Hydroxysafflor yellow A induces autophagy in human liver cancer cells by regulating Beclin 1 and ERK expression.
Hydroxysafflor yellow A (HSYA) is a water-soluble component of the safflower (Carthamus tinctorius), and research has revealed that HSYA exhibits antitumor effects. In the present study, the effects of HSYA on the autophagy of a Hep-G2 liver cancer cell line, as well as the underlying mechanisms, were investigated. Hep-G2 cells were treated with HSYA and the viability of cells was measured using an MTT assay. Western blotting and immunofluorescence assays were performed to determine the expression of light chain 3 II (LC3-II) and p62, as well as the autophagy regulators Beclin 1 and ERK1/2. Transmission electron microscopy was performed to observe the formation of autophagosomes. The combined effects of HSYA and the autophagy inhibitor chloroquine (CQ) were also determined. The results revealed that the viability of Hep-G2 cells decreased with increasing concentrations of HSYA. Furthermore, LC3-II expression increased significantly and the level of p62 decreased significantly in the HYSA group compared with the control group. Additionally, an increase in Beclin 1 expression and a decrease in phosphorylated-ERK1/2 expression was observed in Hep-G2 cells treated with HYSA. Following treatment with CQ and HSYA, a significant increase in the viability of Hep-G2 cells was observed compared with the HSYA group. Collectively, the results indicated that HSYA induced autophagy by promoting the expression of Beclin 1 and inhibiting the phosphorylation of ERK in liver cancer cells. Therefore, HSYA may serve as a potential therapeutic agent for liver cancer.


[The TRIP database. A valuable source of literature on oral health].
Locating the desired evidenced-based literature via the internet is usually time-consuming and not particularly straight-forward. Websites offering evidence-based information should be accessible, efficient and user friendly. Many of these websites, however, only make their own content available, making it necessary to change websites in order to get a complete picture of the required information. The so-called website of ''Turning Research Into Practice'' is a positive exception. This website makes it possible to search the whole range of evidence-based publications on a certain subject with 1 search action, is straight-forward and practical to use, and the presentation is exceptionally good.


The association between dialysis modality and the risk for dialysis technique and non-dialysis technique-related infections.
Infections are a major cause of morbidity and mortality among dialysis patients. Dialysis modality has been hypothesized to be a potential immunomodulatory factor. The objective of this study was to determine the influence of the first dialysis modality on the risk for infections on dialysis. Our study was conducted utilizing the Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD) cohort of incident dialysis patients. Medical records of all patients from two tertiary care university hospitals and three regional hospitals were reviewed using pre-specified criteria. Information about infections was collected from the start of dialysis until death, modality switch, study withdrawal, kidney transplantation or at the end of the study. Age-standardized incidence rates for infections were calculated. Poisson regression analysis was used to calculate adjusted incidence rate ratios (IRRs). In total, 452 patients, of whom 285 started with haemodialysis (HD) and 167 with peritoneal dialysis (PD), were included. The median follow-up time on the first dialysis modality was similar for HD and PD, 1.8 and 2.0 dialysis years, respectively. During the first 6 months, the age-standardized infection incidence rate was higher on HD compared with PD patients (P = 0.02). Overall, PD patients had a higher infection risk [adjusted IRR: 1.65, 95% confidence interval (CI): 1.34-2.03], which could be attributed to a 4-fold increased risk for dialysis technique-related infections. The risk for non-dialysis technique-related infections was lower in PD patients (adjusted IRR: 0.56, 95% CI: 0.40-0.79). Overall, PD patients carry a higher risk for infections. Interestingly, the risk for non-dialysis technique-related infections was higher in HD patients. The links between dialysis modality and the immune system are expected to explain this difference, but future studies are needed to test these assumptions.


[Distribution spaces and catabolism of insulin].
Exact knowledge of the distribution spaces and the loss rate of insulin is the prerequisite of the clinical use of an artificial B-cell. A critical review of the literary findings concerning these problems is performed and the still open problems are shown.


NuA4 links methylation of histone H3 lysines 4 and 36 to acetylation of histones H4 and H3.
Cotranscriptional methylation of histone H3 lysines 4 and 36 by Set1 and Set2, respectively, stimulates interaction between nucleosomes and histone deacetylase complexes to block cryptic transcription in budding yeast. We previously showed that loss of all H3K4 and H3K36 methylation in a set1Δset2Δ mutant reduces interaction between native nucleosomes and the NuA4 lysine acetyltransferase (KAT) complex. We now provide evidence that NuA4 preferentially binds H3 tails mono- and dimethylated on H3K4 and di- and trimethylated on H3K36, an H3 methylation pattern distinct from that recognized by the RPD3C(S) and Hos2/Set3 histone deacetylase complexes (HDACs). Loss of H3K4 or H3K36 methylation in set1Δ or set2Δ mutants reduces NuA4 interaction with bulk nucleosomes in vitro and in vivo, and reduces NuA4 occupancy of transcribed coding sequences at particular genes. We also provide evidence that NuA4 acetylation of lysine residues in the histone H4 tail stimulates SAGA interaction with nucleosomes and its recruitment to coding sequences and attendant acetylation of histone H3 in vivo. Thus, H3 methylation exerts opposing effects of enhancing nucleosome acetylation by both NuA4 and SAGA as well as stimulating nucleosome deacetylation by multiple HDACs to maintain the proper level of histone acetylation in transcribed coding sequences.


Surface effects on PCR reactions in multichip microfluidic platforms.
We evaluated the compatibility of several common plastics, commercially available plastic tubing and disposable syringes which might be useful in the construction of microfluidic platforms with respect to the polymerase chain reaction (PCR). A simple and inexpensive plastic test module was constructed in order to evaluate some of the construction plastics. We also investigated the effect of addition of PEG 8000 to PCR reaction mixtures on the compatibility of materials. These studies identified several common plastics, plastic tubing, and disposable syringes which were compatible with the PCR reaction.


Endogenous proteolysis of membrane-bound red cell cytochrome-b5 reductase in adults and newborns: its possible relevance to the generation of the soluble "methemoglobin reductase".
The problem of the low activity of so-called methemoglobin reductase in red cells from newborns was reinvestigated in view of our current knowledge of this enzyme, i.e., (1) its being cytochrome-b5 reductase and (2) its presence in two forms: soluble and membrane-bound. We found that red cells from cord blood and newborns exhibited a 50% decrease of soluble cytochrome-b5 reductase activity, whereas membrane-bound activity was in the adult range. Ghosts from these cells possessed diminished ability to solubilize membrane-bound cytochrome-b5 reductase in the course of in vitro auto-incubation. This autosolubilizing ability increased with age and reached adult level concomitantly with soluble cytochrome-b5 reductase activity at 6 mo. We conclude that the relative deficiency of soluble cytochrome-b5 reductase observed at birth is due to diminished post-translational processing of the membrane-bound enzyme during erythropoiesis of fetal cells. This processing is calcium-dependent related to calmodulin.


Nonoccupational postexposure prophylaxis for exposure to HIV in New York State emergency departments.
We investigate emergency department (ED) directors' knowledge of protocols and practices for nonoccupational postexposure prophylaxis (nPEP) after potential exposure to HIV after sexual assault and consensual sexual exposures in New York State (NYS) EDs. Every ED director in NYS was queried through an electronic survey about protocols, antiretroviral drugs supplied, resources and barriers to implementation. They were also asked for retrospective data, including the number and type of cases seen and percentage in which nPEP was initiated. One hundred eighty-eight of 207 ED directors (91%) responded. One hundred seventy-eight (95%) have a protocol for sexual assault and 111 (59%) have a protocol for voluntary sexual exposure. After sexual assault, 163 ED directors (87%) reported that they typically initiate nPEP in the ED; 25 (13%) either write a prescription only or refer to another facility. After voluntary sexual exposure 132 (70%) typically initiate nPEP in the ED; 55 (29%) either write a prescription only or refer to another facility (p < 0.001). Self-reported ED data indicate that 3439 sexual assault exposures and 6858 voluntary sexual exposures and were seen in NYS EDs in 2005. The nPEP initiation rate was 65% (2244/3439) for sexual assault exposures and 43% (2931/6858) for consensual sexual exposures (p < 0.001). These results suggest that NYS nPEP guidelines are not widely implemented, and raise several important public health policy issues, including access to medication and follow-up care. Our results indicated resources, primarily number of dedicated staff, and physician education as two major factors contributing to this problem.


Delivery after external cephalic version, is there an increased rate of cesarian section?
The aim of this study was to compare the obstetric outcomes after successful external cephalic version (cases) with a group of pregnant women with a spontaneous cephalic fetal position at delivery (controls). Retrospective review of the cohort of study was performed at the University Hospital of Getafe (Madrid, Spain) between January 2012 and January 2013. 1516 patients (48 cases; 1468 controls). We compared the type of delivery in pregnant women after ECV performed successfully (cases) with spontaneous cephalic presentations (controls). Pregnancies with vaginal delivery contraindicated, elective cesarean section (CS) justified by maternal disease, multiple pregnancies, or pregnancies below 37 weeks were excluded. Maternal age, BMI, parity, gestational age at delivery, and onset of labor (spontaneous or induced) were controlled. Prevalence of CS and operative delivery in both groups. Women who underwent a successful ECV had a significantly higher CS rate compared with the women of the control group (12/48 [25%] vs. 202/1468 [13.76%]; P=0.028). There was no difference in the rate of operative delivery (6/48 [12.5%] vs. 177/1468 [12.05%] P=0.92). Deliveries following a successful ECV are associated with an increased CS rate compared with deliveries of fetuses with spontaneous cephalic presentations.


[Tumor hip prosthesis in fibrous dysplasia of proximal femur. Case report].
fibrous dysplasia is characterized by the formation of fibrous tissue that generates immature malformed trabeculae. Their involvement may be monostotic or poliostotic. Thirty years old female with fibrous dysplasia of the left hip. At age 15 suffered hip fracture without apparent trauma, she was managed conservatively and significant shortening of the same limb was observed. At 30 years old, is pregnant, it had left hip pain, deformity and shortening is exacerbated. Simple radiography showed «shepherds crook deformity», she was treated with bisphosphonates. Computed axial tomography corroborates previous findings. She subsequently underwent subtrochanteric fracture fall with left hip dysplasia site, ground glass image of cystic appearance involving the femoral neck, trochanteric and subtrochanteric area. Tumor prosthesis of the left hip was implanted, four months evolution was favorable. Modular hip prosthesis system, reduces deformity, improves length and reduces pain in patients with resection of fibrous dysplasia of the hip.


C1q induces a rapid up-regulation of P-selectin and modulates collagen- and collagen-related peptide-triggered activation in human platelets.
Blood platelets are emerging as important immunomodulatory cells, but complement interaction with platelets is not well understood. Several platelet structures have been described as complement protein 1q (C1q) binding receptors, such as C1qRp/CD93 and gC1qR. However, there are conflicting results whether these receptors are C1q binding structures, or even at all expressed on the cell surface. Recently, the collagen-binding integrin αIIβI was reported to bind C1q on mast cells, and this receptor is also present on platelets. The aim of this study was to further characterize the effects of C1q on platelets, by quantifying the platelet surface expression of P-selectin (CD62P) and monitoring the formation of platelet-neutrophil aggregates. Using flow cytometry, we found that C1q dose-dependently triggered a rapid but moderate and transient up-regulation of P-selectin already within 5s of C1q exposure. Pre-incubation with an antibody directed against gC1qR significantly inhibited (with 57% compared to control) the up-regulation, whereas an antibody towards the αIIβI-integrin showed no effect. Stimulation with C1q did not change the cytosolic calcium-levels, as measured with the fluorescent ratiometric probe Fura-2, however, a protein kinase C inhibitor (GF109203x) blocked the C1q-induced P-selectin expression. Furthermore, pre-incubation of platelets with C1q diminished both the collagen as well as the collagen-related peptide-induced up-regulation of P-selectin, most evident after 90s of stimulation. This indicates that C1q may regulate platelet activation via the GPVI receptor, which is a novel finding. Moreover, C1q antagonized the collagen-induced formation of platelet-neutrophil aggregates, indicating a reduced interaction between platelet P-selectin and neutrophil P-selectin glycoprotein ligand-1(PSGL-1/CD162). In summary, C1q induces a moderate rapid platelet P-selectin expression, modulates subsequent collagen and collagen-related peptide stimulation of platelets, and inhibits the formation of platelet-neutrophil aggregates. These immuno-regulatory effects of C1q may have a crucial role in innate immunity and inflammation.


Modeling dysbiosis of human NASH in mice: Loss of gut microbiome diversity and overgrowth of Erysipelotrichales.
Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease (NAFLD) that is responsible for a growing fraction of cirrhosis and liver cancer cases worldwide. Changes in the gut microbiome have been implicated in NASH pathogenesis, but the lack of suitable murine models has been a barrier to progress. We have therefore characterized the microbiome in a well-validated murine NASH model to establish its value in modeling human disease. The composition of intestinal microbiota was monitored in mice on a 12- or 24-week NASH protocol consisting of high fat, high sugar Western Diet (WD) plus once weekly i.p injection of low-dose CCl4. Additional mice were subjected to WD-only or CCl4-only conditions to assess the independent effect of these variables on the microbiome. There was substantial remodeling of the intestinal microbiome in NASH mice, characterized by declines in both species diversity and bacterial abundance. Based on changes to beta diversity, microbiota from NASH mice clustered separately from controls in principal coordinate analyses. A comparison between WD-only and CCl4-only controls with the NASH model identified WD as the primary driver of early changes to the microbiome, resulting in loss of diversity within the 1st week. A NASH signature emerged progressively at weeks 6 and 12, including, most notably, a reproducible bloom of the Firmicute order Erysipelotrichales. We have established a valuable model to study the role of gut microbes in NASH, enabling us to identify a new NASH gut microbiome signature.


Reactions to music, touch and object presentation in the final stage of dementia. An exploratory study.
Two patients in the final stage of dementia of Alzheimer type were stimulated with music, touch and object presentation during 12 consecutive days (16 trials per patient). Evaluations were made by direct observations, analysis of video-taped recordings and registrations of pulse and rate of respiration. Both patients reacted differently to music than to touch and object presentation.


Late morbidity of very low birthweight infants.
The use of hospitals in the first year after term was studied in a geographically based group of 111 very low birthweight infants in Liverpool. This was compared with that of 216 term infants without perinatal complications. Of the group with very low birth weight, 59 (53%) were readmitted, with three deaths, compared with 21 (10%) of the term infants. Of the admissions, 67 (40%) related to sequels of neonatal illness or its management. The admissions were repeated and of long duration, resulting in a 16-fold increased load of inpatients, an eightfold increase in surgical procedures, and a twofold increase in attendance by outpatients at the local children's hospitals compared with the term group. This population of infants after intensive care represented a high risk group with specific problems and requirements in infancy, even when problems were not apparent at discharge from the neonatal unit.


Mixed Pluronic/lecithin micelles formulation for oral bioavailability of candesartan cilexetil drug: In-vitro characterization and In-vivo pharmacokinetic investigations.
This study aimed to develop a mixed polymeric micelle formulation incorporating candesartan cilexetil (CAND) drug to enhance its oral bioavailability for the better treatment of hypertension. A Box-Behnken design was utilized to optimize the CAND-incorporated mixed polymeric micelles formulation (CAND-PFLC) consisting of Pluronics (P123 and F68) and lecithin (LC). The optimized CAND-PFLC micelles formulation was characterized for size, shape, zeta potential, polydispersity index (PDI), and entrapment efficiency (%EE). An in-vitro release study, ex-vivo permeability investigation, and an in-vivo pharmacokinetic analysis were carried out to evaluate the performance of the formulation. The optimized CAND-PFLC micelles formulation demonstrated a spherical shape, a particle size of 44 ± 2.03 nm, a zeta potential of -7.07 ± 1.39 mV, a PDI of 0.326 ± 0.06, and an entrapment efficiency of 87 ± 3.12%. The formulation exhibited excellent compatibility, better stability, and a non-crystalline nature. An in-vitro release study revealed a faster drug release of 7.98% at gastric pH in 2 hrs and 94.45% at intestinal pH within 24 hrs. The ex-vivo investigation demonstrated a significantly enhanced permeability of CAND, with 94.86% in the micelle formulation compared to 9.03% of the pure drug. In-vivo pharmacokinetic analysis showed a 4.11-fold increase in oral bioavailability of CAND compared to the marketed formulation. The CAND-PFLC mixed micelle formulation demonstrated improved performance compared to pure CAND, indicating its potential as a promising oral drug delivery system for the effective treatment of hypertension.


Phase I study of thiotepa in combination with the glutathione transferase inhibitor ethacrynic acid.
The glutathione transferases comprise a family of isoenzymes, one or more of which are involved in the conjugation of alkylating agents to glutathione (GSH). Increased GSH transferase activity has been shown to underlie acquired resistance to several alkylating agents. Ethacrynic acid inhibits the isoenzymes of GSH transferase with 50% inhibitory concentration values ranging from 0.3 to 6.0 microM and has been shown to restore sensitivity to alkylating agents in drug-resistant animal tumor models. We entered 27 previously treated patients with advanced cancer on a study of ethacrynic acid (25 to 75 mg/m2 p.o. every 6 h for 3 doses) and thiotepa (30 to 55 mg/m2 i.v. 1 h after the second dose of ethacrynic acid). The major toxicity of ethacrynic acid was diuresis, which was observed at every dose level; in addition, severe metabolic abnormalities occurred at 75 mg/m2. At 50 mg/m2, the diuretic effects were manageable. Myelosuppression was the most important effect of the combination. Two of seven courses of ethacrynic acid, 50 mg/m2, and thiotepa, 55 mg/m2, were associated with grade 3 or 4 neutropenia and/or thrombocytopenia. Nausea/vomiting greater than or equal to grade 2 was observed in 16% of courses. GSH transferase activity was assayed spectrophotometrically in the peripheral mononuclear cells of all patients. At each dose level, activity decreased following ethacrynic acid administration, with recovery by 6 h. Administration of ethacrynic acid, 50 mg/m2, resulted in a mean nadir of transferase activity of 37% of control. The pharmacokinetics of thiotepa and its principal metabolite TEPA were studied in 23 patients. The plasma disappearance of thiotepa fit a two-compartment open model with a terminal half-life of approximately 2 h. Plasma TEPA levels peaked at a mean of 2.16 h following thiotepa administration. The harmonic mean terminal half-life of TEPA was 10.4 h, and the TEPA area under the curve (AUC) did not increase with increasing thiotepa dose. The AUC of thiotepa was approximately twice, and the clearance about one-half, of the values obtained in a previous study of single agent thiotepa. The AUC of TEPA was lower than that previously observed. The data suggest that ethacrynic acid inhibits enzymes involved in the metabolic disposition of thiotepa, including its oxidative desulfuration to TEPA. The severity of the platelet toxicity was correlated with the AUC of thiotepa, but not with that of TEPA. This combination of thiotepa and ethacrynic acid will be tested further in Phase II trials.


Estradiol acts as a competitive inhibitor of the 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase enzyme of cultured Leydig tumor cells.
To study the local regulatory mechanisms involving steroid hormones in steroidogenic cells, the effect of estradiol on steroidogenesis was investigated using MA-10 Leydig tumor cells. Estradiol inhibited progesterone biosynthesis in MA-10 cells in a dose-dependent manner. Inhibition of progesterone biosynthesis by estradiol was associated with a concomitant accumulation of pregnenolone in the incubation medium. Estradiol inhibited the activity of 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase by a chemical mechanism which is not mediated through the cellular estrogen receptor. Thus, the estrogen receptor agonist diethylstilbestrol did not inhibit this enzyme activity, nor could this agent block the effect of estradiol on the enzyme. Furthermore, estradiol inhibited enzyme activity in isolated microsomes which do not contain estradiol receptor protein. Kinetic analysis of the inhibitory effect of estradiol on 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase revealed that this steroid hormone functions as a competitive inhibitor of the enzyme, with an average apparent Ki of 1.8 microM.


Status Report on Topical Hypochlorous Acid: Clinical Relevance of Specific Formulations, Potential Modes of Action, and Study Outcomes.
In-vitro and in-vivo studies have supported antimicrobial, anti-inflammatory, and other biologic properties of hypochlorous acid (HOCl), which has led to its use in the treatment of skin wounds, pruritus, diabetic ulcers, and some inflammatory skin disorders. Research has also shown that the physiochemical properties of HOCl after application to skin are highly dependent on both pH and formulation stability. In this review, the authors discuss a core HOCI formulation (Microcyn® Technology, Sonoma Pharmaceuticals, Petaluma, California) that is stable for up to two years, noncytotoxic, and pH-neutralized to augment therapeutic activity, skin tolerability, and stability. The authors summarize relevant study outcomes and potential modes of action related to this core HOCI formulation, as well as describe its ready-to-use vehicles that are approved and available for topical application.


In vitro conversion of MVM parvovirus single-stranded DNA to the replicative form by DNA polymerase alpha from Ehrlich ascites tumour cells.
A partially purified preparation of DNA polymerase alpha, obtained from the cytosol of Ehrlich ascites tumour cells, has been found to catalyze the conversion of MVM parvovirus, SS DNA (5 kilobases) to RF in vitro. The reaction initiates at a natural 55 base pair hairpin which exists at the 3' terminus of MVM SS DNA. The SS leads to RF conversion is sensitive to aphidicolin, resistant to ddTTP and is promoted by purine ribonucleoside 5' triphosphates, a phenomenon which could not be explained simply by stabilization effects on the in vitro deoxynucleotide precursor pool. In the absence of rNTPs, nascent complementary strands frequently terminate prematurely at a preferred location, between 1300 and 1700 nucleotides from the initiating 3' hairpin terminus. This in vitro system, involving self-primed parvovirus DNA synthesis, provides a convenient assay for those components of the mammalian replicative DNA polymerase complex which are required for the elongation of nascent DNA chains.


A unified explanation for the morphology of raised peatlands.
Raised peatlands, or bogs, are gently mounded landforms that are composed entirely of organic matter1-4 and store the most carbon per area of any terrestrial ecosystem5. The shapes of bogs are critically important because their domed morphology4,6,7 accounts for much of the carbon that bogs store and determines how they will respond to interventions8,9 to stop greenhouse gas emissions and fires after anthropogenic drainage10-13. However, a general theory to infer the morphology of bogs is still lacking4,6,7. Here we show that an equation based on the processes universal to bogs explains their morphology across biomes, from Alaska, through the tropics, to New Zealand. In contrast to earlier models of bog morphology that attempted to describe only long-term equilibrium shapes4,6,7 and were, therefore, inapplicable to most bogs14-16, our approach makes no such assumption and makes it possible to infer full shapes of bogs from a sample of elevations, such as a single elevation transect. Our findings provide a foundation for quantitative inference about the morphology, hydrology and carbon storage of bogs through Earth's history, as well as a basis for planning natural climate solutions by rewetting damaged bogs around the world.


Posterior midgut and hindgut are both sites of acquisition of Cucurbit aphid-borne yellows virus in Myzus persicae and Aphis gossypii.
Members of the family Luteoviridae ('luteovirids') rely strictly on aphid vectors for plant-to-plant transmission. This interaction operates according to a persistent and circulative manner, which implies that the virions are being endocytosed and exocytosed across two epithelial barriers (alimentary tract and accessory salivary glands) in the vector's body. In several luteovirid-aphid vector species combinations, the route of virions in the insect has been investigated ultrastructurally by transmission electron microscopy (TEM). Here, we used TEM to follow the route of Cucurbit aphid-borne yellows virus (CABYV; genus Polerovirus) in its two efficient vector species, Myzus persicae and Aphis gossypii. We demonstrated that CABYV particles are acquired from the gut lumen to the haemocoel through two different sites in both aphid species, i.e. the posterior midgut (as for Beet western yellows virus in M. persicae) and the hindgut (as for Barley yellow dwarf virus complex in cereal aphids). This 'dual' tissue specificity of CABYV represents an original situation among viruses in the family Luteoviridae examined so far by TEM. A variety of virion-containing structures (e.g. clathrin-coated and tubular vesicles, endosome-like bodies) are found in intestinal cells of both types in both aphids. Release of virus particles from midgut and hindgut cells into the haemolymph was confirmed by immunotrapping using CABYV-specific antibodies. In accessory salivary glands, transport of CABYV virions across the cells was similar in each aphid species, and occurred by a transcytosis mechanism involving formation of tubular and coated vesicles before release of free virions in the salivary canal.


Concentrations of organic contaminants in industrial and municipal bioresources recycled in agriculture in the UK.
Many types of bioresource materials are beneficially recycled in agriculture for soil improvement and as alternative bedding materials for livestock, but they also potentially transfer contaminants into plant and animal foods. Representative types of industrial and municipal bioresources were selected to assess the extent of organic chemical contamination, including: (i) land applied materials: treated sewage sludge (biosolids), meat and bone meal ash (MBMA), poultry litter ash (PLA), paper sludge ash (PSA) and compost-like-output (CLO), and (ii) bedding materials: recycled waste wood (RWW), dried paper sludge (DPS), paper sludge ash (PSA) and shredded cardboard. The materials generally contained lower concentrations of polychlorinated dibenzo-p-dioxins/dibenzofurans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (PCBs) relative to earlier reports, indicating the decline in environmental emissions of these established contaminants. However, concentrations of polycyclic aromatic hydrocarbons (PAHs) remain elevated in biosolids samples from urban catchments. Polybrominated dibenzo-p-dioxins/dibenzofurans (PBDD/Fs) were present in larger amounts in biosolids and CLO compared to their chlorinated counterparts and hence are of potentially greater significance in contemporary materials. The presence of non-ortho-polychlorinated biphenyls (PCBs) in DPS was probably due to non-legacy sources of PCBs in paper production. Flame retardent chemicals were one of the most significant and extensive groups of contaminants found in the bioresource materials. Decabromodiphenylether (deca-BDE) was the most abundant polybrominated diphenyl ether (PBDE) and may explain the formation and high concentrations of PBDD/Fs detected. Emerging flame retardant compounds, including: decabromodiphenylethane (DBDPE) and organophosphate flame retardants (OPFRs), were also detected in several of the materials. The profile of perfluoroalkyl substances (PFAS) depended on the type of waste category; perfluoroundecanoic acid (PFUnDA) was the most significant PFAS for DPS, whereas perfluorooctane sulfonate (PFOS) was dominant in biosolids and CLO. The concentrations of polychlorinated alkanes (PCAs) and di-2-ethylhexyl phthalate (DEHP) were generally much larger than the other contaminants measured, indicating that there are major anthropogenic sources of these potentially hazardous chemicals entering the environment. The study results suggest that continued vigilance is required to control emissions and sources of these contaminants to support the beneficial use of secondary bioresource materials.


Designing for Accelerated Translation (DART) of Emerging Innovations in Health.
Accelerating innovation translation is a priority for improving healthcare and health. Although dissemination and implementation (D&I) research has made significant advances over the past decade, it has attended primarily to the implementation of long-standing, well-established practices and policies. We present a conceptual architecture for speeding translation of promising innovations as candidates for iterative testing in practice. Our framework to Design for Accelerated Translation (DART) aims to clarify whether, when, and how to act on evolving evidence to improve healthcare. We view translation of evidence to practice as a dynamic process and argue that much evidence can be acted upon even when uncertainty is moderately high, recognizing that this evidence is evolving and subject to frequent reevaluation. The DART framework proposes that additional factors-demand, risk, and cost, in addition to the evolving evidence base-should influence the pace of translation over time. Attention to these underemphasized factors may lead to more dynamic decision-making about whether or not to adopt an emerging innovation or de-implement a suboptimal intervention. Finally, the DART framework outlines key actions that will speed movement from evidence to practice, including forming meaningful stakeholder partnerships, designing innovations for D&I, and engaging in a learning health system.


Community health priorities: Lessons for malaria prevention from Balaka district, Malawi.
Communication to address priority health challenges typically draws on epidemiological research in conjunction with referencing global and country strategies. While community-level perspectives on health challenges typically align with national priorities, nuances and barriers that constrain health response may be less well known. To deepen understanding of the relation between situational aspects of health and ways of making meaning, community insights into health priorities were explored. Action Media, an established participatory research methodology for informing health communication design and strategy, was undertaken with parents of children under 5 in Balaka District, Malawi. Participants identified malaria as a priority concern in their community. While it was reported that there was strong commitment to consistent use of long lasting insecticide treated nets, there was frustration that malaria incidence remained high. It was observed that risk of exposure to mosquito bites was increased as a result of chores and other activities that extended into the early evenings prior to retiring to bed under a bed net. Bed bug infestations were said to be a common and ongoing concern. Some community members alleviated discomfort by abandoning their beds and sleeping outside without adequate protection while others boiled their bed nets to remove bed bugs. Accessing distant health facilities when ill with malaria was difficult for adults and children. Participants identified the need for effective strategies to address these concerns including accessing mosquito repellant, eradicating bed bugs, treating malaria locally and collaborating in malaria control activities. Meeting targets for malaria prevention requires consideration of contextual factors that undermine effective malaria prevention in affected communities. Such factors are not immediately apparent through epidemiological data. Regularly assessing contextual challenges in high malaria incidence areas provides opportunities to understand gaps, to refine intervention strategies and to inform communication programming.


Why tocilizumab could be an effective treatment for severe COVID-19?
A severe pneumonia-associated respiratory syndrome caused by a new coronavirus was identified in December 2019 (COVID-19), spread rapidly and has become a world-wide public health challenge. About 25% of COVID-19 patients experienced severe complications including acute respiratory distress syndrome (ARDS), and even progressed into an intensive care unit (ICU) admission and died. The exploration for the mortality causes and advancing novel therapeutic development of severe COVID-19 is crucial at the moment. The biopsy samples analysis at autopsy suggested that increased alveolar exudate caused by aberrant host immune response and inflammatory cytokine storm probably impedes alveolar gas exchange and contributes to the high mortality of severe COVID-19 patients. Our research has identified that pathogenic T cells and inflammatory monocytes incite inflammatory storm with large amount of interleukin 6, therefore monoclonal antibody that targets the IL-6 pathways may potentially curb inflammatory storm. Moreover, Tocilizumab treatment that blocking IL-6 receptors showed inspiring clinical results including temperature returned to normal quickly and respiratory function improved. Therefore, we suggest that Tocilizumab is an effective treatment in severe patients of COVID-19 to calm the inflammatory storm and reduce mortality.


Anatomically distinct opiate receptor fields mediate reward and physical dependence.
Rats never before exposed to opioids rapidly learned to press a lever for microinjections of morphine into the ventral tegmental area. Challenge by a narcotic antagonist produced no signs of physical dependence. Dependence was not seen after long-term morphine infusions into the ventral tegmentum but was seen after similar infusions into the periventricular gray region. Thus a major rewarding property of morphine is independent of the drug's ability to produce physical dependence. These data challenge models of drug addiction that propose physical dependence as necessary for the rewarding effects of opioids.


Phosphatidylcholine synthesis influences the diacylglycerol homeostasis required for SEC14p-dependent Golgi function and cell growth.
Phosphatidylcholine and phosphatidylethanolamine are the most abundant phospholipids in eukaryotic cells and thus have major roles in the formation and maintenance of vesicular membranes. In yeast, diacylglycerol accepts a phosphocholine moiety through a CPT1-derived cholinephosphotransferase activity to directly synthesize phosphatidylcholine. EPT1-derived activity can transfer either phosphocholine or phosphoethanolamine to diacylglcyerol in vitro, but is currently believed to primarily synthesize phosphatidylethanolamine in vivo. In this study we report that CPT1- and EPT1-derived cholinephosphotransferase activities can significantly overlap in vivo such that EPT1 can contribute to 60% of net phosphatidylcholine synthesis via the Kennedy pathway. Alterations in the level of diacylglycerol consumption through alterations in phosphatidylcholine synthesis directly correlated with the level of SEC14-dependent invertase secretion and affected cell viability. Administration of synthetic di8:0 diacylglycerol resulted in a partial rescue of cells from SEC14-mediated cell death. The addition of di8:0 diacylglycerol increased di8:0 diacylglycerol levels 20-40-fold over endogenous long-chain diacylglycerol levels. Di8:0 diacylglcyerol did not alter endogenous phospholipid metabolic pathways, nor was it converted to di8:0 phosphatidic acid.


Alpha1-adrenergic receptor mRNA and inflammatory mediator expression in circulating leucocytes after cardiac surgery.
Vasodilation after coronary artery bypass surgery is a common complication. Inflammatory mediators influence the expression of alpha1-adrenergic receptors. Do patients requiring high doses of postoperative inotropic support have down-regulated alpha-adrenergic receptors? Is there a characteristic pattern of preoperative inflammatory mediator expression that could predict a complicated course after the operation? Forty-four patients undergoing cardiac bypass surgery with extracorporeal circulation were prospectively investigated. Five perioperative blood samples were taken (preoperative, two hours, 12 hours, 36 hours and 72 hours postoperative). The leucocyte mRNA-expression of the three alpha1-adrenergic receptor subtypes (A, B and D) and 11 different pro-inflammatory mediators were investigated with the real-time reverse transcriptase polymerase chain reaction. The patients were divided into three groups (No-noradrenaline [No-NA]= 0 microg/min, Low-noradrenaline [Low-NA]=0.1-7 microg/min, High-noradrenaline [High-NA] >7 microg/min), according to their postoperative noradrenaline requirements. Preoperatively, alpha1(A)-receptor expression was 4.9-fold (High-NA) and 18.7-fold (Low-NA) higher than the No-NA group (P=0.005) and plasma noradrenaline levels were higher in the High-NA group (P=0.005). Across all groups at 12 hours after the operation, alpha1(A) -receptor expression decreased to approximately one-fifth of preoperative levels (P=0.01); but with greater duration and magnitude of relative decrease in the High-NA group. Patients in the No-NA group had significant postoperative increases in leucocyte inflammatory mediator expression for IL-1beta, TLR4, TREM, MPO, MMP9 and TNF genes, whereas the changes in the Low-NA and High-NA groups were not significant. Low preoperative levels of noradrenaline and low expression of alpha1(A)-adrenoreceptors in leucocytes was associated with less probability of requiring noradrenaline support after cardiac surgery.


Chaperones in maturation of molybdoenzymes: Why specific is better than general?
Molybdoenzymes play essential functions in living organisms and, as a result, in various geochemical cycles. It is thus crucial to understand how these complex proteins become highly efficient enzymes able to perform a wide range of catalytic activities. It has been established that specific chaperones are involved during their maturation process. Here, we raise the question of the involvement of general chaperones acting in concert with dedicated chaperones or not.


Rapid and simple detection of ascorbic acid and alkaline phosphatase via controlled generation of silver nanoparticles and selective recognition.
Ascorbic acid (AA) and alkaline phosphatase (ALP) serve as an important coenzyme and enzyme in multiple biological metabolism reactions, respectively, and abnormal levels of these substrates have been associated with several diseases. Herein, a new and simple fluorescence strategy has been developed for AA and ALP sensing by exploiting CdTe quantum dots (QDs) as an effective signal indicator. This method is mainly based on the selective fluorescence-quenching reaction between Ag+ and CdTe QDs, as opposed to silver nanoparticles (Ag NPs); Ag+ can be reduced to Ag NPs by AA. Furthermore, by taking advantage of AA as a mediator, this strategy is further exploited for ALP assay given that ALP can cause the hydrolysis of l-ascorbic acid-2-phosphate (AAP), which yields AA. Under optimal conditions, controlled generation of Ag NPs and the selective recognition-based sensing system exhibit high sensitivity toward AA and ALP with limits of detection (LODs) of 3 μM and 0.25 U L-1 and linear ranges of detection from 0 to 800 μM and 1 to 1000 U L-1, respectively. Moreover, the sensor was successfully used for assaying AA in fruit juice and ALP in human serum. The results demonstrate that the proposed fluorescence strategy has significant advantages, such as its simplicity, cost-effectiveness, and rapid runtime, and the operational convenience of this label-free method further demonstrates its potential for constructing effective sensors with biochemical and clinical applications.


Autoxidation and photooxidation of tetrahydrobiopterin: a theoretical study.
Pterins are naturally occurring pigments and enzyme cofactors widespread in living organisms. Tetrahydrobiopterin (H4Bip) is a coenzyme of aromatic amino acid hydroxylases, NO-synthases, and alkylglycerol monooxygenases. This coenzyme is prone to oxidation in the presence of molecular oxygen, a so-called autoxidation. The reactions participating in H4Bip autoxidation are well known. However, our study is an attempt to evaluate theoretically the feasibility of reactions participating in autoxidation. To do so, we have calculated the Gibbs free energy of elementary reactions between H4Bip, its derivatives, molecular oxygen, and reactive oxygen species (ROS). In the last few years, we have established the photosensitized oxidation of H4Bip experimentally. Thus, we have also evaluated the feasibility of H4Bip photooxidation reactions, which may occur according to both type-I and type-II photosensitized oxidation. We calculated Fukui indices for H4Bip and found particular atoms in the molecule that interact with nucleophiles (for example, singlet oxygen 1O2) and radicals (in particular, molecular oxygen 3O2). Therefore, we evaluated the probability of H4Bip autoxidation reactions, photooxidation reactions, and the reactivity of particular atoms in H4Bip molecule using the theoretical methods of quantum chemistry.


1H NMR Mixture Design-Fingerprints and ASCA Analysis in Ilex paraguariensis: Model Stability in Search of a Global Metabolome.
The effects of experimental repetitions and solvent extractors on the 1H NMR fingerprinting of yerba mate extracts, obtained from two genders and two light environments, were analyzed in-depth by ANOVA-simultaneous component analysis (ASCA). Different solvents were used according to a mixture design based on ethanol, dichloromethane, and hexane and their combinations. The number of experimental repetitions significantly affected the ASCA results. Increasing repetitions led to decreases in the percentage effect variance values and an increase in the percentage residual variance. However, secondary sexual dimorphism, light availability, and their interaction effects became more significant with decreasing p-values at or above the 95% confidence level. The choice of a solvent extractor significantly affects the chemical profile and can lead to distinct conclusions regarding the significance of effect values. Pure solvents yielded different conclusions about the significance of factorial design effects, with each solvent extracting unique metabolites and maximizing information for specific effects. However, the use of binary solvent mixtures, such as ethanol-dichloromethane, proved more efficient in extracting sets of compounds that simultaneously differentiate between different experimental conditions. The mixture design-fingerprint strategy provided satisfactory results expanding the range of extracted metabolites with high percentage of residual variances and low explained percentage effect variances in the ASCA models. Ternary and even higher-ordered mixtures could be good alternative extracting media for work-intensive procedures. Our study underscores the significance of experimental design and solvent selection in metabolomic analysis, improving the accuracy, robustness, and interpretability of metabolomic models, leading to a better understanding of the chemical composition and biological implications of plant extracts.


Direct method for video-based navigation using a digital terrain map.
A novel vision-based navigation algorithm is proposed. The gray levels of two images, together with a Digital Terrain Map (DTM), are directly utilized to define constraints on the navigation parameters. The feasibility of the algorithm is examined both under a simulated environment and using real flight data.


Probing Electron Spin Resonance in Monolayer Graphene.
The precise value of the g factor in graphene is of fundamental interest for all spin-related properties and their application. We investigate monolayer graphene on a Si/SiO_{2} substrate by resistively detected electron spin resonance. Surprisingly, the magnetic moment and corresponding g factor of 1.952±0.002 is insensitive to charge carrier type, concentration, and mobility.


Chemical and mechanistic analysis of photodynamic inhibition of Alzheimer's β-amyloid aggregation.
The self-assembly of the beta-amyloid peptide (Aβ) into amyloid aggregates is a central phenomenon associated with Alzheimer's disease. Here, we report chemical modifications of key amino acid residues of Aβ42 (Y10, H13, H14, and M35) by photoexcited thioflavin-T (ThT), a fluorescent probe of amyloid structure. The quantitative chemical kinetics analysis shows that the oxidized monomer species does not self-assemble, nor perturb the aggregation kinetics of non-oxidized Aβ42.


Differential expression of erythropoietin and its receptor in von hippel-lindau-associated and multiple endocrine neoplasia type 2-associated pheochromocytomas.
Pheochromocytoma is a neuroendocrine tumor associated with a variety of genetic disorders, which include von Hippel-Lindau disease (VHL), multiple endocrine neoplasia type 2 (MEN 2), neurofibromatosis type 1, hereditary paraganglioma, and succinate dehydrogenase gene-related tumors. Previous studies of VHL-associated and MEN 2-associated pheochromocytomas suggest morphological, biochemical, and clinical differences exist among the tumors, but the process by which they develop remains unclear. Studies in other VHL-associated tumors suggest that VHL gene deficiency causes coexpression of erythropoietin (Epo) and its receptor (Epo-R), which facilitates tumor growth. The objective of this study was to understand the different process of tumorigenesis for VHL and MEN 2-associated pheochromocytomas. Ten pheochromocytomas (VHL patients n = 5, MEN 2 patients n = 5) were examined for the presence or absence of Epo and Epo-R using Western blot, immunohistochemistry, and RT-PCR analyses. Coexpression of Epo and Epo-R was found in all five VHL-associated pheochromocytomas; in contrast, expression of Epo-R, but not Epo, was documented in all five MEN 2-associated pheochromocytomas. Expression of Epo appears to be a result of VHL gene deficiency, possibly through activation of the hypoxia inducible factor-1 pathway, whereas Epo-R is an embryonal marker whose sustained expression in both VHL- and MEN 2-associated pheochromocytomas reflects an arrest or defect in development. These findings suggest an alternative process of tumorigenesis in VHL- and MEN 2-associated pheochromocytomas and implicate Epo as a clinical biomarker to differentiate these tumors.


Blood pressure, heart rate, and mortality in chronic obstructive pulmonary disease: the SUMMIT trial.
To characterize the relationship between blood pressure (BP) or heart rate and mortality and morbidity in chronic obstructive pulmonary disease (COPD). We performed post hoc analysis of baseline BP or heart rate and all-cause mortality and cardiovascular events in the SUMMIT trial. SUMMIT was a randomized double-blind outcome trial of 16 485 participants (65 ± 8 years, 75% male, and 47% active smokers) enrolled at 1368 sites in 43 countries. Participants with moderate COPD with or at risk for cardiovascular disease (CVD) were randomized to placebo, long-acting beta agonist, inhaled corticosteroid, or their combination. All-cause mortality increased in relation to high systolic [≥140 mmHg; hazard ratio (HR) 1.27, 95% confidence interval (CI) 1.12-1.45] or diastolic (≥90 mmHg; HR 1.35, 95% CI 1.14-1.59) BP and low systolic (<120 mmHg; HR 1.36, 95% CI 1.13-1.63) or diastolic (<80 mmHg; HR 1.15, 95% CI 1.00-1.32) BP. Higher heart rates (≥80 per minute; HR 1.39, 95% CI 1.21-1.60) and pulse pressures (≥80 mmHg; HR 1.39, 95% CI 1.07-1.80) were more linearly related to increases in all-cause mortality. The risks of cardiovascular events followed similar patterns to all-cause mortality. Similar findings were observed in subgroups of patients without established CVD. A 'U-shaped' relationship between BP and all-cause mortality and cardiovascular events exists in patients with COPD and heightened cardiovascular risk. A linear relationship exists between heart rate and all-cause mortality and cardiovascular events in this population. These findings extend the prognostic importance of BP to this growing group of patients and raise concerns that both high and low BP may pose health risks.


Postpartum depression: in relation to life events and patterns of coping.
The purpose of this study was to estimate the prevalence of postpartum depression (PPD) and its relationship with life events (LE) and patterns for coping. We performed a cross-sectional study of 113 women, on the 10(th) day of puerperium, at the Obstetric Clinic of the São Paulo University Medical School. The study was based on the following: Pitt (1967) and Stein (1980) Scales, Beck Depression Inventory (1961), Holmes and Rahe Schedule of Recent Events (1967), Folkman and Lazarus Ways of Coping (1985) and questionnaire of social-demographic and obstetric data. Logistic regression was performed to calculate prevalence of PPD and its association with several risk factors. The significance level was defined at 5%. The prevalence of PPD was 15.9% (IC 9.7% to 24.0%). According to the multivariate analyses, the variables of coping with distancing, number of children and ethnic origin were significant. There were no association between PPD and LE. The depressed puerperal women have a low educational level, greater number of children and resort to inadequate coping strategies, such as distancing. This pattern of coping might be an etiological factor of the PPD as well as a reaction to their difficult life environment.


Obesity and gastrointestinal hormones-dual effect of angiotensin II receptor blockade and a partial agonist of PPAR-γ.
Obesity is strongly associated with type 2 diabetes, hypertension, and hyperlipidemia, which is one of the leading causes of mortality and morbidity worldwide. It is now clear that gut hormones play a role in the regulation of body weight and represent therapeutic targets for the future treatment of obesity. Recent evidence demonstrated that dysregulation of adipocytokine functions seen in abdominal obesity may be involved in the pathogenesis of the metabolic syndrome. Angiotensinogen, the precursor of angiotensin (Ang) II, is produced primarily in the liver, but also in adipose tissue, where it is up-regulated during the development of obesity and involved in blood pressure regulation and adipose tissue growth. Importantly, blockade of the RAS attenuates weight gain and adiposity by enhanced energy expenditure. The favorable metabolic effects of telmisartan have been related to its Ang II receptor blockade and action as a partial agonist of peroxisome proliferators activated receptor (PPAR)-γ. PPARγ plays an important role in regulating carbohydrate and lipid metabolism, and ligands for PPARγ can improve insulin sensitivity and reduce triglyceride levels. We designed a comparative study of telmisartan and losartan in ApoE-deficient mice. Treatment with telmisartan or losartan significantly reduced the development of lipid-rich plaque. However, treatment with telmisartan significantly improved endothelial dysfunction and inhibited lipid accumulation in the liver. These favorable characteristics of telmisartan might be due to its action as a partial agonist of PPAR-γ, beyond its blood pressure-lowering effect, through Ang II blockade, which may be called "metabosartan".


Effect of a Community Health Worker-Led Multicomponent Intervention on Blood Pressure Control in Low-Income Patients in Argentina: A Randomized Clinical Trial.
Despite extensive knowledge of hypertension treatment, the prevalence of uncontrolled hypertension is high and increasing in low- and middle-income countries. To test whether a community health worker-led multicomponent intervention would improve blood pressure (BP) control among low-income patients with hypertension. A cluster randomized trial was conducted in 18 centers for primary health care within a national public system providing free medications and health care to uninsured patients in Argentina. A total of 1432 low-income adult patients with uncontrolled hypertension were recruited between June 2013 and April 2015 and followed up to October 2016. Nine centers (743 patients) were randomized to the multicomponent intervention, which included a community health worker-led home intervention (health coaching, home BP monitoring, and BP audit and feedback), a physician intervention, and a text-messaging intervention over 18 months. Nine centers (689 patients) were randomized to usual care. The coprimary outcomes were the differences in systolic and diastolic BP changes from baseline to the end of follow-up of patients with hypertension. Secondary outcomes included the proportion of patients with controlled hypertension (BP <140/90 mm Hg). Three BP measurements were obtained at each of 2 baseline and 2 termination visits using a standard protocol, the means of which were used for analyses. Of 1432 participants (mean age, 55.8 years [SD, 13.3]; 772 women [53.0%]), 1357 (94.8%) completed the trial. Baseline mean systolic BP was 151.7 mm Hg for the intervention group and 149.8 mm Hg for the usual care group; the mean diastolic BP was 92.2 mm Hg for the intervention group and 90.1 mm Hg for the usual care group. Systolic BP reduction from baseline to month 18 was 19.3 mm Hg (95% CI, 17.9-20.8 mm Hg) for the intervention group and 12.7 mm Hg (95% CI, 11.3-14.2 mm Hg) for the usual care group; the difference in the reduction was 6.6 mm Hg (95% CI, 4.6-8.6; P < .001). Diastolic BP decreased by 12.2 mm Hg (95% CI, 11.2-13.2 mm Hg) in the intervention group and 6.9 mm Hg (95% CI, 5.9-7.8 mm Hg) in the control group; the difference in the reduction was 5.4 mm Hg (95% CI, 4.0-6.8 mm Hg; P < .001). The proportion of patients with controlled hypertension increased from 17.0% at baseline to 72.9% at 18 months in the intervention group and from 17.6% to 52.2% in the usual care group; the difference in the increase was 20.6% (95% CI, 15.4%-25.9%; P < .001). No adverse events were reported. Low-income patients in Argentina with uncontrolled hypertension who participated in a community health worker-led multicomponent intervention experienced a greater decrease in systolic and diastolic BP than did patients who received usual care over 18 months. Further research is needed to assess generalizability and cost-effectiveness of this intervention and to understand which components may have contributed most to the outcome. clinicaltrials.gov Identifier: NCT01834131.


Predictive factors for limb occlusions after endovascular aneurysm repair.
Greater flexibility and smaller sizes for introducer sheaths in the newest stent grafts increase the feasibility of endovascular aneurysm repair but raise concerns about long-term limb patency. The aim of the study was to determine the incidence of and predictive factors for limb occlusion after use of the Endurant stent graft (Medtronic Inc, Minneapolis, Minn) for abdominal aortic aneurysm. The Endurant Stent Graft Natural Selection Global Postmarket Registry (ENGAGE) prospectively included 1143 patients treated with bifurcated devices who were observed for up to 2 years. Limb occlusions were evidenced by computed tomography, angiography, or ultrasound. To predict stent graft limb occlusion, a two-step model-building technique was applied. We first identified predictors from a total of 47 covariates obtained at baseline and in the periprocedural period. Subsequently, we reduced the set of potential predictors to key factors that are clinically meaningful. To handle large numbers of covariates, we used the Classification And Regression Tree (CART) method. Forty-two stent graft limbs occluded in 39 patients (3.4% of the patients). At 2 years, the rate of freedom from stent graft limb occlusion calculated by Kaplan-Meier plot was 97.9% (standard error [SE], 0.33%). Of the 42 occlusions, 13 (31%) were observed within 30 days and 30 (71%) within 6 months. The strongest independent predictors were distal landing zone on the external iliac artery, external iliac artery diameter ≤10 mm, and kinking. High-risk vs low-risk patients were identified according to a decision tree based on the strongest predictors. Freedom from stent graft limb occlusion was 96.1% (SE, 0.64%) in high-risk patients vs 99.6% (SE, 0.19%) in low-risk patients. After Endurant stent grafting, the incidence of limb occlusion was low. Classifying patients as high risk vs low risk according to the algorithm used in this study may help define specific strategies to prevent limb occlusion and improve the overall results of endovascular aneurysm repair using the latest generation of stent grafts.


Body-weight support gait training in neurological intensive care: safety, feasibility, and delays before walking with or without suspension.
Early Mobilization in Intensive Care Units (ICUs) enhances patients' evolution, but has been rarely studied in neurological ICUs. The aim of this study was to assess gait training with body-weight support (BWS) in neuroICU, and to report on its safety, feasibility and on delays before walking with and without BWS. This study was an observational one-year single-center study. Inclusion criteria were adults with a neurological injury requiring mechanical ventilation. Exclusion criteria were early death or ICU transfer. After weaning from ventilation, patients were screened for indications of BWS walking using predefined criteria. Patients' conditions were mostly brain injuries: 32% subarachnoid hemorrhages, 42% focal strokes, and 12% traumatic brain injuries. Out of 272 admissions, 136 patients were excluded, 78 were eligible, and 33 performed BWS walking. Among non-eligible patients, 36 walked unsuspended upon ventilation weaning, 17 presented too severe impairments. Among the 45 eligible patients who did not receive BWS training, main reasons were workload and weekends (31%), medical barriers (29%), and early ICU discharge (22%). 78 BWS sessions were performed on the 33 beneficiaries (median sessions per patient 2, max 10). Pre-session, most patients had inadequate response to pain, orders, or simple orientation questions. Sitting without support was impossible for 74%. Most pre-post changes in hemodynamic, respiratory, and pain parameters were small, and recovered spontaneously after the session. Eight sessions were interrupted; reasons were pain, fatigue or major imbalance (4), syncope (1), occurrence of stool (2), and battery failure (1). None of these adverse events required medical intervention, patients recovered upon session interruption. Median session duration was 31 min, patients walked on median 17 m. First BWS session occurred on median 3 days after ventilation weaning, and 11 days before patients were able to walk unsuspended. Verticalization and walking using a suspension device in patients in neuroICU allows early gait training, despite challenging neurological impairments. It is safe and generally well tolerated. ClinicalTrials database (ID: NCT04300491).


Evidence for the involvement of the serotonergic 5-HT2A/C and 5-HT3 receptors in the antidepressant-like effect caused by oral administration of bis selenide in mice.
The present study investigated a possible antidepressant-like activity of bis selenide using two predictive tests for antidepressant effect on rodents: the forced swimming test (FST) and the tail suspension test (TST). Bis selenide (0.5-5 mg/kg, p.o.) decreased the immobility time in the mouse FST and TST. The anti-immobility effect of bis selenide (1 mg/kg, p.o.) in the TST was prevented by the pretreatment of mice with p-chlorophenylalanine methyl ester (PCPA; 100 mg/kg, i.p., an inhibitor of serotonin synthesis), ketanserin (1 mg/kg, i.p., a 5-HT(2A/2C) receptor antagonist), and ondasentron (1 mg/kg, i.p., a 5-HT(3) receptor antagonist). Pretreatment of mice with prazosin (1 mg/kg, i.p., an alpha(1)-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an alpha(2)-adrenoceptor antagonist), propranolol (2 mg/kg, i.p., a beta-adrenoceptor antagonist), SCH23390 (0.05 mg/kg, s.c., a dopamine D(1) receptor antagonist), sulpiride (50 mg/kg, i.p., a dopamine D(2) receptor antagonist), or WAY 100635 (0.1 mg/kg, s.c., a selective 5-HT(1A) receptor antagonist) did not block the antidepressant-like effect of bis selenide (1 mg/kg, p.o.) in the TST. Administration of bis selenide (0.1 mg/kg, p.o.) and fluoxetine (1 mg/kg), at subeffective doses, produced an antidepressant-like effect in the TST. Bis selenide did not alter Na(+) K(+) ATPase, MAO-A and MAO-B activities in whole brains of mice. Bis selenide produced an antidepressant-like effect in the mouse TST and FST, which may be related to the serotonergic system (5-HT(2A/2C) and 5-HT(3) receptors).


[The physician of II Bayezid's period: Giyas ibn Muhammed].
In the middle of the XV. century, the Ottoman Empire was an powerful government all the Turc and Islam geography. Many wises and students who belong to the Turc's world came here. Isfahanli Giyas b. Muhammed is one of these scientists. He finished education in his country and then he came. Amasya and he took lessons from Sabuncuoğlu about medical information and he returned back to his country. He wrote a medical book which named Mir'atü's-Sihha and he dedicated to Ottoman's sultan II. Bayezid. In this book's within, there was a poem who exalted the II. Bayezid.


The genetics of autism spectrum disorders and related neuropsychiatric disorders in childhood.
Autism spectrum disorders are considered to be among the most heritable mental disorders, a notion based on surprisingly sparse data from small clinical studies. Population-based studies of the heritability of other neuropsychiatric disorders and comorbidities among them have also been sparse. The authors sought to address both of these issues. Parents of all Swedish 9- and 12-year-old twin pairs born between 1992 and 2000 (N=10,895) were interviewed regarding autism spectrum disorders and associated conditions (response rate, 80%). Concordance rates and structural equation modeling were used for evaluating causes for familial aggregation and overlap between conditions. Monozygotic twins had higher concordance rates than dizygotic twins for autism spectrum disorders, attention deficit hyperactivity disorder (ADHD), developmental coordination disorder, and tic disorder. Genetic effects accounted for 80% (95% CI=29-91) of the variation in liability for autism spectrum disorders, 79% (95% CI=61-88) for ADHD, 70% (95% CI=35-83) for developmental coordination disorder, and 56% (95% CI=37-68) for tic disorder. Among monozygotic co-twins of children with autism spectrum disorders, the probability of having a diagnosis of ADHD was 44%, compared with 15% for dizygotic co-twins. Differences in cross-disorder effects between monozygotic and dizygotic twins were observed for most other comorbidities, and substantial proportions of the genetic variance for autism spectrum disorders was shared with each of the other disorders. Different neuropsychiatric disorders seem to have a common genetic etiology, suggesting caution in the use of diagnostic entities and proband status in efforts to uncover genes predisposing to autism spectrum disorders.


Prevalence of Sleep Disordered Breathing among Patients with Nocturia at a Urology Clinic.
We assessed the prevalence of sleep disordered breathing (SDB) and characteristics among patients who visited a urology clinic complaining of nocturia (URO group) and those who visited a sleep apnea (SA) clinic complaining of excessive daytime sleepiness (EDS) (SA group). Additionally, we evaluated the effects of continuous positive airway pressure (CPAP) therapy in the URO group patients with nocturia and SDB resistant to conventional therapy for nocturia. Questionnaires were used to assess EDS, nocturia and lower urinary tract symptoms in 34 URO group patients and 49 age-matched SA group patients. We also compared these factors in the male patients in both groups and the male and female patients in the SA group. Significant SDB was diagnosed as a 3% oxygen desaturation index (3%ODI) on pulse oximeter of >5/h. The treatment response was analyzed in six URO group patients treated with CPAP after not responding to the conventional medical treatment. SDB was found in 91.8% of the SA group patients and 70.6% of the URO group patients. The level of EDS and lower urinary tract symptoms were similar in both groups. The SA group showed higher 3%ODI values, while the frequency of urination during bedtime was higher in the URO group. The frequency of nocturnal urination was reduced after CPAP in the subjects resistant to conventional therapy. SDB is as prevalent in patients who visit a urology clinic complaining of nocturia as in those who visit a sleep apnea clinic. Patients who complains of nocturia must be assessed for SDB before starting therapy for nocturia.


[Directed study as a teaching strategy in nursing education].
This is a descriptive exploratory study aimed at evaluating directed study as a teaching strategy used in professional education. Data was collected by means of a questionnaire applied to 14 students attending a Practical Nursing course; their answers were examined according to Bardin. The strategy was considered good (86%). Eighty-three semantic units were identified in the analysis of the answers, classified as: advantages (53%); not "nice" (16%); difficulties (7%); feelings (12%); and suggestions (12%). In addition, subjects considered as didactic educational purposes of direct study to allow the development of topics that interest the student; to stimulate pleasure in studying; and to encourage the student to be the subject of his own learning process. The authors consider directed study a good teaching strategy, with features that demand skills and competences from teachers and students in order to obtain satisfactory results in the teaching-learning process.


Spatially Invariant Vector Quantization: A pattern matching algorithm for multiple classes of image subject matter including pathology.
HISTORICALLY, EFFECTIVE CLINICAL UTILIZATION OF IMAGE ANALYSIS AND PATTERN RECOGNITION ALGORITHMS IN PATHOLOGY HAS BEEN HAMPERED BY TWO CRITICAL LIMITATIONS: 1) the availability of digital whole slide imagery data sets and 2) a relative domain knowledge deficit in terms of application of such algorithms, on the part of practicing pathologists. With the advent of the recent and rapid adoption of whole slide imaging solutions, the former limitation has been largely resolved. However, with the expectation that it is unlikely for the general cohort of contemporary pathologists to gain advanced image analysis skills in the short term, the latter problem remains, thus underscoring the need for a class of algorithm that has the concurrent properties of image domain (or organ system) independence and extreme ease of use, without the need for specialized training or expertise. In this report, we present a novel, general case pattern recognition algorithm, Spatially Invariant Vector Quantization (SIVQ), that overcomes the aforementioned knowledge deficit. Fundamentally based on conventional Vector Quantization (VQ) pattern recognition approaches, SIVQ gains its superior performance and essentially zero-training workflow model from its use of ring vectors, which exhibit continuous symmetry, as opposed to square or rectangular vectors, which do not. By use of the stochastic matching properties inherent in continuous symmetry, a single ring vector can exhibit as much as a millionfold improvement in matching possibilities, as opposed to conventional VQ vectors. SIVQ was utilized to demonstrate rapid and highly precise pattern recognition capability in a broad range of gross and microscopic use-case settings. With the performance of SIVQ observed thus far, we find evidence that indeed there exist classes of image analysis/pattern recognition algorithms suitable for deployment in settings where pathologists alone can effectively incorporate their use into clinical workflow, as a turnkey solution. We anticipate that SIVQ, and other related class-independent pattern recognition algorithms, will become part of the overall armamentarium of digital image analysis approaches that are immediately available to practicing pathologists, without the need for the immediate availability of an image analysis expert.


Free serum cortisol during the postoperative acute phase response determined by equilibrium dialysis liquid chromatography-tandem mass spectrometry.
In severely ill patients low concentrations of the corticosteroid binding globulin are typically found; the aim of this study was to quantify directly free bioactive cortisol concentrations in the sera of postoperative cardiosurgical patients. Serum samples of 12 consecutive patients undergoing aortocoronary bypass surgery taken preoperatively and on the postoperative days 1 to 4 were analyzed. Total serum cortisol was quantified using liquid chromatography-tandem mass spectrometry with an on-line sample extraction system and tri-deuterated cortisol as the internal standard, and free serum cortisol was measured after over-night equilibrium dialysis. Whereas on the first postoperative day, the median total serum cortisol concentration was approximately two-fold increased compared to preoperative samples (preoperatively, 245 nmol/l (interquartile range (IQR) 203-293 nmol/l); first postoperative day, 512 nmol/l (IQR 410-611 nmol/l)), median dialyzable free cortisol concentration was almost seven-fold increased (preoperatively, 14.2 nmol/l (IOR 10.9-20.7 nmol/l); first postoperative day, 98.3 nmol/l (IQR 81.3-134 nmol/l)). On the fourth postoperative day, median free cortisol was still significantly increased compared to baseline sampling (p < 0.05), whereas median total cortisol was not. A median of 5.7% (IQR 5.4-7.0%) of total cortisol was found as free cortisol on the preoperative day, 21.2% (IQR 18.9-23.5%) on the first postoperative day and 10.5% (IQR 9.8-14.0%) on the fourth postoperative day. It is concluded that during the postoperative period the free-to-bound ratio of cortisol is highly variable and that during the acute phase response direct quantification of free bioactive cortisol concentrations seems to be biologically more appropriate than the measurement of total cortisol concentrations.


Diaphragm position can be accurately estimated from the scattering of a parallel transmit RF coil at 7 T.
To evaluate the use of radiofrequency scattering of a parallel transmit coil to track diaphragm motion. Measurements made during radiofrequency excitation on an 8-channel parallel transmit coil by the directional couplers of the radiofrequency safety monitor were combined and converted into diaphragm position. A 30-s subject-specific calibration with an MRI navigator was used to determine a diaphragm estimate from each directional-coupler measure. Seven healthy volunteers were scanned at 7 T, in which images of the diaphragm were continuously acquired and directional couplers were monitored during excitation radiofrequency pulses. The ability to detect coughing was evaluated in one subject. The method was implemented on the scanner and evaluated for diaphragm gating of a free-breathing cardiac cine. Six of the seven scans were successful. In these subjects, the root mean square difference between MRI and scattering estimation of the superior-inferior diaphragm position was 1.4 ± 0.5 mm. On the scanner, the position was calculated less than 2 ms after every radiofrequency pulse. A prospectively gated (echocardiogram and respiration) high-resolution free-breathing cine showed no respiratory artifact and sharp blood-myocardium definition. Transmit coil scattering is sensitive to diaphragm motion and provides rapid, quantitative, and accurate monitoring of respiration. Magn Reson Med 79:2164-2169, 2018. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.


An analysis of the prognostic factors affecing the clinical outcomes of conventional lumbar open discectomy : clinical and radiological prognostic factors.
This is a retrospective study. We wanted to examine the clinical and radiological prognostic factors affecting the postoperative clinical outcome of patients with lumbar disc herniation and who underwent open discectomy. Conventional open discectomy has been widely used as a treatment regimen for the management of lumbar disc herniation. Still, much controversy exists regarding the factors that affect the postoperative clinical outcomes. The current study was conducted on 40 patients who were diagnosed with lumbar disc herniation by the senior surgeon of our department from March 2004 to June 2007. These patients were refractory to conservative treatment and they could be followed up for more than one year following their surgical treatments. Preoperatively, after postoperative year 1 and at the final follow-up, a comparison was made for the Oswestry disability index (ODI) scores and the visual analogue scale (VAS) scores that indicated low back pain and radiating pain. For identifying prognostic factors, an analysis was also performed for such factors as age, gender, the operated level, the duration of preoperative low back pain and radiating pain, a smoking history, the body mass index and whether the surgery was revision or the primary operation. A radiological analysis, based on the preoperative plain flexion-extension radiography, was performed for the presence of mild segmental instability of < 3 mm, spondylolysis and disc space narrowing. Pfirrmann's degenerative grade of the disc, the degree of herniation and whether a herniation was central or massive on the magnetic resonance imaging scans. At the final follow-up, the ODI was significantly higher in the cases of revision as compared with the cases of primary operation. The female gender also had a tendency for a poor ODI as compared with that of the men, but this had only borderline statistical significance. There was significant correlation between the preoperative ODI and the preoperative VAS indicating radiating pain. At a final follow up, the low back pain VAS score was significantly lower in the extruded cases as compared with that of the protruded or sequestrated cases. Following an analysis for detecting the prognostic factors of open discectomy, the final clinical outcome was found to be poor for the revision surgery cases. In regard to the type of herniation, the degree of low back pain was relatively lower at a final follow-up for the extruded cases as compared with that for the protruded or sequestrated cases. Open discectomy surgery should be performed after evaluating the patients' various prognostic factors that could affect the final clinical outcome.


Validation of the Short Posttraumatic Stress Disorder Rating Interview (expanded version, Sprint-E) as a measure of postdisaster distress and treatment need.
Professionals and paraprofessionals working in disaster settings need tools to identify persons with mental health needs. To validate the Sprint-E as a measure of postdisaster distress and treatment need, the authors tested (1) the concurrent validity of the measure compared with other measures of distress, (2) the sensitivity and specificity of a "3/7 rule" on the Sprint-E relative to probable PTSD diagnosis, and (3) the hypothesis that Sprint-E scores would be stable in the absence of treatment but would improve in its presence. In Study 1, data were collected at the point of enrollment from 165 adults participating in a Florida treatment program implemented in response to the 2004 hurricanes. In Study 2, data were collected at points of referral, pretreatment, and intermediate treatment from 128 adults participating in a Baton Rouge Louisiana treatment program implemented in response to the 2005 hurricanes, Katrina and Rita. The utility of a 3/7 rule for the Sprint-E, with 3 suggesting possible and 7 suggesting probable treatment needs, was supported in Study 1. Tested against the PTSD Checklist, the Sprint-E performed well in ROC analyses (area under the curve = 0.87); a score of 7 achieved sensitivity of 78 percent and specificity of 79 percent. In Study 2, Sprint-E scores evidenced little change between referral and pretreatment but substantial change between pretreatment and intermediate treatment. The Sprint-E is useful as an assessment and referral tool in situations where more in-depth assessment is not feasible and mental health services are available.


Generalized pustular psoriasis - a model disease for specific targeted immunotherapy, systematic review.
Generalized pustular psoriasis (GPP) is a rare, multisystemic skin disease characterized by recurrent episodes of pustulation. GPP can be life-threatening and is often difficult to treat. In the era of precision medicine in dermatology, GPP stands exemplary for both challenges and chances-while new treatments offer great hope, there is urgent need for better definition and stratification of this severe and heterogeneous disease. Our objective was to systematically review the literature for evidence of efficacy of targeted immunotherapy and their mode of action in the context of clinical phenotype, classification and pathogenesis of adult GPP. Classifying GPP is challenging since clinical criteria for description and diagnosis are not consistent between expert centres. We therefore defined diagnostic feasibility of the reviewed cases by assessing four criteria: compatible clinical history, typical dermatological features and/or diagnostic histopathology, consistent clinical pictures and the DITRA status. Pathogenesis of GPP is mediated by pathways that partly overlap plaque type psoriasis, with a more pronounced activity of the innate immune system. Both IL-1 and IL-36 but also IL-17 play a major role in disease formation. We ascertained a total of 101 published cases according to our predefined criteria and identified TNF-α, IL-12/23, IL-17 and IL-1β as targets for immunotherapy for the treatment of GPP. Of those cases, 61% showed complete response and 27% partial response to targeted immunotherapy. Only 12% experienced weak or no response. These data indicate that specific immunotherapy can be used to effectively treat GPP, with most evidence existing for anti-IL-17 agents.


Brain areas and time course of emotional processing.
The aims of the present study were to identify brain regions involved in emotional processing as well as to follow the time sequence of these processes in the millisecond-range resolution using low resolution brain electromagnetic tomography (LORETA). Different emotional (happy, sad, angry, fearful, and disgust) and neutral faces were presented to 17 healthy, right-handed volunteers on a computer screen while 25-channel EEG data were recorded. Subjects were instructed to generate the same emotion as shown in the presented faces. Event-related potentials (ERPs) were computed for each emotion and neutral condition, and analyzed as sequences of potential distribution maps. Paired topographic analysis of variance tests of the ERP maps identified time segments of significant differences between responses to emotional and neutral faces. For these significant segments, statistical analyses of functional LORETA images were performed to identify active brain regions for the different emotions. Significant differences occurred in different time segments within the first 500 ms after stimulus onset. Each emotional condition showed specific activation patterns in different brain regions, changing over time. In the majority of significant time segments, activation was highest in the right frontal areas. Strongest activation was found in the happy, sad, and disgust conditions in extended fronto-temporal areas. Happy, sad, and disgust conditions also produced earlier and more widely distributed differences than anger and fear. Our findings are in good agreement with other brain-imaging studies (PET/fMRI). But unlike other imaging techniques, LORETA allows to follow the time sequence in the millisecond-range resolution.


Are meniscal tears and articular cartilage injury predictive of inferior patient outcome after surgical reconstruction for the dislocated knee?
A paucity of data exists on the effects of articular cartilage and meniscal injury in the setting of knee dislocations. The purpose of this study is to determine whether concomitant intra-articular injuries at the time of multiligament reconstruction for knee dislocation are associated with inferior outcomes. The records of patients who underwent surgical treatment for multiligament knee injury between 1992 and 2012 were retrospectively reviewed. Patients included had a PCL-based multiligament knee injury or a minimum of three disrupted ligaments, both indicative of knee dislocation. A logistic regression model was used to determine whether articular cartilage injuries (grade 2 involving ≥50 % of the condylar width or greater, or any grade III/IV lesions) and meniscus tears are predictors of IKDC outcome scores collected at a minimum of 2 years postoperatively. Of the 121 patients who met inclusion criteria, 2-year minimum follow-up was available on 95 patients (79 %). The cohort was 77 % male and had a median age of 32 years (16-62) at the time of surgery and was followed for an average of 6 years. Articular cartilage injury was present in 40 % of knees: medial femoral condyle (20 %); medial tibial plateau (9 %); lateral femoral condyle (5 %); lateral tibial plateau (4 %); patella (18 %); trochlear (5 %). Meniscal injury was present in 56 % of patients (isolated medial, 22 %; isolated lateral, 22 %; combined, 12 %). IKDC scores were significantly lower for patients with any cartilage damage (p = 0.03), combined medial and lateral meniscus tears (p = 0.02), medial-sided articular cartilage damage (p = 0.03), medial femoral condyle (p = 0.04) and trochlear (p = 0.03) lesions. Articular cartilage damage and meniscus tears are frequently associated with a knee dislocation. This study showed IKDC scores were significantly lower for patients with cartilage damage or combined medial and lateral meniscus tears at mid-term follow-up of 6 years. IV.


Situation Awareness in Obsessive Compulsive Disorder and Their Relatives: an Endophenotype Study.
It has been theorized that endophenotype models will help to understand the etiology of heterogeneous brain disorders such as obsessive-compulsive disorder (OCD). In this study, it was aimed to determine whether "situational awareness" impairments which can be defined as partially naturalistic working memory deficits, are an endofenotype for OCD. In this study, situational awareness (SA) task performances of 67 OCD patients, 50 their unaffected first-degree relatives, and 41 healthy controls who matched with regard to sex, age and years of education were measured to investigate endophenotypes in OCD. For this purpose, a visuospatial working memory test was used. As a result, the relatives showed a task performance between patients with OCD and control group in both SA1 and SA2 tasks. Patients with OCD performed significantly worse than control group on SA1 single and dual task. On the other hand, there were no significant differences between relatives and patients of any SA assessment. These results indicated that poor situational awareness may be a candidate endophenotype for OCD. Early perceptual dysfunctions such as poor performance on SA1 task can mediate the genetic risk for OCD.


An efficient fully unsupervised video object segmentation scheme using an adaptive neural-network classifier architecture.
In this paper, an unsupervised video object (VO) segmentation and tracking algorithm is proposed based on an adaptable neural-network architecture. The proposed scheme comprises: 1) a VO tracking module and 2) an initial VO estimation module. Object tracking is handled as a classification problem and implemented through an adaptive network classifier, which provides better results compared to conventional motion-based tracking algorithms. Network adaptation is accomplished through an efficient and cost effective weight updating algorithm, providing a minimum degradation of the previous network knowledge and taking into account the current content conditions. A retraining set is constructed and used for this purpose based on initial VO estimation results. Two different scenarios are investigated. The first concerns extraction of human entities in video conferencing applications, while the second exploits depth information to identify generic VOs in stereoscopic video sequences. Human face/ body detection based on Gaussian distributions is accomplished in the first scenario, while segmentation fusion is obtained using color and depth information in the second scenario. A decision mechanism is also incorporated to detect time instances for weight updating. Experimental results and comparisons indicate the good performance of the proposed scheme even in sequences with complicated content (object bending, occlusion).


Glutamate Signaling via the AMPAR Subunit GluR4 Regulates Oligodendrocyte Progenitor Cell Migration in the Developing Spinal Cord.
Oligodendrocyte progenitor cells (OPCs) are specified from discrete precursor populations during gliogenesis and migrate extensively from their origins, ultimately distributing throughout the brain and spinal cord during early development. Subsequently, a subset of OPCs differentiates into mature oligodendrocytes, which myelinate axons. This process is necessary for efficient neuronal signaling and organism survival. Previous studies have identified several factors that influence OPC development, including excitatory glutamatergic synapses that form between neurons and OPCs during myelination. However, little is known about how glutamate signaling affects OPC migration before myelination. In this study, we use in vivo, time-lapse imaging in zebrafish in conjunction with genetic and pharmacological perturbation to investigate OPC migration and myelination when the GluR4A ionotropic glutamate receptor subunit is disrupted. In our studies, we observed that gria4a mutant embryos and larvae displayed abnormal OPC migration and altered dorsoventral distribution in the spinal cord. Genetic mosaic analysis confirmed that these effects were cell-autonomous, and we identified that voltage-gated calcium channels were downstream of glutamate receptor signaling in OPCs and could rescue the migration and myelination defects we observed when glutamate signaling was perturbed. These results offer new insights into the complex system of neuron-OPC interactions and reveal a cell-autonomous role for glutamatergic signaling in OPCs during neural development.SIGNIFICANCE STATEMENT The migration of oligodendrocyte progenitor cells (OPCs) is an essential process during development that leads to uniform oligodendrocyte distribution and sufficient myelination for central nervous system function. Here, we demonstrate that the AMPA receptor (AMPAR) subunit GluR4A is an important driver of OPC migration and myelination in vivo and that activated voltage-gated calcium channels are downstream of glutamate receptor signaling in mediating this migration.


Parthenolide inhibits the growth of non-small cell lung cancer by targeting epidermal growth factor receptor.
EGFR tyrosine kinase inhibitors (TKIs) have been developed for the treatment of EGFR mutated NSCLC. Parthenolide, a natural product of parthenolide, which belongs to the sesquiterpene lactone family and has a variety of biological and therapeutic activities, including anti-cancer effects. However, its effect on non-small cell lung cancer is little known. The CCK8 assay and colony formation assays were used to assess cell viability. Flow cytometry was used to measure the cell apoptosis. In silico molecular docking was used to evaluate the binding of parthenolide to EGFR. Network pharmacology analysis was was used to evaluate the key gene of parthenolide target NSCLC. Western blotting was used to evaluate the key proteins involved apoptosis and EGFR signalling. The effect of parthenolide treatment in vivo was determined by using a xenograft mouse model. In this study, parthenolide could induce apoptosis and growth inhibition in the EGFR mutated lung cancer cells. Parthenolide also reduces the phosphorylation of EGFR as well as its downstream signaling pathways MAPK/ERK and PI3K/Akt. Molecular docking analysis of EGFR binding site with parthenolide show that the anti-cancer effect of parthenolide against NSCLC is mediated by a strong binding to EGFR. Network pharmacology analysis show parthenolide suppresses NSCLC via inhibition of EGFR expression. In addition, parthenolide inhibits the growth of H1975 xenografts in nude mice, which is associated with the inhibition of the EGFR signaling pathway. Taken together, these results demonstrate effective inhibition of parthenolide in NSCLC cell growth by targeting EGFR through downregulation of ERK and AKT expression, which could be promisingly used for patients carrying the EGFR mutation.


Expression of functional human retinol-binding protein in Escherichia coli using a secretion vector.
In order to express human serum retinol-binding protein (sRBP) in Escherichia coli in a form that is structurally indistinguishable from the native protein, we placed the coding sequence of the RBP cDNA next to that of the outer membrane protein A (OmpA) signal sequence in the secretion vector, pIN-III-OmpA1. However, this construct did not generate detectable expression of RBP in E. coli. When the DNA fragment consisting of the ribosome-binding site and the OmpA-RBP fusion sequence was subcloned downstream to the T7 promoter of pKS-Bluescript, however, the resultant construct (pOmp-RBP2) gave low but detectable secretion of RBP into the periplasm. Deletion of the 3' untranslated region of the RBP cDNA (pOmp-RBP3) further improved the expression (by approx. 20-fold). After charging with retinol, the secreted RBP was purified from the periplasm on a transthyretin-affinity resin. The purified protein exhibited all the three molecular recognition properties characteristic of sRBP, i.e. it interacted with retinol, transthyretin and its cell-surface receptor. Comparison of the receptor binding properties of the recombinant RBP (rRBP) with those of the serum protein revealed that while the affinity of rRBP is similar to sRBP (50 +/- 20 nM), the Bmax of the rRBP is about 6-8-fold higher. This indicates that a major proportion of RBP, isolated from serum, is incapable of interacting with the receptor.


Broadband infrared supercontinuum generation in hexagonal-lattice tellurite photonic crystal fiber with dispersion optimized for pumping near 1560 nm.
We report on supercontinuum generation (SG) in a hexagonal lattice tellurite photonic crystal fiber (PCF). The fiber has a regular lattice with a lattice constant Λ = 2 μm, linear filling factor d/Λ = 0.75, and a solid core 2.7 μm in diameter. Dispersion, calculated from scanning electron microscope (SEM) image of drawn fiber, has zero dispersion wavelength (ZDW) at 1410 and 4236 nm with a maximum of 193 ps/nm/km at 2800 nm. Under pumping with 150 fs/36 nJ/1580 nm pulses, supercontinuum spectrum in a bandwidth from 800 nm to over 2500 nm was observed in a 2 cm long PCF sample, which is comparable to results reported for suspended core tellurite PCFs pumped at wavelengths over 1800 nm. Measured spectrum is analyzed numerically with good agreement, and observed spectral broadening is interpreted. To our best knowledge, tellurite glass, regular lattice PCFs for successful SG in this bandwidth have not been reported before.


Atlantic Meridional Overturning Circulation slowdown cooled the subtropical ocean.
[1] Observations show that the upper 2 km of the subtropical North Atlantic Ocean cooled throughout 2010 and remained cold until at least December 2011. We show that these cold anomalies are partly driven by anomalous air-sea exchange during the cold winters of 2009/2010 and 2010/2011 and, more surprisingly, by extreme interannual variability in the ocean's northward heat transport at 26.5°N. This cooling driven by the ocean's meridional heat transport affects deeper layers isolated from the atmosphere on annual timescales and water that is entrained into the winter mixed layer thus lowering winter sea surface temperatures. Here we connect, for the first time, variability in the northward heat transport carried by the Atlantic Meridional Overturning Circulation to widespread sustained cooling of the subtropical North Atlantic, challenging the prevailing view that the ocean plays a passive role in the coupled ocean-atmosphere system on monthly-to-seasonal timescales.


Characterization of jack-bean alpha-D-mannosidase as a zinc metalloenzyme.
1. Two methods were used to obtain alpha-mannosidase free from unbound Zn2+, (a) by removal of excess of metal ion from preparations purified in the presence of Zn2+ and (b) by purification under conditions that eliminate the need to add Zn2+. 2. The purified enzyme is homogeneous on ultracentrifugation, polyacrylamide-gel electrophoresis and gel chromatography. 3. The molecular weight is estimated to be 230 000. 4. The enzyme contains between 470 and 565 mug of zinc/g of protein, corresponding to between 1.7 and 2 atoms of zinc/enzyme molecule. The contents of other metals are much lower. 5. The enzyme is inactivated by chelating agents and activity is restored by Zn2+. 6. No other metal ion was found to replace Zn2+ with retention of activity. Some bivalent metal ions, e.g. Cu2+, rapidly inactivate the enzyme. 7. The results indicate that jack-bean alpha-mannosidase exists naturally as a zinc-protein complex and may be considered as a metalloenzyme.


Characterisation of three terpene synthases for β-barbatene, β-araneosene and nephthenol from social amoebae.
The products of three terpene synthases from two social amoebae, Dictyostelium discoideum and Dictyostelium purpureum, were identified, showing sesquiterpene synthase activity for one and diterpene synthase activity for the other two enzymes. Site-directed mutagenesis experiments revealed the importance of a newly identfied highly conserved residue for catalytic activity. For one of the enzyme products, β-araneosene, a bromonium ion induced transannular cyclisation was investigated, yielding the first brominated derivatives of this diterpene.


The Role of Evolutionary Selection in the Dynamics of Protein Structure Evolution.
Homology modeling is a powerful tool for predicting a protein's structure. This approach is successful because proteins whose sequences are only 30% identical still adopt the same structure, while structure similarity rapidly deteriorates beyond the 30% threshold. By studying the divergence of protein structure as sequence evolves in real proteins and in evolutionary simulations, we show that this nonlinear sequence-structure relationship emerges as a result of selection for protein folding stability in divergent evolution. Fitness constraints prevent the emergence of unstable protein evolutionary intermediates, thereby enforcing evolutionary paths that preserve protein structure despite broad sequence divergence. However, on longer timescales, evolution is punctuated by rare events where the fitness barriers obstructing structure evolution are overcome and discovery of new structures occurs. We outline biophysical and evolutionary rationale for broad variation in protein family sizes, prevalence of compact structures among ancient proteins, and more rapid structure evolution of proteins with lower packing density.