring in streptomycin-susceptible and streptomycin-resistant strains. In this study, mutations in gidB appeared in 27% of streptomycin-resistant strains that contained no mutations in the rpsL or rrs genes, and they were associated with low-level streptomycin resistance. However, the association of certain mutations in gidB with streptomycin resistance needs to be further investigated, as we also found mutations in gidB in streptomycin-susceptible strains. This occurred only when the strain was resistant to rifampin and isoniazid. Two specific mutations appeared very frequently in this and other studies of streptomycin-susceptible and -resistant strains; these mutations were not considered related to streptomycin resistance, but as a polymorphism. We stratified the strains according to the different phylogenetic lineages and showed that the gidB(16) polymorphism (16G allele) was exclusively present in the Latin American-Mediterranean (LAM) genotype, while the gidB(92) polymorphism (92C allele) was associated with the Beijing lineage in another population. In the sample studied, the two characterized single-nucleotide polymorphisms could distinguish LAM and Beijing lineages from the other lineages.


Gastrointestinal and hepatobiliary neoplasms in AIDS.
There is an increased frequency of Kaposi's sarcoma and non-Hodgkin's lymphomas in patients with AIDS. These "opportunistic malignancies" establish the diagnosis of AIDS in an HIV-positive patient and are associated with a high likelihood of gastrointestinal and hepatobiliary involvement. Kaposi's sarcoma is a multicentric cutaneous spindle-cell tumor that is associated with luminal lesions in at least 40 per cent of patients. Gastrointestinal KS is usually asymptomatic but may rarely bleed or obstruct. Treatment of KS with either radiation or chemotherapy can reduce tumor bulk, without affecting survival. Non-Hodgkin's lymphomas in AIDS are B-cell neoplasms composed of either noncleaved or blast cells, similar to those seen in Burkitt's lymphoma. The tumors are usually highly aggressive and present in extranodal sites in the majority of cases. Primary or secondary gastrointestinal involvement is frequent, with hepatic and rectal tumors being particularly common. Unlike KS, gastrointestinal lymphomas are usually symptomatic. Obstruction, perforation, and bleeding can occur in patients with luminal involvement. Jaundice due to hepatic infiltration or biliary obstruction may be seen. Treatment with chemotherapy is usually indicated because of the rapid progression of the tumor, although no prolongation of survival has been demonstrated. There may also be an increased incidence of Hodgkin's disease and anorectal neoplasia in patients with AIDS; however, these malignancies do not establish the diagnosis of AIDS in an HIV-positive patient.


Enrichment of Y-chromosome-bearing bull spermatozoa by swim-up through a column.
With the advancement of assisted reproductive biotechnologies, preselecting the sex of offspring has become an important goal for cattle and other livestock breeding as well as for research. The aim of this study was to investigate the feasibility of producing enriched pools of X- or Y-chromosome-bearing sperm by vertical swim-up through a long, narrow column. Sperm recovered from the top portion of the column was predominantly Y-bearing (60%, p < 0.05), which were capable of fertilizing matured oocytes and produce significantly more male embryos compared with standard swim-up protocol.


Epidermodysplasia verruciformis: clinical presentation with varied forms of lesions.
Epidermodysplasia verruciformis is a rare inherited skin disorder spread by HPV, with cases linked to chromosome X. It is characterized by hypo- or hyper-pigmented macular lesions, pityriasis versicolor-like lesions and an early tendency to develop skin malignancies. We present a case of epidermodysplasia verruciformis with a variety of lesions such as multiple plane warts, pityriasis versicolor-like lesions and aggressive squamous cell carcinoma on the face.


Hematopoietic Stem Cell Transplantation in Adult Sickle Cell Disease: Problems and Solutions.
Sickle cell disease-related organ injuries cannot be prevented despite hydroxyurea use, infection prophylaxis, and supportive therapies. As a consequence, disease-related mortality reaches 14% in adolescents and young adults. Hematopoietic stem cell transplantation is a unique curative therapeutic approach for sickle cell disease. Myeloablative allogeneic hematopoietic stem cell transplantation is curative for children with sickle cell disease. Current data indicate that long-term disease-free survival is about 90% and overall survival about 95% after transplantation. However, it is toxic in adults due to organ injuries. In addition, this curative treatment approach has several limitations, such as difficulties to find donors, transplant-related mortality, graft loss, graft-versus-host disease (GVHD), and infertility. Engraftment effectivity and toxicity for transplantations performed with nonmyeloablative reduced-intensity regimens in adults are being investigated in phase 1/2 trials at many centers. Preliminary data indicate that GVHD could be prevented with transplantations performed using reduced-intensity regimens. It is necessary to develop novel regimens to prevent graft loss and reduce the risk of GVHD.


Influence of fly ash on soil physical properties and turfgrass establishment.
A field study (1993-96) assessed the benefits of applying unusually high rates of coal fly ash as a soil amendment to enhance water retention of soils without adversely affecting growth and marketability of the turf species, centipedegrass [Eremochloa ophiuroides (Munro) Hack.]. A Latin Square plot design was employed that included 0 (control, no ash applied), 280, 560, and 1120 Mg ha-1 application rates of unweathered precipitator fly ash. The fly ash was spread evenly over each plot area, rototilled, and allowed to weather under natural conditions for 8 mo before seeding. High levels of soluble salts, indicated by the electrical conductivity (EC) of soil extracts, in tandem with an apparent phytotoxic effect from boron (B), apparently inhibited initial plant establishment as shown by substantially lower germination counts in treated soil. However, plant height and rooting depth were not adversely affected, as were the dry matter (DM) yields throughout the study period. Ash treatment did not significantly influence water infiltration rate, bulk density, or temperature of the soil, but substantially improved water-holding capacity (WHC) and plant-available water (PAW). Enhanced water retention capacity improved the cohesion and handling property of harvested sod.


Domestic tourists' experience in protected natural parks: A new trend in pandemic crisis?
Since December 2019, the Covid-19 pandemic crisis has led to profound changes around the world with a lot of interdictions or constraints to travel outside one's own country. One of the major consequences has been the development of proximity tourism in outdoor spaces less conducive to the spread of the virus. From a study preceding this pandemic, this article seeks to better understand the experiences lived by domestic tourists when they visited protected natural parks in their country. Beyond the health risks, it analyses the dimensions and the influences of experiences lived in these parks by French domestic tourists (n = 500) using Pine and Gilmore's 4Es model (1999). From a literature on the tourism experiences for domestic tourists adapted to natural parks and a critical review on the use and validation of Oh et al.'s scale (2007) in tourism, a structural equation model and a nested SEM show the positive relationship between three dimensions of the 4Es on the arousal and memory outcomes. Theoretically and methodologically speaking, this study extends the 4Es model in the direction of low arousal and mundane experiences for domestic tourists in protected natural parks, and questions Oh, Fiore, and Jeoung (2007) scale through the number of items, the use of EFA and the removal of the aesthetics dimension. This research can help managers of protected natural parks adapt their domestic tourists' experience offer during health crisis by implementing specific marketing strategies for low arousal and mundane experiences with more outdoor activities and digital services.


Photoprotection of human dermal fibroblasts against ultraviolet light by antioxidant combinations present in tomato.
In the current study, we evaluated and compared, for the first time in a cell model, the effect of lycopene alone or in association with various antioxidants present in tomato such as α-tocopherol or naringenin, on their capacity to protect against oxidative stress generated in human dermal fibroblasts (hdf) exposed to ultraviolet-A (UVA) light. UVA irradiation of hdf led to a reduced cell viability in a dose dependent manner. Similar effects were observed when cells were exposed to lycopene. This reduction was suppressed in the presence of naringenin but not with α-tocopherol. Reactive oxygen species production was strongly induced by UVA irradiation. Only co-incubation with naringenin (highest level) was able to inhibit this effect. The combination of lycopene : naringenin further increased the stability of the carotenoid. Heme-oxygenase 1 (HO-1) expression was induced by UVA irradiation but none of the antioxidants inhibited this effect at the concentrations used in the study. Indeed, lycopene (1 μM) led to a further 2.5-fold rise in the UVA-induced HO-1 expression. However, this effect was suppressed by concomitant addition of naringenin. In our study, naringenin prevents oxidative degradation of lycopene. These results strengthen the hypothesis that combinations of dietary antioxidants present in tomato other than lycopene alone could play a role in the health effects of tomato as evidenced by epidemiological studies.


Electron microscopic study of Saccharomyces cerevisiae rDNA chromatin replication.
An electron microscopic study was made of the replication of rDNA chromatin of Saccharomyces cerevisiae. Two different methods were used to synchronize cells. cdc7-1 cells were raised to a restrictive temperature, whereas A364a cells were blocked with mating factor. Replication bubbles typically opened in the nontranscribed spacers of rDNA repeats in both cell types. The mean position of the center of these bubbles corresponds closely to a position where an autonomously replicating sequence previously has been mapped in an rDNA repeat. Clusters of replication bubbles containing up to four bubbles spaced one to three genes apart were seen opening in early S phase.


Calcium density of coronary artery plaque and risk of incident cardiovascular events.
Coronary artery calcium (CAC), measured by computed tomography (CT), has strong predictive value for incident cardiovascular disease (CVD) events. The standard CAC score is the Agatston, which is weighted upward for greater calcium density. However, some data suggest increased plaque calcium density may be protective for CVD. To determine the independent associations of CAC volume and CAC density with incident CVD events. Multicenter, prospective observational MESA study (Multi-Ethnic Study of Atherosclerosis), conducted at 6 US field centers of 3398 men and women from 4 race/ethnicity groups; non-Hispanic white, African American, Hispanic, and Chinese. Participants were aged 45-84 years, free of known CVD at baseline, had CAC greater than 0 on their baseline CT, and were followed up through October 2010. Incident coronary heart disease (CHD) and all CVD events During a median of 7.6 years of follow-up, there were 175 CHD events and an additional 90 other CVD events for a total of 265 CVD events. With both lnCAC volume and CAC density scores in the same multivariable model, the lnCAC volume score showed an independent association with incident CHD, with a hazard ratio (HR) of 1.81 (95% CI, 1.47-2.23) per standard deviation (SD = 1.6) increase, absolute risk increase 6.1 per 1000 person-years, and for CVD an HR of 1.68 (95% CI, 1.42-1.98) per SD increase, absolute risk increase 7.9 per 1000 person-years. Conversely, the CAC density score showed an independent inverse association, with an HR of 0.73 (95% CI, 0.58-0.91) per SD (SD = 0.7) increase for CHD, absolute risk decrease 5.5 per 1000 person-years, and an HR of 0.71 (95% CI, 0.60-0.85) per SD increase for CVD, absolute risk decrease 8.2 per 1000 person years. Area under the receiver operating characteristic curve analyses showed significantly improved risk prediction with the addition of the density score to a model containing the volume score for both CHD and CVD. In the intermediate CVD risk group, the area under the curve for CVD increased from 0.53 (95% CI, 0.48-0.59) to 0.59 (95% CI, 0.54-0.64), P = .02. CAC volume was positively and independently associated with CHD and CVD risk. At any level of CAC volume, CAC density was inversely and significantly associated with CHD and CVD risk. The role of CAC density should be considered when evaluating current CAC scoring systems.


Mycophenolate mofetil versus methotrexate for prevention of graft-versus-host disease in people receiving allogeneic hematopoietic stem cell transplantation.
Allogeneic hematopoietic stem cell transplantation (allo-HCT) is associated with improved outcomes for people with various hematologic diseases; however, the morbidity and mortality resulting from acute and subsequently chronic graft-versus-host disease (GVHD) pose a serious challenge to wider applicability of allo-HCT. Intravenous methotrexate in combination with a calcineurin inhibitor, cyclosporine or tacrolimus, is a widely used regimen for the prophylaxis of acute GVHD, but the administration of methotrexate is associated with a number of adverse events. Mycophenolate mofetil, in combination with a calcineurin inhibitor, has been used extensively in people undergoing allo-HCT. Conflicting results regarding various clinical outcomes following allo-HCT have been observed when comparing mycophenolate mofetil-based regimens against methotrexate-based regimens for acute GVHD prophylaxis. to assess the effect of mycophenolate mofetil versus methotrexate for prevention of acute GVHD in people undergoing allo-HCT. to evaluate the effect of mycophenolate mofetil versus methotrexate for overall survival, prevention of chronic GVHD, incidence of relapse, treatment-related harms, nonrelapse mortality, and quality of life. We searched Cochrane Central Register of Controlled Trials (CENTRAL) and MEDLINE from inception to March 2014. We handsearched conference abstracts from the last two meetings (2011 and 2012) of relevant societies in the field. We searched ClinicalTrials.gov, Novartis clinical trials database (www.novctrd.com), Roche clinical trial protocol registry (www.roche-trials.com), Australian New Zealand Clinical Trials Registry (ANZCTR), and the metaRegister of Controlled Trials for ongoing trials. Two review authors independently reviewed all titles/abstracts and selected full-text articles for inclusion. We included all references that reported results of randomized controlled trials (RCTs) of mycophenolate mofetil versus methotrexate for the prophylaxis of GVHD among people undergoing allo-HCT in this review. Two review authors independently extracted data on outcomes from all studies and compared prior to data entry and analysis. We expressed results as risk ratios (RR) and 95% confidence intervals (CI) for dichotomous outcomes and hazard ratios (HR) and 95% CIs for time-to-event outcomes. We pooled the individual study effects using the random-effects model. Estimates lower than one indicate that mycophenolate mofetil was favored over methotrexate. We included three trials enrolling 177 participants (174 participants analyzed). All participants in the trials by Keihl et al. and Bolwell et al. received cyclosporine while all participants enrolled in the trial by Perkins et al. received tacrolimus. However, the results did not differ by the type of calcineurin inhibitor employed (cyclosporine versus tacrolimus). There was no evidence for a difference between mycophenolate mofetil versus methotrexate for the outcomes of incidence of acute GVHD (RR 1.25; 95% CI 0.75 to 2.09; P value = 0.39, very low quality evidence), overall survival (HR 0.73; 95% CI 0.45 to 1.17; P value = 0.19, low-quality evidence), median days to neutrophil engraftment (HR 0.77; 95% CI 0.51 to 1.17; P value = 0.23, low-quality evidence), incidence of relapse (RR 0.84; 95% CI 0.52 to 1.38; P value = 0.50, low-quality evidence), non-relapse mortality (RR 1.21; 95% CI 0.62 to 2.36; P value = 0.57, low-quality evidence), and incidence of chronic GVHD (RR 0.92; 95% CI 0.65 to 1.30; P value = 0.62, low-quality evidence). There was low-quality evidence that mycophenolate mofetil compared with methotrexate improved platelet engraftment period (HR 0.87; 95% CI 0.81 to 0.93; P value < 0.0001, low-quality evidence). There was low-quality evidence that mycophenolate mofetil compared with methotrexate resulted in decreased incidence of severe mucositis (RR 0.48; 95% CI 0.32 to 0.73; P value = 0.0006, low-quality evidence), use of parenteral nutrition (RR 0.48; 95% CI 0.26 to 0.91; P value = 0.02, low-quality evidence), and medication for pain control (RR 0.76; 95% CI 0.63 to 0.91; P value = 0.002, low-quality evidence). Overall heterogeneity was not detected in the analysis except for the outcome of neutrophil engraftment. None of the included studies reported any outcomes related to quality of life. Overall quality of evidence was low. The use of mycophenolate mofetil compared with methotrexate for primary prevention of GVHD seems to be associated with a more favorable toxicity profile, without an apparent compromise on disease relapse, transplant-associated mortality, or overall survival. The effects on incidence of GVHD between people receiving mycophenolate mofetil compared with people receiving methotrexate were uncertain. There is a need for additional high-quality RCTs to determine the optimal GVHD prevention strategy. Future studies should take into account a comprehensive view of clinical benefit, including measures of morbidity, symptom burden, and healthcare resource utilization associated with interventions.


Inotropic effects and Na+,K+-ATPase inhibition of ouabain in isolated guinea-pig atria and diaphragm.
Effects of ouabain on force of contraction were compared in electrically driven isolated tissue preparations of guinea-pig left atria and diaphragm. A distinct and steady positive inotropic effect of ouabain was observed in atrial preparations, whereas in diaphragm preparations, ouabain produced only a slight and transient positive inotropic effect, followed by the negative inotropic phase. The transient positive inotropic effect of ouabain was observed even in the absence of extracellular calcium, but was markedly dependent on the extracellular sodium concentration. In vitro [3H]ouabain binding studies revealed that the affinity of Na+,K+-ATPase for ouabain was about eight times higher and tissue concentration of the enzyme was significantly lower in diaphragm than in cardiac tissue. The Ki value for ouabain inhibition of the cardiac Na+,K+-ATPase was also approximately ten times higher than for the diaphragm enzyme. Ouabain-sensitive 86Rb uptake, an estimate of sodium pump activity, was inhibited by ouabain at a time when it produced its transient positive inotropic effect in diaphragm preparations. These results indicate that the lack of a distinct and steady positive inotropic effect of ouabain in diaphragm was due neither to the difference in the ouabain-Na+,K+-ATPase interaction between diaphragm and cardiac tissues nor the failure of sodium pump inhibition by ouabain in diaphragm.


A Bayesian adaptive design with biomarkers for targeted therapies.
Targeted therapies are becoming increasingly important for the treatment of various diseases. Biomarkers are a critical component of a targeted therapy as they can be used to identify patients who are more likely to benefit from a treatment. Targeted therapies, however, have created major challenges in the design, conduct, and analysis of clinical trials. In traditional clinical trials, treatment effects for various biomarkers are typically evaluated in an exploratory fashion and only limited information about the predictive values of biomarkers obtained. New study designs are required, which effectively evaluate both the diagnostic and the therapeutic implication of biomarkers. The Bayesian approach provides a useful framework for optimizing the clinical trial design by directly integrating information about biomarkers and clinical outcomes as they become available. We propose a Bayesian covariate-adjusted response-adaptive randomization design, which utilizes individual biomarker profiles and patient's clinical outcomes as they become available during the course of the trial, to assign the most efficacious treatment to individual patients. Predictive biomarker subgroups are determined adaptively using a partial least squares regression approach. A series of simulation studies were conducted to examine the operating characteristics of the proposed study design. The simulation studies show that the proposed design efficiently identifies patients who benefit most from a targeted therapy and that there are substantial savings in the sample size requirements when compared to alternative designs. The design does not control for the type I error in the traditional sense and a positive result should be confirmed by conducting an independent phase III study focusing on the selected biomarker profile groups. We conclude that the proposed design may serve a useful role in the early efficacy phase of targeted therapy development.


Specific chemical modifications in the beta-cleft site of hemoglobin. Potential anti-sickling agents with hybrid functionalities.
Ester and aldehyde groups have been combined to produce molecules with hybrid functionalities that might be effective in modifying hemoglobin. In this series of compounds, the reagents that carry the combination of an anionic charge and an aldehyde as binding groups show a strong preference for the beta-cleft region of the protein and produce selective modification therein. 5-Formylaspirin and related oxalyl, malonyl, and fumaryl monoaldehyde monoester derivatives form a new class of substances for which modification of hemoglobin is very substantial and is inhibited by inositol hexaphosphate.


Implicit mechanistic role of the collagen, smooth muscle, and elastic tissue components in strengthening the air and blood capillaries of the avian lung.
To identify the forces that may exist in the parabronchus of the avian lung and that which may explain the reported strengths of the terminal respiratory units, the air capillaries and the blood capillaries, the arrangement of the parabronchial collagen fibers (CF) of the lung of the domestic fowl, Gallus gallus variant domesticus was investigated by discriminatory staining, selective alkali digestion, and vascular casting followed by alkali digestion. On the luminal circumference, the atrial and the infundibular CF are directly connected to the smooth muscle fibers and the elastic tissue fibers. The CF in this part of the parabronchus form the internal column (the axial scaffold), whereas the CF in the interparabronchial septa and those associated with the walls of the interparabronchial blood vessels form the external, i.e. the peripheral, parabronchial CF scaffold. Thin CF penetrate the exchange tissue directly from the interparabronchial septa and indirectly by accompanying the intraparabronchial blood vessels. Forming a dense network that supports the air and blood capillaries, the CF weave through the exchange tissue. The exchange tissue, specifically the air and blood capillaries, is effectively suspended between CF pillars by an intricate system of thin CF, elastic and smooth muscle fibers. The CF course through the basement membranes of the walls of the blood and air capillaries. Based on the architecture of the smooth muscle fibers, the CF, the elastic muscle fibers, and structures like the interparabronchial septa and their associated blood vessels, it is envisaged that dynamic tensional, resistive, and compressive forces exist in the parabronchus, forming a tensegrity (tension integrity) system that gives the lung rigidity while strengthening the air and blood capillaries.


Hypermethylation of multiple tumor-related genes associated with DNMT3b up-regulation served as a biomarker for early diagnosis of esophageal squamous cell carcinoma.
This study was designed to determine the significance of DNA methyltransferases (DNMTs) in DNA hypermethylation in esophageal squamous cell carcinoma (ESCC) and to identify DNA methylation markers in serum for the early diagnosis of ESCC. A promoter methylation profile of 12 tumor-related genes was assessed using methylation-specific PCR in ESCC and paired non-tumor tissue samples from 47 patients. Expression levels of DNMTs were examined by real-time reverse transcription-PCR and immunohistochemistry. Using MethyLight, the methylation status of 5 genes was analyzed in serum samples from 45 patients and 15 healthy individuals. A total of 46 (97.9%) of 47 ESCC samples showed methylation in at least one of the examined genes, and methylation was most frequent for RAR-β (46.8%), DAPK (46.8%), p16 (44.7%), and CDH1 (42.6%). Methylation of RASSF1A was significantly correlated with the poorly differentiated tumors and the early pathologic tumor classification (P=0.035 and P=0.046, respectively). Tumoral DNMT3b mRNA up-regulation was significantly correlated with hypermethylation of multiple tumor-related genes (P=0.021). In addition, hypermethylation of cell-free serum DNA was common in ESCC patients, and diagnostic accuracy was increased when methylation of multiple genes (RAR-β, DAPK, CDH1, p16 and RASSF1A) were analyzed in combination (ROC AUC 0.911, 82.2% sensitivity and 100% specificity). The present study suggests that hypermethylation of multiple tumor-related genes may be involved in the pathogenesis of ESCC and mediated by the increase of DNMT3b expression. A cluster of multiple methylated genes in serum DNA has the potential as a novel biomarker for ESCC diagnosis.


The effectiveness of antioxidants in reducing paracetamol-induced damage subsequent to paracetamol activation.
Paracetamol toxicity was studied in isolated mouse hepatocytes. This drug produced a concentration- and time-dependent loss of cell viability. Exposure to 5 mM paracetamol produced a rapid fall in intracellular reduced glutathione (GSH) followed by a decrease in plasma membrane integrity. The antioxidant, diphenyl-p-phenylenediamine (DPPD) had no effect on either the loss of GSH, the binding of 14C-paracetamol metabolites to protein or the loss of plasma membrane integrity when hepatocytes were incubated in 5 mM paracetamol. When hepatocytes were exposed to paracetamol for 1 hr they showed a loss of plasma membrane integrity during the subsequent 7 hr incubation. DPPD, alpha-tocopherol and promethazine reduced this effect when added after the paracetamol exposure. It appears that paracetamol exposure initiates toxic events subsequent to the generation of the reactive metabolite but prior to cell death and that the progression of these events can be interrupted by compounds with antioxidant properties.


Regional brain stem activations during capsaicin inhalation using functional magnetic resonance imaging in humans.
Coughing is an airway protective behavior elicited by airway irritation. Animal studies show that airway sensory information is relayed via vagal sensory fibers to termination sites within dorsal caudal brain stem and thereafter relayed to more rostral sites. Using functional magnetic resonance imaging (fMRI) in humans, we previously reported that inhalation of the tussigenic stimulus capsaicin evokes a perception of airway irritation ("urge to cough") accompanied by activations in a widely distributed brain network including the primary sensorimotor, insular, prefrontal, and posterior parietal cortices. Here we refine our imaging approach to provide a directed survey of brain stem areas activated by airway irritation. In 15 healthy participants, inhalation of capsaicin at a maximal dose that elicits a strong urge to cough without behavioral coughing was associated with activation of medullary regions overlapping with the nucleus of the solitary tract, paratrigeminal nucleus, spinal trigeminal nucleus and tract, cardiorespiratory regulatory areas homologous to the ventrolateral medulla in animals, and the midline raphe. Interestingly, the magnitude of activation within two cardiorespiratory regulatory areas was positively correlated ( r2 = 0.47, 0.48) with participants' subjective ratings of their urge to cough. Capsaicin-related activations were also observed within the pons and midbrain. The current results add to knowledge of the representation and processing of information regarding airway irritation in the human brain, which is pertinent to the pursuit of novel cough therapies. NEW & NOTEWORTHY Functional brain imaging in humans was optimized for the brain stem. We provide the first detailed description of brain stem sites activated in response to airway irritation. The results are consistent with findings in animal studies and extend our foundational knowledge of brain processing of airway irritation in humans.


Osteoporosis risk and management in BRCA1 and BRCA2 carriers who undergo risk-reducing salpingo-oophorectomy.
Characterize current management of osteoporosis risk in BRCA carriers following risk-reducing salpingo-oophorectomy (RRSO). Women with a BRCA1 or BRCA2 mutation who underwent RRSO were identified from a community-based health system in Northern California from 1995 to 2012. Retrospective chart review using the electronic medical record was performed. The primary outcome was the number of women who had a dual-energy X-ray absorptiometry scan post-RRSO. Secondary outcomes included new diagnoses of osteopenia, osteoporosis, and fracture. Information on the following risk factors was also recorded: calcium and vitamin D use, history of breast cancer, chemotherapy, use of aromatase inhibitors, and use of hormone replacement therapy. Two hundred and twenty five women tested positive for a BRCA1 or BRCA2 mutation and underwent RRSO. Median follow-up was 41 months from testing. Ninety-nine (44.0%) had at least one DXA scan following testing. The median time from RRSO to a diagnosis of bone disease was 29 months (range 1-170). Seventy-two percent had only one DXA scan (range 1-7) following testing. Thirty-two percent had normal results, 55.6% had osteopenia and 12.1% had osteoporosis. Four percent of women had an atraumatic fracture after surgery. Age, breast cancer history, prior chemotherapy, and tamoxifen or aromatase inhibitor (AI) use were not associated with having osteoporosis or osteopenia. Women with BRCA mutations who undergo RRSO have many risk factors for bone loss. The majority of these women are not being screened for bone loss. A clear guideline for screening needs to be established to improve detection of post-RRSO bone disease.


Fusion of spatially separated vowel formant cues.
Previous studies on fusion in speech perception have demonstrated the ability of the human auditory system to group separate components of speech-like sounds together and consequently to enable the identification of speech despite the spatial separation between the components. Typically, the spatial separation has been implemented using headphone reproduction where the different components evoke auditory images at different lateral positions. In the present study, a multichannel loudspeaker system was used to investigate whether the correct vowel is identified and whether two auditory events are perceived when a noise-excited vowel is divided into two components that are spatially separated. The two components consisted of the even and odd formants. Both the amount of spatial separation between the components and the directions of the components were varied. Neither the spatial separation nor the directions of the components affected the vowel identification. Interestingly, an additional auditory event not associated with any vowel was perceived at the same time when the components were presented symmetrically in front of the listener. In such scenarios, the vowel was perceived from the direction of the odd formant components.


Extensive culturomics of 8 healthy samples enhances metagenomics efficiency.
Molecular approaches have long led to the assumption that the human gut microbiota is dominated by uncultivable bacteria. The recent advent of large-scale culturing methods, and in particular that of culturomics have demonstrated that these prokaryotes can in fact be cultured. This is increasing in a dramatic manner the repertoire of commensal microbes inhabiting the human gut. Following eight years of culturomics approach applied on more than 900 samples, we propose herein a remake of the pioneering study applying a dual approach including culturomics and metagenomics on a cohort of 8 healthy specimen. Here we show that culturomics enable a 20% higher richness when compared to molecular approaches by culturing 1 archaeal species and 494 bacterial species of which 19 were new taxa. Species discovered as a part of previous culturomics studies represent 30% of the cultivated isolates, while sequences derived from these new taxa enabled to increase by 22% the bacterial richness retrieved by metagenomics. Overall, 67% of the total reads generated were covered by cultured isolates, significantly reducing the hidden content of sequencing methods compared to the pioneering study. By redefining culture conditions to recover microbes previously considered fastidious, there are greater opportunities than ever to eradicate metagenomics dark matter.


Prevention of coronary heart disease: a nonhormonal approach.
Coronary heart disease (CHD) is a common and serious health problem facing women as they move beyond the reproductive years. Until recently, many postmenopausal women and their physicians relied heavily on hormone therapy to prevent cardiovascular disease, neglecting the well-recognized nonhormonal aspects of cardiovascular health. Simple lifestyle changes--exercise, diet, weight control, and avoidance of tobacco--can significantly reduce the chance of heart disease and its major risk factors, which are essentially the same for men and women. As with men, obesity, hypertension, hyperlipidemia, and diabetes are the major risk factors for heart disease in women. This review discusses the epidemiologic studies linking these risk factors to CHD in women, the guidelines for screening, and a brief overview of treatment recommendations.


Humans detect snakes more accurately and quickly than other animals under natural visual scenes: a flicker paradigm study.
Threat detection is crucial to survival. Studies using unnatural visual scene settings (i.e. visual search tasks) have shown that humans and primates are able to identify snakes more quickly than they are able to identify other animals. The present study employed a flicker paradigm task to assess whether humans detect snakes more accurately and rapidly than they do other reptiles in natural scene settings. Participants watched a long series of images, consisting of pairs of complex natural scenes. A blank interval was inserted between the two versions of the scene, showing only the scene and the scene plus an added animal (snake or lizard). Participants detected scene changes featuring the snake targets more accurately and rapidly than those with lizard targets. This finding supports the view that there were evolutionary pressures for a visual system which prioritised human detection of snakes.


Integrative Proteomic Analysis Reveals the Cytoskeleton Regulation and Mitophagy Difference Between Ischemic Cardiomyopathy and Dilated Cardiomyopathy.
Ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM) are the two primary etiologies of end-stage heart failure. However, there remains a dearth of comprehensive understanding the global perspective and the dynamics of the proteome and phosphoproteome in ICM and DCM, which hinders the profound comprehension of pivotal biological characteristics as well as differences in signal transduction activation mechanisms between these two major types of heart failure. We conducted high-throughput quantification proteomics and phosphoproteomics analysis of clinical heart tissues with ICM or DCM, which provided us the system-wide molecular insights into pathogenesis of clinical heart failure in both ICM and DCM. Both protein and phosphorylation expression levels exhibit distinct separation between heart failure and normal control heart tissues, highlighting the prominent characteristics of ICM and DCM. By integrating with omics results, Western blots, phosphosite-specific mutation, chemical intervention, and immunofluorescence validation, we found a significant activation of the PRKACA-GSK3β signaling pathway in ICM. This signaling pathway influenced remolding of the microtubule network and regulated the critical actin filaments in cardiac construction. Additionally, DCM exhibited significantly elevated mitochondria energy supply injury compared to ICM, which induced the ROCK1-vimentin signaling pathway activation and promoted mitophagy. Our study not only delineated the major distinguishing features between ICM and DCM but also revealed the crucial discrepancy in the mechanisms between ICM and DCM. This study facilitates a more profound comprehension of pathophysiologic heterogeneity between ICM and DCM and provides a novel perspective to assist in the discovery of potential therapeutic targets for different types of heart failure.


Structural studies suggest aggregation as one of the modes of action for teixobactin.
Teixobactin is a new promising antibiotic that targets cell wall biosynthesis by binding to lipid II and has no detectable resistance thanks to its unique but yet not fully understood mechanism of operation. To aid in the structure-based design of teixobactin analogues with improved pharmacological properties, we present a 3D structure of native teixobactin in membrane mimetics and characterise its binding to lipid II through a combination of solution NMR and fast (90 kHz) magic angle spinning solid state NMR. In NMR titrations, we observe a pattern strongly suggesting interactions between the backbone of the C-terminal "cage" and the pyrophosphate moiety in lipid II. We find that the N-terminal part of teixobactin does not only act as a membrane anchor, as previously thought, but is actively involved in binding. Moreover, teixobactin forms a well-structured and specific complex with lipid II, where the N-terminal part of teixobactin assumes a β conformation that is highly prone to aggregation, which likely contributes to the antibiotic's high bactericidal efficiency. Overall, our study provides several new clues to teixobactin's modes of action.


Selection of putative immunogenic peptides by molecular modelling of the urease of Helicobacter pylori.
Computational methods such as molecular modelling are becoming an increasingly useful means of rationalising experimental data and creating a hypothesis that can suggest new experiments. In this report we discuss the application of molecular modelling methods to aid the selection of feasible peptide epitopes of the urease enzyme from Helicobacter pylori, an important vaccine candidate. Surface exposure was chosen as a criterion for the selection of three peptides which each had different levels of accessibility according to the 3D model. Antibodies raised against these peptides were analysed for their immunoreactivity with the holo enzyme. Only one anti-peptide antibody showed good reactivity with the urease. Our findings emphasise that surface exposure of peptide is not the only important criterion for the selection of immunogenic peptides.


Two-Dimensional Zeolitic Imidazolate Framework/Carbon Nanotube Hybrid Networks Modified Proton Exchange Membranes for Improving Transport Properties.
Metal-organic framework (MOF)/polymer composite proton exchange membranes (PEMs) are being intensively investigated due to their potentials for the systematic design of proton-conducting properties. However, the development of MOF/polymer composite PEMs possessing high selectivity remains exceedingly desirable and challenging for practical application. Herein, two-dimensional (2D) zeolitic imidazolate framework (ZIF-8)/carbon nanotube (CNT) hybrid cross-linked networks (ZCN) were synthesized via the rational design of the physical form of ZIF-8, and then a series of composite PEMs were prepared by hybridizing ZCN with sulfonated poly(ether ether ketone) (SPEEK) matrix. The effect of the incorporation of zero-dimensional (0D) raw ZIF-8 nanoparticles and 2D ZCN on the proton conduction and methanol permeability of the composite membranes was systemically studied. Benefiting from the morphological and compositional advantages of ZCN, the SPEEK/ZCN composite membranes displayed a significant enhancement in proton conductivity under various conditions. In particular, the proton conductivity of SPEEK/ZCN-2.5 membrane was up to 50.24 mS cm-1 at 120 °C-30% RH, which was 11.2 times that of the recast SPEEK membrane (4.50 mS cm-1) and 2.1 times that of SPEEK/ZIF membrane (24.1 mS cm-1) under the same condition. Meanwhile, the methanol permeability of the SPEEK/ZCN composite membranes was greatly reduced. Therefore, novel MOF/polymer composite PEMs with high selectivity were obtained. Our investigation results reveal that the proton conductivity and methanol permeability of the MOF/polymer composite membranes can be effectively tailored via creating more elaborate superstructures of MOFs rather than altering the chemical component. This effective strategy may provide a useful guideline to integrate with other interesting MOFs to design MOF/polymer composite membranes.


Recognition of "real-world" musical excerpts by cochlear implant recipients and normal-hearing adults.
The purposes of this study were (a) to compare recognition of "real-world" music excerpts by postlingually deafened adults using cochlear implants and normal-hearing adults; (b) to compare the performance of cochlear implant recipients using different devices and processing strategies; and (c) to examine the variability among implant recipients in recognition of musical selections in relation to performance on speech perception tests, performance on cognitive tests, and demographic variables. Seventy-nine cochlear implant users and 30 normal-hearing adults were tested on open-set recognition of systematically selected excerpts from musical recordings heard in real life. The recognition accuracy of the two groups was compared for three musical genre: classical, country, and pop. Recognition accuracy was correlated with speech recognition scores, cognitive measures, and demographic measures, including musical background. Cochlear implant recipients were significantly less accurate in recognition of previously familiar (known before hearing loss) musical excerpts than normal-hearing adults (p < 0.001) for all three genre. Implant recipients were most accurate in the recognition of country items and least accurate in the recognition of classical items. There were no significant differences among implant recipients due to implant type (Nucleus, Clarion, or Ineraid), or programming strategy (SPEAK, CIS, or ACE). For cochlear implant recipients, correlations between melody recognition and other measures were moderate to weak in strength; those with statistically significant correlations included age at time of testing (negatively correlated), performance on selected speech perception tests, and the amount of focused music listening following implantation. Current-day cochlear implants are not effective in transmitting several key structural features (i.e., pitch, harmony, timbral blends) of music essential to open-set recognition of well-known musical selections. Consequently, implant recipients must rely on extracting those musical features most accessible through the implant, such as song lyrics or a characteristic rhythm pattern, to identify the sorts of musical selections heard in everyday life.


Nonlinear Flow Process: A New Package to Compute Nonlinear Flow in MODFLOW.
A new MODFLOW package (Nonlinear Flow Process; NLFP) simulating nonlinear flow following the Forchheimer equation was developed and implemented in MODLFOW-2005. The method is based on an iterative modification of the conductance calculated and used by MODFLOW to obtain an effective Forchheimer conductance. The package is compatible with the different layer types, boundary conditions, and solvers as well as the wetting capability of MODFLOW. The correct implementation is demonstrated using four different benchmark scenarios for which analytical solutions are available. A scenario considering transient flow in a more realistic setting and a larger model domain with a higher number of cells demonstrates that NLFP performs well under more complex conditions, although it converges moderately slower than the standard MODFLOW depending on the nonlinearity of flow. Thus, this new tool opens a field of opportunities to groundwater flow simulation with MODFLOW, especially for core sample simulation or vuggy karstified aquifers as well as for nonlinear flow in the vicinity of pumping wells.


Automation in future air traffic management: effects of decision aid reliability on controller performance and mental workload.
Future air traffic management concepts envisage shared decision-making responsibilities between controllers and pilots, necessitating that controllers be supported by automated decision aids. Even as automation tools are being introduced, however, their impact on the air traffic controller is not well understood. The present experiments examined the effects of an aircraft-to-aircraft conflict decision aid on performance and mental workload of experienced, full-performance level controllers in a simulated Free Flight environment. Performance was examined with both reliable (Experiment 1) and inaccurate automation (Experiment 2). The aid improved controller performance and reduced mental workload when it functioned reliably. However, detection of a particular conflict was better under manual conditions than under automated conditions when the automation was imperfect. Potential or actual applications of the results include the design of automation and procedures for future air traffic control systems.


Dissociation of hippocampus and caudate nucleus memory systems by posttraining intracerebral injection of dopamine agonists.
The effect of posttraining intracerebral injections of the indirect dopamine (DA) agonist d-amphetamine, the direct D2 agonist LY 171555, and the direct D1 agonist SKF-38393 on the acquisition of two 8-arm radial maze tasks were examined. On a win-stay task, a light cue signaled the location of food in 4 randomly selected maze arms on each trial, and animals were required to visit each of the lit arms twice within a trial. Posttraining intracaudate injection of d-amphetamine (10.0 and 15.0 micrograms), LY 171555 (2.0 micrograms), and SKF-38393 (5.0 micrograms) all improved win-stay acquisition in relation to saline-injected controls. In contrast, posttraining intrahippocampal injection of DA agonists had no effect on win-stay acquisition. On a win-shift task, rats were allowed to obtain food from 4 randomly selected maze arms, followed by a delay period in which they were removed from the maze. They were returned to the maze for a retention test in which only those arms that had not been visited before the delay contained food. Posttraining intrahippocampal (but not intracaudate) injection of d-amphetamine (5.0 micrograms), LY 171555 (2.0 micrograms), and SKF-38393 (5.0 micrograms) all improved win-shift retention in relation to saline-injected controls. The results demonstrate a double dissociation of hippocampus and caudate nucleus memory functions and show that posttraining injection of both D1 and D2 agonists modulate the memory processes subserved by both hippocampus and caudate nucleus.


Survival impact of rituximab combined with ACVBP and upfront consolidation autotransplantation in high-risk diffuse large B-cell lymphoma for GELA.
As rituximab combined with CHOP improves complete remission and overall survival in diffuse large B-cell lymphoma, intensified chemotherapy followed by autologous stem-cell transplantation has also been advocated for high-risk patients. The aim of this study was to establish whether or not combining rituximab with high-dose chemotherapy and auto-transplantation also benefits patient survival. The LNH2003-3 study was a phase II trial including diffuse large B-cell lymphoma patients with 2 or 3 International Prognostic Index factors. They received four cycles of intensive biweekly chemotherapy with rituximab, doxorubicine, cyclophosphamide, vindesine, bleomycine, prednisolone (R-ACVBP) followed by auto-transplantation in responding patients. Two hundred and nine patients under 60 years of age were included in the study and 155 responding patients underwent auto-transplantation. In addition, a case-control study was performed by matching (1:1) 181 patients treated with R-ACVBP with ACVBP patients not given rituximab but submitted to auto-transplantation from the previous LNH1998-3 trial. With a median follow up of 45 months, 4-year progression-free survival and overall survival were estimated at 76% (CI: 69-81) and 78% (CI: 72-83), respectively. There was no difference between patients with 2 or 3 International Prognostic Index factors. Four year progression-free survival was significantly higher in R-ACVBP than ACVBP patients (74% vs. 58%; P=0.0005). There was also a significant increase in 4-year overall survival (76% vs. 68%; P=0.0494). In high-risk diffuse large B-cell lymphoma patients, treatment with R-ACVBP followed by auto-transplantation results in a 78% 4-year overall survival which should be compared to other approaches.


Estimating the benefits of increasing the recycling rate of lamps from the domestic sector: Methodology, opportunities and case study.
The scope of this paper is to identify the benefits of lamp recycling from the domestic sector. Data related to the recycled lamps was obtained from two recycling companies and were compared to those related to the waste lamps from the domestic sector. This was achieved by a new methodology which uses two alternative approaches. The first one is dependent on previous research data in relation to the number of active lamps while the second one elaborates on electricity consumption and sales data, in order to define the corresponding number of active lamps., The wasted amount of glass, metal and plastic is calculated along with the energy savings, the annual emissions of CO2-eq, the economic benefit from their sale and the potential reduction of hazardous waste, such as mercury to solid waste landfills under various scenarios. The amount of recovered materials collected by the Hellenic recycling companies contributes to a reduction of CO2-eq by 1298 tonnes, which falls significantly short of the CO2-eq that could have been saved 3108-5463tonnes if all the lamps were recycled. Furthermore, the recycling companies have an annual economic benefit of €32,251 which could be increased by €122,725 if all lamps were recycled together with the proper recycling of 3.4 kg of mercury, which was disposed in the environment. Finally, a future scenario was examined, in which all lamps in the domestic sector were assumed to be LEDs, an issue that can affect the viability of the recycling factories and it was proved that these might be affected.


Cox-2 deletion in myeloid and endothelial cells, but not in epithelial cells, exacerbates murine colitis.
Patients with inflammatory bowel diseases are at increased risk for colorectal cancer. Pharmacological inhibition of cyclooxygenase (COX) function exacerbates symptoms in colitis patients. Animal models of colitis using Cox-2-knockout mice and COX inhibitors also indicate that COX-2 has a protective role against colon inflammation. However, because conventional Cox-2 deletion and COX-2 inhibitors eliminate COX-2 function in all cells, it has not been possible to analyze the role(s) of COX-2 in different cell types. Here, we use a Cox-2(flox) conditional knockout mouse to analyze the role of COX-2 expression in distinct cell types in the colon in response to dextran sulfate sodium (DSS)-induced colitis. We generated Cox-2 conditional knockouts in myeloid cells with LysMCre knock-in mice, in endothelial cells with VECadCreERT2 transgenic mice and in epithelial cells with VillinCre transgenic mice. When treated with DSS to induce colitis, both myeloid cell-specific and endothelial cell-specific Cox-2-knockout mice exhibited greater weight loss, increased clinical scores and decreased epithelial cell proliferation after DSS injury when compared with littermate controls. In contrast, epithelial-specific Cox-2 knockouts and control littermates did not differ in response to DSS. These results suggest that COX-2 expression in myeloid cells and endothelial cells, but not epithelial cells, is important for protection of epithelial cells in this murine colitis model.


Effect of medium composition and sludge removal on the production, composition, and architecture of thermophilic (55 degrees C) acetate-utilizing granules from an upflow anaerobic sludge blanket reactor.
A thermophilic upflow anaerobic sludge blanket (UASB) reactor degrading acetate was started by applying published methods (W. M. Wiegant and A. W. A. de Man, Biotechnol. Bioeng. 28:718-77, 1986) for production of granules dominated by Methanothrix spp. The reactor was inoculated with thermophilic digested sludge. No granules were observed during the first 7 months of start-up of the UASB reactor. However, after the concentrations of potassium, phosphate, ammonium, and magnesium in the medium were gradually increased, granules developed, indicating that there was a critical concentration of one or more of the ions required for production of granules from the starting material. After several years of stable operation, the effect of removing 60% of the granular sludge was investigated. Immunologic qualitative and quantitative studies showed that removal of the granular sludge resulted in an increase in the number of the predominant methanogens, antigenically related to Methanosarcina thermophila TM-1 and Methanosarcina mazeii S-6, and Methanobacterium thermoautotrophicum delta H and GC1. These changes were accompanied by modifications of the microanatomy of the granules, as demonstrated histochemically and immunohistochemically. The results indicated that different catabolic pathways dominated in different regions of the granules, i.e., acetate oxidation in the middle of the granules, where there is a low acetate concentration, and an aceticlastic reaction in the outer surfaces, with a high acetate concentration. The results also showed that removal of granules from a UASB reactor which has been under steady-state operation for a long period can improve the reactor's performance via formation of denser and larger granules with improved microbial activities.


The association between cardiovascular risk factors and anthropometric obesity indicators in university students in São Luís in the State of Maranhão, Brazil.
The article aims to evaluate the relation between cardiovascular risk factors (CVRF) and anthropometric indicators in a sample of university students from São Luís-MA, Brazil. It is a cross-sectional study conducted with 968 university students, with median age of 22. Glycemia, triglycerides, HDL-c, smoking, alcohol consumption, physical inactivity, metabolic syndrome (Joint Interim Statement criteria) and insulin resistance (IR), were associated and correlated with anthropometric indicators such as BMI, WC, WHR and WHtR. Associations were found between TGL, SH, SM and higher values of all anthropometric variables. The RI was associated with higher BMI values and WHtR in men and women. The low HDL-c was associated with higher values of all anthropometric variables in women. Consumption of alcohol was associated with higher values of BMI and WC in women and WHR in men and WHtR. Smoking was associated with higher values of WHtR in both sexes. Physical inactivity was associated with higher values of WHR in men only. The highest correlations were established for women between TGL and BMI CC, WHR and WHtR. The indicators most associated with CVRF were BMI, WC and WHtR in females and WHR and WHtR in men.


A histopathological mapping study of the urinary bladder tumors induced by N-butyl-N-(4-hydroxybutyl)nitrosamine in dogs.
Bladder tumors were induced by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in five Beagles and four mongrel dogs. The tumors were observed for long periods and the tumor progression was traced using histopathological mapping. The results indicated (1) that low-dose BBN over a long period induced multiple low-grade (G1-2) and low-stage (pTa-1) papillary tumors, resembling superficial bladder cancer in humans; (2) that high-dose BBN over a short period induced high-grade (G2-3) and high-stage (pT3b) nonpapillary tumors and carcinoma in situ (CIS) resembling invasive cancer and CIS in humans; (3) that beagle dogs required longer periods and higher total doses of BBN as compared with mongrel dogs; (4) that the tumors induced by low-dose BBN in beagles were observed without BBN as long as the animals lived, and neither increasing numbers of tumors nor malignant features such as deep infiltration and metastasis was observed; and (5) that low-dose BBN seems to induce mild dysplasia, which is followed by Brunn's nest-like proliferation in the lamina propria and nodular change, eventually leading to the development of papillary noninvasive transitional cell carcinoma (TCC); and that high-dose BBN seems to induce severe dysplasia which leads to CIS and nonpapillary invasive TCC. These results may contribute to clarifying the natural history of human bladder cancer.


A multicentre study on the reliability of qualitative and quantitative nail-fold videocapillaroscopy assessment.
To investigate the inter- and intra-observer reliability of both qualitative and quantitative parameters used in the assessment of nail-fold capillaroscopy images. Fifty mosaic nail-fold images of healthy controls (n = 10), patients with primary RP (n = 10) and SSc (n = 30) were assessed in random order by two blinded observers on two occasions at centres in Sweden, UK and The Netherlands. Each image was therefore scored by six observers twice. Inter- and intra-observer reliability of quantitative parameters showed substantial to almost perfect agreement [inter- and intra-observer weighted κ's for the number of widened capillaries was 0.75 and 0.87 and giant capillaries was 0.84 and 0.92, intra-class correlation coefficients (ICCs) for capillary density was 0.87 and 0.92 and total loop width was 0.94 and 0.98, respectively]. Qualitative parameters including architecture, avascularity, haemorrhage, crossed, ramified and bushy capillaries showed moderate to substantial inter-observer reproducibility (weighted κ ranging from 0.47 to 0.73), and substantial intra-observer repeatability (weighted κ ranging from 0.71 to 0.80), whereas the scoring of tortuous and bizarre capillaries showed poor inter-observer and substantial intra-observer agreement (inter-observer weighted κ's was 0.39 and 0.21 and intra-observer weighted κ's was 0.68 and 0.76, respectively). All quantitative and certain qualitative parameters are highly reliable in terms of inter- and intra-observer agreement. A combination of parameters with the highest reliability should be incorporated into future capillaroscopic scoring systems in studies of prediction and monitoring of SSc spectrum disorders.


Siglec-F-expressing neutrophils are essential for creating a profibrotic microenvironment in renal fibrosis.
The roles of neutrophils in renal inflammation are currently unclear. On examining these cells in the unilateral ureteral obstruction murine model of chronic kidney disease, we found that the injured kidney bore a large and rapidly expanding population of neutrophils that expressed the eosinophil marker Siglec-F. We first verified that these cells were neutrophils. Siglec-F+ neutrophils were recently detected in several studies in other disease contexts. We then showed that a) these cells were derived from conventional neutrophils in the renal vasculature by TGF-β1 and GM-CSF; b) they differed from their parent cells by more frequent hypersegmentation, higher expression of profibrotic inflammatory cytokines, and notably, expression of collagen 1; and c) their depletion reduced collagen deposition and disease progression, but adoptive transfer increased renal fibrosis. These findings have thus unveiled a subtype of neutrophils that participate in renal fibrosis and a potentially new therapeutic target in chronic kidney disease.


Acute Symptomatic Seizures in Geriatric Patients with Multiple Risk Factors - A Diagnostic Challenge.
Acute symptomatic seizures and epileptic disorders are frequent health problems of elderly patients. An early and reliable distinction of the seizure etiology is important to ensure adequate treatment, and to prevent unwarranted diagnostic and therapeutic procedures. We review the current literature based on a MEDLINE search, describe age-related problems in detail, with particular attention to clinical practice, discuss possible criteria and potential pitfalls for diagnostics, and provide a compilation of etiologic factors for acute symptomatic seizures. The most common causes of acute symptomatic seizures - acute cerebrovascular disorders, metabolic disorders, traumatic brain injury, meningo-encephalitis, cerebral tumors, and withdrawal of alcohol and other central agents - are well-defined and seem to permit straightforward diagnostic and therapeutic strategies. The current classification of seizures and epileptic syndromes apparently provides clear definitions. However, multiple age-related risk factors, as well as a reduced discriminatory power of clinical and technical diagnostic criteria can make the distinction difficult. Typical age-related problems are incomplete or missing medical history, dementia, oligosymptomatic seizures, inconclusive EEG and cerebral imaging results, multiple pathological findings and comorbidity with ambiguous significance, confounding sleep disorders, intake of proconvulsive drugs, and psychogenic seizures. All diagnostic and therapeutic decisions need to be based on an integrative and individual approach that includes diagnostic findings and risk factors, the intake of medications and other agents, and the social situation of the elderly patient.


Syndrome of inappropriate antidiuretic hormone secretion in malignancy: review and implications for nursing management.
Hyponatremia is a common fluid and electrolyte disturbance in adults with cancer. Although a number of etiologies are associated with hyponatremia, the syndrome of inappropriate antidiuretic hormone (SIADH) secretion is one of the most common underlying causes. Early symptoms often associated with SIADH are subtle but, if left untreated, may progress to life-threatening seizures, coma, and death. Because oncology nurses have frequent and ongoing contact with patients, they are in an ideal position to recognize patients who are at increased risk for SIADH and those who present with early symptoms. Beginning signs and symptoms are mild and can be mistakenly attributed to other causes. This article reviews the pathophysiology of SIADH, associated risk factors, signs and symptoms, diagnosis, treatment, and nursing care.


A bibliometric study of the trend in articles related to epidemiology published in occupational health journals.
To study the role assumed by epidemiology in occupational health literature and characterise its change over the years. A bibliometric study was conducted with a MEDLINE search to evaluate 9024 articles published in eight representative occupational health journals for the period 1980-93. Articles related to epidemiology were found by descriptors indexed in the articles and their numbers and proportions among all published articles was tabulated for the study period. The proportion of source items indexed by epidemiology as a descriptor increased over threefold from 7.9% (42/534) in 1980 to over 25% after 1990. Epidemiology was indexed most frequently as a subheading associated with other descriptors-for example, occupational diseases-epidemiology. Cohort studies had the largest increase in the descriptors that indicated epidemiological type of studies during the period studied. Epidemiology is assuming increasing importance in occupational health literature. This was shown quantitatively and qualitatively by the use of descriptors in the MEDLINE database.


Unilateral facial swelling in an infant.
The melanotic neuroectodermal tumour of infancy (MNTI) is an uncommon, usually benign neoplasm which is most commonly found in the maxilla. We describe the case of a 6-month-old boy who was referred with a swiftly increasing swelling of the left cheek. After imaging and biopsy, MNTI was confirmed, and surgical resection was performed. Literature demonstrates that most MNTIs occur in the head and neck area and most of those occur in the maxilla. Although most cases are benign, 6.5% are malignant with metastatic disease. Treatment and outcome are discussed in detail. The case highlights the importance of making the diagnosis MNTI early on in order to achieve an optimal outcome.


Deep learning-based molecular morphometrics for kidney biopsies.
Morphologic examination of tissue biopsies is essential for histopathological diagnosis. However, accurate and scalable cellular quantification in human samples remains challenging. Here, we present a deep learning-based approach for antigen-specific cellular morphometrics in human kidney biopsies, which combines indirect immunofluorescence imaging with U-Net-based architectures for image-to-image translation and dual segmentation tasks, achieving human-level accuracy. In the kidney, podocyte loss represents a hallmark of glomerular injury and can be estimated in diagnostic biopsies. Thus, we profiled over 27,000 podocytes from 110 human samples, including patients with antineutrophil cytoplasmic antibody-associated glomerulonephritis (ANCA-GN), an immune-mediated disease with aggressive glomerular damage and irreversible loss of kidney function. We identified previously unknown morphometric signatures of podocyte depletion in patients with ANCA-GN, which allowed patient classification and, in combination with routine clinical tools, showed potential for risk stratification. Our approach enables robust and scalable molecular morphometric analysis of human tissues, yielding deeper biological insights into the human kidney pathophysiology.


Osteoporosis among Patients with Chronic Obstructive Pulmonary Disease: Systematic Review and Meta-analysis of Prevalence, Severity, and Therapeutic Outcomes.
Chronic obstructive pulmonary disease (COPD) can be associated with systemic inflammatory trademarks and can coexist with other chronic debilitating diseases such as osteoporosis, which is considered among the most serious comorbidities of COPD. In this review, we aimed at finding answers for the following questions and tried to encapsulate the available literature: (1) how prevalent is osteoporosis among patients with COPD? (2) What are severity patterns of osteoporosis in case of COPD? (3) What are the therapeutic outcomes for patients with osteoporotic COPD? The total number of patients with COPD from all studies was 3815, majority of which were male (2658) representing 69.67% of patients. The mean ± standard deviation for percentage of forced expiratory volume in 1s (FEV1%) was 55.43 ± 14.62%, body mass index for almost 91.29% of patients was 24.4 ± 4.45 kg/m2, whereas fat-free mass index (FFMI) was 17 ± 0.93 kg/m2 for 17.66%. The percentage of patients with COPD having osteoporosis varied in the analyzed studies from 14% up to 66.6%. The mean prevalence of reported osteopenia from 14 studies (n = 2107) was 39.91%, whereas for osteoporosis, the mean prevalence was 37.62% for all included studies. Osteoporosis was highly prevalent among patients with COPD. It is reasonable to call for osteoporosis screening in patients with COPD who are above 65 years, in advanced stages, with BMI lower than 21 kg/m2 or with FFMI lower than 16 kg/m2 for males and 15 kg/m2 for females. There is a lack of research investigating severity and treatments of osteoporosis in patients with COPD.


Methylglyoxal-induced fibronectin gene expression through Ras-mediated NADPH oxidase activation in renal mesangial cells.
The formation of methylglyoxal (MGO), a highly reactive dicarbonyl compound, is accelerated under diabetic conditions. Although recent studies have suggested that apoptotic cell death is involved in diabetic nephropathy, the precise mechanism of MGO-induced renal fibrosis remains to be elucidated. Rat kidney mesangial cells with or without pretreatment with inhibitors, including superoxide dismutase, catalase, L-NAME, diphenylene iodonium, rotenone, allopurinol, PD98059, SB203580 and SP600125 were cultured in medium containing 100 microM MGO. In the MGO-treated cell culture system, fibrosis-related signalling pathway was assessed by enzyme-linked immunosorbent assay, reverse transcription-polymerase chain reaction and western blotting. Expression of fibronectin induced by MGO was highest after 48 h treatment. Superoxide production rapidly increased after 2 h and remained at a high level for 24 h. Scavenging O(2) (-) reversed transforming growth factor beta 1 (TGF-beta1) and fibronectin mRNA level. Pretreatment with diphenylene iodonium significantly suppressed MGO-induced superoxide, TGF-beta1 expression and fibronectin gene expression, indicating that NADPH oxidase is responsible for inducing superoxide formation and subsequently induced renal fibrosis. High MGO rapidly enhanced Ras activation in 1 h and progressively increased cytosolic p38 activation. Additionally, SB203580 pretreatment reduced MGO promotion of fibronectin gene activation suggesting that cytosolic p38 activation might affect MGO-induced renal mesangial fibrosis. Inhibiting Ras activity with manumycin A significantly reduced the promoting effect of MGO on superoxide synthesis, and fibronectin expression. Induction of superxoide by Ras via p38 pathway activates fibrotic gene transcription of mesangial cells. Reduction of oxidative stress by scavenging superoxide may offer an alternative strategy for controlling MGO-induced renal fibrosis.


Associations between recreational walking and attractiveness, size, and proximity of neighborhood open spaces.
We examined associations of attractiveness, size, and proximity of multiple neighborhood open spaces (NOSs) with recreational walking. Adults participating in the Residential Environments (RESIDE) study (n=1366) in Perth, Australia, reported time spent engaging in recreational walking within their neighborhoods. Park audit data and geographic information systems were used to identify the most attractive, largest, and nearest NOS within a 1.6-km radius from each participant's residential location. Regression analysis was used to examine attributes (attractiveness, size, and proximity) of these open spaces and their associations with participants' recreational walking. Shorter distance to attractive open spaces was associated with doing any recreational walking, but adults with larger attractive open spaces within 1.6 km of their home were more likely to walk 150 minutes or more in a week. For adults, the presence of a large, high-quality park within walking distance of one's home may be more important in promoting sufficient amounts of walking for health benefits than is the presence of an open space within a shorter distance.


Biotin uptake by cold-shocked cells, spheroplasts, and repressed cells of Saccharomyces cerevisiae: lack of feedback control.
Cold-osmotic-shocked cells and spheroplasts of Saccharomyces cerevisiae (ATCC 9896) display a biotin uptake system similar to that observed in intact cells. 2-Mercaptoethanol was found to inhibit biotin transport. Cells repressed for biotin uptake by growth in excess biotin (25 ng/ml) possess an energy-dependent transport system that has a K(m) for biotin of 6.6 x 10(-7) M and a V(max) equal to 39 pmol per mg (dry weight) per min. A similar K(m) (6.4 x 10(-7) M) but a considerably higher V(max) (530 pmol per mg (dry weight) per min) was determined for biotin uptake by cells grown in sufficient biotin (0.25 ng/ml). The V(max) rates of biotin uptake by both repressed and derepressed cells were increased approximately 35-fold in the presence of glucose. These yeast cells appear to regulate their biotin uptake by two mechanisms. An exit system provides for immediate adjustments, whereas turnover of the transport system and repression of new synthesis establishes a slower adaptation to changes in the environment. Feedback inhibition was ruled out as a mechanism of regulation of transport.


Transition to new global standards on hold.
The nation's major standard-setting body for health care financial transactions has delayed a decision on migrating to new, international standards. An immediate move to EDIFACT standards would have been a setback for efforts to encourage the use of standards-based EDI.


Substrate selected polymorphism of epitaxially aligned tetraphenyl-porphyrin thin films.
Porphyrin molecules, of interest as versatile materials for organic electronics, are highly prone to formation of significantly different polymorphic phases. To elucidate the determinants for the specific polymorphic phase formed in thin films as well as for the arrangement of the molecules on a given substrate two different anisotropic substrate surfaces have been selected: KCl(100) and the oxygen reconstructed Cu(110) surface. We observe that the crystal structure of the thin films depends on the substrate, whereas the relative molecular orientations in both cases are similar. X-Ray and transmission electron diffraction of 30 nm thick tetraphenyl-porphyrin (H(2)TPP) and platinum tetraphenyl-porphyrin (PtTPP) thin films deposited on KCl(100) surfaces reveals that both kinds of molecules crystallize in a tetragonal polymorph with the (001) lattice planes, i.e. with their macrocycles, parallel to the substrate. Films deposited on the oxygen reconstructed Cu(110)-(2 × 1)O surface exhibit in contrast the triclinic polymorph even though molecules again align nearly parallel to the substrate surface as observed by LEED and X-ray diffraction. On both substrates we identify two driving forces for the epitaxial alignment of porphyrins: (i) molecules aligning with their macrocycles (nearly) parallel to the substrate surface and (ii) the porphyrin molecules forming a commensurate unit cell with the respective substrate. The polymorphic phase meeting both requirements is the most favorable to be formed on a given substrate and due to this structural flexibility in both cases well-ordered, epitaxially aligned porphyrin thin films are achieved.


Highly sensitive detection of blood by surface enhanced Raman scattering.
Raman spectroscopy for forensic body fluid analysis has received some attention due to the nondestructive nature and potential application for identification at the crime scene; however, its usage has been limited by low detection sensitivity. Surface enhanced Raman scattering (SERS) was evaluated for blood identification for forensic applications. Specifically, a SERS-active substrate was fabricated, composed of nickel nanotips coated with Ag nanoparticles. Compared with a conventional substrate, the SERS substrate enhanced Raman scattering by more than two orders of magnitude and allowed blood to be identified to a dilution of 1:100,000. Blood was also successfully detected by swabbing the SERS substrate directly on mock evidence. Most importantly, Raman spectra obtained by swabbing the SERS substrate on blood stains were free of luminescence even when blood was deposited on luminescent fabrics. The nondestructive character, simplicity of sample preparation, and high sensitivity make SERS a prime candidate for field and laboratory-based blood identification.


Association Between Knee Anatomic Metrics and Biomechanics for Male Soldiers Landing With Load.
Anterior cruciate ligament (ACL) injury is a military occupational hazard that may be attributed to an individual's knee biomechanics and joint anatomy. This study sought to determine if greater flexion when landing with load resulted in knee biomechanics thought to decrease ACL injury risk and whether knee biomechanics during landing relate to knee anatomic metrics. Anatomic metrics regarding the slope and concavity of the tibial plateau will exhibit a significant relation to the increased anterior shear force on the knee and decreased knee flexion posture during landing with body-borne load. Descriptive laboratory study. Twenty male military personnel completed a drop landing task with 3 load conditions: light (~6 kg), medium (15% body weight), and heavy (30% body weight). Participants were divided into groups based on knee flexion exhibited when landing with the heavy load (high- and low-Δflexion). Tibial slopes and depth were measured on weightbearing volumetric images of the knee obtained with a prototype cone beam computed tomography system. Knee biomechanics were submitted to a linear mixed model to evaluate the effect of landing group and load, with the anatomic metrics considered covariates. Load increased peak proximal anterior tibial shear force (P = .034), knee flexion angle (P = .024), and moment (P = .001) during landing. Only the high flexion group increased knee flexion (P < .001) during weighted landings with medium and heavy loads. The low flexion group used greater knee abduction angle (P = .030) and peak proximal anterior tibial shear force (P = .034) when landing with load. Anatomic metrics did not differ between groups, but ratio of medial-to-lateral tibial slope and medial tibial depth predicted peak proximal anterior tibial shear force (P = .009) and knee flexion (P = .034) during landing, respectively. Increasing knee flexion is an attainable strategy to mitigate risk of ACL injury, but certain individuals may be predisposed to knee forces and biomechanics that load the ACL during weighted landings. The ability to screen individuals for anatomic metrics that predict knee flexion may identify soldiers and athletes who require additional training to mitigate the risk of lower extremity injury.


[Evaluation of the functional activity of the liver following its heterotopic transplantation in experimental acute hepatic insufficiency].
The functional activity of the transplanted (additional) liver and its efficiency in the treatment of critical hepatic insufficiency was studied in experiments on dogs. Without an immunosuppression being used the additionally transplanted liver manifests its functional activity in the recipient's organism within 4 days and is able to support the animal's life for 3-4 days.


Inhibition of Ca2+-Release-Activated Ca2+ Channel (CRAC) and K+ Channels by Curcumin in Jurkat-T Cells.
The increase in cytoplasmic Ca2+ concentration (Δ[Ca2+]c) mediated by the Ca2+-release-activated Ca2+ channel (CRAC) is a critical signal for the activation of lymphocytes. Also, the voltage-gated K+ channel (Kv) and intermediate-conductance Ca2+-activated K+ channel (IKCa1/SK4) have drawn attention as pharmacological targets for regulating immune responses. Since polyphenolic agents have various immunomodulatory effects, here we compared the effects of curcumin, rosmarinic acid, resveratrol, and epigallocatechin gallate on the ionic currents through CRAC (ICRAC), Kv (IKv), SK4 (ISK4) and on the Δ[Ca2+]c of Jurkat-T cells using the patch clamp technique and fura-2 spectrofluorimetry. Curcumin (10 μM) inhibited store-operated Ca2+ entry (SOCE). Consistently, dose-dependent inhibition of ICRAC by curcumin was confirmed in Jurkat-T (IC50, 5.9 μM) and the HEK293 cells overexpressing Orai1 and STIM1 (IC50, 0.6 μM). Also, curcumin inhibited both IKv (IC50, 11.9 μM) and ISK4 (IC50, 4.2 μM). The other polyphenols (rosmarinic acid, resveratrol, and epigallocatechin gallate at 10 - 30 μM) had no effect on SOCE and showed only a partial inhibition of the K+ currents. In summary, among the tested polyphenolic agents, curcumin showed prominent inhibition of major ion channels in lymphocytes, which might contribute to the anti-inflammatory effects of curcumin. [Supplementary Figures: available only at http://dx.doi.org/10.1254/jphs.10209FP].


Predictive markers of clinical outcome in the GRMD dog model of Duchenne muscular dystrophy.
In the translational process of developing innovative therapies for DMD (Duchenne muscular dystrophy), the last preclinical validation step is often carried out in the most relevant animal model of this human disease, namely the GRMD (Golden Retriever muscular dystrophy) dog. The disease in GRMD dogs mimics human DMD in many aspects, including the inter-individual heterogeneity. This last point can be seen as a drawback for an animal model but is inherently related to the disease in GRMD dogs closely resembling that of individuals with DMD. In order to improve the management of this inter-individual heterogeneity, we have screened a combination of biomarkers in sixty-one 2-month-old GRMD dogs at the onset of the disease and a posteriori we addressed their predictive value on the severity of the disease. Three non-invasive biomarkers obtained at early stages of the disease were found to be highly predictive for the loss of ambulation before 6 months of age. An elevation in the number of circulating CD4(+)CD49d(hi) T cells and a decreased stride frequency resulting in a reduced spontaneous speed were found to be strongly associated with the severe clinical form of the disease. These factors can be used as predictive tests to screen dogs to separate them into groups with slow or fast disease progression before their inclusion into a therapeutic preclinical trial, and therefore improve the reliability and translational value of the trials carried out on this invaluable large animal model. These same biomarkers have also been described to be predictive for the time to loss of ambulation in boys with DMD, strengthening the relevance of GRMD dogs as preclinical models of this devastating muscle disease.


A psychophysiological investigation of the interplay between orienting and executive control during stimulus conflict: A heart rate variability study.
It has been hypothesized that resting state cardiac vagal activity (CVA) - an indicator of parasympathetic nervous system activity - is a specific psychophysiological marker of executive control function. Here, we propose an alternative hypothesis - that CVA is associated with early stage attention orientation, promoting the flexible uptake of new information, on which the later operation of such executive control functions depends. We therefore predicted that CVA would predict the interaction between orienting and executive control. This was tested using the revised version of the Attention Network Test (ANT-R) that was developed to distinguish between orienting and executive attention during a stimulus conflict task. Healthy adults (N = 48) performed the ANT-R and their resting CVA was measured over a 5 min period using ECG recordings. Multiple regression analyses indicated that, when other factors were controlled for, CVA was more strongly associated with the interaction between the orienting and executive control terms than with either factor individually. Higher levels of CVA are specifically implicated in the modulation of executive control by intrinsic orientation operating at early stages of conflict detection. These initial findings of higher CVA on orienting attention in conflict detection need to be replicated in larger samples.