Quinazolinone derivatives as orally available ghrelin receptor antagonists for the treatment of diabetes and obesity.
The peptide hormone ghrelin is the endogenous ligand for the type 1a growth hormone secretagogue receptor (GHS-R1a) and the only currently known circulating appetite stimulant. GHS-R1a antagonism has therefore been proposed as a potential approach for obesity treatment. More recently, ghrelin has been recognized to also play a role in controlling glucose-induced insulin secretion, which suggests another possible benefit for a GHS-R1a antagonist, namely, the role as an insulin secretagogue with potential value for diabetes treatment. In our laboratories, piperidine-substituted quinazolinone derivatives were identified as a new class of small-molecule GHS-R1a antagonists. Starting from an agonist with poor oral bioavailability, optimization led to potent, selective, and orally bioavailable antagonists. In vivo efficacy evaluation of selected compounds revealed suppression of food intake and body weight reduction as well as glucose-lowering effects mediated by glucose-dependent insulin secretion.


Efficient Relativistic Density-Matrix Renormalization Group Implementation in a Matrix-Product Formulation.
We present an implementation of the relativistic quantum-chemical density matrix renormalization group (DMRG) approach based on a matrix-product formalism. Our approach allows us to optimize matrix product state (MPS) wave functions including a variational description of scalar-relativistic effects and spin-orbit coupling from which we can calculate, for example, first-order electric and magnetic properties in a relativistic framework. While complementing our pilot implementation ( Knecht , S. J. Chem. Phys. 2014 , 140 , 041101 ), this work exploits all features provided by its underlying nonrelativistic DMRG implementation based on an matrix product state and operator formalism. We illustrate the capabilities of our relativistic DMRG approach by studying the ground-state magnetization, as well as current density of a paramagnetic f9 dysprosium complex as a function of the active orbital space employed in the MPS wave function optimization.


Static and dynamic measures of frailty predicted decline in performance-based and self-reported physical functioning.
To determine the effect of frailty on decline in physical functioning and to examine if chronic diseases modify this effect. The study sample was derived from the Longitudinal Aging Study Amsterdam and included respondents with initial ages 65 and over at T(2) (1995/1996), who participated at T(1) (1992/1993) and T(2) and performed physical performance tests (n = 1,152) or reported functional limitations (n = 1,321) at T(2) and T(3) (1998/1999). Nine frailty markers were determined in two ways: low functioning at T(2) (static definition); and decline in functioning between T(1) and T(2) (dynamic definition). Using logistic regression analyses, the effect of frailty was examined on change in physical functioning between T(2) and T(3), adjusting for sex, age, education, and additionally chronic diseases. Static frailty was associated with performance decline only in the middle-old group (OR 2.43; 95%CI 1.23-4.80) and associated with decline in self-reported functioning (OR 2.44; 95%CI 1.77-3.36). Dynamic frailty was associated with decline in performance only in women (OR 1.72; 95%CI 1.11-2.67) and with self-reported functional decline (OR 1.77; 95%CI 1.29-2.43). These associations were independent of chronic diseases. Frailty is more strongly associated with self-reported functional decline in older persons than with performance decline.


Analysis of Communal Molecular Mechanism Between Chronic Obstructive Pulmonary Disease and Osteoporosis.
Chronic obstructive pulmonary disease (COPD) patients with osteoporosis (OP) usually experience more frequent exacerbations, worse quality of life, and heavier economic burden, however, few studies have investigated common molecular mechanisms of COPD and OP. To explore the relationship between COPD and OP through bioinformatics analysis. The miRNA microarray data of COPD and OP were retrieved from the Gene Expression Database (GEO), and the differentially expressed microRNAs (DEmiRNAs) were screened and the intersection was obtained. The Targetscan, miRDB, and miRWalk databases were used to predict the target genes of DEmiRNA, and the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the R package clusterProfiler, the STRING database was used to analyze the target protein-protein interaction network (PPI) and screens to determine the core modules and core genes. Two DEmiRNAs (miR-23a-5p, miR-194-3p) have been found in COPD and OP, which have predicted 76 and 114 target genes, respectively. GO functional annotations of miR-23a-5p were significantly enriched in CD40 signaling pathway, ubiquitin-conjugating enzyme activity, etc; KEGG pathways of miR-23a-5p were significantly enriched in ubiquitin-mediated proteolysis, folate biosynthesis, and regulation of actin cytoskeleton. GO function annotations of miR-194-3p were significantly enriched in T cell activation regulation, ubiquitin protein ligase activity, and DNA transcription factor binding; KEGG pathways of miR-194-3p were significantly enriched in cell adhesion molecules, intercellular tight junctions, and lysosomal pathway. PPI analysis found target coding proteins formed complex regulatory networks. Ten core genes (TP53, SRC, PXN, CHD4, SYK, TNRC6B, PML, KAT5, BRD1 and IGF2) were picked out among them, then we used the MCODE plugin found three core subnetworks. Two identical DEmiRNAs (miR-23a-5p, miR-194-3p) exist in the peripheral blood of COPD and OP patients, which are important biomarkers for COPD patients with OP and may represent novel targets for diagnosis and treatment of COPD patients with OP.


Hair loss, depigmentation of hair, ichthyosis, and blepharoconjunctivitis produced by dixyrazine.
Four patients developed hair loss, depigmentation of hair, ichthyosis, and blepharoconjunctivitis during treatment with large doses of dixyrazine (Esucos, UCB, Belgium). The hair, skin, and eyes returned to normal within 2 months of withdrawal of dixyrazine, without any other treatment.


Multidimensional Treatment Foster Care: An Alternative to Residential Treatment for High Risk Children and Adolescents.
This paper describes the Multidimensional Treatment Foster Care program (MTFC), an evidence based approach for providing psychotherapeutic treatment for very troubled children and adolescents that is an alternative to residential care. Versions of the MTFC program have been developed and validated for young children with a history of maltreatment as well as for older children and adolescents who are involved with the youth justice system. In the paper we describe the development of the MTFC program and its foundations in the social learning model that originated at the Oregon Social Learning Center in the 1960's and 70's. We present information about program elements. We then review the research that has been conducted on MTFC.


Vesicular catalysis of an S(N)2 reaction: toward understanding the influence of glycolipids on reactions proceeding at the interface of biological membranes.
The kinetics of the S(N)2 reaction of a series of aromatic alkylsulfonates with water and bromide ions in membrane mimetic media have been investigated. These media include vesicles formed from only synthetic amphiphiles, vesicles composed only of phospholipids and mixtures of these components. Special focus is placed on the influence of the addition of n-dodecyl-beta-glucoside as a mimic for glycolipids. The kinetic data have been analyzed by using the pseudophase model for bimolecular reactions. Contrary to previous results on a base-catalyzed E2 reaction (Org. Biomol. Chem. 2004, 2, 1789-1799), the presence of n-dodecyl-beta-glucoside at the vesicular surface does not lead to large rate accelerations for the S(N)2 reaction. In fact, when present at 50 mol % (i.e., the additive covers 34% of the vesicular surface) these glycolipid mimics appear not to affect the bimolecular rate constants, but they only decrease the local water concentration by about 40%. The reactivity of water at the surface of vesicles that are formed from cationic amphiphiles appears to be increased about 10-fold relative to the reactivity of water in the bulk liquid, whereas in zwitterionic vesicles the reactivity is comparable to that in bulk water. The obtained rate constants are also compared to micellar rate constants.


[Ultrasound findings in patients with AIDS].
The ultrasonographic findings of 43 patients with AIDS and ARC were analyzed. In 63% an enlarged liver, in 66% an enlarged spleen, partially with focal lesions, and in 21% enlarged abdominal lymph nodes were diagnosed. The typical parenchymal lesions of the kidney (focal segmental glomerulosclerosis) were not observed. Abdominal ultrasound is the first diagnostic procedure to perform in patients with AIDS and ARC with the suspicion of abdominal pathology. With additional thin needle puncture of the lesions a histological verification of the pathologic findings is possible.


Analysis of bacterial community shifts in the gastrointestinal tract of pigs fed diets supplemented with β-glucan from Laminaria digitata, Laminaria hyperborea and Saccharomyces cerevisiae.
This study was designed to evaluate the effects of algal and yeast β-glucans on the porcine gastrointestinal microbiota, specifically the community of Lactobacillus, Bifidobacterium and coliforms. A total of 48 pigs were fed four diets over a 28-day period to determine the effect that each had on these communities. The control diet consisted of wheat and soya bean meal. The remaining three diets contained wheat and soya bean meal supplemented with β-glucan at 250 g/tonne from Laminaria digitata, Laminaria hyperborea or Saccharomyces cerevisiae. Faecal samples were collected from animals before feeding each diet and after the feeding period. The animals were slaughtered the following day and samples were collected from the stomach, ileum, caecum, proximal colon and distal colon. Alterations in Lactobacillus in the gastrointestinal tract (GIT) were analysed using denaturing gradient gel electrophoresis (DGGE) profiles generated by group-specific 16S rRNA gene PCR amplicons. Plate count analysis was also performed to quantify total coliforms. DGGE profiles indicated that all β-glucan diets provoked the emergence of a richer community of Lactobacillus. The richest community of lactobacilli emerged after feeding L. digitata (LD β-glucan). Plate count analysis revealed that the L. hyperborea (LH β-glucan) diet had a statistically significant effect on the coliform counts in the proximal colon in comparison with the control diet. β-glucan from L. digitata and S. cerevisiae also generally reduced coliforms but to a lesser extent. Nevertheless, the β-glucan diets did not significantly reduce levels of Lactobacillus or Bifidobacterium. DGGE analysis of GIT samples indicated that the three β-glucan diets generally promoted the establishment of a more varied range of Lactobacillus species in the caecum, proximal and distal colon. The LH β-glucan had the most profound reducing effect on coliform counts when compared with the control diet and diets supplemented with L. digitata and S. cerevisiae β-glucans.


Correlation of ERK/MAPK signaling pathway with proliferation and apoptosis of colon cancer cells.
The role of extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling pathway in the proliferation and apoptosis of human colon cancer cells was studied. The transduction process of ERK/MAPK signaling pathway was inhibited using methyl ethyl ketone (MEK) inhibitor U0126. Promoting effect of hepatocyte growth factor (HGF) on proliferation of human colon cancer cells was detected via Cell Counting Kit 8 (CCK8), the cycle and apoptosis of human colon cancer cells were detected via flow cytometry, and the migration of human colon cancer cells was detected via wound healing assay. The results revealed that after drug treatment for 48 h, there were statistically significant differences in 4 and 8 µmol/l U0126 experimental group compared with control group (P<0.05). Compared with those in control group, G1 phase, S phase, G2 phase and proliferation index (PI) in 2, 4 and 8 µmol/l U0126 group had statistically significant differences (P<0.05). There were statistically significant differences in comparison of G1 phase, S phase, G2 phase and PI between control and 8 µmol/l U0126 group (P<0.05). Compared with that in control group, the cell migration distance in 8 µmol/l U0126 group had a statistically significant difference after drug treatment for 24 h (P<0.05). After drug treatment for 48 and 72 h, the cell migration distance in 4 and 8 µmol/l U0126 group was significantly reduced, and the differences were statistically significant compared with that in control group (P<0.05). In conclusion, ERK/MAPK signaling pathway is involved in the effects of HGF of promoting proliferation and regulating cell cycle and apoptosis of human colon cancer cells, providing a new approach for the treatment of colon cancer.


NiftyNet: a deep-learning platform for medical imaging.
Medical image analysis and computer-assisted intervention problems are increasingly being addressed with deep-learning-based solutions. Established deep-learning platforms are flexible but do not provide specific functionality for medical image analysis and adapting them for this domain of application requires substantial implementation effort. Consequently, there has been substantial duplication of effort and incompatible infrastructure developed across many research groups. This work presents the open-source NiftyNet platform for deep learning in medical imaging. The ambition of NiftyNet is to accelerate and simplify the development of these solutions, and to provide a common mechanism for disseminating research outputs for the community to use, adapt and build upon. The NiftyNet infrastructure provides a modular deep-learning pipeline for a range of medical imaging applications including segmentation, regression, image generation and representation learning applications. Components of the NiftyNet pipeline including data loading, data augmentation, network architectures, loss functions and evaluation metrics are tailored to, and take advantage of, the idiosyncracies of medical image analysis and computer-assisted intervention. NiftyNet is built on the TensorFlow framework and supports features such as TensorBoard visualization of 2D and 3D images and computational graphs by default. We present three illustrative medical image analysis applications built using NiftyNet infrastructure: (1) segmentation of multiple abdominal organs from computed tomography; (2) image regression to predict computed tomography attenuation maps from brain magnetic resonance images; and (3) generation of simulated ultrasound images for specified anatomical poses. The NiftyNet infrastructure enables researchers to rapidly develop and distribute deep learning solutions for segmentation, regression, image generation and representation learning applications, or extend the platform to new applications.


The chemoreceptors and odorant binding proteins of the soybean and pea aphids.
We examined the genome of the soybean aphid, Aphis glycines, and an updated genome assembly of the pea aphid, Acyrthosiphon pisum, for members of the three major families of chemoreceptors, the Odorant Receptors (ORs), Gustatory Receptors (GRs) and Ionotropic Receptors (IRs), as well as the Odorant Binding Proteins (OBPs). The soybean aphid has 47 ORs, 61 GRs, 19 IRs, and 10 OBPs, compared with 87 ORs, 78 Grs, 19 IRs, and 18 OBPs in the pea aphid, with variable numbers of pseudogenes in the OR and GR families. Phylogenetic analysis reveals that while all of the IRs are simple orthologs between these two species, the OR, GR, and OBP families in the pea aphid have experienced major expansions of particular gene lineages and fewer losses of gene lineages. This imbalance in birth-and-death of chemosensory genes has led to the larger pea aphid gene repertoire, which might be related to the broader host range of pea aphids versus the specialization of soybean aphids on a single summer host plant. Examination of the expression levels of these chemosensory genes in parthenogenetic and sexual females and males of pea aphids revealed multiple genes that are differentially expressed in sexual females or males and might be involved in reproductive biology. Examination of the soybean aphid genes in parthenogenetic females under multiple stressors revealed multiple genes whose expression levels changed with heat or starvation stress, the latter potentially important in finding new food sources.


Feasibility of Weighted Vest Use during a Dietary Weight Loss Intervention and Effects on Body Composition and Physical Function in Older Adults.
While intentional weight loss in older adults with obesity yields clinically important health benefits there is a need to minimize the negative effects of weight loss on concomitant loss of muscle mass and strength. Data show wearing weighted vests during exercise improves lean mass and lower extremity strength, however the efficacy of wearing a weighted vest during a period of weight loss to mitigate muscle and strength loss is not known. This study examined the feasibility of daily weighted vest use during a dietary weight loss intervention, and examined effects of vest use on body composition and physical function in well-functioning older adults with obesity. Randomized, controlled pilot study. Wake Forest Baptist Medical Center in Winston-Salem, NC. 37 older (age=65-79 yrs), obese (BMI=30-40 kg/ m2) sedentary men and women. 22-week behavioral diet intervention (targeting 10% weight loss, 1100-1300 kcals/day) with (Diet+Vest; n=20) or without (Diet; n=17) weighted vest use (goal of 10 hours/ day with weight added weekly according to individual loss of body mass). Body composition by dual-energy x-ray absorptiometry and measures of physical function, mobility, and muscle strength/power. Average weighted vest use was 6.7±2.2 hours/day and the vest-wear goal of 10 hrs/day was achieved for 67±22% of total intervention days. Five participants reported adverse events from wearing the vest (all back pain or soreness). Both groups lost a similar amount of weight (Diet= -11.2±4.4 kg; Diet+Vest = -11.0±6.3 kg; p<0.001), with no differences between groups (p=0.25). Fat mass, lean mass, and % body fat decreased significantly (p<0.0001), with no differences between groups. Compared to Diet+Vest, the Diet intervention resulted in greater decreases in leg power (p<0.02), with no other between group differences in physical function. This pilot study showed that vest use during dietary weight loss is feasible and safe in well-functioning older adults with obesity. Larger studies are needed to definitively determine whether external replacement of lost weight during caloric restriction may preserve lower extremity muscle strength and power.


Development of chronic lung injury and pulmonary fibrosis in mice following acute exposure to nitrogen mustard.
Objective: Sulfur mustards are toxic agents used as a chemical warfare in the twentieth century. Exposure to nitrogen mustards (NM), their more water-soluble analogs, is associated with respiratory, dermatological, neurological, and systemic symptoms whose severity depends on dose and length of contact. Long-term effects of acute inhalation have been related to the development of chronic lung injury and pulmonary fibrosis whose precise mechanisms and potential antidotes are yet to be discovered.Materials and methods: We have developed a model of NM-induced pulmonary fibrosis by intratracheally instilling mechlorethamine hydrochloride into C57Bl/6J male mice.Results and Discussion: Following mechlorethamine exposure, strong early and milder late inflammatory responses were observed. Initially, the number of white blood cells and levels of protein and pro-inflammatory cytokines in the bronchoalveolar lavage fluid (BALF) increased, followed by increases in the number of macrophages and the levels of transforming growth factor-β (TGF-β), a pro-fibrotic mediator. Analysis of lung homogenates revealed increased phosphorylation of pro-fibrotic biomarkers, serine/threonine-selective protein kinases (p-ERK), and heat shock protein 90 (P-HSP90) at 10 and 30 days after exposure. Total collagen expression and deposition of extracellular matrix proteins also increased. Lung function measurements demonstrated the presence of both obstructive and restrictive disease in agreement with evidence of increased lower airway peribronchial collagen deposition and parenchymal fibrosis.Conclusions: We conclude that the mouse represents a useful model of NM-induced acute lung injury and chronic pulmonary fibrosis, the latter driven by the overexpression of TGF-β, p-ERK, and P-HSP90. This model may prove useful in the pre-clinical development of antidotes and other countermeasures.


Preoperative Lymphedema-Related Risk Factors in Early-Stage Breast Cancer.
Prolongation of survival in patients with breast cancer due to early diagnosis and modern methods of treatment has turned the attention on lymphedema, which is the most important morbidity secondary to the treatment of the disease. Determination of lymphedema and related risk factors in patients before a surgical intervention may provide protection for patients and early treatment. The aim of this study was to determine the presence of lymphedema before surgery by bioimpedance analysis in patients with breast cancer and to establish risk factors associated with lymphedema. A total of 277 patients who were diagnosed as having breast cancer, were planned to undergo a surgical intervention, and had no clinical lymphedema were included in the study. The presence of lymphedema was evaluated with clinical examination, measurement of arm circumference, and bioimpedance analysis. Lymphedema was found in 59 (21.3%) patients with no detected differences in arm circumferences. A significant relationship was found between the presence of lymphedema and body mass index (BMI), number of positive lymph nodes, and capsule invasion of the tumor (p = 0.001, p = 0.003, p = 0.002, respectively). Multiple regression analysis revealed that BMI and the number of positive lymph nodes were independent variables (p = 0.024, p = 0.002). ROC curve analysis resulted in an increased risk of preoperative lymphedema when the number of positive lymph nodes was ≥8. Correlation analysis revealed a positive correlation between the number of positive lymph nodes and L-dex score (p = 0.001, r = 0.219). Preoperative bioimpedance analysis demonstrated that ∼1/5 of the patients had subclinical lymphedema. Preoperative subclinical lymphedema is associated with obesity and the number of positive lymph nodes, and thus, treatment of the axilla in patients who are preoperatively detected to have subclinical lymphedema should be revised.


An unusual form of pemphigus vegetans.
Numerous vegetating plaques developed in a 63-year-old man followed up for the management of pemphigus vulgaris of 5 years' duration. These lesions occurred over the trunk and right upper arm with no involvement in the intertriginous area, and were controlled with systemic steroid and ODT. Direct immunofluorescence test showed heavy deposition of fibrinogen in the papillary dermis. To our knowledge, the occurrence of pemphigus vegetans in the non-intertriginous area is rare.


Differential in vivo expression of mycobacterial antigens in Mycobacterium tuberculosis infected lungs and lymph node tissues.
The clinical course of tuberculosis (TB) infection, bacterial load and the morphology of lesions vary between pulmonary and extrapulmonary TB. Antigens expressed in abundance during infection could represent relevant antigens in the development of diagnostic tools, but little is known about the in vivo expression of various M. tuberculosis antigens in different clinical manifestations. The aim of this study was to study the differences in the presence of major secreted as well as somatic mycobacterial antigens in host tissues during advanced rapidly progressing and fatal pulmonary disease with mainly pneumonic infiltrates and high bacterial load, and to compare this to the presence of the same antigens in TB lymphadenitis cases, which is mainly chronic and self-limiting disease with organised granulomas and lower bacterial load. Human pulmonary (n = 3) and lymph node (n = 17) TB biopsies, and non-TB controls (n = 12) were studied. Ziehl-Neelsen stain, nested PCR 1S6110 and immunohistochemistry were performed. Major secreted (MPT32, MPT44, MPT46, MPT51, MPT53, MPT59, MPT63, and MPT64) and somatic mycobacterial antigens (Mce1A, Hsp65, and MPT57) were detected by using rabbit polyclonal antibodies. Plenty of bacilli were detectable with Ziehl-Neelsen stain in the lung biopsies while no bacilli were detected in the lymph node biopsies. All the cases were shown to be positive by PCR. Both secretory and somatic antigens were expressed in abundance in pulmonary infiltrates, while primarily somatic antigens were detected in the lymphadenitis cases. Of the secreted antigens, only MPT64 was consistently detected in both cases, indicating a preferential accumulation of this antigen within the inflammatory cells, even if the cells of the granuloma can efficiently restrict bacterial growth and clear away the secreted antigens. This study shows that major secreted mycobacterial antigens were found in high amounts in advanced pulmonary lesions without proper granuloma formation, while their level of staining was very low, or absent, in the lymph node TB lesions with organised granulomas and very low bacillary load, with one exception of MPT64, suggesting its role in the persistence of chronic infection. These findings have implication for development of new diagnostic tools.


Modulation by 6-hydroxydopamine of expression of the phenylethanolamine N-methyltransferase (PNMT) gene in the rat heart during immobilization stress.
Phenylethanolamine N-methyltransferase (PNMT) is the final enzyme in the catecholamine synthesizing cascade that converts noradrenaline (NA) to adrenaline (Adr). Both of these catecholamines are physiologically important hormones and neurotransmitters in mammals with profound influence on the activity of the cardiovascular system. Although PNMT activity and gene expression have been reported in the neonatal and also adult rat heart, little is known about the identity of the cells expressing PNMT mRNA. In this study, we have shown that besides PNMT in neuronal and intrinsic cardiac cells, this enzyme is expressed also in rat cardiomyocytes, as shown by immunofluorescence in isolated cardiomyocytes. To determine which cells in the heart more sensitively show stress-induced changes in PNMT mRNA expression, we performed chemical sympathectomy by administration of 6-hydroxydopamine (6-OHDA), which destroys catecholaminergic terminals. We determined PNMT mRNA levels in the left atria and ventricles of control and stressed rats. In the rats treated with 6-OHDA, PNMT mRNA levels were not changed under normal, physiological conditions compared to vehicle treated rats. Similar results were observed on isolated cardiomyocytes from control and 6-OHDA treated rats. However, 6-OHDA treatment prevented immobilization-induced increase in PNMT mRNA expression. The results allow us to propose that in the heart, the immobilization-induced increase in PNMT gene expression is probably not in cardiomyocytes, but in neuronal cells.


Markers of Early Vascular Ageing.
Cardiovascular damage is clinically manifested as coronary artery disease, heart failure, stroke and peripheral artery disease. The prevalence of these adverse conditions is higher with advancing age. Although many patients present cardiovascular damage late in their life, it is common to see patients with early atherosclerosis in cardiovascular intensive care units at ages lower than 50 years in men and 55 for women. In this review of the literature we identified risk factors of early vascular damage. The classic risk factors such as age, gender, diabetes mellitus, dyslipidemia, smoking, alcohol, hypertension, obesity, family history and newer biomarkers such as hs-CRP, folic acid, homocysteine, fibrinogen are neither strong nor predictive of the individual patient's risk to present early cardiovascular disease. All these risk factors have been used to propose risk scores for possible future events but we still lack a single strong marker indicating new onset of disease that will predict the future independently of the classical factors. The role of vascular imaging techniques to identify patients with subclinical atherosclerotic vascular damage before clinical disease, including the effect of known and unknown risk factors on the vascular tree, seems to be very important for intensifying preventive measures in high risk patients. Early arteriosclerosis measured from pulse wave velocity is associated with reduced arterial elasticity and is associated with future cardiovascular events. Vascular measurements may better represent the continuum of cardiovascular disease from a young healthy to an aged diseased vessel that is going to produce adverse clinical events.


Folate-based inhibitors of thymidylate synthase: synthesis and antitumor activity of gamma-linked sterically hindered dipeptide analogues of 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583).
In an effort to synthesize inhibitors of thymidylate synthase (TS) that do not undergo polyglutamation, a series of gamma-linked sterically hindered dipeptide analogues of 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583) was prepared. A methyl, ethyl, or propargyl group was incorporated into the gamma-glutamyl amide bond of gamma-linked L,L dipeptide derivatives of ICI 198583, such as ICI 198583-gamma-L-Glu. In addition, steric bulk was introduced on either side of the gamma-glutamyl bond of ICI 198583-gamma-L-Glu or ICI 198583-gamma-L-Ala. The resulting dipeptide analogues, e.g., ICI 198583-gamma-MeGlu and ICI 198583-gamma-Aib, were apparently stable to in vivo hydrolysis but poorer inhibitors of TS and L1210 cell growth. However, introduction of 7-Me, 2'-F substitution into the quinazoline nucleus gave significant improvement in the inhibitory activity against thymidylate synthase. Compounds 28-30, the 7-Me, 2'-F derivatives of ICI 198583-gamma-MeGlu, ICI 198583-gamma-EtGlu, and ICI 198583-gamma-PgGlu, respectively, were potent inhibitors of TS (K(iapp) = 0.21-1.1 nM) and L1210 cell growth (IC50 = 0.05-0.34 microM) and were similar to that seen with the most potent gamma-linked L,D dipeptide derivatives of ICI 198583 previously synthesized. Furthermore, the low cross-resistance ratios for the L1210:R(D1694)/L1210 cell line indicated that 28-30 do not undergo polyglutamation.


The economics of adoption of children from foster care.
Federal initiatives since 1996 have intensified the efforts of states to achieve adoption for children in foster care. For many waiting children, the path to adoption is long. The authors offer an economic analysis of adoption from foster care, with an emphasis on the reasons why achieving the goal of adoption for all waiting children may be so difficult. The authors then estimate the determinants of adoptions from foster care across the states using data for fiscal years 1996 and 1997. Adoption assistance subsidy rates stand out as the most important determinant of adoptions from foster care, followed by use of alternatives (e.g., intercountry adoption). Adoptive matching on the basis of race does not appear to prevent adoptions from foster care in the aggregate, leaving flaws in the matching process, such as a lack of information and difficulty using the Interstate Compact on the Placement of Children (ICPC), as a primary reason why children wait.


Primary percutaneous coronary intervention without on-site cardiac surgery backup in unselected patients with ST-segment-elevation myocardial infarction: the Rivoli ST-segment elevation myocardial infarction (RISTEMI) registry.
Primary percutaneous coronary intervention (PCI) is the preferred reperfusion strategy for patients with ST-segment-elevation myocardial infarction (STEMI), but some concerns remain about its safety and efficacy in centers without on-site cardiac surgery (OCS). The Infermi Hospital in Rivoli, Italy, is a community hospital without OCS with a high volume catheterization laboratory (>800 PCI and >150 primary PCI per year), which provides a 24-hour primary PCI service to a population of 583.000 and is only 14 km far from the nearest OCS hospital. We analyzed clinical and procedural data, as well as 30-day outcome, of all STEMI patients treated by primary PCI within 12 hours from symptom onset. From September 2001 to June 2010, 1302 patients with a suspect of STEMI underwent urgent coronary angiography. Of these, 1251 (96.1%), underwent primary PCI. A successful myocardial revascularization was achieved in 1172 patients (93.7%). Thirty-day mortality occurred in 7.1%. Multivariate predictors of 30-day mortality were: age ≥75 years (OR 3.96, p=0.0003), left ventricular ejection fraction ≤40% (OR 35.0, p=0.02), cardiogenic shock at presentation (OR 33.4, p<0.0001), anterior STEMI (OR 1.82, p=0.036) and total ischemic time ≤3 hours (OR 0.55, p=0.05). Primary PCI is a reperfusion strategy feasible and effective in unselected high-risk STEMI patients even in hospitals without OCS with a high volume of routine and emergency interventional procedures.


One-Step Fabrication of Fe(OH)3@Cellulose Hollow Nanofibers with Superior Capability for Water Purification.
The conventional strategies employed for the synthesis of hollow nanofibers (HNFs) require either multistep treatments or special design of the equipment. An additional annealing process is always required, which inevitably consumes more energy and raises the manufacturing cost. In addition, the annealing process may also cause a waste of the matrix materials and the release of toxic gases. Herein, we report for the first time a novel one-step synthesis of hollow hybrid nanofibers via electrospinning. Cellulose was chosen as the polymer matrix, and Fe(OH)3 nanoparticles were grown in situ on the nanofibers during electrospinning. There was no need to remove cellulose to create the hollow nanofiber structure. This can significantly simplify the fabrication process without any negative influence to the air. The obtained Fe(OH)3@cellulose HNF membranes exhibited great mechanical properties and an extremely high water flux of 11 200 L m-2 h-1 bar-1. They could effectively remove various pollutants in water, including phosphate, heavy metal ions, and organic dyes, with excellent reusability. Importantly, this approach could also be applied for the fabrication of other hybrid HNFs, which may serve in a broad range of scientific and engineering applications, including water purification, energy conversion and storage, catalysts, sensors, and so on.


The effects of corticosteroids on the healing of tracheal anastomoses in a rat model.
The deleterious effects of corticosteroids on anastomotic healing have been widely demonstrated in various tissues. This study is designed to investigate the effects of corticosteroids on the healing of tracheal anastomoses. Forty-two adult female Wistar rats, randomly divided into five groups, underwent tracheal transection and primary anastomoses. The groups were assigned as follows: Group I, sham, ( N= 6); Group II, control, ( N= 6); Group III, dexamethasone, 0.1 mg kg (-1) per day, intramuscularly for a week ( N= 10); Group IV, dexamethasone, 1 mg kg (-1) per day, intramuscularly for a week (N= 10); Group V, dexamethasone, 6 mg kg (-1) intramuscularly as a single dose ( N= 10). After 7 days, anastomotic healing was assessed by measurement of bursting pressure and hydroxyproline content. Histological examination was performed according to the modified Ehrlich/Hunt scale. The bursting pressure was significantly decreased in Group III and Group IV when compared to the control group (P< 0.0001 for both groups). There was also significance between the bursting pressures of Group III and Group IV (P< 0.01). However, the difference failed to reach significance between Group V and the control group. The reduction of bursting pressure was not reflected in diminished hydroxyproline content. The hydroxyproline content of the study groups (GIII, GIV and GV) were not statistically different compared with the control group. Except for inflammatory cell infiltration, histological parameters including epithelial regeneration, fibroblast proliferation, collagen content, and angiogenesis also demonstrated significant differences among the groups (P< 0.05). The present study demonstrates that daily administration of dexamethasone for a week significantly impairs the healing of tracheal anastomoses in a dose-dependent manner while a single-dose postoperatively does not affect the healing process.


Hemicraniectomy for malignant middle cerebral artery territory infarction: an updated review.
A decompressive hemicraniectomy is frequently performed for patients with malignant middle cerebral artery territory infarction (MMI) to reduce the intracranial hypertension, which may otherwise result in transtentorial herniation. However, certain clinically significant issues ‑ diagnostic criteria, predictors of the MMI clinical course, benefit of surgery in certain populations, timing of surgery ‑ are unresolved. In this article, we provide an updated review on the diagnosis and management of MMI. An extensive search of the PubMed, EMBASE, and Cochrane was conducted using varying combinations of the search terms, "hemicraniectomy," "decompressive craniectomy," "malignant middle cerebral artery territory infarction," "massive middle cerebral artery territory infarction," "massive ischemic stroke," "decompressive surgery," and "neurosurgery for ischemic stroke." Several large, randomized trials within the past decade have firmly established the benefit of decompressive hemicraniectomy (DHC) as a treatment of MMI. Further studies since then have not only better characterized the diagnosis and predictors of MMI, but have also shown that this benefit extends to patients with additional clinical and demographic characteristics. Future randomized studies should continue to evaluate the benefit of a DHC in other subgroups, and assess neurocognitive and psychosocial secondary outcomes.


The ethics of learning and teaching medicine.
During the second half of the twentieth century, medicine turned its attention to the ethics of practice. A large and important literature has developed that clarifies the problems generated in the treatment of illness. The same focused attention now should be given to ethical issues and relationships connected with teaching and learning in medicine and to elaborating an ethics of education. Pedagogic relationships anticipate professional relationships. The associations that medical students form with teachers, patients, school, and each other, and the values that shape them have a great influence in determining the sort of physicians students will be. This article examines ethical principles and their application to the relationships and pedagogic problems encountered in studying and teaching medicine. It shows how the introduction of ethics into these areas can not only help students and teachers but also enhance the standing of teaching itself.


Illness Cognitions and Coping Self-Efficacy in Depression Among Persons With Low Vision.
To investigate the mediating role of coping self-efficacy (CSE) between two types of illness cognitions (i.e., acceptance and helplessness) and depressive symptoms in persons with low vision. This was a single-group, cross-sectional study. Patients with visual acuity < 6/12 in the better eye and at least minimal depressive symptoms (≥5 on the Patient Health Questionnaire-9 [PHQ-9]) were recruited from vision rehabilitation services and participated in telephone-administered structured interviews at one time point. Measures were the PHQ-9, CSE Scale, and Illness Cognition Questionnaire. Structural equation modeling (SEM) devised the causal flow of illness cognitions and their observed indirect effects on depressive symptoms via the CSE mediators: problem focused, emotion focused, and social support. The study comprised 163 patients (mean age 62 years; 61% female), most with age-related macular degeneration (26%) and moderate vision impairment (44%, <6/18-6/60). Structural equation modeling indices indicated a perfect fit (χ2 < 0.001, P = 1.00), accounting for 55% of the variance in depressive symptoms. Lower levels of acceptance and higher levels of helplessness illness cognitions were associated with lower self-efficacy in problem-focused coping (β = 0.38, P < 0.001, β = -0.28, P < 0.01, respectively), which in turn was associated with greater depressive symptom severity (β = -0.54, P < 0.001). Lack of acceptance and greater helplessness relating to low vision led to a lack of perceived capability to engage in problem-focused coping, which in turn promoted depressive symptoms. Third-wave cognitive-behavioral treatments that focus on acceptance may be efficacious in this population.


Solution-processed, high-performance nanoribbon transistors based on dithioperylene.
Solution-processed, high-performance 1D single-crystalline nanoribbon transistors fabricated from dithioperylene are described. The integration of two sulfur atoms into the perylene skeleton induces a compressed highly ordered packing mode directed by S···S interactions. The mobilities of up to 2.13 cm(2) V(-1) s(-1) for a dithioperylene individual nanoribbon make it particularly attractive for electronic applications.


Application of the Liver Maximum Function Capacity Test in Acute Liver Failure: A Helpful Tool for Decision-Making in Liver Transplantation?
Background. Despite aggressive intensive medical management acute liver failure (ALF) may require high-urgency liver transplantation (LTx). Available prognostic scores do not apply for all patients; reliable tools to identify individuals in need of LTx are highly required. The liver maximum function capacity test (LiMAx) might represent an appropriate option. Referring to a case of ALF after Amanita phalloides-intoxication the potential of the LiMAx-test in this setting is discussed. Presentation of Case. LiMAx was performed in a 27-year-old patient prior to and after high-urgency LTx. In accordance with clinical appearance of hepatic encephalopathy, coagulopathy, and acute kidney failure, the LiMAx-test constituted a fulminant course of ALF with hardly any detectable metabolic activity. Following LTx with a marginal donor organ (95% hepatosteatosis), uptake of liver function was demonstrated by postoperative increase of the LiMAx-value. The patient was discharged from hospital on postoperative day 26. Discussion. ALF often is associated with a critical state of the patient that requires almost immediate decision-making regarding further therapy. Application of a noninvasive liver function test might help to determine the prognosis of ALF and support decision-making for or against LTx as well as acceptance of a critical donor organ in case of a critically ill patient.


A Review of Robot-Assisted Lower-Limb Stroke Therapy: Unexplored Paths and Future Directions in Gait Rehabilitation.
Stroke affects one out of every six people on Earth. Approximately 90% of stroke survivors have some functional disability with mobility being a major impairment, which not only affects important daily activities but also increases the likelihood of falling. Originally intended to supplement traditional post-stroke gait rehabilitation, robotic systems have gained remarkable attention in recent years as a tool to decrease the strain on physical therapists while increasing the precision and repeatability of the therapy. While some of the current methods for robot-assisted rehabilitation have had many positive and promising outcomes, there is moderate evidence of improvement in walking and motor recovery using robotic devices compared to traditional practice. In order to better understand how and where robot-assisted rehabilitation has been effective, it is imperative to identify the main schools of thought that have prevailed. This review intends to observe those perspectives through three different lenses: the goal and type of interaction, the physical implementation, and the sensorimotor pathways targeted by robotic devices. The ways that researchers approach the problem of restoring gait function are grouped together in an intuitive way. Seeing robot-assisted rehabilitation in this unique light can naturally provoke the development of new directions to potentially fill the current research gaps and eventually discover more effective ways to provide therapy. In particular, the idea of utilizing the human inter-limb coordination mechanisms is brought up as an especially promising area for rehabilitation and is extensively discussed.


CellSighter: a neural network to classify cells in highly multiplexed images.
Multiplexed imaging enables measurement of multiple proteins in situ, offering an unprecedented opportunity to chart various cell types and states in tissues. However, cell classification, the task of identifying the type of individual cells, remains challenging, labor-intensive, and limiting to throughput. Here, we present CellSighter, a deep-learning based pipeline to accelerate cell classification in multiplexed images. Given a small training set of expert-labeled images, CellSighter outputs the label probabilities for all cells in new images. CellSighter achieves over 80% accuracy for major cell types across imaging platforms, which approaches inter-observer concordance. Ablation studies and simulations show that CellSighter is able to generalize its training data and learn features of protein expression levels, as well as spatial features such as subcellular expression patterns. CellSighter's design reduces overfitting, and it can be trained with only thousands or even hundreds of labeled examples. CellSighter also outputs a prediction confidence, allowing downstream experts control over the results. Altogether, CellSighter drastically reduces hands-on time for cell classification in multiplexed images, while improving accuracy and consistency across datasets.


Secondary velocity fields in the conducting airways of the human lung.
An understanding of flow and dispersion in the human respiratory airways is necessary to assess the toxicological impact of inhaled particulate matter as well as to optimize the design of inhalable pharmaceutical aerosols and their delivery systems. Secondary flows affect dispersion in the lung by mixing solute in the lumen cross section. The goal of this study is to measure and interpret these secondary velocity fields using in vitro lung models. Particle image velocimetry experiments were conducted in a three-generational, anatomically accurate model of the conducting region of the lung. Inspiration and expiration flows were examined under steady and oscillatory flow conditions. Results illustrate secondary flow fields as a function of flow direction, Reynolds number, axial location with respect to the bifurcation junction, generation, branch, phase in the oscillatory cycle, and Womersley number. Critical Dean number for the formation of secondary vortices in the airways, as well as the strength and development length of secondary flow, is characterized. The normalized secondary velocity magnitude was similar on inspiration and expiration and did not vary appreciably with generation or branch. Oscillatory flow fields were not significantly different from corresponding steady flow fields up to a Womersley number of 1 and no instabilities related to shear were detected on flow reversal. These observations were qualitatively interpreted with respect to the simple streaming, augmented dispersion, and steady streaming convective dispersion mechanisms.


Chromosomal transposition of PiggyBac in mouse embryonic stem cells.
Transposon systems are widely used for generating mutations in various model organisms. PiggyBac (PB) has recently been shown to transpose efficiently in the mouse germ line and other mammalian cell lines. To facilitate PB's application in mammalian genetics, we characterized the properties of the PB transposon in mouse embryonic stem (ES) cells. We first measured the transposition efficiencies of PB transposon in mouse embryonic stem cells. We next constructed a PB/SB hybrid transposon to compare PB and Sleeping Beauty (SB) transposon systems and demonstrated that PB transposition was inhibited by DNA methylation. The excision and reintegration rates of a single PB from two independent genomic loci were measured and its ability to mutate genes with gene trap cassettes was tested. We examined PB's integration site distribution in the mouse genome and found that PB transposition exhibited local hopping. The comprehensive information from this study should facilitate further exploration of the potential of PB and SB DNA transposons in mammalian genetics.


Hormonal therapy of breast cancer: state of the art.
Hormonal therapy has an established role in the treatment of women with metastatic breast cancer and also is now a major component of adjuvant systemic therapy for those with early-stage disease. Moreover, recent data suggest that hormonal agents may have a potential use in the prevention of breast cancer in high-risk groups. This article will provide a general overview of the current roles of hormonal therapy and describe future directions that show particular promise.


High number of asymptomatic dogs as leptospiral carriers in an endemic area indicates a serious public health concern.
Asymptomatic dogs can be potential hosts of leptospirosis. However, the extension of this phenomenon in endemic areas has not yet been clearly defined. This study is aimed at evaluating the role of asymptomatic dogs as carriers of Leptospira in an endemic area of Brazil. A total of 131 male dogs without apparent leptospirosis symptoms were included in the study based on clinical and hematologic exams. Serum and urine samples were collected for microscopic agglutination tests (MAT) and polymerase chain reactions (PCR) targeted the LipL32 gene, respectively. Forty-two dogs (32·1%) presented seroreactivity (titres ⩾100). The serogroup Icterohaemorrhagiae was predominant, representing 92·7% of the seropositive samples. Overall, leptospiral DNA was detected on 26 urine samples (19·8%). PCR positivity was more common (28·6%) on seropositive dogs than on seronegative (15·7%) ones. Nevertheless, MAT was not correlated to PCR (P > 0·05). Age was not associated with seroreactivity, but dogs older than 5 years of age had 4·07 more chances (odds ratio) of being carriers (PCR positive) than younger ones. Although the fact of knowing that asymptomatic dogs can act as leptospiral carriers is not new, the extension of this fact is impressive in an endemic region, and its role and impact on public health cannot be neglected.


[Puncture of the anonymous vein].
To introduce a caval catheter means especially in the hands of a beginner, a certain number of potentially dangerous complications. Due to that the way of its application is a subject of further perfectioning. The puncture of anonymous vein is an innovation, thanks to the technical development of a necessary equipment such as a catheter which is introduced by a Seldinger technique, at the typical place over the clavicula, as the catheter is long only 12 cm. (for the right side); the x-ray control is necessary to exclude event. pneumothorax. Experience over a 75 patients is presented, in 6 of whom it was not possible to puncture the anonymous vein, in another 6% there was a puncture of the artery. The catheter has been left 8 days in average for infusion therapy, transfusion and measurement of C. V. P., and for taking blood samples. On the basis of this experience it can be concluded that this treatment can have the clinical application.


T-cell responses against tyrosinase 368-376(370D) peptide in HLA*A0201+ melanoma patients: randomized trial comparing incomplete Freund's adjuvant, granulocyte macrophage colony-stimulating factor, and QS-21 as immunological adjuvants.
We conducted a randomized trial in HLA*A0201+ patientswith American Joint Committee on Cancer stage III or IV melanoma immunized with tyrosinase 368-376(370D) peptide and gp100 209-217(210M) peptide to compare the potency of three different adjuvants. Patients received 3 monthly immunizations with 500 microg of each peptide either with incomplete Freund's adjuvant (IFA), QS-21, or granulocyte macrophage colony-stimulating factor (GM-CSF). The primary end point was induction of IFN-gamma release by CD8+ T cells against tyrosinase and gp100 peptides measured by enzyme-linked immunospot assays without in vitro prestimulation measured pretreatment, 2 and 8 weeks after the third vaccination. Four of 9 and 4 of 8 patients immunized using QS-21 and GM-CSF, respectively, developed increased frequencies of CD8+ T cells against tyrosinase 370D peptide compared with 0 of 9 patients immunized using IFA (P = 0.045). T-cell responses against a gp100-related peptide showed similar results, but their relevance to T-cell reactivity against native gp100 209-217 is uncertain. These results show that: (a) QS-21 and GM-CSF are superior to IFA as immunological adjuvants for vaccination against tyrosinase 370D peptide; and (b) with appropriate adjuvants, increased frequencies of peptide-specific T cells after vaccination can be detected by enzyme-linked immunospot without prolonged prestimulation in vitro.


Women receive more inpatient resections and ablations for hepatocellular carcinoma than men.
To evaluate disparities in the treatment of hepatocellular carcinoma (HCC) based on gender. A retrospective database analysis using the Nationwide Inpatient Sample (NIS) was performed between 2010 and 2013. Adult patients with a primary diagnosis of hepatocellular carcinoma determined by International Classification of Disease 9 (ICD-9) codes were included. Univariate analysis and multivariate logistic regressions were performed to analyze differences in treatment, mortality, features of decompensation, and metastatic disease based on the patient's gender. The analysis included 62582 patients with 45908 men and 16674 women. Women were less likely to present with decompensated liver disease (OR = 0.84, P < 0.001) and had less risk of inpatient mortality when compared to men (OR = 0.75, P < 0.001). Women were more likely to receive inpatient resection (OR = 1.31, P < 0.001) or an ablation (OR = 1.22, P = 0.028) than men. There was no significant difference between men and women in regard to liver transplantation and transcatheter arterial chemoembolization (TACE). Gender impacts treatment for hepatocellular carcinoma. Women are more likely to undergo an ablation or resection then men. Gender disparities in transplantation have resolved.


Association of a specific major histocompatibility complex class IIβ single nucleotide polymorphism with resistance to lactococcosis in rainbow trout, Oncorhynchus mykiss (Walbaum).
Major histocompatibility complex (MHC) loci encode glycoproteins that bind to foreign peptides and initiate immune responses through their interaction with T cells. MHC class II molecules are heterodimers consisting of α and β chains encoded by extremely variable genes; variation in exon 2 is responsible for the majority of observed polymorphisms, mostly concentrated in the codons specifying the peptide-binding region. Lactococcus garvieae is the causative agent of lactococcosis, a warm-water bacterial infection pathogenic for cultured freshwater and marine fish. It causes considerable economic losses, limiting the profitability and development of fish industries in general and the intensive production of rainbow trout, Oncorhynchus mykiss (Walbaum), in particular. The disease is currently controlled with vaccines and antibiotics; however, vaccines have short-term efficacy, and increasing concerns regarding antibiotic residues have called for alternative strategies. To explore the involvement of the MHC class II β-1 domain as a candidate gene for resistance to lactococcosis, we exposed 400 rainbow trout to naturally contaminated water. One single nucleotide polymorphism (SNP) and one haplotype were associated with resistance (P < 0.01). These results are promising for using MHC class IIβ as a molecular marker in breeding rainbow trout resistant to lactococcosis.


Evidence-based medicine for consumers: a role for the Cochrane Collaboration.
Quality of health information on the Internet has been a concern since health information first began appearing on the Web. Evidence-based medicine tools, traditionally intended for physicians, may benefit consumers as they participate in making health care decisions. This article describes a rationale for Cochrane reviews as an evidence-based medicine tool for consumers. The Cochrane Collaboration, a global force for systematic literature reviews, has strict procedures for developing literature reviews. Criteria for Cochrane reviews are compared with critical evaluation skills commonly taught to consumers regarding the use of Websites. The Cochrane Collaboration's Consumer Network has established a separate Website, with review synopses written for an audience of consumers. Suggestions for further research into consumer use of the Cochrane Library and consumer involvement with the Cochrane Collaboration are discussed.


Maximizing Archimedes spiral packing density area.
In this paper, we experimentally demonstrate a broadband Archimedes spiral delay line with high packing density on a silicon photonic platform. This high density is achieved by optimizing the gap between the adjacent waveguides (down to sub-micron scale) in the spiral configuration. However, care must be taken to avoid evanescent coupling, the presence of which will cause the spiral to behave as a novel type of distributed spiral resonator. To this end, an analytical model of the resonance phenomenon was developed for a simple spiral. Moreover, it is demonstrated that this distributed spiral resonator effect can be minimized by ensuring that adjacent waveguides in the spiral configuration have different propagation constants (β). Experimental validations were accomplished by fabricating and testing multiple spiral waveguides with varying lengths (i.e., 0.4, 0.8, and 1.4 mm) and separation gaps (i.e., 300 and 150 nm). Finally, a Linear Density Figure of Merit (LDFM) is introduced to evaluate the packing efficiency of various spiral designs in the literature. In this work, the optimum experimental design with mitigated resonance had a length of 1.4mm and occupied an area of 60 × 60µm, corresponding to an LDFM of 388km-1.


[Criteria of scientific validity in research].
The purpose of this article is to present the evaluative criteria of qualitative and quantitative research. Philosophical foundations of positivism, postpositivism and constructivism are explored. Triangulation and crystallization expose the controversies about them. Finally, Lincoln and Guba criteria are retained for the evaluation of qualitative and quantitative research.


The Emergence of Deschloro-N-ethyl-ketamine, a Ketamine Analog, in Drug Seizures and Drug Driving Cases in Hong Kong.
The study reports the detection of a newly emerged drug, deschloro-N-ethyl-ketamine (2-oxo-PCE), an analog of ketamine, through forensic drug and toxicological examinations of exhibits from drug seizure cases and blood samples taken from drivers of driving under the influence of drug (DUID) cases, respectively, in Hong Kong. The submission of 2-oxo-PCE in both types of cases was firstly encountered in October 2017. A total of 31 drug seizure cases (52 items) and 4 DUID cases were found positive with 2-oxo-PCE till October 2018. Drug seizures with 2-oxo-PCE found were all in physical form (mostly in powdery or crystalline solid), resembling those samples commonly found with ketamine but having much lower purity. Although the majority of the relevant items was found with 2-oxo-PCE as the only psychoactive substance (36 items, ~69%) or as a mixture with ketamine (10 items, ~19%), other psychoactive substances including methamphetamine, methylenedioxymethamphetamine and pentylone have also been encountered (6 items, 12%). For the four DUID cases, 2-oxo-PCE and its metabolite, deschloronorketamine, were detected in all blood samples. The 2-oxo-PCE concentrations in the four blood samples were in the range of 0.08-0.31 μg/mL, being higher than the concentrations of deschloronorketamine (in the range of 0.04-0.09 μg/mL) for each sample. The 2-oxo-PCE levels found were generally lower than the ketamine levels found in reported DUID cases. With items found with 2-oxo-PCE, which were physically indistinguishable from ketamine but having lower drug purity in seizures, the lower 2-oxo-PCE blood levels with more severe impairment signs observed for the drivers in DUID cases, it is not unreasonable to speculate that users might have taken it as ketamine without knowing of its real identity and hence was adversely affected by the more potent 2-oxo-PCE.


Reduction-controlled viologen in bisolvent as an environmentally stable n-type dopant for carbon nanotubes.
Various viologens have been used to control the doping of single-walled carbon nanotubes (SWCNTs) via direct redox reactions. A new method of extracting neutral viologen (V(0)) was introduced using a biphase of toluene and viologen-dissolved water. A reductant of sodium borohydride transferred positively charged viologen (V(2+)) into V(0), where the reduced V(0) was separated into toluene with high separation yield. This separated V(0) solution was dropped on carbon nanotube transistors to investigate the doping effect of CNTs. With a viologen concentration of 3 mM, all the p-type CNT transistors were converted to n-type with improved on/off ratios. This was achieved by donating electrons spontaneously to CNTs from neutral V(0), leaving energetically stable V(2+) on the nanotube surface again. The doped CNTs were stable in water due to the presence of hydrophobic V(0) at the outermost CNT transistors, which may act as a protecting layer to prevent further oxidation from water.


Validation and redescription of the hyperiidean amphipod Brachyscelus rapacoides Stephensen, 1925 (Crustacea: Amphipoda: Hyperiidea: Brachyscelidae), a new record of association with the scyphozoan jellyfish Rhopilema nomadica Galil, 1990 (Scyphozoa: Rhizostomeae: Rhizostomatidae) in the Mediterranean Sea.
The hyperiidean amphipod Brachyscelus rapacoides Stephensen, 1925 is recorded from the scyphozoan jellyfish Rhopilema nomadica Galil, 1990, a new record of association for the genus Brachyscelus, as well as the first record of hyperiid infestation of a non-indigenous scyphozoan host. Because of some past confusion concerning the status of B. rapacoides and the closely related species B. rapax (Claus, 1871) a redescription of B. rapacoides and molecular analysis are provided in order to validate it as a species distinguished from B. rapax.


Current status of digital mammography for screening and diagnosis of breast cancer.
Digital mammography is becoming the preferred technique for investigation of the breast. It is important, therefore, to analyze not only the accuracy of this technique in the screening and the diagnostic environment but also to evaluate its strengths and limits. In addition, communication with other specialists inside and outside the hospital is essential. Recent publications of large clinical trials have shown that digital mammography is as accurate as film-screen mammography in a screening setting. Technical protocols for acceptance testing of these modalities are emerging but they are not yet complete. The literature shows that reading on soft copy may be preferred to hard copy. The high cost is still an important limiting factor in the easy introduction of full-field digital mammography in a hospital. Digital mammography is becoming the method of choice in the detection and characterization of breast cancer. Today, physical and technical protocols as well as large clinical trials are assessing the performance of this technology. A lot of work remains in the optimization of the different parts of the imaging chain: exposure setting, acceptability of detectors, dedicated post processing, viewing conditions and computer-aided detection. In parallel with these developments, newer digital technologies are being explored (tomosynthesis).


Impact of Work Task-Related Acute Occupational Smoke Exposures on Select Proinflammatory Immune Parameters in Wildland Firefighters.
A repeated measures study was used to assess the effect of work tasks on select proinflammatory biomarkers in firefighters working at prescribed burns. Ten firefighters and two volunteers were monitored for particulate matter and carbon monoxide on workdays, January to July 2015. Before and after workshift dried blood spots were analyzed for inflammatory mediators using the Meso Scale Discovery assay, while blood smears were used to assess leukocyte parameters. Firefighters lighting with drip-torches had higher cross-work-shift increases in interleukin-8, C-reactive protein, and serum amyloid A compared with holding, a task involving management of fire boundaries. A positive association between interleukin-8 and segmented-neutrophil was observed. Results from this study suggest that intermittent occupational diesel exposures contribute to cross-work-shift changes in host systemic innate inflammation as indicated by elevated interleukin-8 levels and peripheral blood segmented-neutrophils.


Cytologic diagnosis of fibrolamellar carcinoma of the liver by fine-needle aspiration.
Two cases in which the diagnosis of fibrolamellar carcinoma of the liver was made by fine-needle aspiration are presented. The cytologic findings were characteristic and permitted these tumors to be differentiated from the usual hepatocellular carcinoma. Since fibrolamellar carcinoma has unique clinical and pathologic features, and is much more likely to be resectable, making this diagnosis is important.


Targeted mutation of EphB1 receptor prevents development of neuropathic hyperalgesia and physical dependence on morphine in mice.
EphB receptor tyrosine kinases, which play important roles in synaptic connection and plasticity during development and in matured nervous system, have recently been implicated in processing of pain after nerve injury and morphine dependence. Subtypes of the EphB receptors that may contribute to the neuropathic pain and morphine dependence have not been identified. Here we demonstrate that the subtype EphB1 receptor is necessary for development of neuropathic pain and physical dependence on morphine. The results showed that peripheral nerve injury produced thermal hyperalgesia in wild-type (EphB1+/+) control littermate mice, but not in EphB1 receptor homozygous knockout (EphB1-/-) and heterozygous knockdown (EphB1+/-) mice. Hyperalgesia in the wild-type mice was inhibited by intrathecal administration of an EphB receptor blocking reagent EphB2-Fc (2 microg). Intrathecal administration of an EphB receptor activator ephrinB1-Fc (1 microg) evoked thermal hyperalgesia in EphB1+/+, but not EphB1-/- and EphB1+/- mice. Cellularly, nerve injury-induced hyperexcitability of the medium-sized dorsal root ganglion neurons was prevented in EphB1-/- and EphB1+/- mice. In chronically morphine-treated mice, most of the behavioral signs and the overall score of naloxone-precipitated withdrawal were largely diminished in EphB1-/- mice compared to those in the wild-type. These findings indicate that the EphB1 receptor is necessary for development of neuropathic pain and physical dependence on morphine and suggest that the EphB1 receptor is a potential target for preventing, minimizing, or reversing the development of neuropathic pain and opiate dependence.


Differential contributions to the interception of occluded ballistic trajectories by the temporoparietal junction, area hMT/V5+, and the intraparietal cortex.
The ability to catch objects when transiently occluded from view suggests their motion can be extrapolated. Intraparietal cortex (IPS) plays a major role in this process along with other brain structures, depending on the task. For example, interception of objects under Earth's gravity effects may depend on time-to-contact predictions derived from integration of visual signals processed by hMT/V5+ with a priori knowledge of gravity residing in the temporoparietal junction (TPJ). To investigate this issue further, we disrupted TPJ, hMT/V5+, and IPS activities with transcranial magnetic stimulation (TMS) while subjects intercepted computer-simulated projectile trajectories perturbed randomly with either hypo- or hypergravity effects. In experiment 1, trajectories were occluded either 750 or 1,250 ms before landing. Three subject groups underwent triple-pulse TMS (tpTMS, 3 pulses at 10 Hz) on one target area (TPJ | hMT/V5+ | IPS) and on the vertex (control site), timed at either trajectory perturbation or occlusion. In experiment 2, trajectories were entirely visible and participants received tpTMS on TPJ and hMT/V5+ with same timing as experiment 1 tpTMS of TPJ, hMT/V5+, and IPS affected differently the interceptive timing. TPJ stimulation affected preferentially responses to 1-g motion, hMT/V5+ all response types, and IPS stimulation induced opposite effects on 0-g and 2-g responses, being ineffective on 1-g responses. Only IPS stimulation was effective when applied after target disappearance, implying this area might elaborate memory representations of occluded target motion. Results are compatible with the idea that IPS, TPJ, and hMT/V5+ contribute to distinct aspects of visual motion extrapolation, perhaps through parallel processing.NEW & NOTEWORTHY Visual extrapolation represents a potential neural solution to afford motor interactions with the environment in the face of missing information. We investigated relative contributions by temporoparietal junction (TPJ), hMT/V5+, and intraparietal cortex (IPS), cortical areas potentially involved in these processes. Parallel organization of visual extrapolation processes emerged with respect to the target's motion causal nature: TPJ was primarily involved for visual motion congruent with gravity effects, IPS for arbitrary visual motion, whereas hMT/V5+ contributed at earlier processing stages.


Three-dimensional scan of the uterine cavity of infertile women before assisted reproductive technology use.
The primary objective was to assess the utility of routine 3-dimensional (3D) ultrasound in the evaluation of infertile women and to estimate the prevalence of uterine anomalies before the use of assisted reproductive technology (ART), using the European Society of Human Reproduction and Embryology and the European Society for Gynaecological Endoscopy classification system. A second objective was to assess the effect of uterine anomalies on the pregnancy rate in patients who underwent assisted reproductive techniques.We retrospectively studied 668 patients treated in the Department Obstetrics Gynecology and Neonatology "Sf Ioan" Clinical Emergency Hospital and in the Department of Medical and Surgical Specialties, Faculty of Medicine "'Transilvania" University of Brasov between July 2016 and February 2017 for subfertility. Patients were examined using 2-dimensional (2D) and 3-dimensional (3D) transvaginal ultrasound. Müllerian duct anomalies were present in 6.13% of patients, with the most common anomaly being a dysmorphic uterus (class U1c in 42.68% of patients), 17 patients (20.73%) with incompletely septate uterus (class U2a), 12 patients (14.63%) with a completely septate uterus (classU2b), 8 patients (9.75%) with a partly bicorporeal uterus (classU3a), and 6 patients (7.31%) with a completely bicorporeal uterus (class U3b). Only 1 (1.21%) patient had an aplastic uterus without a rudimentary cavity (class U5b). The pregnancy rate in the presence of uterine anomalies was 55% and the pregnancy rate in control group patients was 39.8%. The incidence of pregnancy in the group with uterine anomalies was statistically similar with the control group of normal uterus (P < .11). For ongoing pregnancy rate and live birth rate, our data indicated a slightly elevated rate for both of those indexes in the anomalies group. The incidence of miscarriage in the presence of uterine anomalies was 24% and 6.7% in the control group, which is statistically significant (P = .05).3D ultrasound evaluation of the uterus should be considered before ART in order to make an accurate diagnosis of the uterine congenital anomaly and improve ART results.


Tooth-colored inlays and onlays.
Today's dental patient concerned about attractive restorations is looking for a dentist who incorporates the newest and best techniques into practice. This article discusses a newer concept that pleases both the patient and dentist: restorations that are bonded into acid-etched tooth preparations with composite resin cement--tooth-colored inlays and onlays. Basic questions asked by practitioners about these esthetic restorations are addressed; characteristics, performance expectations, comparisons with cast gold inlays and onlays, and comparisons with amalgam are presented, in addition to other relevant information for today's dental practitioner.


Dobrava hantavirus variants found in Apodemus flavicollis mice in Kırklareli Province, Turkey.
Hantaviruses infect humans via inhalation of viral particles within secretions of infected rodents or rarely through direct contact with infected rodents. Determining the prevalence of hantavirus infections among rodent populations is of vital importance to obtain information on hantavirus-related cases and to predict possible outbreaks. We hypothesized that DOBV strains circulating in the Thrace Region in Turkey would be related to other Balkan DOBV strains. In this study, hantavirus infections in the rodent population of the Kırklareli-İğneada Region (north-western Turkey, near the Bulgarian border) were investigated. This region is of particular importance, as it is located in the south-eastern margin of the European continent and was used as an entrance point of Asian faunal elements into Europe. DOBV infection was detected in eight of 73 rodents; all were of the Apodemus flavicollis species. Partial sequences of the viral S-, M-, and L-genome segments were recovered and compared with previously reported DOBV sequences. The newly characterized Turkish strains were similar to other DOBV variants. Silent nucleotide mutations were dominant. The hantavirus prevalence in the İğneada region was similar to what has been reported in Greece and Bulgaria. For the first time, the M-segment sequences of DOBV from Turkey were recovered and genetic data of hantaviruses from Thrace region of Turkey were obtained.


Prolonged rooming-in in infancy is associated with generalized anxiety disorder in the adolescent period.
This study aims to investigate whether anxiety disorders in adolescents have a link with the separation time of bed/bedroom sharing with parents. It also aims to raise awareness in society about the issue of minimizing anxiety disorders in childhood. A case-control study was conducted in Şevket Yılmaz Training and Research Hospital between June 2013 and May 2014. The participants included 51 adolescents who were diagnosed as generalized anxiety disorder (GAD) with no-comorbidity and 71 healthy adolescents as the control group, who were chosen randomly. Diagnosis of GAD was based on the criteria from the Diagnostic and Statistical Manual of Mental Disorders (4th ed) by child and adolescent psychiatry doctors. The Turkish version of the State-Trait Anxiety Inventory (STAI) was used for the control group. A special survey about demographics and bed-sharing statements was constructed for the purpose of the study. The groups were analyzed in terms of duration of co-sleeping (bed-sharing) and rooming-in (keeping the mother and the baby in same room) with parents during infancy and the development of anxiety disorders in later period. Mean duration of rooming-in was significantly longer in the case group than in the control group (p=0.009). Similarly, mean duration of co-sleeping in the case group was longer than that of the control group. However, this difference was not statistically significant (p=0.529). Sleeping in the same room with children for a long time may result in anxiety disorders in later period due to possible difficulties in bonding and/or less self-confidence.


Reactivity toward Bifidobacterium longum and Enterococcus hirae demonstrate robust CD8+ T cell response and better prognosis in HBV-related hepatocellular carcinoma.
Recent studies suggest that several bacterial species are involved in tumor immunosurveillance and antitumor immunity. The role of bacteria in immune responses in HBV-related hepatocellular carcinoma (HCC) patients is still unknown. In this study, we examined the bacteria-reactive CD8+ T cell response in patients with HBV-related HCC. We found that circulating CD8+ T cells from healthy individuals demonstrated minimal or zero specificity toward a series of commensals and bacteria previously associated with antitumor effects, including Escherichia coli, Enterococcus faecium, Bifidobacterium longum, Bacteroides fragilis, and Enterococcus hirae. In contrast, the circulating CD8+ T cells from HBV-related HCC patients presented significantly elevated bacteria-reactive responses, albeit with high variations among different HCC individuals. Reactivity toward bacteria was also identified in tumor-infiltrating CD8+ T cells. These bacteria-reactive responses were not primarily induced by TLR ligand, but were dependent on the presence of antigen-presenting monocytes, and were MHC class I-restricted. Interestingly, we observed that the CD8+ T cell-to-Foxp3+ regulatory T cell ratio was positively correlated with the proportions of Bifidobacterium longum-reactive and Enterococcus hirae-reactive CD8+ T cells, while the frequency of PD-1+ CD8+ T cells was negatively correlated with the frequency of Enterococcus hirae-reactive CD8+ T cells. Furthermore, the disease-free survival time of HCC patients after tumor resection was positively correlated with the frequencies of Bifidobacterium longum-reactive and Enterococcus hirae-reactive CD8+ T cells. Together, these results suggested that certain bacterial species might present valuable antitumor effects.


Substitution reactions of iron(ii) carbamoyl-thioether complexes related to mono-iron hydrogenase.
A C,N,S pincer complex has been synthesized for structural modeling of the organometallic active site of mono-[Fe] hydrogenase (HMD). The C,N,S chelate allows for systematic investigation of the substitution reactions of CO and other exogenous X/L-type ligands, as well as examination of the exact roles of the Fe-carbamoyl and {Fe(CO)2}2+ units in stabilizing the low-spin Fe(ii) center. Reaction of the 'apo-ligand' 6-(2-(methylthio)phenyl)pyridin-2-amine (H2NNpySMe) with [Fe(CO)4(Br)2] affords the organometallic complex [(O[double bond, length as m-dash]CNHNpySMe)Fe(CO)2(Br)] (1). Facile substitutions of the halide with L-type ligands such as MeCN, PR3 (R = C6H5, OEt, Me), pyridine and tBuNC afford diamagnetic cations of the type [(O[double bond, length as m-dash]CNHNpySMe)Fe(CO)2(L)]+ (2a-f). Treatment of 1 with Na[S(2,6-Me2C6H3)] affords the neutral complex [(O[double bond, length as m-dash]CNHNpySMe)Fe(CO)2(S(2,6-Me2C6H3))] (2g). Substitution for CO ligand(s) was achieved with trimethylamine-N-oxide (TMAO), and in the presence of PPh3 or pyridine it afforded the six-coordinate monocarbonyl complexes [(O[double bond, length as m-dash]CNHNpySMe)Fe(CO)(Br)(PPh3)] (3a), [(O[double bond, length as m-dash]CNHNpySMe)Fe(CO)(PPh3)2](BArF4) (3b), and [(O[double bond, length as m-dash]CNHNpySMe)Fe(CO)(py)2](BArF4) (3c). Interestingly the stable low-spin Fe(ii), 5-coordinate complex of the formula [(O[double bond, length as m-dash]CNHNpySMe)Fe(CO)2](BArF4) (4) was accessed by treating 1 with TlBArF4 in non-coordinating solvents (DCE, FPh); notably, 4 does not react with H2 in the presence (or absence) of a base. To elucidate the electronic structure differences between the five-coordinate versus six-coordinate complexes, DFT calculations for 4 and 1 were performed. Geometry optimization indicates that 4+ maintains a square-pyramidal geometry, and the Hessian calculation accurately simulates the ν(C[triple bond, length as m-dash]O) in 4+. The electronic structure of 4+ predicts that the HOMO (comprised of Fe|Ncarb) and LUMO (Fe only) orbitals in 4+ are properly oriented to interact with an incoming ligand. However, we postulate that codirectional orientation of the HOMO and LUMO orbitals explains the lack of H2 reactivity with this equatorial CNS donor set, despite many other structural similarities to the endogenous active site. Based on a related work from our lab, we conclude that a facial C,N,S coordination mode is necessary to promote H2 activation and cleavage.


Graphene Oxide Modified TiO2 Micro Whiskers and Their Photo Electrochemical Performance.
Harnessing the solar energy and producing clean fuel hydrogen through efficient photo-electrochemical water splitting has remained one of the most challenging endeavors in materials science. The core problem is to develop a suitable photo-catalyst material that absorbs a significant part of the solar spectrum and produces electron-hole pairs that can be easily separated without recombination. In the recent times, the composite of Titanium dioxide with graphene have been investigated to explore the advantages of both class of materials. Here we report on the photo-electrochemical properties of reduced graphene oxide functionalised TiO2 whiskers. The TiO2 whiskers are obtained from potassium titanium oxide (KTi8O16) synthesized through hydrothermal technique followed by ion exchange method and heat treatment. Graphene oxide was deposited on the as prepared TiO2 whiskers using hydrothermal method. As formed samples were characterized by Raman spectroscopy to confirm the presence of reduced graphene oxide (RGO) attached to TiO2 whiskers. Comparative photo electrochemical studies were carried out for TiO2 and reduced graphene oxide modified TiO2 whiskers. Among these, RGO modified TiO2 whiskers show significantly higher photo current density possibly due to enhancement in charge separation ability and longer electron life times.


Potassium bicarbonate attenuates the urinary nitrogen excretion that accompanies an increase in dietary protein and may promote calcium absorption.
Protein is an essential component of muscle and bone. However, the acidic byproducts of protein metabolism may have a negative impact on the musculoskeletal system, particularly in older individuals with declining renal function. We sought to determine whether adding an alkaline salt, potassium bicarbonate (KHCO3), allows protein to have a more favorable net impact on intermediary indices of muscle and bone conservation than it does in the usual acidic environment. We conducted a 41-d randomized, placebo-controlled, double-blind study of KHCO3 or placebo with a 16-d phase-in and two successive 10-d metabolic diets containing low (0.5 g/kg) or high (1.5 g/kg) protein in random order with a 5-d washout between diets. The study was conducted in a metabolic research unit. Nineteen healthy subjects ages 54-82 yr participated. KHCO3 (up to 90 mmol/d) or placebo was administered for 41 d. We measured 24-h urinary nitrogen excretion, IGF-I, 24-h urinary calcium excretion, and fractional calcium absorption. KHCO3 reduced the rise in urinary nitrogen excretion that accompanied an increase in protein intake (P = 0.015) and was associated with higher IGF-I levels on the low-protein diet (P = 0.027) with a similar trend on the high-protein diet (P = 0.050). KHCO3 was also associated with higher fractional calcium absorption on the low-protein diet (P = 0.041) with a similar trend on the high-protein diet (P = 0.064). In older adults, KHCO3 attenuates the protein-induced rise in urinary nitrogen excretion, and this may be mediated by IGF-I. KHCO3 may also promote calcium absorption independent of the dietary protein content.


Studies concerning the regional lymph node in cancer. VIII. Effect of two asynchronous tumor foci on lymph node cell cytotoxicity.
Results suggest that cytotoxicity by cells from nodes regional to a primary tumor is unique. While a primary tumor was present, A) cytotoxicity was displayed by cells from lymph nodes (RLNs) to that tumor, B) cells from nonregional lymph nodes regional (NRLNs) possessed lesser cytotoxicity which failed to increase in response to a second tumor focus in an area drained by those nodes, and C) the second focus attenuated cytotoxicity of cells from LNs regional to the primary tumor. Following removal of the primary tumor, cells from RLNs rapidly lost cytotoxicity and with passage of time were unable to regain that function in response to a second tumor focus. In contrast, cells from NRLNs demonstrated increased cytotoxicity at any time following removal of the primary tumor when exposed to a second focus. These observations suggest that nodes regional to a distant metastatic focus may be unable to react to it and thus contribute little to the host response generated by the primary tumor. In addition, since nodes regional to a primary tumor manifest diminished cytotoxicity in the presence of a distant tumor focus, tumor cells gaining access and lodging in those nodes subsequent to the development of other metastatic foci are likely to proliferate, resulting in the "positive" lymph node. The findings are in keeping with our contention that host factors responsible for metastases, and perhaps metastases themselves, are at least in part responsible for growth of tumor in RLNs. They also have relevance to the site of administration of specific immunotherapeutic agents and to the significance of the removal of RLNs with a primary tumor.


The alteration of plasminogen activator inhibitor-1 expression by linoleic acid and fenofibrate in HepG2 cells.
The present study investigated the influence of linoleic acid and fenofibrate on plasminogen activator inhibitor-1 (PAI-1) expression in HepG2 cells and the mechanism possibly involved. Using gene recombination techniques, chloromycetin acetyltransferase (CAT) reporter gene plasmids containing nuclear factor-kappaB response element deletion (del1-PAI-pCAT) or very-low-density lipoprotein/fatty acid response element deletion (del2-PAI-pCAT) in the PAI-1 promoter were constructed and transiently transfected into HepG2 cells, respectively. Linoleic acid and fenofibrate were added to induce the transfected cells. The PAI-1 expression in mRNA and protein level was significantly induced by linoleic acid, but suppressed by fenofibrate. In the HepG2 cells transfected with PAI-pCAT plasmid, the PAI-1 transcription activity was significantly induced by linoleic acid, but suppressed by fenofibrate. Under transfection with del1-PAI-pCAT, both linoleic acid and fenofibrate increased the PAI-1 transcriptional activity; whereas in those cells transfected with del2-PAI-pCAT, fenofibrate significantly reduced PAI-1 transcriptional activity but no change was found with linoleic acid stimulation. Peroxisome proliferator-activated receptor alpha may be one of transcription factors playing a role in the upregulation of PAI-1 gene expression by linoleic acid in HepG2 cells. The inhibition of the nuclear factor-kappaB signaling pathway may be involved in the downregulation of PAI-1 gene expression by fenofibrate.


Cost-sharing for emergency care and unfavorable clinical events: findings from the safety and financial ramifications of ED copayments study.
To evaluate the effect of emergency department (ED) copayment levels on ED use and unfavorable clinical events. Data Source/Study Setting. Kaiser Permanente-Northern California (KPNC), a prepaid integrated delivery system. In a quasi-experimental longitudinal study with concurrent controls, we estimated rates of ED visits, hospitalizations, ICU admissions, and deaths associated with higher ED copayments relative to no copayment, using Poisson random effects and proportional hazard models, controlling for patient characteristics. The study period began in January 1999; more than half of the population experienced an employer-chosen increase in their ED copayment in January 2000. Using KPNC automated databases, the 2000 U.S. Census, and California state death certificates, we collected data on ED visits and unfavorable clinical events over a 36-month period (January 1999 through December 2001) among 2,257,445 commercially insured and 261,091 Medicare insured health system members. Among commercially insured subjects, ED visits decreased 12 percent with the $20-35 copayment (95 percent confidence interval [CI]: 11-13 percent), and 23 percent with the $50-100 copayment (95 percent CI: 23-24 percent) compared with no copayment. Hospitalizations, ICU admissions, and deaths did not increase with copayments. Hospitalizations decreased 4 percent (95 percent CI: 2-6 percent) and 10 percent (95 percent CI: 7-13 percent) with ED copayments of $20-35 and $50-100, respectively, compared with no copayment. Among Medicare subjects, ED visits decreased by 4 percent (95 percent CI: 3-6 percent) with the $20-50 copayments compared with no copayment; unfavorable clinical events did not increase with copayments, e.g., hospitalizations were unchanged (95 percent CI: -3 percent to +2 percent) with $20-50 ED copayments compared with no copayment. Relatively modest levels of patient cost-sharing for ED care decreased ED visit rates without increasing the rate of unfavorable clinical events.


Effects of scientific advances on the decision-making process: analytical chemistry.
The analytical chemist has taken the science of identification and quantitation of chemical compounds far beyond the capability of the toxicologist to correlate with the results of animal experiments. In pursuing the vanishing zero, however, the analytical chemist has failed to acknowledge the inherent variability of chemical measurements at very low concentrations that manifest itself not only as discrepant values but as an appreciable fraction of false positive and false negative results and as real negative values (the blank or control is greater than the determination). These are the symptoms of a system not in statistical control. The same type of variable results, evident in biological systems as "biological variability," are then manipulated by statisticians as if they were reproducible measurements. Progress in characterizing biological uncertainty cannot be made until the invisible systematic error of individual laboratories is transformed into random error, amenable to the application of statistical principles. In measurement theory, an examination and correction of systematic error requires knowledge or assignment of a "true value," a concept that does not appear to exist in many biological systems.


Self-consistent approach for neutral community models with speciation.
Hubbell's neutral model provides a rich theoretical framework to study ecological communities. By incorporating both ecological and evolutionary time scales, it allows us to investigate how communities are shaped by speciation processes. The speciation model in the basic neutral model is particularly simple, describing speciation as a point-mutation event in a birth of a single individual. The stationary species abundance distribution of the basic model, which can be solved exactly, fits empirical data of distributions of species' abundances surprisingly well. More realistic speciation models have been proposed such as the random-fission model in which new species appear by splitting up existing species. However, no analytical solution is available for these models, impeding quantitative comparison with data. Here, we present a self-consistent approximation method for neutral community models with various speciation modes, including random fission. We derive explicit formulas for the stationary species abundance distribution, which agree very well with simulations. We expect that our approximation method will be useful to study other speciation processes in neutral community models as well.


Comparison of research trends in korean and international family medicine in journals of family medicine.
Research is important for the development of family medicine as a professional field in primary care. The aim of this study was to suggest directions for the development of family medicine research by analyzing research trends in original papers published in the Korean Journal of Family Medicine (KJFM) and international journals. We investigated original research papers published in KJFM and 4 international journals from August 2009 to July 2010. Analysis was conducted according to research topics, authors, methods, participants, and data sources. 'Clinical research' was the most common research topic in both the KJFM (88.3%) and international journals (57.3%); however, international journals had more studies in other domains ('education and research,' 'health service,' and 'family medicine'). More authors other than family physicians participated in international journals than in the KJFM (58% and 3.3%, respectively). Most studies were 'cross-sectional' in KJFM (77.0%) and international journals (51.5%): however, the latter had more 'qualitative' studies, 'cohort' studies, and 'systematic reviews' than the former. The largest study population was 'visitors of health promotion center' in the KJFM and 'outpatients' in international journals. Most of the study sources were 'survey' and 'medical records' in both. There were limitations of diversity in the papers of the KJFM. Future investigation on papers of other than family medicine journals should be planned to assess research trends of family physicians.


[Assessment and treatment of sexual offenders].
Sexual offences are a heterogeneous group of offences that entail very different diagnostic categories relevant for key issues of expert assessment. Sexual offender trials usually deal with issues related to (diminished) responsibility and the necessity of a referral to a forensic psychiatric hospital ( section sign 63 StGB, German penal code). Furthermore, risk assessment is seen as a necessary precondition for relapse prevention and consequently, it forms part of any expert assessment in sex offender trials. In terms of treatment, manualized treatment programs prevail. Usually they lend themselves to psycho-educative, cognitive-behavioral and psychodynamic concepts. Notwithstanding the focus of any individual program, core elements of all programs pertain to offence related (e.g., victim empathy, attitudes and individual values, minimizations, etc.) and more general psychotherapy modules (anger management, substance abuse, social skills training, etc.). Advantages and disadvantages of these programs are named and discussed.


A comparative study on the stability of the furfural molecule on the low index Ni, Pd and Pt surfaces.
We present a comparative density functional theory investigation of the furfural (Ff) molecule on the low index Ni, Pd and Pt surfaces to understand its geometrical and electronic properties to gain mechanistic insights into the experimentally measured catalytic reactivities of these metal catalysts. We show that the number of metal d-states, which hybridize with the nearest C and O p-orbitals of the Ff molecule, can be used to explain the stability of the Ff molecule on these surfaces. We find that the hybridization between atoms with higher electronegativity and the metal d-states plays a crucial role in determining the stability of these systems. Furthermore, we also find electron transfer from metal to the Ff molecule on the Ni and Pd surfaces, with a reverse process occurring on the Pt surface.


A Comparison of Magnetic Resonance Imaging and SPECT-CT Imaging in Complex Spine Pathology: Does SPECT-CT Provide Additional Diagnostic Information Over Magnetic Resonance Imaging?
Retrospective cohort study. Magnetic Resonance Imaging (MRI) is often regarded as the gold standard for spinal pathology, as it provides good structural visualisation. SPECT-CT, however, provides combined structural and functional information. There is a paucity of literature comparing SPECT-CT with MRI in the spine. Our aim was to determine whether SPECT-CT provides additional information to MRI in individuals with complex spinal pathology, including deformity, which altered management. We conducted a retrospective review of all individuals seen at our tertiary spinal unit that were investigated with both MRI and SPECT-CT of the spine between 2007-2020. We reviewed imaging reports, and collated diagnoses, surgical treatment and the relative contributions of MRI and SPECT-CT to management decisions. 104 individuals identified, with a mean age of 30 years (89 females and 15 males). Diagnostic categories were adolescent, adult, and congenital deformity, degenerative pathology, and miscellaneous pathology. MRI returned positive findings in 58 (55.8%), and SPECT-CT in 41 (39.4%) cases. SPECT-CT identified 10 cases of facet joint degeneration, 5 of increased uptake around metalwork suggestive of loosening, 1 pseudoarthrosis, 1 partial failure of fusion and 1 osteoid osteoma which were not reported on MRI, all in individuals who had previously undergone spinal instrumentation. Despite this, SPECT-CT only altered management for 6 individuals (5.8%). MRI is less useful in the setting of previous instrumentation due to metal artefact. Where MRI is inconclusive, particularly in individuals with previous spinal instrumentation, SPECT-CT may provide a diagnosis, but is not recommended as primary imaging.