Raman spectroscopy: the gateway into tomorrow's virology.
In the molecular world, researchers act as detectives working hard to unravel the mysteries surrounding cells. One of the researchers' greatest tools in this endeavor has been Raman spectroscopy. Raman spectroscopy is a spectroscopic technique that measures the unique Raman spectra for every type of biological molecule. As such, Raman spectroscopy has the potential to provide scientists with a library of spectra that can be used to unravel the makeup of an unknown molecule. However, this technique is limited in that it is not able to manipulate particular structures without disturbing their unique environment. Recently, a novel technology that combines Raman spectroscopy with optical tweezers, termed Raman tweezers, evades this problem due to its ability to manipulate a sample without physical contact. As such, Raman tweezers has the potential to become an incredibly effective diagnostic tool for differentially distinguishing tissue, and therefore holds great promise in the field of virology for distinguishing between various virally infected cells. This review provides an introduction for a virologist into the world of spectroscopy and explores many of the potential applications of Raman tweezers in virology.


European ACP1*C allele has recessive deleterious effects on early life viability.
The acid phosphatase locus (ACP1) is a classical polymorphism that has been surveyed in hundreds of human populations worldwide. Among individuals of European ancestry, the ACP1*C allele occurs with an average frequency of approximately 0.05, whereas it is nearly absent in all other human populations. It has been hypothesized that this allele is maintained by overdominant selection among European populations. Here, we analyze ACP1 protein polymorphism data from more than 50,000 individuals previously surveyed in 67 populations across Europe as well as inheritance data from more than 6,000 European parent-offspring pairs to assess the signature of natural selection currently acting on this allele. Although we see a significant excess of ACP1*C heterozygotes relative to Hardy-Weinberg expectations, we find no evidence that natural selection favors ACP1*C heterozygotes. Instead, ACP1*C appears to have a strongly deleterious and recessive fitness effect. We observed only 48.9% of expected homozygous offspring from heterozygous parents and significantly fewer homozygotes than expected within populations. Because parent-offspring pairs indicate a significant deficiency of ACP1*C homozygotes, we infer that viability selection is acting on ACP1*C homozygotes very early in life, perhaps before birth. We estimate that approximately 1.2% of all couples of European ancestry are composed of individuals who both carry the APC1*C allele. As such, selection against ACP1*C homozygotes may represent a nonnegligible contribution to the overall number of spontaneous abortions among women of European ancestry and may cause substantial fertility reductions among some combinations of parental genotypes.


A stochastic filtering technique for fluid flow velocity fields tracking.
In this paper, we present a method for the temporal tracking of fluid flow velocity fields. The technique we propose is formalized within a sequential Bayesian filtering framework. The filtering model combines an Itô diffusion process coming from a stochastic formulation of the vorticity-velocity form of the Navier-Stokes equation and discrete measurements extracted from the image sequence. In order to handle a state space of reasonable dimension, the motion field is represented as a combination of adapted basis functions, derived from a discretization of the vorticity map of the fluid flow velocity field. The resulting nonlinear filtering problem is solved with the particle filter algorithm in continuous time. An adaptive dimensional reduction method is applied to the filtering technique, relying on dynamical systems theory. The efficiency of the tracking method is demonstrated on synthetic and real-world sequences.


Artemisia absinthium (AA): a novel potential complementary and alternative medicine for breast cancer.
Natural products have become increasingly important in pharmaceutical discoveries, and traditional herbalism has been a pioneering specialty in biomedical science. The search for effective plant-derived anticancer agents has continued to gain momentum in recent years. The present study aimed to investigate the role of crude extracts of the aerial parts of Artemisia absinthium (AA) extract in modulating intracellular signaling mechanisms, in particular its ability to inhibit cell proliferation and promote apoptosis in a human breast carcinoma estrogenic-unresponsive cell line, MDA-MB-231, and an estrogenic-responsive cell line, MCF-7. Cells were incubated with various concentrations of AA, and anti-proliferative activity was assessed by MTT assays, fluorescence microscopy after propidium iodide staining, western blotting and cell cycle analysis. Cell survival assays indicated that AA was cytotoxic to both MDA-MB-231 and MCF-7 cells. The morphological features typical of nucleic staining and the accumulation of sub-G1 peak revealed that the extract triggered apoptosis. Treatment with 25 μg/mL AA resulted in activation of caspase-7 and upregulation of Bad in MCF-7 cells, while exposure to 20 μg/mL AA induced upregulation of Bcl-2 protein in a time-dependent response in MDA-MB-231 cells. Both MEK1/2 and ERK1/2 was inactivated in both cell lines after AA treatment in a time-dependent manner. These results suggest that AA-induced anti-proliferative effects on human breast cancer cells could possibly trigger apoptosis in both cell lines through the modulation of Bcl-2 family proteins and the MEK/ERK pathway. This might lead to its possible development as a therapeutic agent for breast cancer following further investigations.


Characterization of the VIER F-BOX PROTEINE genes from Arabidopsis reveals their importance for plant growth and development.
E3 ubiquitin ligases (E3s) target proteins for degradation by the 26S proteasome. In SKP1/CDC53/F-box protein-type E3s, substrate specificity is conferred by the interchangeable F-box protein subunit. The vast majority of the 694 F-box proteins encoded by the Arabidopsis thaliana genome remain to be understood. We characterize the VIER F-BOX PROTEINE (VFB; German for FOUR F-BOX PROTEINS) genes from Arabidopsis that belong to subfamily C of the Arabidopsis F-box protein superfamily. This subfamily also includes the F-box proteins TRANSPORT INHIBITOR RESPONSE1 (TIR1)/AUXIN SIGNALING F-BOX (AFB) proteins and EIN3 BINDING F-BOX proteins, which regulate auxin and ethylene responses, respectively. We show that loss of VFB function causes delayed plant growth and reduced lateral root formation. We find that the expression of a number of auxin-responsive genes and the activity of DR5:beta-glucuronidase, a reporter for auxin response, are reduced in the vfb mutants. This finding correlates with an increase in the abundance of an AUXIN/INDOLE-3-ACETIC ACID repressor. However, we also find that auxin responses are not affected in the vfb mutants and that a representative VFB family member, VFB2, cannot functionally complement the tir1-1 mutant. We therefore exclude the possibility that VFBs are functional orthologs of TIR1/AFB proteins.


Deciphering the complexity of Toll-like receptor signaling.
Toll-like receptors (TLRs) are essential players in the innate immune response to invading pathogens. Although extensive research efforts have provided a considerable wealth of information on how TLRs function, substantial gaps in our knowledge still prevent the definition of a complete picture of TLR signaling. However, several recent studies describe additional layers of complexity in the regulation of TLR ligand recognition, adaptor recruitment, posttranslational modifications of signaling proteins, and the newly described, autonomous role of the TLR4 co-receptor CD14. In this review, by using it as model system for the whole TLR family, we attempt to provide a complete description of the signal transduction pathways triggered by TLR4, with a particular emphasis on the molecular and cell biological aspects regulating its function. Finally, we discuss a recently reported model of CD14-dependent signaling and highlight its biological implications.


Downregulation of Aquaporin 4 Expression through Extracellular Signal-regulated Kinases1/2 Activation in Cultured Astrocytes Following Scratch-injury.
To investigate the role of extracellular signal-regulated kinase1/2 (ERK1/2) pathway in the regulation of aquaporin 4 (AQP4) expression in cultured astrocytes after scratch-injury. The scratch-injury model was produced in cultured astrocytes of rat by a 10-μL plastic pipette tip. The morphological changes of astrocytes and lactate dehydrogenase (LDH) leakages were observed to assess the degree of scratch-injury. AQP4 expression was detected by immunofluorescence staining and Western blot, and phosphorylated-ERK1/2 (p-ERK1/2) expression was determined by Western blot. To explore the effect of ERK1/2 pathway on AQP4 expression in scratch-injured astrocytes, 10 µmol/L U0126 (ERK1/2 inhibitor) was incubated in the medium at 30 min before the scratch-injury in some groups. Increases in LDH leakage were observed at 1, 12, and 24 h after scratch-injury, and AQP4 expression was reduced simultaneously. Decrease in AQP4 expression was associated with a significant increase in ERK1/2 activation. Furthermore, pretreatment with U0126 blocked both ERK1/2 activation and decrease in AQP4 expression induced by scratch-injury. These results indicate that ERK1/2 pathway down-regulates AQP4 expression in scratch-injured astrocytes, and ERK1/2 pathway might be a novel therapeutic target in reversing the effects of astrocytes that contribute to traumatic brain edema.


Tezosentan increases nitric oxide signaling via enhanced hydrogen peroxide generation in lambs with surgically induced acute increases in pulmonary blood flow.
We have previously shown that acute increases in pulmonary blood flow (PBF) are limited by a compensatory increase in pulmonary vascular resistance (PVR) via an endothelin-1 (ET-1) dependent decrease in nitric oxide synthase (NOS) activity. The mechanisms underlying the reduction in NO signaling are unresolved. Thus, the purpose of this study was to elucidate mechanisms of this ET-1-NO interaction. Pulmonary arterial endothelial cells were acutely exposed to shear stress in the presence or absence of tezosentan, a combined ET(A) /ET(B) receptor antagonist. Shear increased NO(x) , eNOS phospho-Ser1177, and H(2) O(2) and decreased catalase activity; tezosentan enhanced, while ET-1 attenuated all of these changes. In addition, ET-1 increased eNOS phospho-Thr495 levels. In lambs, 4 h of increased PBF decreased H(2) O(2) , eNOS phospho-Ser1177, and NO(X) levels, and increased eNOS phospho-Thr495, phospho-catalase, and catalase activity. These changes were reversed by tezosentan. PEG-catalase reversed the positive effects of tezosentan on NO signaling. In all groups, opening the shunt resulted in a rapid increase in PBF by 30 min. In vehicle- and tezosentan/PEG-catalase lambs, PBF did not change further over the 4 h study period. PVR fell by 30 min in vehicle- and tezosentan-treated lambs, and by 60 min in tezosentan/PEG-catalase-treated lambs. In vehicle- and tezosentan/PEG-catalase lambs, PVR did not change further over the 4 h study period. In tezosentan-treated lambs, PBF continued to increase and LPVR to decrease over the 4 h study period. We conclude that acute increases in PBF are limited by an ET-1 dependent decrease in NO production via alterations in catalase activity, H(2) O(2) levels, and eNOS phosphorylation.


A Year in the Life of the EU-CardioRNA COST Action: CA17129 Catalysing Transcriptomics Research in Cardiovascular Disease.
The EU-CardioRNA Cooperation in Science and Technology (COST) Action is a European-wide consortium established in 2018 with 31 European country members and four associate member countries to build bridges between translational researchers from academia and industry who conduct research on non-coding RNAs, cardiovascular diseases and similar research areas. EU-CardioRNA comprises four core working groups (WG1-4). In the first year since its launch, EU-CardioRNA met biannually to exchange and discuss recent findings in related fields of scientific research, with scientific sessions broadly divided up according to WG. These meetings are also an opportunity to establish interdisciplinary discussion groups, brainstorm ideas and make plans to apply for joint research grants and conduct other scientific activities, including knowledge transfer. Following its launch in Brussels in 2018, three WG meetings have taken place. The first of these in Lisbon, Portugal, the second in Istanbul, Turkey, and the most recent in Maastricht, The Netherlands. Each meeting includes a scientific session from each WG. This meeting report briefly describes the highlights and key take-home messages from each WG session in this first successful year of the EU-CardioRNA COST Action.


Core-shell hydrogel particles harvest, concentrate and preserve labile low abundance biomarkers.
The blood proteome is thought to represent a rich source of biomarkers for early stage disease detection. Nevertheless, three major challenges have hindered biomarker discovery: a) candidate biomarkers exist at extremely low concentrations in blood; b) high abundance resident proteins such as albumin mask the rare biomarkers; c) biomarkers are rapidly degraded by endogenous and exogenous proteinases. Hydrogel nanoparticles created with a N-isopropylacrylamide based core (365 nm)-shell (167 nm) and functionalized with a charged based bait (acrylic acid) were studied as a technology for addressing all these biomarker discovery problems, in one step, in solution. These harvesting core-shell nanoparticles are designed to simultaneously conduct size exclusion and affinity chromatography in solution. Platelet derived growth factor (PDGF), a clinically relevant, highly labile, and very low abundance biomarker, was chosen as a model. PDGF, spiked in human serum, was completely sequestered from its carrier protein albumin, concentrated, and fully preserved, within minutes by the particles. Particle sequestered PDGF was fully protected from exogenously added tryptic degradation. When the nanoparticles were added to a 1 mL dilute solution of PDGF at non detectable levels (less than 20 picograms per mL) the concentration of the PDGF released from the polymeric matrix of the particles increased within the detection range of ELISA and mass spectrometry. Beyond PDGF, the sequestration and protection from degradation for a series of additional very low abundance and very labile cytokines were verified. We envision the application of harvesting core-shell nanoparticles to whole blood for concentration and immediate preservation of low abundance and labile analytes at the time of venipuncture.


Fast and selective separation of carbon dioxide from dilute streams by pressure swing adsorption using solid ionic liquids.
The need to create a new approach to carbon capture processes that are economically viable has led to the design and synthesis of sorbents that selectively capture carbon dioxide by physisorption. Solid Ionic Liquids (SoILs) were targeted because of their tunable properties and solid form under operational conditions. Molecular modelling was used to identify candidate SoILs and a number of materials based on the low cost, environmentally friendly acetate anion were selected. The materials showed excellent selectivity for carbon dioxide over nitrogen and oxygen and moderate sorption capacity. However, the rate of capture was extremely fast, in the order of a few seconds for a complete adsorb-desorb cycle, under pressure swing conditions from 1 to 10 bar. This showed the importance of rate of sorption cycling over capacity and demonstrates that smaller inventories of sorbents and smaller process equipment are required to capture low concentration CO2 streams. Concentrated CO2 was isolated by releasing the pressure back to atmospheric. The low volatility and thermal stability of SoILs mean that both plant costs and materials costs can be reduced and plant size considerably reduced.


Systematic review of randomized trials comparing lumbar fusion surgery to nonoperative care for treatment of chronic back pain.
Systematic review of randomized trials comparing surgical to nonsurgical treatment of discogenic back pain. Compare research methods and results. Recent reports have increased debate about the role of surgery in the treatment of chronic back pain associated with lumbar disc degeneration. We conducted a systematic review of randomized trials comparing lumbar fusion surgery to nonsurgical treatment of chronic back pain associated with lumbar disc degeneration. A literature search identified 5 randomized trials that compared fusion to nonoperative treatment for chronic low back pain. Excluding 1 trial for spondylolisthesis, we compared study participants, interventions, analyses, and outcomes in 4 trials that focused on nonspecific chronic back. All trials enrolled similar subjects. One study suggested greater improvement in back-specific disability for fusion compared to unstructured nonoperative care at 2 years, but the trial did not report data according to intent-to-treat principles. Three trials suggested no substantial difference in disability scores at 1-year and 2-years when fusion was compared to a 3-week cognitive-behavior treatment addressing fears about back injury. However, 2 of these trials were underpowered to identify clinically important differences. The third trial had high rates of cross-over (>20% for each treatment) and loss to follow-up (20%); it is unclear how these affected results. Surgery may be more efficacious than unstructured nonsurgical care for chronic back pain but may not be more efficacious than structured cognitive-behavior therapy. Methodological limitations of the randomized trials prevent firm conclusions.


Young women with polycystic ovary syndrome have raised levels of circulating annexin V-positive platelet microparticles.
Are circulating microparticles (MPs) altered in young women with polycystic ovary syndrome (PCOS)? Women with PCOS have elevated concentrations of circulating platelet-derived MPs, which exhibit increased annexin V binding and altered microRNA (miR) profiles compared with healthy volunteers. Some studies have shown that cardiovascular risk is increased in young women with PCOS but the mechanisms by which this occurs are uncertain. Circulating MPs are elevated in patients with cardiovascular disease but the characteristics of MPs in patients with PCOS are unclear. Case-control study comprising 17 women with PCOS (mean ± SD; age 31 ± 7 years, BMI 29 ± 6 kg/m(2)) and 18 healthy volunteers (age 31 ± 6 years, BMI 30 ± 6 kg/m(2)). The study was conducted in a University hospital. Nanoparticle tracking analysis (NTA) and flow cytometry (CD41 platelet, CD11b monocyte, CD144 endothelial) were used to determine MP size, concentration, cellular origin and annexin V positivity (reflecting phosphatidylserine exposure). Fatty acid analysis was performed by gas chromatography and MP miR expression profiles were compared by microarray. PCOS subjects showed increased MP concentrations compared with healthy volunteers (mean ± SD; 11.5 ± 5 × 10(12)/ml versus 10.0 ± 4 × 10(12)/ml, respectively; P = 0.03), which correlated with the homeostasis model of insulin resistance (r = 0.53, P = 0.03). This difference was predominantly seen in MPs whose size was in the small exosomal range (<150 nm in diameter, P< 0.05). PCOS patients showed a greater percentage of annexin V(+) MPs compared with healthy volunteers (84 ± 18 versus 74 ± 24%, respectively, P = 0.05) but the cellular origin of MPs, which were predominantly platelet-derived (PCOS: 99 ± 0.9%; controls: 99 ± 2.5%), did not differ. MP fatty acid concentration and composition was similar between groups but 16 miRs were differentially expressed (P < 0.05). Patients with PCOS were classified by the Rotterdam criteria, which describes a less severe metabolic phenotype than other definitions of the syndrome. Our findings may thus not be generalizable to all patients with PCOS. MicroRNA expression analysis was only undertaken in an exploratory subset of the overall study population hence, validation of our findings in a larger cohort is mandatory. Furthermore, miR levels were unaltered for the highly expressed miRs and it is unclear whether differences in the lowly expressed miRs carries pathological relevance. This study suggests that women with PCOS have an altered MP profile but further studies are needed to confirm this, to explore the mechanisms by which these alterations develop and to establish whether therapies that improve insulin sensitivity are able to reduce circulating MP concentrations. The study was funded by grants from the Wales Heart Research Institute and Mrs John Nixon Scholarship. The authors have no conflicts of interest to declare.


The incidence of high-grade prostatic intraepithelial neoplasia and atypical glands suspicious for carcinoma on first-time saturation needle biopsy, and the subsequent risk of cancer.
To investigate the detection rate and extent of high-grade prostatic intraepithelial neoplasia (HGPIN) and atypical glands (AG) suspicious for prostate cancer, and the cancer risk in subsequent biopsies, diagnosed by a first 24-core saturation biopsy, as although the optimum extent of biopsy is controversial there is a trend to increase the number of cores taken, and apart from detecting prostate cancer, identifying HGPIN and AG is associated with a greater risk of finding cancer in subsequent biopsies, thus warranting a closer follow-up. The study included 100 men with consecutive first-time saturation biopsies; the indications for biopsy were an abnormal digital rectal examination and/or a serum prostate-specific antigen (PSA) level of >2.5 ng/mL. Each biopsy specimen was reviewed retrospectively by two pathologists to confirm the histological diagnosis. The number and percentage of cores positive for HGPIN, bilateral involvement and multifocality (HGPIN involving two or more cores) were recorded in each case. The presence of AG and cancer was also recorded. An extended (10-12 cores) repeat biopsy was available in 23 patients. The median (range) age and PSA level of the patients was 63 (41-80) years and 4.9 (1.5-67.0) ng/mL, respectively. Of the 100 patients, 34% had normal findings (benign prostatic tissue, BPT), 39% had cancer, 26% had HGPIN and cancer, 22% had HGPIN alone, and 5% had AG. Repeat biopsies were available in nine of the 22 (41%) patients with HGPIN, four of five with AG, and 10 of the 34 (29%) with BPT. The median (range) interval between the first and second biopsy was 13 (4-36) months. Prostate cancer was detected at the second biopsy in a third of patients with isolated HGPIN on the first biopsy, and one of the four with AG. None of the patients with BPT had cancer on re-biopsy. The cancer detection rate was significantly greater in patients with multifocal than in those with unifocal HGPIN (80% vs none, P = 0.010). The median number of cores and percentage of tissue involved by HGPIN was 3.5 (2-5) and 1.0 (0.5-1.2)%, respectively, in patients with cancer detected in repeat biopsies, compared to 1.0 (1-3) and 0.2 (0.2-0.6)% in patients without cancer on repeat biopsy (P = 0.023 and 0.015, respectively). Identifying multifocal HGPIN on first saturation biopsy is associated with an overall cancer detection rate of 80% on repeat 10-12-core biopsy. Although there were few patients, the detection of multifocal HGPIN warrants additional searches for concurrent invasive carcinoma by repeated biopsy.


Highly conserved residues in the helical domain of dengue virus type 1 precursor membrane protein are involved in assembly, precursor membrane (prM) protein cleavage, and entry.
The envelope and precursor membrane (prM) proteins of dengue virus (DENV) are present on the surface of immature virions. During maturation, prM protein is cleaved by furin protease into pr peptide and membrane (M) protein. Although previous studies mainly focusing on the pr region have identified several residues important for DENV replication, the functional role of M protein, particularly the α-helical domain (MH), which is predicted to undergo a large conformational change during maturation, remains largely unknown. In this study, we investigated the role of nine highly conserved MH domain residues in the replication cycle of DENV by site-directed mutagenesis in a DENV1 prME expression construct and found that alanine substitutions introduced to four highly conserved residues at the C terminus and one at the N terminus of the MH domain greatly affect the production of both virus-like particles and replicon particles. Eight of the nine alanine mutants affected the entry of replicon particles, which correlated with the impairment in prM cleavage. Moreover, seven mutants were found to have reduced prM-E interaction at low pH, which may inhibit the formation of smooth immature particles and exposure of prM cleavage site during maturation, thus contributing to inefficient prM cleavage. Taken together, these results are the first report showing that highly conserved MH domain residues, located at 20-38 amino acids downstream from the prM cleavage site, can modulate the prM cleavage, maturation of particles, and virus entry. The highly conserved nature of these residues suggests potential targets of antiviral strategy.


Computer-enhanced robotic surgery in gynecologic oncology.
This study aimed to report the computer-enhanced robotic surgery experience of the authors' gynecologic oncology division. From January 2001 to August 2006, 41 patients underwent laparoscopic surgery by our gynecologic oncology service using a computer-enhanced surgical robot. This report describes a retrospective review of these patients. The patients ranged in age from 27 to 77 years (mean, 44.2 years), in weight from 44 to 131 kg (mean, 72.1 kg), in operative time from 1 h and 50 min to 9 h (mean, 5 h and 2 min), and in estimated blood loss from 50 to 1,500 ml (mean, 253 ml). Of the 20 patients with gynecologic malignancies, 14 had cervical cancer. A total of 21 patients had benign indications for surgery. Complications included shoulder palsy, robot failure, colotomy, bradycardia, and intraabdominal bleeding requiring minilaparotomy and ligation of a bleeding pedicle. This case series is one of the first to report the use of a computer-enhanced surgical robot in gynecologic oncology. This approach proved to be feasible and well tolerated in this series of patients and deserves further study for clarification of its indications, benefits, and safety.


Psychotherapy in hospitalized research patients.
Operations at the clinical-research interface exert a signal influence on the therapy of patients being treated on investigative units. The effect on the treatment milieu has been described but the impact of a research climate on individual psychotheraphy of hospitalized patients has not. We observed research-therapy interaction in 25 acutely schizophrenic patients. Analytically oriented psychotherapy was carried out on a National Institutes of Health clinical research unit where drugs are only occasionally used, and patients are subjects in psychobiological investigation. The subtle, and often neglected, interplay between therapy and research is examined, with emphasis on the shifting meanings of the patient's participation or refusal to participate in therapy, research, or both. A research transference and countertransference are defined, and some special behavioral patterns of research patients receiving dynamic therapy are considered in this framework.


Phase-shift estimation in sinusoidally illuminated images for lateral superresolution.
Sinusoidally patterned illumination has been used to obtain lateral superresolution and axial sectioning in images. In both of these techniques multiple images are taken with the object illuminated by a sinusoidal pattern, the phase of the sinusoidal illumination being shifted differently in each image. The knowledge of these phase shifts is critical for image reconstruction. We discuss a method to estimate this phase shift with no prior knowledge of the shifts. In postprocessing we estimate randomly introduced, unknown phase shifts and process the images to obtain a superresolved image. Results of computer simulations are shown.


Erythrocytes in sickle cell anemia are heterogeneous in their rheological and hemodynamic characteristics.
To understand the contribution to the pathophysiology of sickle cell anemia of the different erythrocyte density types present in the blood of these patients, we have studied the viscosimetric and hemodynamic characteristics of four major classes of hemoglobin SS erythrocytes. We have isolated reticulocytes, discocytes, dense discocytes, and irreversibly sickled cells (fractions I-IV) on Percoll-Renografin density gradients. Bulk viscosity was studied in a coneplate viscosimeter and the hemodynamic studies were performed on the isolated, artificially perfused mesoappendix vasculature of the rat (Baez preparation). Bulk viscosity measurements at shear rates of 230 S-1 demonstrate that when the cells are oxygenated, fraction I (reticulocyte rich) has a higher viscosity than expected from its low intracellular hemoglobin concentration. The rest of the fractions exhibit moderate increases in bulk viscosity pari-passu with the corresponding increases in density (mean corpuscular hemoglobin concentration). When deoxygenated, all cell fractions nearly doubled their bulk viscosity and the deoxy-oxy differences remained constant. The Baez preparation renders a different picture: oxygenated fractions behave as predicted by the viscosimetric data, but, when deoxygenated, cell fractions exhibit dramatically increased peripheral resistance and the deoxy-oxy difference are directly proportional to cell density, thus, the largest increases were observed for fractions III and IV. The differences between the rheological and the hemodynamic measurements are most probably due to the different sensitivity of the two methods to the extent of intracellular polymerization. These results also demonstrate that the hitherto unrecognized fraction III cells (very dense discocytes that change shape very little on deoxygenation) are as detrimental to the microcirculation as the irreversibly sickled cell-rich fraction IV. They may, however, induce obstruction by a different mechanism. As the extent to which these fractions are populated by erythrocytes varies considerably from patient to patient, the distribution function of cell densities in each sickle cell anemia patient might have consequences for the type of pathophysiological events occurring in their microcirculation.


Towards the establishment of a consensus real-time qPCR to monitor Trypanosoma cruzi parasitemia in patients with chronic Chagas disease cardiomyopathy: a substudy from the BENEFIT trial.
Quantitative real-time PCR (qPCR) is an accurate method to quantify Trypanosoma cruzi DNA and can be used to follow-up parasitemia in Chagas disease (CD) patients undergoing chemotherapy. The Benznidazole Evaluation for Interrupting Trypanosomiasis (BENEFIT) study is an international, multicenter, randomized, double-blinded and placebo-controlled clinical trial to evaluate the efficacy of benznidazole (BZ) treatment in patients with chronic Chagas cardiomyopathy (CCC). One important question to be addressed concerns the effectiveness of BZ in reducing overall parasite load in CCC patients, even in the absence of parasitological cure. This report describes the evaluation of multiple procedures for DNA extraction and qPCR-based protocols aiming to establish a standardized methodology for the absolute quantification of T. cruzi DNA in Guanidine-EDTA blood (GEB) samples. A panel of five primer sets directed to the T. cruzi nuclear satellite DNA repeats (Sat-DNA) and to the minicircle DNA conserved regions (kDNA) was compared in either SYBR Green or TaqMan systems. Standard curve parameters such as, amplification efficiency, coefficient of determination and intercept were evaluated, as well as different procedures to generate standard samples containing pre-established T. cruzi DNA concentration. Initially, each primer set was assayed in a SYBR Green qPCR to estimate parasite load in GEB samples from chronic Chagas disease patients. The results achieved from Bayesian transmutability analysis elected the primer sets Cruzi1/Cruzi2 (p=0.0031) and Diaz7/Diaz8 (p=0.0023) coupled to the QIAamp DNA Kit extraction protocol (silica gel column), as the most suitable for monitoring parasitemia in these patients. Comparison between the parasite burden of 150 GEB samples of BENEFIT patients from Argentina, Brazil and Colombia, prior to drug/placebo administration, was performed using Cruzi1/Cruzi2 primers in a SYBR Green approach. The median parasitemia found in patients from Argentina and Colombia (1.93 and 2.31 parasite equivalents/mL, respectively) was around 20 times higher than the one estimated for the Brazilian patients (0.1 parasite equivalents/mL). This difference could be in part due to the complexity of T. cruzi genetic diversity, which is a factor possibly implicated in different clinical presentations of the disease and/or influencing parasitemia levels in infected individuals from different regions of Latin America. The results of SYBR Green qPCR assays herein presented prove this methodology to be more cost efficient than the alternative use of internal fluorogenic probes. In addition, its sensitivity and reproducibility are shown to be adequate to detect low parasitemia burden in patients with chronic Chagas disease.


Neuroanatomical and neuropharmacological approaches to postictal antinociception-related prosencephalic neurons: the role of muscarinic and nicotinic cholinergic receptors.
Several studies have suggested the involvement of the hippocampus in the elaboration of epilepsy. There is evidence that suggests the hippocampus plays an important role in the affective and motivational components of nociceptive perception. However, the exact nature of this involvement remains unclear. Therefore, the aim of this study was to determine the role of muscarinic and nicotinic cholinergic receptors in the dorsal hippocampus (dH) in the organization of postictal analgesia. In a neuroanatomical study, afferent connections were found from the somatosensory cortex, the medial septal area, the lateral septal area, the diagonal band of Broca, and the dentate gyrus to the dH; all these areas have been suggested to modulate convulsive activity. Outputs to the dH were also identified from the linear raphe nucleus, the median raphe nucleus (MdRN), the dorsal raphe nucleus, and the locus coeruleus. All these structures comprise the endogenous pain modulatory system and may be involved either in postictal pronociception or antinociception that is commonly reported by epileptic patients. dH-pretreatment with cobalt chloride (1.0 mmol/L CoCl2/0.2 μL) to transiently inhibit local synapses decreased postictal analgesia 10 min after the end of seizures. Pretreatment of the dH with either atropine or mecamylamine (1.0 μg/0.2 μL) attenuated the postictal antinociception 30 min after seizures, while the higher dose (5.0 μg/0.2 μL) decreased postictal analgesia immediately after the end of seizures. These findings suggest that the dH exerts a critical role in the organization of postictal analgesia and that muscarinic and nicotinic cholinergic receptor-mediated mechanisms in the dH are involved in the elaboration of antinociceptive processes induced by generalized tonic-clonic seizures.


C-type lectin receptor DCIR modulates immunity to tuberculosis by sustaining type I interferon signaling in dendritic cells.
Immune response against pathogens is a tightly regulated process that must ensure microbial control while preserving integrity of the infected organs. Tuberculosis (TB) is a paramount example of a chronic infection in which antimicrobial immunity is protective in the vast majority of infected individuals but can become detrimental if not finely tuned. Here, we report that C-type lectin dendritic cell (DC) immunoreceptor (DCIR), a key component in DC homeostasis, is required to modulate lung inflammation and bacterial burden in TB. DCIR is abundantly expressed in pulmonary lesions in Mycobacterium tuberculosis-infected nonhuman primates during both latent and active disease. In mice, we found that DCIR deficiency impairs STAT1-mediated type I IFN signaling in DCs, leading to increased production of IL-12 and increased differentiation of T lymphocytes toward Th1 during infection. As a consequence, DCIR-deficient mice control M. tuberculosis better than WT animals but also develop more inflammation characterized by an increased production of TNF and inducible NOS (iNOS) in the lungs. Altogether, our results reveal a pathway by which a C-type lectin modulates the equilibrium between infection-driven inflammation and pathogen's control through sustaining type I IFN signaling in DCs.


Recent status of self-measured home blood pressure in the Japanese general population: a modern database on self-measured home blood pressure (MDAS).
Despite the clinical usefulness of self-measured home blood pressure (BP), reports on the characteristics of home BP have not been sufficient and have varied due to the measurement conditions in each study. We constructed a database on self-measured home BP, which included five Japanese general populations as subdivided aggregate data that were clustered and meta-analyzed according to sex, age category, and antihypertensive drug treatment at baseline (treated and untreated). The self-measured home BPs were collected after a few minutes of rest in a sitting position: (1) the morning home BP was measured within 1 h of waking, after urination, before breakfast, and before taking antihypertensive medication (if any); and (2) the evening home BP was measured just before going to bed. The pulse rate was simultaneously measured. Eligible data from 2000 onward were obtained. The morning BP was significantly higher in treated participants than in untreated people of the same age category, and the BP difference was more marked in women. Among untreated residents, home systolic/diastolic BPs measured in the morning were higher than those measured in the evening; the differences were 5.7/5.0 mmHg in women (ranges across the cohorts, 5.3-6.8/4.7-5.4 mmHg) and 7.3/7.7 mmHg in men (ranges, 6.4-8.5/7.0-8.7 mmHg). In contrast, the home pulse rate in women and men was 2.4 (range, 1.5-3.7) and 5.6 (range, 4.6-6.6) beats per minute, respectively, higher in the evening than in the morning. We demonstrated the current status of home BP and home pulse rate in relation to sex, age, and antihypertensive treatment status in the Japanese general population. The approach by which fine-clustered aggregate statistics were collected and integrated could address practical issues raised in epidemiological research settings.


Evodiamine Prevents Glioma Growth, Induces Glioblastoma Cell Apoptosis and Cell Cycle Arrest through JNK Activation.
Evodiamine (EVO) is an active medicinal compound derived from the traditional herbal medicine Evodia rutaecarpa. It has been reported that evodiamine has several beneficial biological properties, including anticancer and anti-inflammatory activities. However, the in vitro and in vivo anticancer activities of EVO against the growth of glioblastoma cells remain undefined. EVO induced significant decreases in the viability of U87 and C6 glioma cells, but not of primary astrocytes, according with the occurrence of apoptotic characteristics including DNA ladders, caspase-3 and poly(ADP ribose) polymerase (PARP) protein cleavage, and hypodiploid cells. The disruption of the mitochondrial membrane potential (MMP) was detected, and it was found that the peptidyl caspase-9 inhibitor, Z-LEHD-FMK, significantly prevented glioma cells from EVO-induced apoptosis. Increased c-Jun N-terminal kinase (JNK) protein phosphorylation by EVO was observed, and the addition of JNK inhibitors, SP600125 and JNKI inhibited the EVO-induced apoptosis was inhibited. Additionally, EVO treatment induced G2/M arrest with increased polymerized tubulin protein expression in U87 and C6 cells. Elevated expressions of the cyclin B1, p53, and phosphorylated (p)-p53 proteins were detected in EVO-treated glioma cells, and these were inhibited by JNK inhibitors. An in vivo study showed that EVO significantly reduced the growth of gliomas elicited by the subcutaneous injection of U87 cells with increases in cyclin B1, p53, and p-p53 protein expressions in tumors. An analysis of eight EVO-related chemicals showed that alkyl groups at position 14 in EVO are important for its anti-glioma effects which involve both apoptosis and G2/M arrest. Evidence is provided that supports EVO induction of apoptosis and G2/M arrest via the activation of JNK-mediated gene expression and disruption of MMP in glioblastoma cells. EVO was shown to penetrate the blood-brain barrier; EVO is therefore predicted to be a promising compound for the chemotherapy of glioblastomas and deserves further investigations.


Melphalan and dexamethasone with or without bortezomib in newly diagnosed AL amyloidosis: a matched case-control study on 174 patients.
Oral melphalan and dexamethasone (MDex) is a standard treatment for patients with AL amyloidosis who are not eligible for stem cell transplantation at many referral centers. However, following encouraging reports on the activity of bortezomib combined with alkylators and dexamethasone, these combinations are being moved to frontline therapy. We compared the outcome of 87 patients treated with bortezomib plus MDex (BMDex) with that of 87 controls treated with MDex. Patients and controls were matched for age, cardiac and renal function and free light chain burden. A higher rate of complete responses was observed with BMDex (42 vs 19%), but this did not result in a survival improvement in the overall population. However, a significant survival advantage for BMDex was observed in patients without severe (New York Heart Association class III or IV) heart failure and with N-terminal pro-natriuretic peptide type-B <8500 ng/l. Patients treated with full-dose dexamethasone had similar response rates and survival whether they received bortezomib or not. Intermediate-risk patients who are not fit enough to receive high-dose dexamethasone are likely to take the greatest advantage from the addition of bortezomib to MDex.


Adjuvant radiotherapy for rectal cancer: a systematic overview of 8,507 patients from 22 randomised trials.
At least 28 randomised, controlled trials have compared outcomes of surgery for rectal cancer combined with preoperative or postoperative radiotherapy with those of surgery alone. We have done a collaborative meta-analysis of these results to give a more balanced view of the total evidence and to increase statistical precision. We centrally checked and analysed individual patient data from 22 randomised comparisons between preoperative (6,350 patients in 14 trials) or postoperative (2157 in eight trials) radiotherapy and no radiotherapy for rectal cancer. Overall survival was only marginally better in patients who were allocated to radiotherapy than in those allocated to surgery alone (62% vs 63% died; p=0.06). Rates of apparently curative resection were not improved by preoperative radiotherapy (85% radiotherapy vs 86% control). Yearly risk of local recurrence was 46% (SE 6) lower in those who had preoperative radiotherapy than in those who had surgery alone (p=0.00001), and 37% (10) lower in those who had postoperative treatment than those who had surgery alone (p=0.002). Fewer patients who had preoperative radiotherapy died from rectal cancer than did those who had surgery alone (45% vs 50%, respectively, p=0.0003), but early (</=1 year after treatment) deaths from other causes increased (8% vs 4% died, p<0.0001). Preoperative radiotherapy (at biologically effective doses >/=30 Gy) reduces risk of local recurrence and death from rectal cancer. If safety can be improved without compromising effectiveness, then overall survival would be moderately improved by use of preoperative radiotherapy, especially for young, high risk patients. Postoperative radiotherapy also reduces local recurrence, but short preoperative radiation schedules seem to be at least as effective as longer schedules.


A pilot Web based positive parenting intervention to help bipolar parents to improve perceived parenting skills and child outcomes.
Children of bipolar parents are at elevated risk for psychiatric disorders including bipolar disorder. Helping bipolar parents to optimize parenting skills may improve their children's mental health outcomes. Clear evidence exists for benefits of behavioural parenting programmes, including those for depressed mothers. However, no studies have explored web-based self-directed parenting interventions for bipolar parents. The aim of this research was to conduct a pilot study of a web-based parenting intervention based on the Triple P-Positive Parenting Programme. Thirty-nine self-diagnosed bipolar parents were randomly allocated to the web-based intervention or a waiting list control condition. Parents reported on their index child (entry criterion age 4-10 years old). Perceived parenting behaviour and child behaviour problems (internalizing and externalizing) were assessed at inception and 10 weeks later (at course completion). Fifteen participants (4 control group and 11 intervention group) did not provide follow-up data. Levels of child behaviour problems (parent rated; Strengths and Difficulties Questionnaire) were above clinical thresholds at baseline, and problematic perceived parenting (self-rated; Parenting Scale) was at similar levels to those in previous studies of children with clinically significant emotional and behavioural problems. Parents in the intervention group reported improvements in child behaviour problems and problematic perceived parenting compared to controls. A web-based positive parenting intervention may have benefits for bipolar parents and their children. Initial results support improvement in child behaviour and perceived parenting. A more definitive study addressing the limitations of the current work is now called for.


Aligning financial incentives with "Get With The Guidelines" to improve cardiovascular care.
To describe the impact of a commercial insurer's financial incentives to hospitals in conjunction with collaboration with the American Heart Association (AHA) to accelerate implementation of Get With The Guidelines-Coronary Artery Disease (GWTG-CAD), a quality improvement program to rapidly improve cardiovascular secondary prevention in hospitalized patients. Observational assessment of quality improvement program participation and implementation in response to financial incentives. The study population included all hospitals that participated with the Hawaii Medical Service Association (HMSA, Blue Cross Blue Shield of Hawaii) Hospital Quality and Service Recognition Program and had more than 30 annual admissions for acute coronary artery disease. These 13 hospitals were given encouragement and financial incentives to implement GWTG-CAD. Financial incentives were determined by a prorated amount of the total HMSA hospital reimbursement for all acute services, as part of a more comprehensive hospital "pay for performance" program. Incentives to 10 of 13 eligible hospitals included reimbursement for half the annual cost of the AHA Patient Management Tool. In addition, HMSA's pay for performance program--the Hospital Quality and Service Recognition Program--distributed monetary awards totaling 354,883 dollars, based on points awarded for GWTG-CAD workshop attendance documentation (10 hospitals), recognition by the AHA as a GWTG-CAD hospital, and attainment of 85% adherence to the GWTG-CAD performance measures (4 hospitals). Community-based promotion of GWTG-CAD and financial incentives provided by a commercial insurer resulted in the rapid implementation of a secondary prevention program for coronary artery disease in most hospitals in the State of Hawaii within a single year.


Sub-pixel Area Calculation Methods for Estimating Irrigated Areas.
The goal of this paper was to develop and demonstrate practical methods forcomputing sub-pixel areas (SPAs) from coarse-resolution satellite sensor data. Themethods were tested and verified using: (a) global irrigated area map (GIAM) at 10-kmresolution based, primarily, on AVHRR data, and (b) irrigated area map for India at 500-mbased, primarily, on MODIS data. The sub-pixel irrigated areas (SPIAs) from coarse-resolution satellite sensor data were estimated by multiplying the full pixel irrigated areas(FPIAs) with irrigated area fractions (IAFs). Three methods were presented for IAFcomputation: (a) Google Earth Estimate (IAF-GEE); (b) High resolution imagery (IAF-HRI); and (c) Sub-pixel de-composition technique (IAF-SPDT). The IAF-GEE involvedthe use of "zoom-in-views" of sub-meter to 4-meter very high resolution imagery (VHRI)from Google Earth and helped determine total area available for irrigation (TAAI) or netirrigated areas that does not consider intensity or seasonality of irrigation. The IAF-HRI isa well known method that uses finer-resolution data to determine SPAs of the coarser-resolution imagery. The IAF-SPDT is a unique and innovative method wherein SPAs aredetermined based on the precise location of every pixel of a class in 2-dimensionalbrightness-greenness-wetness (BGW) feature-space plot of red band versus near-infraredband spectral reflectivity. The SPIAs computed using IAF-SPDT for the GIAM was within2 % of the SPIA computed using well known IAF-HRI. Further the fractions from the 2 methods were significantly correlated. The IAF-HRI and IAF-SPDT help to determine annualized or gross irrigated areas (AIA) that does consider intensity or seasonality (e.g., sum of areas from season 1, season 2, and continuous year-round crops). The national census based irrigated areas for the top 40 irrigated nations (which covers about 90% of global irrigation) was significantly better related (and had lesser uncertainties and errors) when compared to SPIAs than FPIAs derived using 10-km and 500-m data. The SPIAs were closer to actual areas whereas FPIAs grossly over-estimate areas. The research clearly demonstrated the value and the importance of sub-pixel areas as opposed to full pixel areas and presented 3 innovative methods for computing the same.


Clinical quality performance in U.S. health centers.
To describe current clinical quality among the nation's community health centers and to examine health center characteristics associated with performance excellence. National data from the 2009 Uniform Data System. Health centers reviewed patient records and reported aggregate data to the Uniform Data System. Six measures were examined: first-trimester prenatal care, childhood immunization completion, Pap tests, low birth weight, controlled hypertension, and controlled diabetes. The top 25 percent performing centers were compared with lower performing (bottom 75 percent) centers on these measures. Logistic regressions were utilized to assess the impact of patient, provider, and institutional characteristics on health center performance. Clinical care and outcomes among health centers were generally comparable to national averages. For instance, 67 percent of pregnant patients received timely prenatal care (national = 68 percent), 69 percent of children achieved immunization completion (national = 67 percent), and 63 percent of hypertensive patients had blood pressure under control (national = 48 percent). Depending on the measure, centers with more uninsured patients were less likely to do well, while centers with more physicians and enabling service providers were more likely to do well. Health centers provide quality care at rates comparable to national averages. Performance may be improved by increasing insurance coverage among patients and increasing the ratios of physicians and enabling service providers to patients.


EXPERTS 1-experiences of long-term life-limiting conditions among patients and carers: protocol for a qualitative meta-synthesis and conceptual modelling study.
Increasing numbers of the population are living with long-term life-limiting conditions with a significant proportion characterised by multimorbidity. Patients with these conditions often experience high volumes of clinical interaction involving them, their caregivers and healthcare providers in complex patterns of organising, coordinating, negotiating and managing care. A better understanding of the sources of experienced complexity and multimorbidity, from the patient perspective is paramount to improve capacity and manage workload to promote improved experience of illness, more effective healthcare utilisation and improved healthcare outcomes. To better understand the sources of complexity we will undertake an evidence synthesis of qualitative studies of patient and informal carer experiences of three common long-term life-limiting conditions. We will investigate what is known about these diseases at different stages in disease progression, treatment regimens and places of care. We will include qualitative studies of patients' and carers' (aged >18) accounts of their experiences of healthcare provision in a range of settings and healthcare systems. We will conduct an extensive electronic database search of publications in English between 2000 and 2014. Results and discussions sections of the papers will be regarded as formal data using the constant comparison method of qualitative analysis. From the meta-synthesis results, we will build a conceptual model of mechanisms and processes that shape patients' journeys towards end of life to suggest where in the patient journey new interventions to improve patient and carer experience can be developed and delivered. The study is being conducted between 1 December 2014 and 31 December 2015. No human subjects or personal data are involved and no ethical issues are anticipated. An important element of dissemination is informing user communities about the practical implications of the work through workshops, meetings and social media. Scientific results will be published in peer reviewed journals and disseminated through conferences. PROSPERO CRD42014014547.


Ubiquitin chains are remodeled at the proteasome by opposing ubiquitin ligase and deubiquitinating activities.
The ubiquitin ligase Hul5 was recently identified as a component of the proteasome, a multisubunit protease that degrades ubiquitin-protein conjugates. We report here a proteasome-dependent conjugating activity of Hul5 that endows proteasomes with the capacity to extend ubiquitin chains. hul5 mutants show reduced degradation of multiple proteasome substrates in vivo, suggesting that the polyubiquitin signal that targets substrates to the proteasome can be productively amplified at the proteasome. However, the products of Hul5 conjugation are subject to disassembly by a proteasome-bound deubiquitinating enzyme, Ubp6. A hul5 null mutation suppresses a ubp6 null mutation, suggesting that a balance of chain-extending and chain-trimming activities is required for proper proteasome function. As the association of Hul5 with proteasomes was found to be strongly stabilized by Ubp6, these enzymes may be situated in proximity to one another. We propose that through dynamic remodeling of ubiquitin chains, proteasomes actively regulate substrate commitment to degradation.


Reversibility of metabolic and morphological changes associated with chronic exposure of pancreatic islet beta-cells to fatty acids.
Pancreatic beta-cells metabolise both lipid and glucose nutrients but chronic exposure (>24 h) to elevated fatty acid (FA) concentrations results in deleterious metabolic and morphological changes. The aims of this study were to assess the adaptive morphological, metabolic and secretory responses of islet beta-cells to exposure and removal of FA. Isolated mouse islets and INS-1 beta-cells were exposed to oleate or palmitate (0.5 mM) or a 1:1 mixture of both FA for 48 h prior to a 24 h period without FA. Subsequent changes in lipid storage and composition (triglycerides, TG and phospholipids, PL), gene expression, beta-cell morphology and glucose-stimulated insulin secretion (GSIS) were determined. Intracellular TG content increased during exposure to FA and was lower in cells subsequently incubated in FA-free media (P < 0.05); TG storage was visible as oil red O positive droplets (oleate) by light microscopy or 'splits' (palmitate) by electron microscopy. Significant desaturation of beta-cell FA occurred after exposure to oleate and palmitate. After incubation in FA-free media, there was differential handling of specific FA in TG, resulting in a profile that tended to revert to that of control cells. FA treatment resulted in elevated lipolysis of intracellular TG, increased FA oxidation and reduced GSIS. After incubation in FA-free media, oxidation remained elevated but inhibition of FA oxidation with etomoxir (10 microM) had no effect on the improvement in GSIS. The beta-cell demonstrates metabolic flexibility as an adaptive response to ambient concentrations of FA.


Studies on the fibronectin receptors of human peripheral blood leukocytes. Morphologic and functional characterization.
We have investigated the interactions between plasma fibronectin (Fn) and human peripheral blood phagocytic cells. As shown by studies of the binding of Fn-coated fluorescent microspheres (Fn-ms), both polymorphonuclear leukocytes (PMN) and monocytes had specific binding sites for Fn at the plasma membrane. However, as purified from blood, only monocytes were stimulated by Fn to become more actively phagocytic. This increase in phagocytosis was reflected by an Fn-induced increase in the ingestion of IgG-coated erythrocytes and, more dramatically by an Fn-dependent initiation of phagocytosis of C3b-coated erythrocytes. Despite this difference between PMN and monocytes in the functional consequences of Fn binding, the cell surface molecules responsible for Fn binding on the two cell types shared many characteristics. On both cells, binding of Fn-ms was inhibited by sufficient concentrations of fluid-phase Fn; both PMN and monocytes bound fewer Fn-ms at 4 degrees C than at 37 degrees C; both achieved maximal binding at similar Fn-ms/cell ratios; and phenylmethylsulfonyl fluoride did not inhibit Fn-ms binding to either cell type. Most dramatically, monoclonal anti-Fn antibodies that inhibited binding of Fn-ms to one cell type inhibited binding to both; conversely, monoclonal anti-Fn antibodies that did not inhibit Fn-ms binding to either cell type did not inhibit binding to the other. Fn will stimulate PMN to a more actively phagocytic state, like that induced in monocytes, if the PMN are first exposed to C5a or N-formyl-methionyl-leucylphenylalanine. This effect occurs without apparent change in the number of Fn receptors. We conclude that the PMN and monocyte receptors for Fn are very similar, but that their milieu is very different in the two cells as purified from peripheral blood. Whereas Fn induces increased phagocytosis in monocytes, PMN must be activated before the Fn can be effective.


The emotional Stroop task and psychopathology.
Attentional bias is a central feature of many cognitive theories of psychopathology. One of the most frequent methods of investigating such bias has been an emotional analog of the Stroop task. In this task, participants name the colors in which words are printed, and the words vary in their relevance to each theme of psychopathology. The authors review research showing that patients are often slower to name the color of a word associated with concerns relevant to their clinical condition. They address the causes and mechanisms underlying the phenomenon, focusing on J.D. Cohen, K. Dunbar, and J.L. McClelland's (1990) parallel distributed processing model.


ATP-citrate lyase links cellular metabolism to histone acetylation.
Histone acetylation in single-cell eukaryotes relies on acetyl coenzyme A (acetyl-CoA) synthetase enzymes that use acetate to produce acetyl-CoA. Metazoans, however, use glucose as their main carbon source and have exposure only to low concentrations of extracellular acetate. We have shown that histone acetylation in mammalian cells is dependent on adenosine triphosphate (ATP)-citrate lyase (ACL), the enzyme that converts glucose-derived citrate into acetyl-CoA. We found that ACL is required for increases in histone acetylation in response to growth factor stimulation and during differentiation, and that glucose availability can affect histone acetylation in an ACL-dependent manner. Together, these findings suggest that ACL activity is required to link growth factor-induced increases in nutrient metabolism to the regulation of histone acetylation and gene expression.


Dietary intake and status of n-3 polyunsaturated fatty acids in a population of fish-eating and non-fish-eating meat-eaters, vegetarians, and vegans and the product-precursor ratio [corrected] of α-linolenic acid to long-chain n-3 polyunsaturated fatty acids: results from the EPIC-Norfolk cohort.
Intakes of n-3 (omega-3) polyunsaturated fatty acids (PUFAs) are important for health. Because fish is the major source of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), non-fish-eaters may have suboptimal n-3 PUFA status, although the importance of the conversion of plant-derived α-linolenic acid (ALA) to EPA and DHA is debated. The objective was to determine intakes, food sources, and status of n-3 PUFAs according to dietary habit (fish-eaters and non-fish-eating meat-eaters, vegetarians, or vegans) and estimated conversion between dietary ALA and circulating long-chain n-3 PUFAs. This study included 14,422 men and women aged 39-78 y from the EPIC (European Prospective Investigation into Cancer and Nutrition)-Norfolk cohort with 7-d diary data and a substudy in 4902 individuals with plasma phospholipid fatty acid measures. Intakes and status of n-3 PUFAs were measured, and the product-precursor ratio [corrected] of ALA to circulating n-3 PUFAs was calculated. Most of the dietary intake of EPA and DHA was supplied by fish; however, meat was the major source in meat-eaters, and spreading fats, soups, and sauces were the major sources in vegetarians. Total n-3 PUFA intakes in non-fish-eaters were 57-80% of those in fish-eaters, but status differences were considerably smaller [corrected]. The estimated product-precursor ratio [corrected] was greater in women than in men and greater in non-fish-eaters than in fish-eaters. Substantial differences in intakes and in sources of n-3 PUFAs existed between the dietary-habit groups, but the differences in status were smaller than expected, possibly because the product-precursor ratio [corrected] was greater in non-fish-eaters than in fish-eaters, potentially indicating increased estimated conversion of ALA. If intervention studies were to confirm these findings, it could have implications for fish requirements.


Locally controlling mesenchymal stem cell morphogenesis by 3D PDGF-BB gradients towards the establishment of an in vitro perivascular niche.
The perivascular niche is a complex microenvironment containing mesenchymal stem cells (MSCs), among other perivascular cells, as well as temporally organized biochemical and biophysical gradients. Due to a lack of conclusive phenotypic markers, MSCs' identity, heterogeneity and function within their native niche remain poorly understood. The in vitro reconstruction of an artificial three-dimensional (3D) perivascular niche would offer a powerful alternative to study MSC behavior under more defined conditions. To this end, we here present a poly(ethylene glycol)-based in vitro model that begins to mimic the spatiotemporally controlled presentation of biological cues within the in vivo perivascular niche, namely a stably localized platelet-derived growth factor B (PDGF-BB) gradient. We show that 3D-encapsulated MSCs respond to soluble PDGF-BB by proliferation, spreading, and migration in a dose-dependent manner. In contrast, the exposure of MSCs to 3D matrix-tethered PDGF-BB gradients resulted in locally restricted morphogenetic responses, much as would be expected in a native perivascular niche. Thus, the herein presented artificial perivascular niche model provides an important first step towards modeling the role of MSCs during tissue homeostasis and regeneration.


Postoperative High-Sensitivity Troponin and Its Association With 30-Day and 12-Month, All-Cause Mortality in Patients Undergoing On-Pump Cardiac Surgery.
Troponin T is a predictor of cardiac morbidity and mortality after cardiac surgery with most data examining fourth generational troponin T assays. We hypothesize that postoperative high-sensitivity troponin T (hsTnT) measured in increments of the upper limit of the norm independently predicts 30-day all-cause mortality. We included consecutive patients undergoing on-pump cardiac surgery from February 2010 to March 2012 in a prospective cohort that measured hsTnT at 0600 of the first and second postoperative day. Our primary end point was 30-day, all-cause mortality. The secondary end point was 12-month, all-cause mortality in patients surviving the first 30 days. We divided hsTnT into 5 predetermined categorizes based on the upper limit of the norm (ULN). We used Cox regression to examine an association of hsTnT independent of the EuroSCORE II at both 30 days as well as at 12 months in patients surviving the first 30 days. We assessed the area under the receiver operating characteristics curve and the net reassignment improvement for examining the benefit of adding of hsTnT to the EuroSCORE II for prognostication and restratification of 30-day, all-cause mortality. We included 1122 of 1155 eligible patients (75% male; mean age 66 ± 11 years). We observed 58 (5.2%) deaths at 30 days and another 35 (3.4%) deaths at 12 months in patients surviving 30 days. HsTnT categorized by ULN exhibited a graded response for the mortality. Furthermore, hsTnT remained an independent predictor of all-cause mortality at 30 days (adjusted hazard ratio 1.019 [1.014-1.024] per 10-fold increase in ULN) as well as at 12 months (adjusted hazard ratio 1.019 [1.007-1.032]) in patients surviving the first 30 days. The addition of hsTnT to the EuroSCORE II significantly increased the area under the receiver operating characteristics curve (area under curve: 0.816 [95% confidence interval, 0.754-0.878] versus area under curve: 0.870 [95% confidence interval, 0.822-0.917], respectively; P = .012). Finally, adding hsTnT to the EuroSCORE II improved restratification by the net reassignment improvement, primarily by improving rule-out of events. This analysis suggests that, similar to previous assays, higher postoperative concentrations of hsTnT are independently associated with all-cause mortality in patients undergoing on-pump cardiac surgery.


Physical activity, muscle strength, and calcium intake in fracture of the proximal femur in Britain.
Regular exercise and high calcium intake possibly help to preserve bone mass. Little is known, however, about their role in preventing hip fracture. The physical activity and calcium intake of 300 elderly men and women with hip fractures were compared with those of 600 controls matched for age and sex. In both sexes increased daily activity, including standing, walking, climbing stairs, carrying, housework, and gardening protected against fracture. This was independent of other known risk factors, including body mass, cigarette smoking, and alcohol consumption. Strength of grip correlated with activity and was inversely related to the risk of fracture. Calcium intake was not related to the risk of fracture in women. Men with daily calcium intakes above 1g had lower risks. These findings point to the importance of elderly people in Britain maintaining physical activity in their day to day lives.


Exercise modulation of the host-tumor interaction in an orthotopic model of murine prostate cancer.
The purpose of this study is to investigate the effects of exercise on cancer progression, metastasis, and underlying mechanisms in an orthotopic model of murine prostate cancer. C57BL/6 male mice (6-8 wk of age) were orthotopically injected with transgenic adenocarcinoma of mouse prostate C-1 cells (5 × 10(5)) and randomly assigned to exercise (n = 28) or a non-intervention control (n = 31) groups. The exercise group was given voluntary access to a wheel 24 h/day for the duration of the study. Four mice per group were serially killed on days 14, 31, and 36; the remaining 38 mice (exercise, n = 18; control, n = 20) were killed on day 53. Before death, MRI was performed to assess tumor blood perfusion. Primary tumor growth rate was comparable between groups, but expression of prometastatic genes was significantly modulated in exercising animals with a shift toward reduced metastasis. Exercise was associated with increased activity of protein kinases within the MEK/MAPK and PI3K/mTOR signaling cascades with subsequent increased intratumoral protein levels of HIF-1α and VEGF. This was associated with improved tumor vascularization. Multiplex ELISAs revealed distinct reductions in plasma concentrations of several angiogenic cytokines in the exercise group, which was associated with increased expression of angiogenic and metabolic genes in the skeletal muscle. Exercise-induced stabilization of HIF-1α and subsequent upregulation of VEGF was associated with "productive" tumor vascularization with a shift toward suppressed metastasis in an orthotopic model of prostate cancer.


Eletriptan for acute migraine.
Eletriptan (Relpax) is a new triptan soon to be made available by prescription for the treatment of acute migraine. Currently five triptans are available by prescription and more are under development. In light of the many drugs for treating acute migraine, there is a need for evidence-based assessments to help determine the relative efficacy and harm of these treatments. To determine the efficacy of eletriptan for treating a single migraine attack using the outcomes of headache response and pain-free response at 0.5, 1, 2 and 4 hours, and sustained relief over 24 hours. To express efficacy in terms of number-needed-to-treat (NNT). To determine the adverse effects of a single dose of eletriptan and express this in terms of number-needed-to-harm (NNH). To allow for the comparison of the efficacy of eletriptan with other migraine treatments evaluated systematically in the same way. Data from all Phase III randomised placebo-controlled trials were made available by the manufacturer, Pfizer Inc. To date, these trials comprise the only data on eletriptan relevant to this review in a published or unpublished form; thus, searches of electronic databases for further trials of eletriptan were not conducted. Trials of eletriptan for acute migraine; randomised allocation to treatment groups, including a placebo group; double-blind design; International Headache Society diagnostic criteria for migraine with or without aura; single migraine attack; single-dose treatment at standard doses; adult population; baseline pain of moderate or severe intensity using a 4-point standardised rating scale (0 = no pain, 1 = mild pain, 2 = moderate pain and 3 = severe pain); and dichotomous or percentage data for at least one of the main efficacy outcomes. Trials were scored for quality and data extracted by two independent reviewers. Dichotomous or percentage data were extracted and pooled to calculate the relative benefit (RB) or relative risk (RR) and NNTs or NNHs for a number of outcomes for eletriptan 20 mg, 40 mg and 80 mg. The main outcomes considered were headache response at 1 and 2 hours, pain-free response at 2 hours, sustained relief over 24 hours and adverse effects. Minor outcomes considered were headache response at 0.5 and 4 hours, and pain-free response at 0.5, 1 and 4 hours. Six trials met the inclusion criteria. Significant benefit of eletriptan over placebo was shown for eletriptan 20 mg, 40 mg and 80 mg for the primary efficacy outcomes of headache response and pain-free response at 2 hours. For headache response at 2 hours, the NNTs (with 95% confidence intervals) were 4.4 (3.4 to 6.2), 2.9 (2.6 to 3.3) and 2.6 (2.4 to 3.0) for eletriptan 20 mg, 40 mg and 80 mg, respectively. For pain-free response at 2 hours, the NNTs were 9.9 (6.9 to 18), 4.5 (4.0 to 5.1) and 3.7 (3.4 to 4.2), for eletriptan 20 mg, 40 and 80 mg, respectively. There was no significant difference in the incidence of major adverse effects between any dose of eletriptan and placebo. The incidence of minor adverse effects was significantly higher for all eletriptan doses than for placebo, with NNHs of 11 (95% confidence interval, 6.2 to 39), 7.0 (5.2 to 11) and 3.7 (3.1 to 4.5) for eletriptan 20 mg, 40 mg and 80 mg, respectively. Eletriptan 20 mg, 40 mg and 80 mg are effective for the treatment of an acute migraine attack. Effectiveness is dose-related, with statistically significant differences between doses for pain-free response and 24-hour outcomes. Eletriptan compares well with other triptans available for outcomes measured up to 2 hours and provides meaningful relief for 24 hours. Taken as a single dose, eletriptan was well tolerated and caused no major harm. The incidence of minor harm was dose-dependent, with 80 mg giving significantly more adverse effects than 40 mg.


Epistasis and Pleiotropy Affect the Modularity of the Genotype-Phenotype Map of Cross-Resistance in HIV-1.
The genotype-phenotype (GP) map is a central concept in evolutionary biology as it describes the mapping of molecular genetic variation onto phenotypic trait variation. Our understanding of that mapping remains partial, especially when trying to link functional clustering of pleiotropic gene effects with patterns of phenotypic trait co-variation. Only on rare occasions have studies been able to fully explore that link and tend to show poor correspondence between modular structures within the GP map and among phenotypes. By dissecting the structure of the GP map of the replicative capacity of HIV-1 in 15 drug environments, we provide a detailed view of that mapping from mutational pleiotropic variation to phenotypic co-variation, including epistatic effects of a set of amino-acid substitutions in the reverse transcriptase and protease genes. We show that epistasis increases the pleiotropic degree of single mutations and provides modularity to the GP map of drug resistance in HIV-1. Moreover, modules of epistatic pleiotropic effects within the GP map match the phenotypic modules of correlated replicative capacity among drug classes. Epistasis thus increases the evolvability of cross-resistance in HIV by providing more drug- and class-specific pleiotropic profiles to the main effects of the mutations. We discuss the implications for the evolution of cross-resistance in HIV.


Macrophage colony stimulating factor-induced macrophage differentiation influences myotube elongation.
Unaccustomed exercise, high-intensity dynamic sports activities, or the resumption of normal weight-bearing after a period of disuse can induce skeletal muscle injury, which activates an inflammatory response followed by muscle regeneration. Specific subsets of macrophages are involved in muscle regeneration. But the exact role of macrophage differentiation during muscle regeneration remains to be elucidated. The objective of the study was to examine the effect of macrophage colony stimulating factor (M-CSF)-differentiated, lipopolysaccharides (LPS)-stimulated-macrophage-conditioned medium on muscle-cell proliferation, fusion, and elongation, which are key events during muscle regeneration and myogenesis. Murine C2C12 myoblasts were cultured in conditioned medium obtained from PU5-1R macrophages that were (a) undifferentiated, unstimulated; (b) M-CSF-differentiated, unstimulated; (c) undifferentiated, LPS-stimulated; or (d) M-CSF-differentiated, LPS-stimulated. Myoblast proliferation ratio, nuclei number, and length were measured. C2C12 cells cultured in conditioned medium from M-CSF-differentiated, LPS-stimulated macrophages had significantly more nuclei and greater length than cells cultured in conditioned medium from undifferentiated, LPS-stimulated macrophages. Dilution and denaturization of the M-CSF-differentiated, LPS-stimulated-macrophage medium prevented a marked increase in C2C12 nuclei number and length. However, the C2C12 myoblast proliferation ratio was significantly greater in conditioned medium from undifferentiated, LPS-stimulated macrophages than in conditioned medium from M-CSF-differentiated, LPS-stimulated macrophages. M-CSF-differentiated, LPS-stimulated macrophages may influence myogenesis and the early and terminal stages of muscle regeneration. This knowledge may aid in developing therapies that will directly expedite muscle repair and lead to faster rehabilitation and reduced rehabilitation costs.


Familial hypertrophic cardiomyopathy: A case with a new mutation in the MYBPC3 gene.
Familial hypertrophic cardiomyopathy is a genetically heterogeneous disease with variable clinical features that is inherited as autosomal dominant with variable penetrance. Recent developments in genetics of hereditary cardiomyopathy have not only enlightened many points about pathogenesis, but have also provided great benefit to diagnostic approaches of clinicians. Heterozygous mutation of c3691-3692insTTCA in MYBPC3 gene was identified in a pediatric patient with diagnosis of hypertrophic cardiomyopathy at clinic. Hypertrophy was observed in sister and father of the patient in echocardiography screening, and it was subsequently determined that they also had same mutation. This mutation has not previously been defined and reported previously in the literature as cause of hypertrophic cardiomyopathy.


Generation of Infectious Recombinant Human Rotaviruses from Just 11 Cloned cDNAs Encoding the Rotavirus Genome.
The generation of recombinant group A rotaviruses (RVAs) entirely from cloned cDNAs has been described only for a single animal RVA strain, simian SA11-L2. We recently developed an optimized RVA reverse genetics system based on only RVA cDNAs (11-plasmid system), in which the concentration of cDNA plasmids containing the NSP2 and NSP5 genes is 3- or 5-fold increased in relation to that of the other plasmids. Based on this approach, we generated a recombinant human RVA (HuRVA)-based monoreassortant virus containing the VP4 gene of the simian SA11-L2 virus using the 11-plasmid system. In addition to this monoreassortant virus, authentic HuRVA (strain KU) was also generated with the 11-plasmid system with some modifications. Our results demonstrate that the 11-plasmid system involving just RVA cDNAs can be used for the generation of recombinant HuRVA and recombinant HuRVA-based reassortant viruses.IMPORTANCE Human group A rotavirus (HuRVA) is a leading pathogen causing severe diarrhea in young children worldwide. In this paper, we describe the generation of recombinant HuRVA (strain KU) from only 11 cloned cDNAs encoding the HuRVA genome by reverse genetics. The growth properties of the recombinant HuRVA were similar to those of the parental RVA, providing a powerful tool for better understanding of HuRVA replication and pathogenesis. Furthermore, the ability to manipulate the genome of HuRVAs "to order" will be useful for next-generation vaccine production for this medically important virus and for the engineering of clinical vectors expressing any foreign genes.


Seroepidemiology and molecular epidemiology of Kaposi's sarcoma-associated herpesvirus among Jewish population groups in Israel.
The incidence of classic Kaposi's sarcoma among Jews in Israel is among the highest in the developed world. Kaposi's sarcoma-associated herpesvirus (KSHV or human herpesvirus 8) is causally linked to Kaposi's sarcoma. Very little is known about the prevalence of KSHV in the Middle East or about the modes of transmission in Mediterranean countries. From 1992 through 1995, sera were obtained from 1648 adults who had tested positive for hepatitis B virus (HBV) surface antigen 20 years earlier at blood donations; sera were also obtained from 2403 of their family members. All sera were tested for anti-KSHV antibodies with the use of an indirect immunofluorescence assay. To analyze the effects of various factors on the risk of KSHV infection for both the HBV-positive cohort and their families, logistic regression for cluster data and generalized estimating equations were used. All statistical tests were two-sided. Among family members, the seroprevalence of antibodies against KSHV was 9.9% (95% confidence interval [CI] = 8.7% to 11.1%); among the former blood donors who had tested positive for hepatitis B, it was 22% (95% CI = 19.9% to 24.1%). Overall, the best predictor of KSHV status was the place of birth. The most important risk factors found for both husband and wife to test KSHV positive were their own places of birth and their spouse's seropositivity. For a child to test positive, the most important risk factor was maternal seropositivity. The crude prevalence rate of KSHV among the Jewish population in Israel is 9.9%. Important routes of KSHV transmission in the families studied are spouse to spouse and mother to child. The presence of KSHV in Jews in Israel of all ethnic origins and their high incidence of reported Kaposi's sarcoma suggest that KSHV was introduced into the Jewish population prior to the major Diaspora.


Gill morphometry of the red drum, Sciaenops ocellatus.
The structure and morphometry of the gills of the marine teleost, red drum, have been studied. The present analysis of gas exchange area of fish gills is one of the most intensive and the results are compared to less intense averaging methods. Based on the gill area estimates, red drum falls into the category of a fish of intermediate activity. Its gill clearly has an exchange area less than that of the tunas, but is slightly greater than that of trout or bass. The three components that contribute to total exchange area (filament length, lamellar density, and area of individual lamellae) are not all greater in species with a greater total exchange area. The best correlate is total filament length.


Makorin 1 controls embryonic patterning by alleviating Bruno1-mediated repression of oskar translation.
Makorins are evolutionary conserved proteins that contain C3H-type zinc finger modules and a RING E3 ubiquitin ligase domain. In Drosophila, maternal Makorin 1 (Mkrn1) has been linked to embryonic patterning but the mechanism remained unsolved. Here, we show that Mkrn1 is essential for axis specification and pole plasm assembly by translational activation of oskar (osk). We demonstrate that Mkrn1 interacts with poly(A) binding protein (pAbp) and binds specifically to osk 3' UTR in a region adjacent to A-rich sequences. Using Drosophila S2R+ cultured cells we show that this binding site overlaps with a Bruno1 (Bru1) responsive element (BREs) that regulates osk translation. We observe increased association of the translational repressor Bru1 with osk mRNA upon depletion of Mkrn1, indicating that both proteins compete for osk binding. Consistently, reducing Bru1 dosage partially rescues viability and Osk protein level in ovaries from Mkrn1 females. We conclude that Mkrn1 controls embryonic patterning and germ cell formation by specifically activating osk translation, most likely by competing with Bru1 to bind to osk 3' UTR.


Estimating the efficacy of medical abortion.
Comparisons of the efficacy of different regimens of medical abortion are difficult because of the widely varying protocols (even for testing identical regimens), divergent definitions of success and failure, and lack of a standard method of analysis. In this article we review the current efficacy literature on medical abortion, highlighting some of the most important differences in the way that efficacy has been analyzed. We then propose a standard conceptual approach and the accompanying statistical methods for analyzing clinical trials of medical abortion and to explain how clinical investigators can implement this approach. Our review reveals that research on the efficacy of medical abortion has closely followed the conceptual model used for analysis of surgical abortion. The problem, however, is that, whereas surgical abortion is a discrete event occurring in the space of a few minutes or less, medical abortion is a process typically lasting from several days to several weeks. In this process, two events may occur that are not possible with surgical abortion. First, the woman can opt out of the process before a fair determination of efficacy can be made. Second, the process of medical abortion allows time for surgical interventions that may be convenient for the clinician but not strictly necessary from a medical perspective. Another difference from surgical abortions is that, for medical abortions, different medical abortion protocols specify different waiting periods, giving the drugs less time to work in some studies than in others before a determination of efficacy is made. We argue that, when analyzing efficacy of medical abortion, researchers should abandon their close reliance on the analogy to surgical abortion. In fact, medical abortion is more appropriately analyzed by life table procedures developed for the study of another fertility regulation technology; contraception. As with medical abortion, a woman initiating use of a contraceptive method can change her mind after some period of exposure and opt out. Also, as with medical abortion, a contraceptive can fail, usually with the risk of failure depending heavily on whether or not the woman follows the protocol for that method precisely. Finally, as with medical abortion, medical conditions may arise that necessitate discontinuing use of the contraceptive method. In both cases, these medical conditions are sometimes open to interpretation or subject to the skill, judgment, or experience of the clinician involved. The appropriate information to collect for a multiple decrement life table analysis of medical abortion includes data on compliance with the protocol, timing of the event of interest (abortion) when it is observable, and, because we argue that these should be regarded as events of interest, a typology of any surgical interventions that are conducted during the woman's participation in the study.


Does psychological functioning mediate the relationship between bullying involvement and weight loss preoccupation in adolescents? A two-stage cross-sectional study.
Adolescent bullying is associated with a range of adversities for those who are bullied i.e., victims and bully-victims (e.g., those who bully others and get victimised), including reduced psychological functioning and eating disorder symptoms. Bullies are generally well-adjusted psychologically, but previous research suggests that bullies may also engage in problematic diet behaviours. This study investigates a) whether adolescents involved in bullying (bullies, victims, bully-victims) are at increased risk of weight loss preoccupation, b) whether psychological functioning mediates this relationship and c) whether sex is a key moderator. A two-stage design was used. In stage 1, adolescents (n = 2782) from five UK secondary schools were screened for bullying involvement using self and peer reports. In stage 2, a sample of bullies, victims, bully-victims and uninvolved adolescents (n = 767) completed a battery of assessments. The measures included the eating behaviours component of the Child and Adolescent Psychiatric Assessment, which was reduced to one factor (weight loss preoccupation) and used as the outcome variable. Measures of self-esteem, body-esteem and emotional problems were reduced to a latent (mediator) variable of psychological functioning. Multi-group analysis examined the effects of sex and all models were adjusted for covariates (BMI, pubertal stage, age, parental education and ethnicity). Bullies, victims and bully-victims were at increased risk of weight loss preoccupation compared to adolescents uninvolved in bullying. The mechanism by which bullying involvement related to increased weight loss preoccupation varied by bullying role: in bullies the effect was direct, in victims the effect was indirect (via reduced psychological functioning) and in bully-victims the effect was both direct and indirect. Sex significantly moderated the relationship in bullies: weight loss preoccupation was only statistically significant in bullies who were boys. Bullying involvement during adolescence is associated with weight loss preoccupation. Bullies are likely driven by a desire to increase attractiveness and social status; whereas weight loss preoccupation in bullied adolescents may have maladaptive influences on diet and exercise behaviours due to its association with reduced psychological functioning. Future research should consider peer victimisation as a potential modifiable risk factor for reduced psychological functioning and weight loss preoccupation, which if targeted, may help to prevent maladaptive diet and exercise behaviours.


Recent Advances in Metal-Based Antimicrobial Coatings for High-Touch Surfaces.
International interest in metal-based antimicrobial coatings to control the spread of bacteria, fungi, and viruses via high contact human touch surfaces are growing at an exponential rate. This interest recently reached an all-time high with the outbreak of the deadly COVID-19 disease, which has already claimed the lives of more than 5 million people worldwide. This global pandemic has highlighted the major role that antimicrobial coatings can play in controlling the spread of deadly viruses such as SARS-CoV-2 and scientists and engineers are now working harder than ever to develop the next generation of antimicrobial materials. This article begins with a review of three discrete microorganism-killing phenomena of contact-killing surfaces, nanoprotrusions, and superhydrophobic surfaces. The antimicrobial properties of metals such as copper (Cu), silver (Ag), and zinc (Zn) are reviewed along with the effects of combining them with titanium dioxide (TiO2) to create a binary or ternary contact-killing surface coatings. The self-cleaning and bacterial resistance of purely structural superhydrophobic surfaces and the potential of physical surface nanoprotrusions to damage microbial cells are then considered. The article then gives a detailed discussion on recent advances in attempting to combine these individual phenomena to create super-antimicrobial metal-based coatings with binary or ternary killing potential against a broad range of microorganisms, including SARS-CoV-2, for high-touch surface applications such as hand rails, door plates, and water fittings on public transport and in healthcare, care home and leisure settings as well as personal protective equipment commonly used in hospitals and in the current COVID-19 pandemic.


Positive Patch-Test Reactions to Essential Oils in Consecutive Patients From North America and Central Europe.
Synthetic fragrances and natural essential oils (EOs) are used in perfumery and found in various cosmetics. Essential oils are also increasingly used to promote wellness. In previous studies, the sensitization potential of some EOs has been identified; however, the current prevalence of sensitivity is largely unknown. The aim of this study was to determine frequency of positive patch-test reactions to EOs tested in the baseline series, along with 3 fragrance markers (FMs) (fragrance mix I, fragrance mix II, and Myroxylon pereirae), in consecutive patients in the US/Canadian North American Contact Dermatitis Group (NACDG) (2009-2014) and the central European, trinational Information Network of Departments of Dermatology (IVDK) (2010-2014). This study used a retrospective analysis of patch-test results and relevant demographic/clinical data collected electronically by the networks, obtained with Santalum album 10% petrolatum (pet) (IVDK only); Cananga odorata 2% (NACDG) and 10% (IVDK) pet; Jasminum species 2% (NACDG) and 5% (IVDK) pet; Mentha piperita 2% pet; Melaleuca alternifolia, oxidized (tea tree oil), 5% pet; and Lavandula angustifolia 2% pet (latter 3 NACDG only). Overall, 62,354 patients were tested to 3 FMs and EOs (NACDG, 13,398; IVDK, 48,956); 11,568 (18.6%) reacted to at least 1 FM or EO, whereas 857 (1.4%) reacted to 1 or more EOs but none of the 3 FMs. For both the NACDG and IVDK populations, individuals who were positive to 1 or more of the 9 study allergens were significantly less likely to be male, have occupational skin disease, or have hand involvement and significantly more likely to have leg dermatitis and be 40 years and older (P's ≤ 0.005). Prevalence rates for EOs were as follows: S. album, 1.4% IVDK; C. odorata, 1.1% NACDG and 2.4% IVDK; Jasminum species, 0.7% NACDG and 1.4% IVDK; M. piperita, 0.9% NACDG; L. angustifolia, 0.3% NACDG; and M. alternifolia, 0.3% NACDG. Of the 140 NACDG patients who reacted to 1 or more of the 5 NACDG EOs but none of the FMs, M. alternifolia yielded most positive reactions (45%); half of these reactions were strong (++ or +++, 50.8%) and of definite/probable clinical relevance (52.4%). Of the 717 IVDK patients who reacted to 1 or more of the 3 IVDK EOs but none of the 3 FMs, 38% were positive to C. odorata, 38% to S. album and 36% to Jasminum species.' Testing to EOs may be important for detecting sensitivity not detected by FMs alone. In North America, M. alternifolia is an important and clinically relevant sensitizer often not detected by FM. In Europe, as well as in North America, clinical relevance is often difficult to evaluate because (1) labeling of EOs when used as fragrance is not mandatory, and (2) these mixtures may indicate sensitization to 1 or more of their individual constituents from other sources, including synthetic fragrances.


[Linkage analysis of serial sex crimes].
The purpose of this study was twofold: first, to create an index for a behavioral linkage analysis of serial sex crimes, and second, to construct a predictive model for the analysis. Data on 720 sex crimes (rape, indecent assault) committed by 360 offenders arrested between 1993 and 2005 throughout Japan were collected. The following seven behaviors were examined during a series of analyses aimed at illustrating the effectiveness of crime linkage in serial sex crimes: victim age group, area type, publicness of offense site, weapon, time, contact method, and day of the week. The results indicated that six of the seven behaviors (excluding "day of the week") significantly distinguished between linked and unlinked crime pairs. Under a logistic regression of these six variables, which were dichotomously coded in terms of the concordance or discordance between each pair of incidents, the area under the receiver operating characteristic (ROC) curve was 0.85 (95% CI = 0.82-0.87), indicating a high level of discriminative accuracy in identifying disparate sex crimes committed by the same person.


Trading-off fish biodiversity, food security, and hydropower in the Mekong River Basin.
The Mekong River Basin, site of the biggest inland fishery in the world, is undergoing massive hydropower development. Planned dams will block critical fish migration routes between the river's downstream floodplains and upstream tributaries. Here we estimate fish biomass and biodiversity losses in numerous damming scenarios using a simple ecological model of fish migration. Our framework allows detailing trade-offs between dam locations, power production, and impacts on fish resources. We find that the completion of 78 dams on tributaries, which have not previously been subject to strategic analysis, would have catastrophic impacts on fish productivity and biodiversity. Our results argue for reassessment of several dams planned, and call for a new regional agreement on tributary development of the Mekong River Basin.


In depth analysis of risk factors for coeliac disease amongst children under 18 years old in the Gaza strip. A cross sectional study.
Coeliac disease is an important clinical disorder affecting the human gastrointestinal tract leading to multiple signs and symptoms in different body organs. This disease was the subject of a cross sectional descriptive-analytic study conducted in the Gaza Strip during 2010. Objectives were oriented to identify and verify several variables and attributes affecting the prognosis of coeliac disease in the patients. Ninety five children out of 113 patients were arranged into two groups according to age from 2 to 11 years and from 12 to 18 years old. Results showed the poor interest of health professionals regarding coeliac disease in the Gaza Strip. The mean age of study population was 5.47 years for males and 8.93 years for females. The lifestyle of coeliac patients was directly proportional with better nutritional indictors. Poor recognition of the emblem illustrating gluten in foods implicates effective health awareness or promotion. The more knowledgeable patients or mothers (P = 0.036) were the more compliant. The compliance to giving gluten free foods outside home was statistically significant (P = 0.037). Similarly, cautious approach when buying foods or detergents (P = 0.011). According to BMI 74.4%, 23.4% and 3.2% of all patients were normal, underweight and overweight respectively. Albumin blood level was normal in 32.6% and low in 67.4%. Meanwhile, blood calcium level was normal in 76.8%, low in 21.1% and high in 2.1% of all patients. The study showed that recreation and social activities for coeliac patients are substantially missing in the Gaza Strip. Moreover, the study proved that AEI is a reliable centre for care of coeliac disease patients and conducting relevant studies. There is a need for thorough and continuous community and institutional mobilization regarding coeliac disease in the Gaza Strip and in Palestine.