Involvement of signaling through protein kinase C and phosphatidylinositol 3-kinase in the excystation and metacystic development of Entamoeba invadens.
Using an axenic excystation system in vitro, we examined the effect of protein kinase C (PKC) and phosphatidylinositol 3-kinase (PI3K), which are signaling molecules responsible for numerous cellular responses, on the excystation and metacystic development of Entamoeba invadens. Excystation, which was assessed by counting the number of metacystic amoebae after the induction of excystation, was inhibited by the PKC inhibitors staurosporine, chelerythrine chloride and calphostin C in a concentration-dependent manner during incubation, compared with the controls. As cyst viability was not affected by these inhibitors, reduced excystation was not due to their direct toxic effects on cysts. Metacystic development, when determined by the number of nuclei in the amoebae, was delayed by these PKC inhibitors, because the percentage of 1-nucleate amoebae was lower than in controls at day 3 of incubation. Wortmannin, a potent inhibitor of PI3K, also inhibited excystation and metacystic development of E. invadens in a concentration-dependent manner, compared with the controls. These results indicate that signaling through PKC and PI3K contributes to the excystation and metacystic development of E. invadens.


A Review of the Ethnomedicinal, Phytochemical, and Anticancer Properties of Melicope Species.
The genus Melicope, which consists of 230 species, stands out as the largest genus within the Rutaceae family. Melicope species are characterized by their evergreen nature and can range from shrubs to predominantly dioecious trees. The Melicope species have been utilized in traditional medicine to address a wide range of ailments, including fever, colds, cramps, and inflammation. These plants have gained significant attention due to their noteworthy ethnopharmacological and ethnomedicinal significance. Researchers have isolated numerous biologically active secondary metabolites from different Melicope species, which include polymethoxylated flavonoids, furanocoumarins, acetophenones, benzenoids, and quinolone alkaloids. These compounds exhibit diverse biological activities, such as antibacterial, antidiabetic, antifungal, and antiproliferative properties against human cancer cell lines. This review provides an update on the chemical constituents of the selected species of Melicope. The study also highlights the anticancer and cytotoxicity properties of the plant extracts and phytochemical constituents from Melicope species. Furthermore, the molecular mechanisms underlying the anticancer effects are elucidated. Overall, this review contributes to understanding the significant pharmacological potential of Melicope species and unlocking their chemical composition, emphasizing their relevance in the development of therapeutic agents, particularly in the field of cancer research.


Electronic Health Record (EHR) As a Vehicle for Successful Health Care Best Practice.
application of EHR in journey toward the development and adaptation of best practice approach in health care has particular importance. The aim of this review article is survey of successful best practice through EHR. In this literature review articles were searched with keywords like Electronic Health Record, Best Practice in Science Direct, Google Scholar and Pub Med databases since 1999. best practice in health care through some services like utilization management, case management, and information technology tools can perform. Utilization management in combination with evidence based medicine facilitate determine best decision. Health records are based on evidence medicine and be the richest source of health information. Definitely use of EHR has play pivotal role in journey toward the development and adaptation of best practice approach. Because of potential capabilities, EHR can be regarded as a main core and fundamental element in best practice approach. Success implementation of EHR relies on many factors that should be considered. Some critical success factors for EHR implementation that should be noted are change management, Physicians, nurses and key stakeholders involvement, leadership, provide reliable information technology infrastructure, system design, privacy and security, right budget, support high level management, clear communicate, determine goals and user needs, and define roles and responsibilities, interoperability standards.


Effect of aminophylline on the human diaphragm.
The effect of intravenous aminophylline on the contractile function of the diaphragm was studied in four normal subjects. The contractility of the diaphragm was assessed by the measurement of transdiaphragmatic pressure (Pdi) after right phrenic nerve stimulation at 1 Hz. Pdi was measured before and during aminophylline infusion (6 mg/kg over 30 minutes), during which therapeutic concentrations of theophylline were attained (mean 13.8 mg/l, range 8.5-20.2). The Pdi achieved was not affected by aminophylline. This result suggests that theophylline at therapeutic concentrations has little effect on the contractility of the normal human diaphragm.


Advanced imaging of bone macrostructure and microstructure in bone fragility and fracture repair.
Research into the molecular and cellular pathways focusing on bone fragility and fracture-healing has led to new potential treatments to aid in fracture-healing. This research has focused on physical as well as biological modes of treatment. As new products and methods are derived, it is essential to develop effective and sensitive noninvasive means by which early changes in the fracture repair process can be detected. Specialized noninvasive and/or nondestructive techniques can provide structural information about local and systemic skeletal health, the propensity to fracture, and the pathophysiology of bone fragility. The methods available to quantitatively assess macrostructure include computed tomography and, particularly, volumetric quantitative computed tomography. Methods for assessing microstructure of trabecular bone include high-resolution computed tomography, microquantitative computed tomography, high-resolution magnetic resonance imaging, and micromagnetic resonance imaging. These new techniques help to illustrate the process of fracture-healing by defining the skeletal response to innovative therapies and assessing biomechanical relationships. This review presents perspectives on the advanced imaging modalities that are currently available and on recent developments that may improve the detection and understanding of bone fragility and fracture-healing.


Split-operon control of a prophage gene.
Both prophage integration in bacteriophage P2 and the reverse event, prophage excision, are known to require a specific phage gene product, the so-called int function. We find that P2 can integrate efficiently at a free attachment site also in an immune host (i.e., in the presence of phage specific repressor) provided the superinfecting phage is not deficient in int function. Prophage P2, on the other hand, is not excised from the host chromosome even in a derepressed lysogen unless int function is supplied by a superinfecting phage. Thus, the int function of P2 is expressed constitutively by the superinfecting phage, but is not expressed by the prophage even in the absence of phage repressor. It is proposed that the int function of P2 is not controlled by phage repressor, but belongs instead to a constitutive operon that is physically disrupted by prophage integration.


Nutritional Outcome in Home Gastrostomy-Fed Children with Chronic Diseases.
The aim of the study was to assess the anthropometric outcomes after gastrostomy tube (GT) placement in children with chronic diseases and the influence of primary diagnosis, age, and nutritional support. A longitudinal, multicenter, and prospective study was performed evaluating 65 children with GT feeding and chronic diseases (61.5% with neurological disease). Each child was evaluated three times (at baseline and at 6 and 12 months after GT placement) and the following data was collected: primary diagnosis, age at GT placement, anthropometry, and feeding regime. Repeated measures ANOVA were used to analyze the main effects (intra and intergroup) and the interactions effects on weight gain and linear growth at 6 and 12 months after GT placement. All patients significantly improved their body mass index (BMI)-for-age z-score (p < 0.001) and height-for-age z-score (p < 0.05) after 6 and 12-month of follow-up. BMI gain increased significantly the first 6 months, followed by a plateau, while height followed a linear trend. Children with GT placement before 18 months old experienced an accelerated growth rate during the first 6 months post-GT. This technique showed the effectiveness of GT placement improving nutritional status and growth catch up regardless of their primary diagnosis and the type of nutritional support.


A new model for extinction and recolonization in two dimensions: quantifying phylogeography.
Classical models of gene flow fail in three ways: they cannot explain large-scale patterns; they predict much more genetic diversity than is observed; and they assume that loosely linked genetic loci evolve independently. We propose a new model that deals with these problems. Extinction events kill some fraction of individuals in a region. These are replaced by offspring from a small number of parents, drawn from the preexisting population. This model of evolution forwards in time corresponds to a backwards model, in which ancestral lineages jump to a new location if they are hit by an event, and may coalesce with other lineages that are hit by the same event. We derive an expression for the identity in allelic state, and show that, over scales much larger than the largest event, this converges to the classical value derived by Wright and Malécot. However, rare events that cover large areas cause low genetic diversity, large-scale patterns, and correlations in ancestry between unlinked loci.


Iron-Quercetin Complex Preconditioning of Human Peripheral Blood Mononuclear Cells Accelerates Angiogenic and Fibroblast Migration: Implications for Wound Healing.
Cell-based therapy is a highly promising treatment paradigm in ischemic disease due to its ability to repair tissue when implanted into a damaged site. These therapeutic effects involve a strong paracrine component resulting from the high levels of bioactive molecules secreted in response to the local microenvironment. Therefore, the secreted therapeutic can be modulated by preconditioning the cells during in vitro culturing. Herein, we investigated the potential use of magnetic resonance imaging (MRI) probes, the "iron-quercetin complex" or IronQ, for preconditioning peripheral blood mononuclear cells (PBMCs) to expand proangiogenic cells and enhance their secreted therapeutic factors. PBMCs obtained from healthy donor blood were cultured in the presence of the iron-quercetin complex. Differentiated preconditioning PBMCs were characterized by immunostaining. An enzyme-linked immunosorbent assay was carried out to describe the secreted cytokines. In vitro migration and tubular formation using human umbilical vein endothelial cells (HUVECs) were completed to investigate the proangiogenic efficacy. IronQ significantly increased mononuclear progenitor cell proliferation and differentiation into spindle-shape-like cells, expressing both hematopoietic and stromal cell markers. The expansion increased the number of colony-forming units (CFU-Hill). The conditioned medium obtained from IronQ-treated PBMCs contained high levels of interleukin 8 (IL-8), IL-10, urokinase-type-plasminogen-activator (uPA), matrix metalloproteinases-9 (MMP-9), and tumor necrosis factor-alpha (TNF-α), as well as augmented migration and capillary network formation of HUVECs and fibroblast cells, in vitro. Our study demonstrated that the IronQ-preconditioning PBMC protocol could enhance the angiogenic and reparative potential of non-mobilized PBMCs. This protocol might be used as an adjunctive strategy to improve the efficacy of cell therapy when using PBMCs for ischemic diseases and chronic wounds. However, in vivo assessment is required for further validation.


A dominant-negative effect drives selection of TP53 missense mutations in myeloid malignancies.
TP53, which encodes the tumor suppressor p53, is the most frequently mutated gene in human cancer. The selective pressures shaping its mutational spectrum, dominated by missense mutations, are enigmatic, and neomorphic gain-of-function (GOF) activities have been implicated. We used CRISPR-Cas9 to generate isogenic human leukemia cell lines of the most common TP53 missense mutations. Functional, DNA-binding, and transcriptional analyses revealed loss of function but no GOF effects. Comprehensive mutational scanning of p53 single-amino acid variants demonstrated that missense variants in the DNA-binding domain exert a dominant-negative effect (DNE). In mice, the DNE of p53 missense variants confers a selective advantage to hematopoietic cells on DNA damage. Analysis of clinical outcomes in patients with acute myeloid leukemia showed no evidence of GOF for TP53 missense mutations. Thus, a DNE is the primary unit of selection for TP53 missense mutations in myeloid malignancies.


Evolution of recognition of ligands from Gram-positive bacteria: similarities and differences in the TLR2-mediated response between mammalian vertebrates and teleost fish.
We investigated the role of the TLR2 receptor in the recognition of ligands from Gram-positive bacteria in fish. Comparative sequence analysis showed a highly conserved Toll/IL-1 receptor domain. Although the leucine-rich repeat domain was less conserved, the position of the critical peptidoglycan (PGN)-binding residues in the leucine-rich repeat domain of carp TLR2 were conserved. Transfection of human embryonic kidney 293 cells with TLR2 corroborated the ability of carp TLR2 to bind the prototypical mammalian vertebrate TLR2 ligands lipoteichoic acid (LTA) and PGN from Staphylococcus aureus. The synthethic triacylated lipopeptide N-palmitoyl-S-(2,3-bis(palmitoyloxy)-(2RS)-propyl)-(R)-Cys-(S)-Ser-(S)-Lys(4) trihydrochloride (Pam(3)CSK(4)) but not the diacylated lipopeptide macrophage-activating lipopeptide-2 (MALP-2) also activated TLR2 transfected human cells. We identified clear differences between the mammalian vertebrates and carp TLR2-mediated response. The use of the same ligands on carp macrophages indicated that fish cells require high concentrations of ligands from Gram-positive bacteria (LTA, PGN) for activation and signal transduction, react less strongly (Pam(3)CSK(4)) or do not react at all (MALP-2). Overexpression of TLR2 in carp macrophages confirmed TLR2 reactivity of the response to LTA and PGN, low-responsiveness to Pam(3)CSK(4) and nonresponsiveness to MALP-2. A putative relation with the apparent absence of accessory proteins such as CD14 from the fish TLR2-containing receptor complex is discussed. Moreover, activation of carp macrophages by PGN resulted in increased TLR2 gene expression and enhanced TLR2 mRNA stability, MAPK-p38 phosphorylation and increased radical production. Finally, we could show that NADPH oxidase-derived radicals and MAPK-p38 activation cooperatively determine the level of PGN-induced TLR2 gene expression. We propose that the H(2)O(2)-MAPK-p38-dependent axis is crucial for regulation of TLR2 gene expression in fish macrophages.


Prophylactic etanercept treatment in cisplatin ototoxicity.
The aim of our study was to evaluate the audiological protective effects of etanercept using distortion product otoacoustic emission (DPOAE) in rats with hearing loss due to cisplatin ototoxicity. The study began with 36 healthy female albino rats; 31 rats had good measurements in DPOAE and were included in the study. On day 0, a single dose of etanercept was given by intraperitoneal administration to 15 rats (etanercept group). No medication was given to the control group. After 24 h, 16 mg/kg cisplatin was given to all rats. DPOAE measurements were performed on the 3rd, 7th, and 21st day. After the DPOAE test on the 21st day, the animals were killed by decapitation. Between-group and intra-group comparisons were made using the data of the two groups. A statistically significant difference was observed on the 3rd day at 4921 Hz and higher frequencies, on the 7th day at 6064 Hz and higher frequencies, and on the 21st day at 6494 Hz and higher frequencies (p < 0.05). We observed 10% ototoxicity in the etanercept group and 56% ototoxicity in the control group. A single dose of etanercept 1 day before cisplatin administration decreases cisplatin ototoxicity in the early period. This effect comes to the fore especially over 4500 Hz frequencies at 65 dB and higher.


Factor XI regulates pathological thrombus formation on acutely ruptured atherosclerotic plaques.
Coagulation factor XI is proposed as therapeutic target for anticoagulation. However, it is still unclear whether the antithrombotic properties of factor XI inhibitors influence atherosclerotic disease and atherothrombosis. Our aim is to investigate whether factor XI antisense oligonucleotides could prevent thrombus formation on acutely ruptured atherosclerotic plaques. Atherosclerotic plaques in the carotid arteries of Apoe(-/-) mice were acutely ruptured using ultrasound. The subsequent thrombus formation was visualized and quantified by intravital microscopy and immunohistochemistry. Mice were pretreated with either factor XI antisense or nonsense oligonucleotides (50 mg/kg) to lower factor XI plasma levels. A tail bleeding assay was used to determine the safety. On plaque rupture, initial platelet adhesion and platelet plug formation were not impaired in animals treated with factor XI antisense oligonucleotides. However, the ensuing thrombus formation and fibrin deposition were significantly lower after 5 to 10 minutes (P<0.05) in factor XI antisense oligonucleotide-treated animals without inducing a bleeding tendency. Furthermore, thrombi from antisense-treated animals were less stable than thrombi from placebo-treated animals. Moreover, macrophage infiltration and collagen deposition were lower in the carotid arteries of factor XI antisense-treated animals. No neutrophils were present. Factor XI antisense oligonucleotides safely prevent thrombus formation on acutely ruptured atherosclerotic plaques in mice. Furthermore, perturbed carotid arteries from factor XI antisense-treated animals show a less severe inflammatory response.


Modifications of electrode design for recording monophasic action potentials in animals and humans.
An Ag-AgCl electrode for recording monophasic action potentials by pressure contact is described. The electrode is mounted in a hand-held support designed for epicardial recordings during open-heart surgery from both the anterior and lateral walls of the left ventricle with minimal displacement of the heart. The support allows the electrode to be manipulated without the need for direct vision by the surgeon to any desired position while ensuring perpendicular apposition of the electrode without risk of damage to the myocardium. The permanently mounted electrode is also suitable for animal experiments. The electrode may be used for endocardial recordings in animals by direct puncture. Either a straight or curved electrode may be chosen as dictated by the recording site. The monophasic action potentials recorded by this electrode are of a high quality in terms of configuration, lack of drift, and amplitude.


Phosphorus equivalency of exogenous phytase relative to phosphorus in monosodium phosphate in broiler chickens.
The objective of this study was to estimate phosphorus (P) equivalency of exogenous phytase relative to P from monosodium phosphate (MSP) in broiler chickens. To attain this objective, the impact of dietary MSP or exogenous phytase on growth performance, ileal digestibility of P, and bone characteristics in broiler chickens was assessed. Six experimental diets consisting of a P-deficient basal diet based on corn and soybean meal, basal diet plus 0.9 or 1.8 g/kg of inorganic P from MSP, and basal diet plus 500, 1,000, or 2,000 FYT/kg of exogenous phytase. Calcium to P ratio in all diets was maintained at 1.5:1. A total of 576 male broiler chickens (Cobb 500; initial BW = 190 ± 17 g) on d 8 post hatching were allotted to the 6 dietary treatments in a randomized complete block design using BW as a blocking factor. Each dietary treatment contained 8 replicate cages with 12 birds per cage. On d 11 post hatching, 7 birds from each cage were euthanized by CO2 asphyxiation and dissected for the collection of ileal digesta. On d 18, ileal digesta were also collected from the remaining 5 birds in each cage. The left femur and tibia were collected from the bird with the median BW on d 11 and 18 from each cage, and analyzed for bone breaking strength and bone ash. Weight gain and gain-to-feed ratio linearly or quadratically increased (P < 0.05) in every period as the inclusion rate of MSP or phytase increased. Ileal digestibility of P linearly increased (P < 0.05) on d 11 with increasing MSP, but there was no significant effect on d 18. Increasing phytase concentration linearly increased (P < 0.05) ileal digestibility of P on d 11 and 18. Increasing dietary MSP or phytase linearly increased ileal digestible P concentration in diets (P < 0.05). Bone breaking strength and bone ash linearly or quadratically increased (P < 0.05) with increasing inclusion rate of MSP or phytase on d 11 and 18. The equivalency of 1,000 FYT/kg of exogenous phytase based on dietary ileal digestible P concentration was 1.5 and 1.2 g/kg of inorganic P in diets on d 11 and 18, respectively. The current results showed that the supplementation of MSP or exogenous phytase can increase growth performance, ileal P digestibility, bone breaking strength, and bone ash in young broiler chickens.


Neverland regulates embryonic moltings through the regulation of ecdysteroid synthesis in the water flea Daphnia magna, and may thus act as a target for chemical disruption of molting.
Embryo development in arthropods is accompanied by a series of moltings. A cladoceran crustacean Daphnia magna molts three times before reaching first instar neonate during embryogenesis. Previous studies argued ecdysteroids might regulate D. magna embryogenesis. However, no direct evidence between innate ecdysteroids fluctuation and functions has been forthcoming. Recently, we identified genes involved in ecdysteroid synthesis called, neverland (neverland1 and neverland 2) and shade and in the ecdysteroid degradation (Cyp18a1). To understand the physiological roles of ecdysteroids in D. magna embryos, we performed expression and functional analyzes of those genes. Examining innate ecdysteroids titer during embryogenesis showed two surges of ecdysteroids titer at 41 and 61 h after oviposition. The first and second embryonic moltings occurred at each ecdysteroid surge. Expression of neverland1 and shade began to increase before the first peak in ecdysteroid. Knockdown of neverland1 or shade by RNAi technique caused defects in embryonic moltings and subsequent development. The ecdysteroids titer seemingly decreased in nvd1-knowckdown embryos. Knockdown of Cyp18a1 resulted in early embryonic lethality before the first molting. Our in situ hybridization analysis revealed that nvd1 was prominently expressed in embryonic gut epithelium suggesting the site for an initial step of ecdysteroidgenesis, a conversion of cholesterol to 7-dehydrocholesterol and possibly for ecdysone production. Taken together, de novo ecdysteroid synthesis by nvd1 in the gut epithelial cells stimulates molting, which is indispensable for D. magna embryo development. These findings identify neverland as a possible target for chemicals, including various pesticides that are known to disrupt molting, development and reproduction. Copyright © 2016 John Wiley & Sons, Ltd.


The inhalers of the future? A review of dry powder devices on the market today.
International agreements to ban the use of environmentally damaging chlorofluorocarbons (CFCs) have signalled an end to the traditional CFC-propelled pressurised metered dose inhaler (pMDI) which has long been the mainstay of topical asthma therapy. The need for acceptable and cost-effective replacement inhalers, combined with opportunities to develop generic formulations of patent-expired drugs, has fueled a lively response from the pharmaceutical industry. Improvements in pMDI design and reformulation with propellants such as hydrofluoroalkanes may offer significant advantages over CFC-pMDIs and prolong the widespread use of pressurised drug delivery systems for many years to come. In the longer term, however, another likely candidate for success in providing economical, efficient and acceptable inhaled therapies is the breath-actuated, multiple-dose dry powder inhaler (DPI). This review concentrates on the multiple-dose DPIs available within Europe today.


The blueprint for building a biofilm the Clostridioides difficile way.
Clostridioides difficile is an opportunistic pathogen that causes by a high rate of recurrent infections. Persistence in the gastrointestinal tract is thought to be mediated by sporulation and/or biofilm formation. There is an increase interest in C. difficile biofilm formation and recent findings have provided a framework to model surface-attached biofilm formation. For in vitro biofilm formation, C. difficile must undergo a metabolic reprogramming as it enters stationary phase. This helps maintain long-term viability and increases responsiveness to signals leading to biofilm formation. Metabolic reprogramming and biofilm formation requires several regulatory factors and these overlap with the sporulation cascade. Despite recent advances, further research is needed to answer outstanding questions in the field.


The class-origin wage gap: heterogeneity in education and variations across market segments.
This paper uses unique population-level matched employer-employee data on monthly wages to analyse class-origin wage gaps in the Swedish labour market. Education is the primary mediator of class origin advantages in the labour market, but mobility research often only considers the vertical dimension of education. When one uses an unusually detailed measure of education in a horizontal dimension, the wage gap between individuals of advantaged and disadvantaged class origin is found to be substantial (4-5 per cent), yet considerably smaller than when measures are used which only control for level of education and field of study. This is also the case for models with class or occupation as outcome. The class-origin wage gap varies considerably across labour market segments, such as those defined by educational levels, fields of education, industries and occupations in both seemingly unsystematic and conspicuous ways. The gap is small in the public sector, suggesting that bureaucracy may act as a leveller.


Illness, biomedicine, and alternative healing in Brittany, France.
Through the lens of an illness narrative, this article focuses on the complex relationships between biomedicine and alternative therapies in Brittany, France. Themes drawn from the illness narrative highlight Breton ideas about the body, the source of healers' legitimacy, and the authority of the biomedical system. I argue that in this region, both biomedical and religious authorities are perceived to be allied to non-local elites, and both are subject to antagonistic criticism. Nonetheless, resistance to biomedicine through recourse to alternative therapies is mixed with ongoing dependence on the biomedical system, since patients seek strategic combinations of both systems to maximize health and other benefits. Pursuing alternative therapies empowers patients by enabling them to negotiate treatment options and to choose among competing narrative constructions of illness. By highlighting parallels between the Breton material and published work based elsewhere in Europe and North America, I argue that this case study has useful implications for anthropologists and medical practitioners working in broader Western contexts.


How silence affects memory, self, and society: foreword to the special issue.
This special issue of Memory focuses on silence and its implications for memory, and also on the implications of silences that extend beyond memory, to the functioning of individuals, groups, and societies. Silence can represent things taken for granted, and also things unsayable. The memory implications of silencing are complex. In terms of traditional memory research concerns-with accuracy and completeness-silencing has clearly negative implications. But silencing is also a means by which self and group become aligned in their views of the past. The contributions here make a strong case for memory researchers to consider what is not recalled, as well as what is.


[Solubilization of glycoproteins from enveloped viruses by detergents].
The effects of some known ionic and nonionic detergents as well as that of a novel nonionic detergent MESK on various enveloped viruses were investigated. It was found that nonionic detergens (MESK, Triton X-100, octyl-beta-D-glucopyranoside) selectively solubilize glycoproteins of enveloped viruses. The most mild selective action is exerted by the nonionic detergent MESK. Using this detergent, pure preparations of glycoproteins of influenza, parainfluenza, equine Venezuela encephalomyelitis, rabies, vesicular stomatitis and herpes viruses were obtained. The procedure of isolation of purified glycoproteins includes incubation of viral suspensions with MESK, removal of subviral structures by centrifugation and purification of glycoproteins from detergent admixtures by dialysis. Purified glycoproteins retain their native structure and a high biological activity and immunogenicity. MESK seems to be due a perspective tool in the production of subunit vaccines.


Vernonia amygdalina Ethanol Extract Protects against Doxorubicin-Induced Cardiotoxicity via TGFβ, Cytochrome c, and Apoptosis.
Doxorubicin (DOX) has been extensively utilized in cancer treatment. However, DOX administration has adverse effects, such as cardiac injury. This study intends to analyze the expression of TGF, cytochrome c, and apoptosis on the cardiac histology of rats induced with doxorubicin, since the prevalence of cardiotoxicity remains an unpreventable problem due to a lack of understanding of the mechanism underlying the cardiotoxicity result. Vernonia amygdalina ethanol extract (VAEE) was produced by soaking dried Vernonia amygdalina leaves in ethanol. Rats were randomly divided into seven groups: K- (only given doxorubicin 15 mg/kgbw), KN (water saline), P100, P200, P400, P4600, and P800 (DOX 15 mg/kgbw + 100, 200, 400, 600, and 800 mg/kgbw extract); at the end of the study, rats were scarified, and blood was taken directly from the heart; the heart was then removed. TGF, cytochrome c, and apoptosis were stained using immunohistochemistry, whereas SOD, MDA, and GR concentration were evaluated using an ELISA kit. In conclusion, ethanol extract might protect the cardiotoxicity produced by doxorubicin by significantly reducing the expression of TGF, cytochrome c, and apoptosis in P600 and P800 compared to untreated control K- (p < 0.001). These findings suggest that Vernonia amygdalina may protect cardiac rats by reducing the apoptosis, TGF, and cytochrome c expression while not producing the doxorubicinol as doxorubicin metabolite. In the future, Vernonia amygdalina could be used as herbal preventive therapy for patient administered doxorubicin to reduce the incidence of cardiotoxicity.


New aryl-/heteroarylpiperazine derivatives of 1,7-dimethyl-8,9-diphenyl-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5,10-trione: Synthesis and preliminary studies of biological activities.
Compounds containing dicarboximide skeleton such as succinimides, maleimides, glutarimides, and phthalimides possess broad biological properties including anti-fungal, antibacterial, antidepressant, or analgesic activities. The piperazine ring is found in a wide range of molecules that have demonstrated a variety of biological functions such as anticancer action and 5-HT receptors agonist/antagonist activity. In the present study, we combined both structures to develop new antitumor agents, a series of piperazine derivatives of 1,7-dimethyl-8,9-diphenyl-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5,10-trione and evaluated their biological activity. The structures of all tested compounds were confirmed by 1H and 13C NMR and by ESI MS spectral analysis. Their cytotoxicity was assessed in vitro against eight human cancer cell lines, namely prostate (PC3), colon (HCT116, SW480, SW620), leukemia (K562), liver (HepG2), lung (A549) and breast (MDA-Mb-231) in contrast to normal HMEC-1 cell line, by using MTT and Trypan blue method. The tested compounds showed significant activity toward cancer cells. The most pronounced cytotoxic effect was observed in K562 and HCT116 with IC50 values below 10 μM for all studied compounds. Importantly, the most promising derivatives for each cancer cell line (IC50 < 10 μM) exerted a weaker cytotoxic effect toward normal HMEC-1 cells than cancer cells. The evaluation of proapoptotic and inhibitory effects on IL-6 release showed that K562 and HCT116 cells were more sensitive to studied compounds than other cancer cell lines. Furthermore, for all piperazine derivatives, the functional activities at the 5-HT1A, D2 receptors as well as their binding affinities at the 5-HT2A, H1 and M receptors, were determined. The current investigation was able to successfully design compounds with both serotoninergic and anticancer properties. It serves as a good starting point for a multimodal approach for the management of cancer and cancer-related symptoms.


Antimicrobial Nitric Oxide Releasing Contact Lens Gels for the Treatment of Microbial Keratitis.
Microbial keratitis is a serious sight threatening infection affecting approximately two million individuals worldwide annually. While antibiotic eye drops remain the gold standard treatment for these infections, the significant problems associated with eye drop drug delivery and the alarming rise in antimicrobial resistance has meant that there is an urgent need to develop alternative treatments. In this work, a nitric oxide releasing contact lens gel displaying broad spectrum antimicrobial activity against two of the most common causative pathogens of microbial keratitis is described. The contact lens gel is composed of poly-ε-lysine (pεK) functionalized with nitric oxide (NO) releasing diazeniumdiolate moieties which enables the controlled and sustained release of bactericidal concentrations of NO at physiological pH over a period of 15 h. Diazeniumdiolate functionalization was confirmed by Fourier transform infrared (FTIR), and the concentration of NO released from the gels was determined by chemiluminescence. The bactericidal efficacy of the gels against Pseudomonas aeruginosa and Staphylococcus aureus was ascertained, and between 1 and 4 log reductions in bacterial populations were observed over 24 h. Additional cell cytotoxicity studies with human corneal epithelial cells (hCE-T) also demonstrated that the contact lens gels were not cytotoxic, suggesting that the developed technology could be a viable alternative treatment for microbial keratitis.


The impact of repetitive long-duration water immersion on vascular function.
While physiological responses to water immersion (WI) are well-studied, the vascular responses after WI are less understood. Fifteen male subjects performed six-hour resting thermoneutral water immersions (WI) at 1.35 atmospheres absolute for four consecutive days, with follow-up on the fifth day. Measurements included peripheral endothelial function and augmentation index (PAT, peripheral arterial tonometry), beat-to-beat blood pressure (BP, photoplethysmography), heart rate (HR), and plasma volume (PV) calculated from changes in hemoglobin and hematocrit. The reactive hyperemia index (RHI), a marker of peripheral endothelial function, increased with repeated immersions (p = 0.008). By WI2 and WI3, RHI increased 12% and 16%, respectively, compared to WI1 values, but no significant differences were detected between WI4 and WI1 for either measure. Absolute augmentation index (AI) increased by an average of 33% (p<0.001) and AI normalized for HR (AI@75) by 11% (p = 0.12) following each WI. PV decreased significantly by 13.2% following WI and remained 6.8% lower at follow-up compared to pre-WI. Systolic blood pressure significantly decreased by an average of 2.5% following each WI (p = 0.012). Compared to pre-WI HR, average post-WI HR decreased 4.3% lower (p<0.001), but increased overall by 8.2% over the course of repeated WI (p<0.001). Total peripheral resistance increased by an average of 13.1% following WI (p = 0.003). Thus, peripheral endothelial function increases after two days of WI, and PAT-derived measures of arterial stiffness increase transiently post-WI. Additionally, BP and PAT-derived endothelial function diverge from their usual associations with arterial stiffness (i.e. augmentation index) in the context of WI.


Phonon-mediated interlayer conductance in twisted graphene bilayers.
Conduction between graphene layers is suppressed by momentum conservation whenever the layer stacking has a rotation. Here we show that phonon scattering plays a crucial role in facilitating interlayer conduction. The resulting dependence on orientation is radically different than previously expected, and far more favorable for device applications. At low temperatures, we predict diode-like current-voltage characteristics due to a phonon bottleneck. Simple scaling relationships give a good description of the conductance as a function of temperature, doping, rotation angle, and bias voltage, reflecting the dominant role of the interlayer beating phonon mode.


[Evaluation of two methods for correcting the impact factor using the investigation done at the "Del Río Hortega" University Hospital (1999-2004) as the data source].
To adjust the Impact Factor (IF) provided by the Institute for Scientific Information (ISI) is necessary for improving bibliometric analysis among the various areas of knowledge. Our objective was to evaluate two parameters (the maximum and the median value of each subject area) for IF adjustment using the original (not corrected) IF as the reference method in a tertiary hospital biomedical investigation model. We retrieved articles from Hospital Universitario "Del Río Hortega" from Valladolid (Spain) for the period 1999-2004 as data source. We have describe the characteristics of the followed IF distributions: IF Corrected by the Maximum value (IFCORMAX), IF Corrected by the Median value (IFCORMED) and IF without adjustments (IF). Besides, we have analyzed both the inter-annual and the inter-subject differences obtained by the three methods. The three analyzed IF series shown not normal distributions that are positively skewed. The IF adjusted by the median showed the highest coefficient of variation (CV = 357.3%). The IF adjusted by the Maximum value increased the "weight" of journals with the highest not corrected IF for each subject category. Inter-annual differences were similarly estimated by the three methods. The IF adjusted by the median increased the inter-subject difference from 7.3% to 12.4%. Our results suggests that IF adjusted by the maximum value of each discipline is the best method to correct the ISI-IF values, because journals with the high IF are always rewarded, while IF adjusted by the median infra-estimated most of them.


Chemotherapeutic value of 2-deoxy-D-glucose in infectious bovine rhinotracheitis viral infection in calves.
Daily injection of 2-deoxy-D-glucose (2-dG) had no protective effect against respiratory tract infection in calves caused by infectious bovine rhinotracheitis virus. It also did not reduce the severity of this infection. Ocular instillation of the drug, however, markedly reduced the severity of viral-induced conjunctivitis and keratoconjunctivitis. The drug was effective when given at the time of ocular infection or after clinical conjunctivitis developed.


Platelet-activating factor--a powerful lipid autacoid possibly involved in microangiopathy.
Microvascular injury includes diffuse endothelial and periendothelial damage and increased leukocyte/platelet-endothelium interactions including cell adhesion and liberation of powerful autacoids, growth and coagulation factors, all capable of causing vessel wall injury. Platelet-activating factor (PAF) is an ether-lipid mediator of inflammation, produced by and active on both platelets and endothelial cells (EC) at nanomolar concentrations. Its structure, biosynthesis and origin as well as some regulatory properties of the related enzymes are considered. The in vivo effects of PAF, as well as its action on selected cell types, such as platelets, neutrophils and EC, are briefly reviewed. PAF production may explain the intervention of platelets and neutrophils as well as increased vascular permeability in kidney, lung and retinal diseases. Pharmacological modulation of PAF production and activity is discussed with particular attention to the inhibitory effect of calcium dobesilate, a drug used in human diabetic retinopathy, on PAF production from the human endothelial cell line EA926.


Metallic nanoparticles irradiated by low-energy protons for radiation therapy: Are there significant physical effects to enhance the dose delivery?
To identify which physical properties of nanoparticles are correlated with the survival fraction of cells exposed in vitro to low-energy protons in combination with nanoparticles. The Geant4 simulation toolkit (version 10.3) was used to model nanoparticles of different sizes (5-50 nm) and materials (Ti, Zr, Hf, Ta, Au, Pt), with or without an organic capping ensuring biocompatibility and to irradiate them with 1.3 or 4 MeV protons and 5.3 MeV alpha particles. The spectra of secondary electrons inside and at the nanoparticle surface were computed, as well as electron yields, Auger and organic capping contribution, trapping in metal bulk and linear energy transfer profiles as a function of distance from the nanoparticle center. In a next step, an in silico cell model was designed and loaded with gold nanoparticles, according to experimental uptake values. Dose to the cell was evaluated macroscopically and microscopically in 100 × 100 × 100 nm³ voxels for different radiation qualities. The cell geometry showed that radiation enhancement is negligible for the gold concentration used and for any radiation quality. However, when the single nanoparticle geometry is considered, we observed a local LET in its vicinity considerably higher than for the water equivalent case (up to 5 keV/μm at the titanium nanoparticle surface compared to 2.5 keV/μm in the water case). The yield of secondary electrons per primary interaction with 1.3 MeV protons was found to be most favorable for titanium (1.54), platinum (1.44), and gold (1.32), although results for higher Z metals are probably underestimated due to the incomplete simulation of de-excitation cascade in outer shells. It was also found that the organic capping contributed mostly to the production of low-energy electrons, adding a spike of dose near the nanoparticle surface. Indeed, the yield for the coated gold nanoparticle increased to 1.53 when exposed to 1.3 MeV protons. Although most electrons are retained inside larger nanoparticles (50 nm), it was shown that their yield is comparable to smaller sizes and that the linear energy transfer profile is better. From a combination of ballistic and nanoparticle size factors, it was concluded that 10-nm gold nanoparticles were better inducers of additional cell killing than 5-nm gold nanoparticles, matching our previous in vitro study. Although effects from a physical standpoint are limited, the high linear energy transfer profile at the nanoparticle surface generates detrimental events in the cell, in particular ROS-induced damage and local heating.


Single- vs double-lung transplantation in patients with chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis since the implementation of lung allocation based on medical need.
Outcomes of single- and double-lung transplantation have not been rigorously assessed since the allocation of donor lungs according to medical need as quantified by the Lung Allocation Score, which began in 2005. To compare outcomes in single- and double-lung transplant recipients since the Lung Allocation Score was implemented. In this exploratory analysis, adults with idiopathic pulmonary fibrosis (IPF) or chronic obstructive pulmonary disease (COPD) who underwent lung transplantation in the United States between May 4, 2005, and December 31, 2012, were identified in the United Network for Organ Sharing thoracic registry, with follow-up to December 31, 2012. Posttransplantation graft survival was assessed with Kaplan-Meier analysis. Propensity scores were used to control for treatment selection bias. A multivariable flexible parametric prognostic model was used to characterize the time-varying hazard associated with single- vs double-lung transplantation. Single- or double-lung transplantation. Composite of posttransplant death and graft failure (retransplantation). Patients with IPF (n = 4134, of whom 2010 underwent single-lung and 2124 underwent double-lung transplantation) or COPD (n = 3174, of whom 1299 underwent single-lung and 1875 underwent double-lung transplantation) were identified as having undergone lung transplantation since May 2005. Median follow-up was 23.5 months. Of the patients with IPF, 1380 (33.4%) died and 115 (2.8%) underwent retransplantation; of the patients with COPD, 1138 (34.0%) died and 59 (1.9%) underwent retransplantation. After confounders were controlled for with propensity score analysis, double-lung transplants were associated with better graft survival in patients with IPF (adjusted median survival, 65.2 months [interquartile range {IQR}, 21.4-91.3 months] vs 50.4 months [IQR, 17.0-87.5 months]; P < .001) but not in patients with COPD (adjusted median survival, 67.7 months [IQR, 25.2-89.6 months] vs 64.0 months [IQR, 25.2-88.7 months]; P = .23). The interaction between diagnosis type (COPD or IPF) and graft failure was significant (P = .049). Double-lung transplants had a time-varying association with graft survival; a decreased instantaneous late hazard for death or graft failure among patients with IPF was noted at 1 year and persisted at 5 years postoperatively (instantaneous hazard at 5 years, hazard ratio, 0.67 [95% CI, 0.52-0.84] in patients with IPF and 0.89 [95% CI, 0.71-1.13] in patients with COPD). In an exploratory analysis of registry data since implementation of a medical need-based lung allocation system, double-lung transplantation was associated with better graft survival than single-lung transplantation in patients with IPF. In patients with COPD, there was no survival difference between single- and double-lung transplant recipients at 5 years.


NRF2/HO-1 axis, BIRC5, and TP53 expression in ESCC and its correlation with clinical pathological characteristics and prognosis.
Many types of cancer exhibit high nuclear factor erythroid 2-related factor 2 (NRF2), which is effective in resisting drugs and radiation. However, the role of NRF2 gene expression in predicting the prognosis of esophageal squamous cell carcinoma (ESCC) remains unclear. The association between NRF2, heme oxygenase-1 (HO-1), baculovirus IAP repeat 5 (BIRC5), P53 gene expression levels and their relationship to immune-infiltrating cells were assessed using the Cancer Genome Atlas dataset, the Human Protein Atlas and the TISDB database. The expression of NRF2, HO-1, BIRC5, and TP53 in 118 ESCC patients was detected by immunohistochemistry, and the relationship between their expression level and clinicopathological parameters and prognosis was analyzed. In ESCC, NRF2 overexpression was significantly associated with Han ethnicity, lymph node metastasis, and distant metastasis. HO-1 overexpression was significantly associated with differentiation, advanced clinical staging, lymph node metastasis, nerve invasion, and distant metastasis. BIRC5 overexpression was significantly associated with Han ethnicity and lymph node metastasis. TP53 overexpression was significantly associated with Han ethnicity and T staging. The NRF2/HO-1 axis expression was positively correlated with BIRC5 and TP53. Kaplan-Meier and multivariate Cox regression analysis showed that NRF2, BIRC5, and TP53 genes co-expression was an independent prognostic risk factor. TISIDB dataset analysis showed that immune-infiltrating cells were significantly negatively correlated with NRF2 and BIRC5. NRF2, BIRC5, and TP53 axis gene expressions are predictors of poor prognosis for ESCC. The overexpression of the NRF2/HO-1/BIRC5 axis may not be related to immune-infiltrating cells.


[Clinical observation of one-visit root canal therapy by microwave instrument]
OBJECTIVE:To analysis post-treatmental reaction and long-term effect of one-visit root canal therapy by microwave instrument. METHODS:Applying heat effect and the other ones of microwave,the changes of dentine tissue of extracted teeth were observated by SEM examination.48hs and 1 year post-treatmental effect of 47 patients of periapical periodontitis treated by one-visit root canal therapy were observated and compared with the results of 54 cases treated with common method.RESULTS:In the cases of acute and chronic periapical periodontitis microwave applied in root canal therapy can close the openings of dentine,enhance the effects of sterilization and decrease times of treatment.CONCLUSION:Microwave applied in one-visit root canal therapy is competent.


Weight reduction is associated with decreased CRP levels.
Obesity is very costly for society and weight reduction is important to reduce obesity related diseases. We have evaluated the effect of weight reduction on CRP values to see if high sensitivity CRP could be used to provide persons on life style intervention programs with positive feedback. Study subjects (n = 26) were recruited to a life style intervention program aiming for weight loss among the laboratory staff at Uppsala University Hospital, Sweden. Blood samples for high sensitivity CRP were collected at inclusion and after 4 weeks. Body composition was estimated by measurements performed on an inexpensive bioimpedance analyzer. CRP reduction was significantly associated with weight reduction after four weeks (p = 0.00005) and eight weeks (p = 0.0002). Data from the bioimpedance analyzer were not useful on an individual level. High sensitivity CRP could be used to provide positive feedback in workplace weight reduction programs.


Global report on COVID-19 vaccination and reasons not to vaccinate among adults with intellectual disabilities: Results from secondary analyses of Special Olympics' program planning.
The COVID-19 pandemic has disproportionately affected people with intellectual disabilities worldwide. The objective of this study was to identify global rates of COVID-19 vaccination and reasons not to vaccinate among adults with intellectual disabilities (ID) associated with country economic income levels. The Special Olympics COVID-19 online survey was administered in January-February 2022 to adults with ID from 138 countries. Descriptive analyses of survey responses include 95% margins of error. Logistic regression and Pearson Chi-squared tests were calculated to assess associations with predictive variables for vaccination using R 4.1.2 software. Participants (n = 3560) represented 18 low (n = 410), 35 lower-middle (n = 1182), 41 upper-middle (n = 837), and 44 high (n = 1131) income countries. Globally, 76% (74.8-77.6%) received a COVID-19 vaccination while 49.5% (47.9-51.2%) received a COVID-19 booster. Upper-middle (93% (91.2-94.7%)) and high-income country (94% (92.1-95.0%)) participants had the highest rates of vaccination while low-income countries had the lowest rates (38% (33.3-42.7%)). In multivariate regression models, country economic income level (OR = 3.12, 95% CI [2.81, 3.48]), age (OR = 1.04, 95% CI [1.03, 1.05]), and living with family (OR = 0.70, 95% CI [0.53, 0.92]) were associated with vaccination. Among LLMICs, the major reason for not vaccinating was lack of access (41.2% (29.5-52.9%)). Globally, concerns about side effects (42%, (36.5-48.1%)) and parent/guardian not wanting the adult with ID to vaccinate (32% (26.1-37.0%)) were the most common reasons for not vaccinating. Adults with ID from low and low-middle income countries reported fewer COVID-19 vaccinations, suggesting reduced access and availability of resources in these countries. Globally, COVID-19 vaccination levels among adults with ID were higher than the general population. Interventions should address the increased risk of infection for those in congregate living situations and family caregiver apprehension to vaccinate this high-risk population.


Paradoxically decreased aortic wall stiffness in response to vitamin D3-induced calcinosis. A biphasic analysis of segmental elastic properties in conscious dogs.
We studied the aortic elastic behavior in response to vitamin D3-induced accelerated calcinosis in conscious dogs chronically instrumented with a pressure microtransducer and a pair of ultrasonic diameter dimension gauges in the upper descending thoracic aorta. The two functional phases of the elastic segmental properties of the aorta in vivo were discriminated by computation on a beat-by-beat basis from the phasic pressure-diameter (P-D) hysteresis loops in basal conditions and during the transient state of a wide range of pressures obtained mechanically (aortic occlusion) or pharmacologically (angiotensin bolus). The overall P-D curve formed by all P-D hysteresis loops was comprised of two linear relations according to a model that assumes that only elastin is stretched at lower pressures, whereas both elastin and collagen are stretched at higher pressures. The slope of the first linear portion of the P-D curve was considered as the elastin P-D elastic modulus, and the slope of the curve obtained by subtraction between the P-D curve and the extrapolation of the elastin straight line was assumed to be the collagen P-D elastic modulus. After vitamin D3-induced calcinosis, the elastin elastic modulus was unaffected, whereas the collagen elastic modulus decreased significantly during occlusion maneuvers (58.6%, p less than 0.01) and during bolus injections of angiotensin (37.2%, p less than 0.05). The collagen elastic modulus correlated with the serum calcium concentration (r = -0.65, p less than 0.001) and with the aortic pulse pressure (r = 0.51, p less than 0.01), and this relation persisted at constant heart rate. Histopathologic analysis evidenced calcium-depositing elastic lamina, focal disappearance of collagen, and rupture of elastic fibers. The present study shows that accelerated, severe, experimental calcinosis-inducing calcium deposition inside the large artery walls is accompanied by a clear-cut paradoxical reduction in arterial rigidity that is mainly due to functional and structural modification of collagen elasticity.


Foliar Application with Iron Oxide Nanomaterials Stimulate Nitrogen Fixation, Yield, and Nutritional Quality of Soybean.
Sustainable strategies for the management of iron deficiency in agriculture are warranted because of the low use efficiency of commercial iron fertilizer, which confounds global food security and induces negative environmental consequences. The impact of foliar application of differently sized γ-Fe2O3 nanomaterials (NMs, 4-15, 8-30, and 40-215 nm) on the growth and physiology of soybean seedlings was investigated at different concentrations (10-100 mg/L). Importantly, the beneficial effects on soybean were size- and concentration-dependent. Foliar application with the smallest size γ-Fe2O3 NMs (S-Fe2O3 NMs, 4-15 nm, 30 mg/L) yielded the greatest growth promotion, significantly increasing the shoot and nodule biomass by 55.4 and 99.0%, respectively, which is 2.0- and 2.6-fold greater than the commercially available iron fertilizer (EDTA-Fe) with equivalent molar Fe. In addition, S-Fe2O3 NMs significantly enhanced soybean nitrogen fixation by 13.2% beyond that of EDTA-Fe. Mechanistically, transcriptomic and metabolomic analyses revealed that (1) S-Fe2O3 NMs increased carbon assimilation in nodules to supply more energy for nitrogen fixation; (2) S-Fe2O3 NMs activated the antioxidative system in nodules, with subsequent elimination of excess reactive oxygen species; (3) S-Fe2O3 NMs up-regulated the synthesis of cytokinin and down-regulated ethylene and jasmonic acid content in nodules, promoting nodule development and delaying nodule senescence. S-Fe2O3 NMs also improved 13.7% of the soybean yield and promoted the nutritional quality (e.g., free amino acid content) of the seeds as compared with EDTA-Fe with an equivalent Fe dose. Our findings demonstrate the significant potential of γ-Fe2O3 NMs as a high-efficiency and sustainable crop fertilizer strategy.


The effects of church attendance and marital status on the longitudinal trajectories of depressed mood among older adults.
Objective. The present study investigated the potential effects of church attendance and marital status on mood trajectories among older adults and whether these effects varied by gender. Method. Data from the Australian Longitudinal Study of Aging were used to examine the effects of church attendance and marital status on changes in depressed mood. Participants included 791 older adults (42.4% men; mean age at study entry = 75.62) who were interviewed at three time points over 8 years. Results. Using multilevel modeling to assess change, church attendance was found to have a protective effect against the emergence of mood problems among older adults. Also, although becoming married was associated with a decrease in depressed mood, becoming nonmarried was associated with an increase in depressed mood. Discussion. A sense of purpose as a potential explanation for the association between church attendance and changes in depressed mood in old age was discussed.


[Treatment adherence to guidelines for the management of chronic heart failure].
Chronic heart failure is a growing public health problem with a bad prognosis. Despite the seriousness of this syndrome and the well defined therapeutic approach, adherence to guidelines remains poor. After briefly recalling the main points of these guidelines, we present statistical data regarding therapeutic care of these patients. We then present factors influencing prescription or non prescription of heart failure drugs and emphasize the importance of a team management programme and patients pathways.


The effects of infection and probenecid on the transport of carbenicillin from the rabbit vitreous humor.
We examined the effects of inflammation (S. aureus endophthalmitis) and of probenecid on the kinetics of intravitreally injected carbenicillin in rabbits. The half-life of antibiotic in the vitreous of animals with normal eyes was only 5 hr and levels in anterior ocular sites (cornea, aqueous, iris) were low. There findings are consistent with an active retinal transport pump for organic anions. Concomitant intraperitoneal administration of probenecid caused a marked prolongation of the ocular half-life of carbenicillin to 13 hr and augmentation of the levels in anterior sites, as might be anticipated from inhibition of the retinal transport pump. Inflammation produced an intermediate effect that is most readily explained by postulating two opposing consequences: partial inhibition of the transport pump and simultaneous "leakiness" of the normal retinal barrier. There findings suggest that the intraocular kinetics of antibiotics in inflamed eyes are markedly different from those in normal ones and that systemic probenecid significantly augments the intraocular levels of carbenicillin.


Dispositional Mindfulness and Memory Problems: The Role of Perceived Stress and Sleep Quality.
There is a growing body of evidence exploring the beneficial effects of mindfulness on stress, sleep quality, and memory, though the mechanisms involved are less certain. The present study explored the roles of perceived stress and sleep quality as potential mediators between dispositional mindfulness and subjective memory problems. Data were from a Boston area subsample of the Midlife in the United States study (MIDUS-II) assessed in 2004-2006, and again approximately one year later (N=299). As expected, higher dispositional mindfulness was associated with lower perceived stress and better sleep quality. There was no direct association found between mindfulness and subjective memory problems, however, there was a significant indirect effect through perceived stress, although not with sleep quality. The present findings suggest that perceived stress may play a mediating role between dispositional mindfulness and subjective memory problems, in that those with higher mindfulness generally report experiencing less stress than those with lower mindfulness, which may be protective of memory problems in everyday life.


Immunoenhanced enteral nutrition formulas in head and neck cancer surgery: a prospective, randomized clinical trial.
Significant malnutrition exists in a high percentage of patients with head and neck cancer. Malnutrition is associated with defects in immune function that may impair the host response to malignancy. Malnutrition and immunosupression make patients highly susceptible to postoperative infections and complications. Compare two immunoenhanced enteral nutritions with a control diet, and evaluate the effect in postoperative infections, length of stay and inflammatory markers. A population of 44 patients with oral and laryngeal cancer was enrolled in a randomized trial. At surgery, patients were randomly allocated to three groups: (group I); patients receiving an arginine-enhanced formula (group II); patients receiving a standard polymeric formula, and (group III) patients receiving an arginine, RNA and omega-3 fatty acids enhanced formula, in an isonitrogenous way. The duration of enteral nutrition in the three groups was similar with an average duration of 14,5 +/- 8 days. The length of postoperative stay was similar, with an average of 19,8 +/- 8,5 days. Wound infections and general infections were more frequent in the control group. Fistula rates were not improved in the enhanced diet groups. No significant intergroup differences in the trend of the two plasma proteins (albumin, transferrin), lymphocytes, weight, IL-6, CPR and TNFalpha were detected. The control group showed the highest levels of TNFalpha at the fourteenth postoperative day. Gastrointestinal tolerance and diarrhoea rate were similar in all the patients. Immunoenhanced enteral nutrition formulas improved the infection rate in the postoperative of head and neck cancer patients. In the fistula rates, we observed that technical problems and nutritional status might have played an equally important role, and therefore the positive effect of immunonutrition in this parameter might have been overestimated.


Robo3.1A suppresses slit-mediated repulsion by triggering degradation of Robo2.
Slits and Robos control the midline crossing of commissural axons, which are not sensitive to the midline repellent Slit before crossing but gain Slit responsiveness to exit the midline and avoid recrossing. Robo3.1A promotes midline crossing of commissural axons by suppressing the axonal responsiveness to the midline repellent Slit, but the underlying mechanism remains unclear. By using a cell surface binding assay and immunoprecipitation, we observed that Robo3.1A did not bind Slit on its own but prevented the specific binding of Slit to the cell surface when it was coexpressed with its close homologue Robo1 or Robo2 (Robo1/2), which are known to mediate the Slit repulsion. Cotransfection with Robo3.1A significantly reduced the protein level of Robo2 in HEK293 cells, and overexpression of Robo3.1A also significantly decreased Robo2 protein level in cerebellar granule cells. Downregulation of endogenous Robo3 by specific small interference RNA (siRNA) significantly increased Robo1 protein level, Slit binding to the cell surface was significantly elevated, and Slit-triggered growth cone collapse appeared after downregulation of Robo3 in cultured cortical neurons. Immunocytochemical staining showed that Robo2 and Robo3 colocalized in intracellular vesicles positive for the marker of late endosomes and lysosomes, but not trans-Golgi apparatus and early endosomes. Thus Robo3.1A may prevent the Slit responsiveness by recruiting Robo1/2 into a late endosome- and lysosome-dependent degradation pathway.


Endogenous catalase delays high-fat diet-induced liver injury in mice.
Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent liver disease in parallel with worldwide epidemic of obesity. Reactive oxygen species (ROS) contributes to the development and progression of NAFLD. Peroxisomes play an important role in fatty acid oxidation and ROS homeostasis, and catalase is an antioxidant exclusively expressed in peroxisome. The present study examined the role of endogenous catalase in early stage of NAFLD. 8-week-old male catalase knock-out (CKO) and age-matched C57BL/6J wild type (WT) mice were fed either a normal diet (ND: 18% of total calories from fat) or a high fat diet (HFD: 60% of total calories from fat) for 2 weeks. CKO mice gained body weight faster than WT mice at early period of HFD feeding. Plasma triglyceride and ALT, fasting plasma insulin, as well as liver lipid accumulation, inflammation (F4/80 staining), and oxidative stress (8-oxo-dG staining and nitrotyrosine level) were significantly increased in CKO but not in WT mice at 2 weeks of HFD feeding. While phosphorylation of Akt (Ser473) and PGC1α mRNA expression were decreased in both CKO and WT mice at HFD feeding, GSK3β phosphorylation and Cox4-il mRNA expression in the liver were decreased only in CKO-HF mice. Taken together, the present data demonstrated that endogenous catalase exerted beneficial effects in protecting liver injury including lipid accumulation and inflammation through maintaining liver redox balance from the early stage of HFD-induced metabolic stress.


Discovery and characterization of new microsatellite loci in Dipteryx alata Vogel (Fabaceae) using next-generation sequencing data.
The use of next-generation sequencing (NGS) technologies provides a great volume of genome sequence data even for non-model species. The development of microsatellite markers using these data is a relatively quick and easy process. Dipteryx alata Vogel (Fabaceae) is an arboreal species from the Cerrado biome and is considered an important plant genetic resource. Here, we report the development of microsatellite markers for D. alata using NGS data. DNA samples from four individuals were sequenced using the Illumina MiSeq platform and high-quality reads were assembled into contigs of the D. alata genome sequence. Microsatellite regions were identified using the IMEX webserver and primer pairs were designed using the Primer3 software. The amplification settings for each locus were optimized. Fluorescent-labeled primers were developed and used to genotype individuals derived from three natural populations of D. alata. Fifty-four microsatellite regions were identified, from which 27 were elected to primer design. Among the amplified loci, 11 were polymorphic, with the number of alleles ranging from 2 to 10. The expected heterozygosity under Hardy-Weinberg Equilibrium (HWE) per locus varied from 0.191 to 0.807. Genotype and allele frequencies for all loci agreed with those expected under HWE and linkage disequilibrium was not significant for all pairs of loci. The probabilities of exclusion of paternity and of combined identity were equal to 0.993 and 5.65 x 10-8, respectively. The markers developed in this study are useful to several types of population genetic studies with D. alata and, eventually, for closely related species.


Students' Satisfaction with a Web-Based Pharmacy Program in a Re-Regulated Pharmacy Market.
In response to the shortage of pharmacists in Northern Sweden, a web-based Bachelor of Science in Pharmacy program was established at Umeå University in 2003. In 2009, the Swedish pharmacy market was re-regulated from a state monopoly to an open market, but it is unknown what impact this has had on education satisfaction. The objectives of this study were to examine the level of satisfaction among graduates from a web-based pharmacy program and to describe what subjects and skills students would have liked more or less of in their education. A secondary objective was to compare the level of satisfaction before and after the Swedish pharmacy market was re-regulated. A cross-sectional survey was conducted in 2015 with all alumni who had graduated from the pharmacy program between 2006 and 2014 (n = 511), and responses to questions about graduates' satisfaction with the program were analyzed (n = 200). Most graduates (88%) agreed or strongly agreed that the knowledge and skills acquired during their education were useful in their current job. The graduates stated that they would have wanted more applied pharmacy practice and self-care counselling, and fewer social pharmacy and histology courses. Further, 82% stated that they would start the same degree program if they were to choose again today, and 92% agreed or strongly agreed that they would recommend the program to a prospective student. Graduates were more likely to recommend the program after the re-regulation (p = 0.007). In conclusion, pharmacy graduates were very satisfied with their education, and no negative effects of the re-regulation could be observed on program satisfaction.


Occurrence of mixed populations of influenza A viruses that can be maintained through transmission in a single host and potential for reassortment.
Reassortment, which is the rearrangement of viral gene segments in a host cell infected with two different viruses, is an important mechanism for the evolution of influenza viruses. Mixed infections with multiple virus types could lead to reassortment. To better understand the occurrence of quasispecies in a single host, we investigated mixed infections in individual isolates of seasonal influenza A viruses using amantadine sensitivity as a marker. We cultured viruses with amantadine and performed sequencing, restriction fragment length polymorphism analysis, cloning, and quantitative PCR to detect mixed populations. Culturing with amantadine showed evidence of a high number of mixed populations, while the other assays could hardly detect mixed populations. The existence of quasispecies in each isolate was common. However, the proportion of these, which can be less than 1%, is too low to be detected by conventional methods. Such mixed populations in which reassortment occurs may have a significant role in the evolution of viruses.


Modification of ovine opsin with the photosensitive hydrophobic probe 1-azido-4-[125I]iodobenzene. Labelling of the chromophore-attachment domain.
The hydrophobic photosensitive probe 1-azido-4-[125I]iodobenzene (AIB) partitioned preferentially into photoreceptor disc membranes and, upon u.v. irradiation, became covalently bound to opsin and phospholipid. The labelling of both protein and phospholipid was linearly related to AIB concentration. The amount of probe incorporated into protein was not significantly different when membranes were irradiated at -100 degrees, 4 degrees or 25 degrees C, but irreversible aggregation of monomeric opsin was dramatically reduced by performing the photolysis at -100 degrees C. Labelling of opsin after irradiation at -100 degrees or 4 degrees was not significantly reduced by the presence of lysine in the aqueous buffer, indicating that significant amounts of reactive species did not enter the aqueous phase. The incorporation into phospholipid, unlike that into opsin, decreased as the temperature of irradiation increased. Some labelling of opsin occurred on incubation with pre-photoactivated AIB, indicating that reaction may also occur with reactive species of longer lifetimes than the nitrene. Proteolysis of labelled opsin with Staphylococcus aureus V8 proteinase yielded two radiolabelled membrane-bound fragments. The location of the modified sites (cysteine, tryptophan, tyrosine, lysine and histidine residues: all nucleophiles) in the smaller fragment was entirely consistent with putative models for the protein derived from other studies.


COVID-19: An Emerging Threat to Antibiotic Stewardship in the Emergency Department.
While current research efforts focus primarily on identifying patient level interventions that mitigate the direct impact of COVID-19, it is important to consider the collateral effects of COVID-19 on antimicrobial resistance. Early reports suggest high rates of antibiotic utilization in COVID-19 patients despite their lack of direct activity against viral pathogens. The ongoing pandemic is exacerbating known barriers to optimal antibiotic stewardship in the ED, representing an additional direct threat to patient safety and public health. There is an urgent need for research analyzing overall and COVID-19 specific antibiotic prescribing trends in the ED. Optimizing ED stewardship during COVID-19 will likely require a combination of traditional stewardship approaches (e.g. academic detailing, provider education, care pathways) and effective implementation of host response biomarkers and rapid COVID-19 diagnostics. Antibiotic stewardship interventions with demonstrated efficacy in mitigating the impact of COVID-19 on ED prescribing should be widely disseminated and inform the ongoing pandemic response.


Measuring trapped DNA at the liquid-air interface for enhanced single molecule sensing.
Nanopore sensing is a promising tool with widespread application in single-molecule detection. Borosilicate glass nanopores are a viable alternative to other solid-state nanopores due to low noise and cost-efficient fabrication. For dielectric materials, including borosilicate glass, the capacitive noise is one of the major contributors to noise, which depends on the wall thickness and the surface area submerged in an ionic solution. Here, we investigated the root mean square (IRMS) noise and ionic conductance for borosilicate nanopores in different depths (i.e., tip submersion depth) ranging from the solution surface (assumed to be zero) to 5000 μm. Our findings demonstrate a decrease in IRMS noise as the pipette moves toward the surface. We further demonstrate that borosilicate nanopores can detect single lambda DNA (λ-DNA) molecules with a high signal-to noise ratio close to the liquid-air interface. Specifically, our results indicate a higher signal to noise ratio as the submersion depth is reduced owing to the reduced surface area and thus capacitive noise. Further, our experimental results show higher DNA capture frequency at the air-water interface due to a combined effect of evaporation and an evaporation-induced thermal gradient at the surface. Therefore, our findings demonstrate that borosilicate glass nanopores are suitable for studying interfacial concentration gradients of molecules, specifically DNA, with a higher signal to noise.


Tumor antigen-targeted, monoclonal antibody-based immunotherapy: clinical response, cellular immunity, and immunoescape.
Tumor antigen (TA) -targeted monoclonal antibodies (mAb), rituximab, trastuzumab, and cetuximab, are clinically effective for some advanced malignancies, especially in conjunction with chemotherapy and/or radiotherapy. However, these results are only seen in a subset (20% to 30%) of patients. We discuss the immunologic mechanism(s) underlying these clinical findings and their potential role in the variability in patients' clinical response. We reviewed the evidence indicating that the effects of TA-targeted mAb-based immunotherapy are mediated not only by inhibition of signaling pathways, but also by cell-mediated cytotoxicity triggered by the infused TA-targeted mAb. We analyzed the immunologic variables that can influence the outcome of antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro and in animal model systems. We also analyzed the correlation reported between these variables and the clinical response to mAb-based immunotherapy. Of the variables that influence ADCC mediated by TA-targeted mAb, only polymorphisms of Fcγ receptors (FcγR) expressed by patients' lymphocytes were correlated with clinical efficacy. However, this correlation is not absolute and is not observed in all malignancies. Thus other variables may be responsible for the antitumor effects seen in mAb-treated patients. We discuss the evidence that triggering of TA-specific cellular immunity by TA-targeted mAb, in conjunction with immune escape mechanisms used by tumor cells, may contribute to the differential clinical responses to mAb-based immunotherapy. Identification of the mechanism(s) underlying the clinical response of patients with cancer treated with TA-targeted mAb is crucial to optimizing their application in the clinic and to selecting the patients most likely to benefit from their use.


Alcohol use, working conditions, job benefits, and the legacy of the "Dop" system among farm workers in the Western Cape Province, South Africa: hope despite high levels of risky drinking.
This study describes alcohol consumption in five Western Cape Province communities. Cross-sectional data from a community household sample (n = 591) describe the alcohol use patterns of adult males and females, and farm workers vs. others. Data reveal that men were more likely to be current drinkers than women, 75.1% vs. 65.8% (p = 0.033); farm laborers were more likely to be current drinkers than individuals in other occupations 83.1% vs. 66.8% (p = 0.004). Group, binge drinking on weekends was the norm; men were more likely to be binge drinkers in the past week than women 59.8% vs. 48.8% (p = 0.086); farm workers were more likely to binge than others 75.0% vs. 47.5% (p < 0.001). The legacy of "Dop" contributes to current risky drinking behaviors. Farm owners or managers were interviewed on 11 farms, they described working conditions on their farms and how the legacy of "Dop" is reflected in the current use of alcohol by their workers. "Dop" was given to farm workers in the past on six of the 11 farms, but was discontinued for different reasons. There is zero tolerance for coming to work intoxicated; farm owners encourage responsible use of alcohol and assist farm workers in getting help for alcohol problems when necessary. The farm owners report some positive initiatives, were ahead of the movement to provide meaningful wages, and provide other important amenities. Further research is needed to assess whether progressive practices on some farms will reduce harmful alcohol use.


Development of an electronic health records datamart to support clinical and population health research.
Electronic health record (EHR) data have emerged as an important resource for population health and clinical research. There have been significant efforts to leverage EHR data for research; however, given data security concerns and the complexity of the data, EHR data are frequently difficult to access and use for clinical studies. We describe the development of a Clinical Research Datamart (CRDM) that was developed to provide well-curated and easily accessible EHR data to Duke University investigators. The CRDM was designed to (1) contain most of the patient-level data elements needed for research studies; (2) be directly accessible by individuals conducting statistical analyses (including Biostatistics, Epidemiology, and Research Design (BERD) core members); (3) be queried via a code-based system to promote reproducibility and consistency across studies; and (4) utilize a secure protected analytic workspace in which sensitive EHR data can be stored and analyzed. The CRDM utilizes data transformed for the PCORnet data network, and was augmented with additional data tables containing site-specific data elements to provide additional contextual information. We provide descriptions of ideal use cases and discuss dissemination and evaluation methods, including future work to expand the user base and track the use and impact of this data resource. The CRDM utilizes resources developed as part of the Clinical and Translational Science Awards (CTSAs) program and could be replicated by other institutions with CTSAs.


Mycobacterium mucogenicum meningitis due to external ventricular drain.
Mycobacterium mucogenicum is a rare non-tuberculous organism associated with catheter-related infections when pathogenic in humans. We present the first case of an external ventricular drain (EVD)-associated M. mucogenicum meningitis. A 55-year-old woman had EVD placement for obstructive hydrocephalus following traumatic subarachnoid haemorrhage. Cerebrospinal fluid (CSF) was obtained 5 days later for fever and neurological changes. M. mucogenicum was ultimately isolated from the CSF and the patient was placed on appropriate antibiotics. Her management included replacement of the EVD and a prolonged course of anti-mycobacterial antibiotics. CSF findings showed her response to therapy and neurological exam improved after 6 weeks. M. mucogenicum infections are very rare and existing reports indicate that it may be a device- or catheter-related pathogen. This microorganism has not been previously associated with an EVD. Ours may be the first documented report of EVD-related M. mucogenicum infection.


Alternating chemo-immunotherapy with temozolomide and low-dose interleukin-2 in patients with metastatic melanoma.
Temozolomide is a rapidly absorbed chemotherapeutic agent, achieving significant central nervous system penetration. Previous clinical trials suggested that temozolomide in sequence with low-dose recombinant human interleukin-2 might be an efficacious and relatively non-toxic chemo-immunotherapeutic treatment, which may synergistically eliminate tumours. The primary objective was to determine the safety and tolerance of temozolomide administered orally 200 mg/m days 1-5, in sequential combination with subcutaneous injections of 4.5x10 IU recombinant human interleukin-2 on days 8-11, 15-18 and 22-25 in patients with measurable, progressive metastatic malignant melanoma without radiological signs of central nervous system metastases. The secondary objectives were to determine tumour response and time to progression. Twenty-seven patients were included, of which four were non-evaluable for response. Twenty-three patients tolerated the regimen with side effects below grade 3 according to the World Health Organization (WHO) scale. Three patients suspended the treatment because of WHO grade 3 side effects already during the first 3 days of the first course of temozolomide. Seven patients showed no tumour progression during the first four treatment cycles. Two patients had complete responses, three partial responses and two stable disease at the end of the four cycles defined by the protocol and they continued the treatment until signs of relapse or a maximum of 21 courses. Five of these patients are still alive. Thrombocytopenia was significantly more pronounced in patients with objective response and stable disease than in non-responders to therapy. The median time to progression for all patients was 3.1 months and for responding and stable disease patients was 15 months. Five of 23 treated patients (22%) developed brain metastases during follow-up. Temozolomide in combination with recombinant human interleukin-2 is a well-tolerated regimen for outpatient treatment and the bio-chemotherapy combination induced durable clinical responses. Thrombocytopenia might be a positive predictive factor for response to therapy.


Maternal Hypothyroidism during Pregnancy and the Risk of Pediatric Endocrine Morbidity in the Offspring.
Previous studies suggested maternal hypothyroidism during pregnancy to be associated with cognitive impairment of the offspring. Scarce data exist regarding long-term endocrine health of the offspring. This study was aimed to assess whether children born to mothers with hypothyroidism during pregnancy are at an increased risk for long-term endocrine morbidity. A retrospective population-based cohort study compared long-term endocrine morbidity of children born between the years 1991 and 2014 to mothers with and without hypothyroidism. Multiple gestations, fetuses with congenital malformations, and women lacking prenatal care were excluded. Hospitalizations of the offspring up to the age of 18 years involving endocrine morbidity were evaluated according to a predefined set of ICD-9 codes. Kaplan-Meier's survival curves were used to compare the cumulative risk and a Cox multivariable model was used to adjust for confounders. During the study period, 217,910 deliveries met the inclusion criteria; 1.1% of which were with maternal hypothyroidism (n = 2,403). During the follow-up period, the cumulative incidence of endocrine morbidity among children born to mothers with hypothyroidism was 27 per 1,000 person-years and 0.47 per 1,000 person-years in the comparison group (relative risk: 2.14; 95% confidence interval [CI]: 1.21-3.79). The Kaplan-Meier's survival curve demonstrated a significantly higher cumulative endocrine morbidity in children born to mothers with hypothyroidism (log-rank test, p = 0.007). In the Cox regression model controlled for maternal age, birth weight, preterm birth, maternal diabetes, hypertensive disorders of pregnancy, induction of labor, and mode of delivery, maternal hypothyroidism was found to be independently associated with pediatric endocrine morbidity in the offspring (adjusted hazard ratio = 1.92, 95% CI: 1.08-3.4, p = 0.025). Maternal hypothyroidism appears to be independently associated with long-term pediatric endocrine morbidity of the offspring.


Ectopic pro-opiolipomelanocortin: sequence of cDNA coding for beta-melanocyte-stimulating hormone and beta-endorphin.
A recombinant bacterial plasmid, pMS1, was constructed that contains 318 nucleotides complementary to a portion of pro-opiolipomelanocortin (proOLMC) messenger RNA from an ectopic adrenocorticotropin-producing tumor. The cloned complementary DNA insert, which contains the sequence that codes for all of the beta-melanocyte-stimulating hormone and beta-endorphin portions of proOLMC, as well as the 3' nontranslated section, is identical to the genomic sequence. Hybridization of tumor proOLMC complementary DNA to RNA subjected to electrophoresis and transferred to a nitrocellulose filter revealed two proOLMC messenger RNA species in the tumor polyadenylated RNA, but only one in pituitary polyadenylated RNA. At least one of the tumor proOLMC messenger RNA's is similar, if not identical, to human pituitary proOLMC messenger RNA.


Node-based measures of connectivity in genetic networks.
At-site environmental conditions can have strong influences on genetic connectivity, and in particular on the immigration and settlement phases of dispersal. However, at-site processes are rarely explored in landscape genetic analyses. Networks can facilitate the study of at-site processes, where network nodes are used to model site-level effects. We used simulated genetic networks to compare and contrast the performance of 7 node-based (as opposed to edge-based) genetic connectivity metrics. We simulated increasing node connectivity by varying migration in two ways: we increased the number of migrants moving between a focal node and a set number of recipient nodes, and we increased the number of recipient nodes receiving a set number of migrants. We found that two metrics in particular, the average edge weight and the average inverse edge weight, varied linearly with simulated connectivity. Conversely, node degree was not a good measure of connectivity. We demonstrated the use of average inverse edge weight to describe the influence of at-site habitat characteristics on genetic connectivity of 653 American martens (Martes americana) in Ontario, Canada. We found that highly connected nodes had high habitat quality for marten (deep snow and high proportions of coniferous and mature forest) and were farther from the range edge. We recommend the use of node-based genetic connectivity metrics, in particular, average edge weight or average inverse edge weight, to model the influences of at-site habitat conditions on the immigration and settlement phases of dispersal.


Hepatic stellate cell-targeted imatinib nanomedicine versus conventional imatinib: A novel strategy with potent efficacy in experimental liver fibrosis.
Liver fibrosis is a global health problem without approved treatment. Imatinib inhibits two key profibrotic pathways; platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-β) and thus can be used to treat liver fibrosis. However, conventional imatinib therapy is hampered by low concentration at target tissue and increased toxicity to other tissues especially heart, lung and liver. Since hepatic stellate cells (HSCs) are the main contributors to liver fibrosis pathogenesis and sole hepatic vitamin A (VA) storage cells, they can be actively targeted by coupling liposomes to VA. In this study, novel VA-coupled imatinib-loaded liposomes (ILC) were prepared and optimized regarding VA-coupling efficiency, imatinib entrapment efficiency, and particle size. Preferential accumulation of the selected formula in liver was proved by tracing intraperitoneally (i.p.)-injected VA-coupled liposomes loaded with Nile Red (LCNR) to rats with CCl4-induced liver fibrosis using live animal imaging. Co-localization of LCNR with immunofluorescently-labeled PDGFR-β in frozen liver tissue sections confirmed HSCs targeting. ILC bio-distribution, following single i.p. injection, revealed 13.5 folds higher hepatic accumulation than conventional imatinib in addition to limited bio-distribution to other organs including heart and lung reflecting diminished adverse effects. ILC therapy resulted in a potent inhibition of phosphorylated PDGFR-β expression when compared to conventional imatinib. Subsequently, there was a statistically significant improvement in liver function tests and reversal of hepatotoxicity along with liver fibrosis. Anti-fibrotic effect was evident from histopathologic Ishak score reduction as well as normalization of the level of profibrotic mediators (hydroxyproline, TGF-B and matrix metalloproteinase-2). Thus, HSC-targeted imatinib therapy shows outstanding anti-fibrotic effects with reduced cytotoxicity compared to conventional imatinib. It can represent a promising novel approach for liver fibrosis treatment.


A molecular circuit composed of CPEB-1 and c-Jun controls growth hormone-mediated synaptic plasticity in the mouse hippocampus.
Cytoplasmic polyadenylation element binding protein 1 (CPEB-1) resides at postsynaptic sites in hippocampal neurons in which it controls polyadenylation-induced translation. CPEB-1 knock-out (KO) mice display defects in some forms of synaptic plasticity and hippocampal-dependent memories. To identify CPEB-1-regulated mRNAs, we used proteomics to compare polypeptides in wild-type (WT) and CPEB-1 KO hippocampus. Growth hormone (GH) was reduced in the KO hippocampus, as were the GH signaling molecules phospho-JAK2 and phospho-STAT3. GH mRNA and pre-mRNA were reduced in the KO hippocampus, suggesting that CPEB-1 controls GH transcription. The transcription factor c-Jun, which binds the GH promoter, was also reduced in the KO hippocampus, as was its ability to coimmunoprecipitate chromatin containing the GH promoter. CPEB-1 binds c-Jun 3' untranslated region CPEs in vitro and coimmunoprecipitates c-Jun RNA in vivo. GH induces long-term potentiation (LTP) when applied to hippocampal slices from WT and CPEB-1 KO mice, but the magnitude of LTP induced by GH in KO mice is reduced. Pretreatment with GH did not reverse the LTP deficit observed in KO mice after theta-burst stimulation (TBS). Cordycepin, an inhibitor of polyadenylation, disrupted LTP induced by either GH application or TBS. Finally, GH application to hippocampal slices induced JAK2 phosphorylation in WT but not KO animals. These results indicate that CPEB-1 control of c-Jun mRNA translation regulates GH gene expression and resulting downstream signaling events (e.g., synaptic plasticity) in the mouse hippocampus.


Effects of specific D-1 and D-2 dopamine agonists (LY141865 and SKF-38393) and pergolide on urinary output of rats.
Pergolide, LY141865 and SKF-38393 were compared to clonidine for their effects on urine output in normally hydrated rats. SKF-38393 and LY141865 have been considered to be specific D-1 and D-2 dopamine receptor agonists, respectively. Clonidine had a marked effect to increase urine output (17-18 ml at doses as low as 0.08 mg/kg s.c.), whereas the specific dopamine agonists SKF-38393 (0.32-5 mg/kg s.c.) and LY141865 (0.16-1.25 mg/kg s.c.) did not affect urine output. Pergolide, a nonspecific dopamine agonist, slightly increased urine output at the highest dose (0.64 mg/kg s.c.). Specific dopamine agonists do not increase urine output in normally hydrated rats.


Bariatric surgery - effects on obesity and related co-morbidities.
Laparoscopic adjustable gastric banding (LAGB), laparoscopic Roux-en-Y gastric bypass (RYGB) and laparoscopic sleeve gastrectomy (SG) are the three most commonly performed bariatric procedures. Obesity responds well to bariatric surgery, with major long-lasting weight loss that is most pronounced after RYGB and SG, where the mean weight loss is about 40 kg or 15 body mass index (BMI) units. Some of the benefits after RYGB and SG are independent of weight loss, and the remission of type 2 diabetes is observed a few days after the operation; this depends on changes in insulin sensitivity and gut hormone responses, especially a 10-fold increase in glucagon-like peptide-1 (GLP-1), which improves insulin secretion. After gastric banding, the remission of diabetes depends more on weight loss. Bariatric surgery reduces cardiovascular risk factors including hypertension, lipid disturbances, non-alcoholic fatty liver, musculoskeletal pain and reduces mortality of diabetes, cardiovascular diseases and cancers. Bariatric surgery also improves quality of life. The acute complications of surgery are infection, bleeding and anastomotic leak. Long-term complications are nutritional deficiencies, including vitamins and minerals, and anemia. Some patients have dumping after meals, and a few patients will develop postprandial hypoglycemia after RYGB. About 25% of patients require plastic surgery to provide relief from excessive skin tissue.


Policy statement on multidisciplinary cancer care.
Cancer care is undergoing an important paradigm shift from a disease-focused management to a patient-centred approach, in which increasingly more attention is paid to psychosocial aspects, quality of life, patients' rights and empowerment and survivorship. In this context, multidisciplinary teams emerge as a practical necessity for optimal coordination among health professionals and clear communication with patients. The European Partnership for Action Against Cancer (EPAAC), an initiative launched by the European Commission in 2009, addressed the multidisciplinary care from a policy perspective in order to define the core elements that all tumour-based multidisciplinary teams (MDTs) should include. To that effect, a working group conference was held in January 2013 within the EPAAC Work Package 7 (on Healthcare) framework. The consensus group consisted of high-level representatives from the following European scientific societies, patient associations and stakeholders: European CanCer Organisation (ECCO), European SocieTy for Radiology & Oncology (ESTRO), European Society for Medical Oncology (ESMO), European Society of Surgical Oncology (ESSO), International Society of Geriatric Oncology (SIOG), European Association for Palliative Care (EAPC), European Oncology Nursing Society (EONS), International Psycho-Oncology Society (IPOS),European Cancer Patient Coalition (ECPC), EuropaColon, Europa Donna - The European Breast Cancer Coalition, Association of European Cancer Leagues (ECL), Organisation of European Cancer Institutes (OECI), EUSOMA - European Society of Breast Cancer Specialists, European Hospital and Healthcare Federation (HOPE) and EPAAC Work Packages 5 (Health promotion and prevention), 7, 8 (Research), 9 (Information systems) and 10 (Cancer plans). A background document with a list of 26 core issues drawn from a systematic review of the literature was used to guide the discussion. Five areas related to MDTs were covered: care objectives, organisation, clinical assessment, patients' rights and empowerment and policy support. Preliminary drafts of the document were widely circulated for consultation and amendments by the working group before final approval. The working group unanimously formulated a Policy Statement on Multidisciplinary Cancer Care to define the core elements that should be implemented by all tumour-based MDTs. This document identifies MDTs as the core component in cancer care organisation and sets down the key elements to guide changes across all European health systems. MDTs are an essential instrument of effective cancer care policy, and their continued development crucial to providing patients the care they need and deserve. While implementation must remain in local hands, European health systems can still benefit from having a basis for an effective multidisciplinary model of cooperation. This policy statement is intended to serve as a reference for policymakers and healthcare providers who wish to improve the services currently provided to the cancer patients whose lives and well-being depend on their action.