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Effect of polymer-filler interaction strengths on the thermodynamic and dynamic properties of polymer nanocomposites. The structural and dynamical properties of polymer nanocomposites are investigated using stochastic molecular dynamics simulations. For spherical nanoparticles dispersed in a polymer matrix, the results indicate that the polymer-nanoparticle interaction strength and the overall system temperature are primarily responsible for the type of dispersed state (clustering and homogeneous dispersion) achieved. A systematic study probing temperature, polymerization, and polymer-nanoparticle and nanoparticle-nanoparticle interaction strengths has been performed. In this paper, however, we focus the discussion on the results for varying polymer-nanoparticle interaction strengths at different temperatures. By examining the structure and dynamics, we show that there are two kinds of "clustering transitions:" one due to thermodynamic and another due to the dynamical response of the system. From these results, a representative phase diagram is developed that captures the entire simulated space and allows the easy identification of the highly dispersed and the clustered states.

High cyclin D3 expression confers erlotinib resistance in aerodigestive tract cancer. Prior studies highlighted cyclin D1 as a key biomarker of response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. This study builds on prior work by examining the roles of cyclin D1, cyclin D3, and cyclin E in mediating erlotinib sensitivity or resistance. Expression plasmids for G1 cyclins were independently transfected into NIH 3T3 cells and effects on erlotinib sensitivity were examined. The expression profiles of G1 cyclins were compared in erlotinib-sensitive and erlotinib-resistant lung cancer cell lines. A549 and H358 cells were treated with erlotinib and changes in cyclin protein expression were assessed. Cyclin D3 immunohistochemical staining was measured in biopsy tissues obtained from patients before and after treatment with erlotinib. Erlotinib-sensitive lung cancer cells were transfected with cyclin D3 and changes in erlotinib sensitivity were examined. Individual transfection of cyclin D1, cyclin D3, and cyclin E expression plasmids each significantly reduced erlotinib sensitivity in NIH-3T3 cells. The erlotinib-resistant A549 cell line expressed high basal levels of cyclin D3 mRNA and protein. Comparison of tumor biopsies obtained from patients before and after treatment with erlotinib indicated an increase in the percentage of cancer cells expressing cyclin D3 following treatment with erlotinib (P=.02). Transfection of cyclin D3 into an erlotinib-sensitive lung cancer cell line inhibited erlotinib-induced signaling changes and reduced the growth-suppressive effects of erlotinib. High expression of cyclin D3 confers resistance to erlotinib in vitro and in vivo. Cyclin D3 immunohistochemical staining warrants investigation as a biomarker for predicting erlotinib resistance.

The ability in adhesion and invasion of drug-resistant human glioma cells. Drug-resistance is critical in treating malignant tumors, and a variety of treatments are given to control it. Little study has been done, however, on biological changes in tumor cell activity in the course of acquiring drug-resistance. We used a glioma cell line to study changes in cell adhesion and invasion on acquiring drug-resistance. Human glioma culture cell line IN157 was used to establish the cell lines resistant to etoposide (VP-16), vincristine sulfate (VCR), and doxorubicin hydrochloride (DOX). Expressions of integrin alpha2, alpha3, alpha5, and beta1, neuronal cell adhesion molecule (NCAM), and matrix metalloproteinases (MMPs) were examined by flow cytometry. In drug-resistant cells, integrin expression was enhanced and NCAM expression was reduced. Adhesions to the extracellar matrix (ECM) proteins (laminin, fibronectin or type IV collagen) were studied. The adhesive ability of all cell lines increased in a concentration-dependent manner. Adhesion of drug-resistant cells was significantly stronger than that of IN157. The cell invasion of drug-resistant cell lines to the basal membrane was significantly lower than that of IN157. The cell invasion of IN157 was significantly suppressed by adding anti-NCAM antibody. In the case of IN157 with the acquisition of drug-resistance, an increase in the expression of integrins may have enhanced the adhesion to ECM proteins. This finding may be concerned with the decreased activity of drug-resistant cell lines in invading the basement membrane. NCAM expression in drug-resistant cell lines was reduced and anti-NCAM antibody abated invasion of IN157, suggesting that NCAM is involved in IN157 invasion.

Suppression of drinking by naloxone in the rat: a further characterization. The effects of naloxone, an opiate antagonist, were examined on drinking induced by various dipsogenic stimuli. In rats deprived of water for 24 h, naloxone (0.1-10 mg/kg) produced a dose-related suppression of drinking immediately following water presentation but did not alter the latency to begin drinking. Naloxone also produced a dose-related suppression of water consumption induced by isoproterenol and angiotensin II, agents simulating conditions of extracellular dehydration. Naltrexone, a congener of naloxone, was more potent than naloxone in reducing isoproterenol-induced water intake. Schedule-induced polydipsia, which occurs in the absence of body fluid deficits, was not altered by either naloxone or naltrexone at doses attenuating drinking induced by the other methods. These data suggest that the suppressant effects of naloxone on water consumption are not a manifestation of an increased latency to drink or an impairment in the motor components of drinking activity. Furthermore, narcotic antagonists appear to attenuate regulatory, but not adjunctive drinking.

Mutations in the adrenoleukodystrophy gene. Adrenoleukodystrophy (ALD) is a peroxisomal disorder that commonly manifests as demyelination of the central nervous system (CNS). The isolation of the ALD gene by positional cloning has led to the identification of a variety of mutations in the ALD gene. One hundred and ten mutations have been identified to date, of which approximately 50% are missense mutations. While rapid DNA-based diagnoses of ALD is now possible, there appears to be no simple correlation between genotype and phenotype.

Gas-phase thermochemical properties of pyrimidine nucleobases. The gas-phase acidity and proton affinity of thymine, cytosine, and 1-methyl cytosine have been examined using both theoretical (B3LYP/6-31+G*) and experimental (bracketing, Cooks kinetic) methods. This paper represents a comprehensive examination of multiple acidic sites of thymine and cytosine and of the acidity and proton affinity of thymine, cytosine, and 1-methyl cytosine. Thymine exists as the most stable "canonical" tautomer in the gas phase, with a DeltaH(acid) of 335 +/- 4 kcal mol(-1) (DeltaG(acid) = 328 +/- 4 kcal mol(-1)) for the more acidic N1-H. The acidity of the less acidic N3-H site has not, heretofore, been measured; we bracket a DeltaH(acid) value of 346 +/- 3 kcal mol(-1) (DeltaG(acid) = 339 +/- 3 kcal mol(-1)). The proton affinity (PA = DeltaH) of thymine is measured to be 211 +/- 3 kcal mol(-1) (GB = DeltaG = 203 +/- 3 kcal mol(-1)). Cytosine is known to have several stable tautomers in the gas phase in contrast to in solution, where the canonical tautomer predominates. Using bracketing methods in an FTMS, we measure a DeltaH(acid) for the more acidic site of 342 +/- 3 kcal mol(-1) (DeltaG(acid) = 335 +/- 3 kcal mol(-1)). The DeltaH(acid) of the less acidic site, previously unknown, is 352 +/- 4 kcal mol(-1) (345 +/- 4 kcal mol(-1)). The proton affinity is 228 +/- 3 kcal mol(-1) (GB = 220 +/- 3 kcal mol(-1)). Comparison of these values to calculations indicates that we most likely have a mixture of the canonical tautomer and two enol tautomers and possibly an imine tautomer under our conditions in the gas phase. We also measure the acidity and proton affinity of cytosine using the extended Cooks kinetic method. We form the proton-bound dimers via electrospray of an aqueous solution, which favors cytosine in the canonical form. The acidity of cytosine using this method is DeltaH(acid) = 343 +/- 3 kcal mol(-1), PA = 227 +/- 3 kcal mol(-1). We also examined 1-methyl cytosine, which has fewer accessible tautomers than cytosine. We measure a DeltaH(acid) of 349 +/- 3 kcal mol(-1) (DeltaG(acid) = 342 +/- 3 kcal mol(-1)) and a PA of 230 +/- 3 kcal mol(-1) (GB = 223 +/- 3 kcal mol(-1)). Our ultimate goal is to understand the intrinsic reactivity of nucleobases; gas-phase acidic and basic properties are of interest for chemical reasons and also possibly for biological purposes because biological media can be quite nonpolar.

Performance of compliance and persistence measures in predicting clinical and economic outcomes using administrative data from German sickness funds. To compare the performance of various compliance and persistence measures in predicting schizophrenia-related hospitalization rates and inpatient costs. Retrospective, nonrandomized cohort study. Prescription claims databases from three German sickness funds (public health insurance programs). A total of 1484 patients who were hospitalized in 2003 for a schizophrenia-related episode and subsequently received long-term antipsychotic pharmacotherapy. Data on age, sex, schizophrenia, prescription drugs, hospitalizations, and inpatient expenditures were collected for each patient from the three German sickness funds. Refill compliance measures based on single-interval availability and multiple-interval availability, as well as refill persistence, were calculated for each patient over 1 year. Ten measurement variables were compared with respect to their performance in predicting disease-related hospitalization and inpatient expenditure, using multivariate logistic regression and gamma regression, respectively. C-statistics were calculated to determine each measure's predictive performance. Likelihood ratio tests showed that inclusion of compliance and persistence measures significantly improved (p<0.05) outcomes prediction in 6 of 10 hospitalization models and in 3 of 10 inpatient cost models compared with a baseline model that included only age, sex, and disease severity covariates. Refill compliance as a continuous variable of drug persistence, including transfer of oversupplies into subsequent periods, performed best in predicting hospitalization (C = 0.669). Availability ratios, capped at 100%, were superior to default availability ratios in predicting hospitalization. Allowing for cross-period carryover improved the discriminatory performance of the persistence models. Refill persistence measures appear sufficiently flexible to account for hospitalizations common in schizophrenia and other psychiatric diseases. A continuous refill persistence measure should be used to assess compliance in psychiatric conditions when working with administrative data.

[Levels of anemia and hemoglobin in pregnant adolescents who attended health care facilities of Ministry of Health of Peru, 2009-2012]. To determine hemoglobin levels and anemia in pregnant adolescents who attended the health care facilities of the Ministry of Health of Peru between the years 2009 and 2012. Cross-sectional study of secondary data analysis using the Information System of the Nutritional Status of Children and Pregnant Women (SIEN). 265,788 records of pregnant women aged 10 to 19 years were reviewed. Hemoglobin levels (g/dL) and the percentage of anemia in the first, second and third trimesters were measured. Descriptive statistics with confidence intervals at 95% were applied. 3.4% of pregnant women were aged 10 to 14 years (early adolescence), 21.6% between 15 to 16 years (middle adolescence) and 75% between 17 to 19 years (late adolescence). Hemoglobin levels in pregnant adolescents were 11.6 ± 1.3 g/dL in 2009 and 11.5 ± 1.3 g/dL during the years 2010, 2011 and 2012. The overall incidence of anemia for 2009 was 25.1% (95% CI 24.4-25.8); for 2010 was 26.0% (95% CI 25.3-26.6) for 2011 was 26.4% (95% CI 25.8-27.1) and 25.2% for 2012 (95% CI 24.6-25.9). Hemoglobin levels were on average lower for pregnant residents in high Andean areas. About a quarter of pregnant adolescents in our sample had anemia.

Whole genome sequence of Auricularia heimuer (Basidiomycota, Fungi), the third most important cultivated mushroom worldwide. Heimuer, Auricularia heimuer, is one of the most famous traditional Chinese foods and medicines, and it is the third most important cultivated mushroom worldwide. The aim of this study is to develop genomic resources for A. heimuer to furnish tools that can be used to study its secondary metabolite production capability, wood degradation ability and biosynthesis of polysaccharides. The genome was obtained from single spore mycelia of the strain Dai 13782 by using combined high-throughput Illumina HiSeq 4000 system with the PacBio RSII long-read sequencing platform. Functional annotation was accomplished by blasting protein sequences with different public available databases to obtain their corresponding annotations. It is 49.76Mb in size with a N50 scaffold size of 1,350,668bp and encodes 16,244 putative predicted genes. This is the first genome-scale assembly and annotation for A. heimuer, which is the third sequenced species in Auricularia.

The intentional stance as structure learning: a computational perspective on mindreading. Recent theories of mindreading explain the recognition of action, intention, and belief of other agents in terms of generative architectures that model the causal relations between observables (e.g., observed movements) and their hidden causes (e.g., action goals and beliefs). Two kinds of probabilistic generative schemes have been proposed in cognitive science and robotics that link to a "theory theory" and "simulation theory" of mindreading, respectively. The former compares perceived actions to optimal plans derived from rationality principles and conceptual theories of others' minds. The latter reuses one's own internal (inverse and forward) models for action execution to perform a look-ahead mental simulation of perceived actions. Both theories, however, leave one question unanswered: how are the generative models - including task structure and parameters - learned in the first place? We start from Dennett's "intentional stance" proposal and characterize it within generative theories of action and intention recognition. We propose that humans use an intentional stance as a learning bias that sidesteps the (hard) structure learning problem and bootstraps the acquisition of generative models for others' actions. The intentional stance corresponds to a candidate structure in the generative scheme, which encodes a simplified belief-desire folk psychology and a hierarchical intention-to-action organization of behavior. This simple structure can be used as a proxy for the "true" generative structure of others' actions and intentions and is continuously grown and refined - via state and parameter learning - during interactions. In turn - as our computational simulations show - this can help solve mindreading problems and bootstrap the acquisition of useful causal models of both one's own and others' goal-directed actions.

Flow of water through carbon nanotubes predicted by different atomistic water models. Nonequilibrium molecular dynamics simulations are reported to investigate the influence of different atomistic water models on the predicted flow behavior in carbon nanotubes (CNTs) with diameters between 0.81 nm and 1.9 nm. The comparison was made using rigid three-site [simplified point charge (SPC), extended SPC (SCP/E), and transferable intermolecular potential three point (TIP3P)] and four-site (TIP4P and TIP4P/2005) models. In addition, a flexible three-site model (SPC/Fw) was also investigated. The effect of different simulation conditions was determined by generating a flux across the CNT using either a pressure gradient across a membrane separating two water reservoirs or a periodic CNT with a constant force applied to each water molecule. Simulations involving the two water reservoirs indicate that the flux is strongly dependent on the choice of water model, which confirms earlier work. By contrast, this strong model dependency is not a feature of the periodic CNT simulations. Instead, the flux depends mainly on the pore diameter and the molecular density of water inside the CNT. The influence of the water model becomes very small in the periodic CNT simulations, which eliminates distorting entrance/exit effects.

Secretion and crinophagy in prolactin cells. The mammotroph or prolactin-secreting cell, due to its distinctive fine structure, large granules, and sustained survival in vitro, has been a favorite object for studying mechanisms of pituitary secretion and its control. In this review the structural basis of prolactin secretion is summarized and the proposed sequence of intracellular events involved in prolactin secretion together with their site of loaction is outlined. The available evidence validating the various steps in prolactin secretion and their regulation is summarized. Finally, some of the unresolved problems remaining for the future are pinpointed.

Expression of a CD20-specific chimeric antigen receptor enhances cytotoxic activity of NK cells and overcomes NK-resistance of lymphoma and leukemia cells. Despite the clinical success of CD20-specific antibody rituximab, malignancies of B-cell origin continue to present a major clinical challenge, in part due to an inability of the antibody to activate antibody-dependent cell-mediated cytotoxicity (ADCC) in some patients, and development of resistance in others. Expression of chimeric antigen receptors in effector cells operative in ADCC might allow to bypass insufficient activation via FcgammaRIII and other resistance mechanisms that limit natural killer (NK)-cell activity. Here we have generated genetically modified NK cells carrying a chimeric antigen receptor that consists of a CD20-specific scFv antibody fragment, via a flexible hinge region connected to the CD3zeta chain as a signaling moiety. As effector cells we employed continuously growing, clinically applicable human NK-92 cells. While activity of the retargeted NK-92 against CD20-negative targets remained unchanged, the gene modified NK cells displayed markedly enhanced cytotoxicity toward NK-sensitive CD20 expressing cells. Importantly, in contrast to parental NK-92, CD20-specific NK cells efficiently lysed CD20 expressing but otherwise NK-resistant established and primary lymphoma and leukemia cells, demonstrating that this strategy can overcome NK-cell resistance and might be suitable for the development of effective cell-based therapeutics for the treatment of B-cell malignancies.

Efficacy of a triple therapy with rabeprazole, amoxicillin, and faropenem as second-line treatment after failure of initial Helicobacter pylori eradication therapy. Triple therapy consisting of lansoprazole, amoxicillin, and clarithromycin (LAC regimen) is widely used to eradicate Helicobacter pylori in Japan. However, the need for appropriate treatment after failure of initial therapy to eradicate H. pylori has been increasing. We therefore assessed the efficacy of a combination of rabeprazole, amoxicillin, and faropenem for second-line eradication therapy. The subjects were 116 patients positive for H. pylori infection. Patients initially received lansoprazole 60 mg/day, amoxicillin 1500 mg/day and clarithromycin 400 mg/day in two divided doses for 7 days. Patients in whom eradication treatment failed were given rabeprazole 20 mg/day and amoxicillin 1500 mg/day in two divided doses, and faropenem 600 mg/day in three divided doses (RAF regimen) for 7 consecutive days. H. pylori status was assessed by the 13C-urea breath test combined with rapid urease test or H. pylori culture method 8 weeks after completion of therapy. Susceptibility to clarithromycin was determined by the agar dilution method, and genetic polymorphism of CYP2C19 was analyzed by polymerase chain reaction-restriction fragment length polymorphism. The initial H. pylori eradication rate with the LAC regimen was 76.4% (84/110). Assessment of the CYP2C19 genotypes of the patients in whom eradication therapy failed revealed that homozygous extensive metabolizers accounted for 70.0% (16/23) and heterozygous extensive metabolizers for 30.0% (7/23), with no poor metabolizers. The acquired resistance rate for clarithromycin was 52.0% (12/23). The success rate of re-eradication with the RAF regimen was 91.3% (21/23) with no serious adverse effects. Triple therapy comprising rabeprazole, amoxicillin, and faropenem is effective for second-line eradication treatment of H. pylori infection, regardless of the genetic polymorphism of CYP2C19 or the presence of resistance to clarithromycin.

Coordination of Tri-Substituted Nona-Germanium Clusters to Cu(I) and Pd(0). The recently developed approach for the rational functionalization of deltahedral nona-germanium clusters Ge9(4-) with three substituents to form Ge9R3(-) (R = Si(SiMe3)3) in large amounts has made the latter a convenient starting material for further reactivity studies. Reported here are the synthesis, structures, and solution studies of two compounds where Ge9R3(-) are used as ligands to transition metals, [(Ge9R3)Cu(I)(Ge9R3)Cu(I)PPh3] (1) and [(Ge9R3)Pd(0)(Ge9R3)](2-) (2). The former adds to the families of anionic [(Ge9R3)M(I)(Ge9R3)](-) (M(I) = Cu, Ag, and Au) as a neutral member and of the neutral [(Ge9R3)M(II)(Ge9R3)] (M(II) = Zn, Cd, and Hg), while the latter represents the first compound involving a metal from group 10.

Atypical mitoses in elevated dysplasias of the stomach. The number and topographic localization of spontaneously occurring mitotic figures were studied in 22 elevated dysplasias of the stomach. The lesions were divided into 3 equally thick zones. Mitoses occurred in 5 of 7 slight dysplasias, in 7 of 8 moderate dysplasias, and in all 7 severe dysplasias. When present, mitoses were localized to the superficial zone in slight, moderate and severe dysplasias, in the middle zone in some moderate dysplasias, and in almost all severe dysplasias. In the deeper zone, mitoses were seen in one of the moderate dysplasias and in as much as 5 of the severe dysplasias. The number of mitoses were significantly higher in moderate and severe dysplasia, when compared to slight dysplasia. The percentage of atypical mitoses increased gradually from 27% in slight dysplasia to 41% in moderate, and 52% in severe dysplasias. In the adjacent, non-dysplastic gastric mucosa, a 1.5% of atypical mitoses was found. Significantly higher amounts of atypical mitoses were recorded in severe dysplasias, as compared to slight and moderate dysplasias. The results suggest that the various types of elevated dysplasias (slight, moderate and severe) of the stomach may be distinguished, not only by the characteristics of the atypical cells in interphase--as is the case today--but also by the topographic distribution of mitoses and by the difference in percentage of atypical mitoses occurring in these lesions. The possible significance of the mitosis as a biohistological marker of the behaviour of elevated dysplasias of the stomach is discussed.

Nutritional characteristics of a neoglycoprotein, casein modified covalently by glucose. Glucose was combined covalently with the epsilon-amino groups of lysyl residues of bovine casein in the presence of sodium cyanoborohydride as a reducing reagent by reductive alkylation, forming stable secondary amine linkages. Solubility characteristics and nutritional values of the neoglycoprotein were examined. The degree of modification (%) of the glucosylated casein was 82.5. Solubility of the modified casein was increased by the attachment of glucose. The modification did not disturb the digestion of casein by pepsin or trypsin. Rat feeding experiments using 10% protein diets demonstrated that the protein efficiency ratio (PER) of the modified casein was 0.35 +/- 0.33 compared with 2.99 +/- 0.29 for the unmodified casein. When the modified casein was supplemented with L-lysine to equal the level of total lysine of unmodified casein, the PER value was increased to 2.21 +/- 0.29. Nitrogen balance experiments showed that the modified casein was digested completely. On the other hand, biological value and net protein utilization of the modified protein were shown to be considerably lower than those of the unmodified casein.

Enterohepatic circulation of clioquinol in the rat. The existence of the enterohepatic circulation (EHC) of clioquinol was confirmed by using paired rats, donor and recipient, which were connected to each other with a bile duct-to-duodenum cannula. The concentrations of clioquinol and its metabolites appearing in the plasma of the recipient following intraduodenal 10 mg/kg dose of clioquinol to the donor were fairly low. However, within 24 h after the administration ca. 12% of the dose was reexcreted in the bile of the recipient as clioquinol glucuronide and ca. 2% in the urine as clioquinol sulfate. From these results and the data of biliary excretion in our previous paper, the glucuronide was found to play a role on the EHC. Further, both in vitro and in situ results suggested that clioquinol glucuronide excreted in the bile may be absorbed partially after return to the parent drug in the intestinal tract and partially as such without deconjugation.

Retinal nerve fiber layer birefringence evaluated with polarization sensitive spectral domain OCT and scanning laser polarimetry: a comparison. A polarization-sensitive spectral domain optical coherence tomography (PS-SD-OCT) system is used to measure phase retardation and birefringence of the human retinal nerve fiber layer (RNFL) in vivo. The instrument records three parameters simultaneously: intensity, phase retardation and optic-axis orientation. 3D data sets are recorded in the optic nerve-head area of a healthy and a glaucomatous eye, and the results are presented in various ways: En-face phase-retardation maps of the RNFL are generated from the recorded 3D data and results are compared with scanning laser polarimetry (SLP). The depth information provided by OCT is used to segment the RNFL in the intensity image and measure the RNFL thickness. From the retardation and thickness data, 2D birefringence maps of the RNFL are derived. Circumpapillary plots of RNFL retardation and thickness obtained by PS-SD-OCT are quantitatively compared with those obtained by SLP.

Kinetic interactions of glycine with substrates and effectors of phosphenolpyruvate carboxylase from maize leaves. Glycine enhanced the sensitivity of maize phosphenolpyruvate carboxylase to the activator glucose 6-phosphate and reduced the sensitivity of the enzyme to the inhibitors malate and aspartate. The effects of glycine on the kinetic constants for these other effectors were greater than its effect on the Km for substrate, raising the Ki(malate) 11-fold and reducing Ka(glucose6-P) 7-fold, while reducing the Km(PEP) by 3-fold. Kinetically saturating levels of glycine and glucose 6-phosphate acted synergistically to raise Ki(malate) higher than that observed with either activator alone. Glycine and glucose 6-phosphate also synergistically reduced aspartate inhibition. Dual inhibitor analysis indicated that aspartate and malate bind in a mutually exclusive manner, and thus probably compete for the same inhibitor site. In contrast, the synergism between glycine and glucose 6-phosphate indicate that these activators bind at separate sites. Glycine also reduced the Km(Mg) by 3-fold but had no significant effect on the Km of bicarbonate.

Early hyperglycemia following alloxan administration in vivo is not associated with altered hepatic mitochondrial function: acceptable model for type 1 diabetes? Alloxan and oxidative stress, which have been detected in livers of laboratory animals shortly after in vivo alloxan administration, cause in vitro mitochondrial dysfunction, thus questioning alloxan diabetes as an acceptable model for type 1 diabetes, a model that cannot legitimately be used to investigate mitochondrial metabolism in a diabetic state. In the current study, the blood glucose concentration increased in the drug-treated group of Sprague-Dawley rats (compared with the placebo group) 45 or 60 min after alloxan treatment, whereas at 30 min the blood glucose concentration was unchanged. State 4, state 3, respiratory control, efficiency of oxidative phosphorylation, and mitochondrial ATP synthase activity, assayed using glutamate plus malate, pyruvate plus malate, or succinate as a substrate, were not negatively altered during the entire study. These results indicated that early increases of blood glucose concentration, after in vivo alloxan administration, did not lead to liver mitochondrial dysfunction, suggesting that alloxan diabetes can be used for the study of liver mitochondrial respiration in a diabetic state.

Not just about sunburn--the ozone hole's profound effect on climate has significant implications for Southern Hemisphere ecosystems. Climate scientists have concluded that stratospheric ozone depletion has been a major driver of Southern Hemisphere climate processes since about 1980. The implications of these observed and modelled changes in climate are likely to be far more pervasive for both terrestrial and marine ecosystems than the increase in ultraviolet-B radiation due to ozone depletion; however, they have been largely overlooked in the biological literature. Here, we synthesize the current understanding of how ozone depletion has impacted Southern Hemisphere climate and highlight the relatively few documented impacts on terrestrial and marine ecosystems. Reviewing the climate literature, we present examples of how ozone depletion changes atmospheric and oceanic circulation, with an emphasis on how these alterations in the physical climate system affect Southern Hemisphere weather, especially over the summer season (December-February). These potentially include increased incidence of extreme events, resulting in costly floods, drought, wildfires and serious environmental damage. The ecosystem impacts documented so far include changes to growth rates of South American and New Zealand trees, decreased growth of Antarctic mosses and changing biodiversity in Antarctic lakes. The objective of this synthesis was to stimulate the ecological community to look beyond ultraviolet-B radiation when considering the impacts of ozone depletion. Such widespread changes in Southern Hemisphere climate are likely to have had as much or more impact on natural ecosystems and food production over the past few decades, than the increased ultraviolet radiation due to ozone depletion.

Normal pharyngoesophageal motility. A study of 50 healthy subjects. Upper esophageal manometry is technically problematic. Published normal values are, therefore, few and wide ranging, reflecting catheter and recording-system variables, while the reproducibility of measurements and the influence of food consistency have been little studied. In this investigation, 50 healthy volunteers were studied with (1) a 2.8-mm-diameter six-sensor catheter-mounted transducer assembly and (2) a 3.2 X 7.2-mm sleeve device linked to a computerized recorder with a pressure-sample rate of 32/sec. The study protocol included water, bread, and semisolid swallows. Upper esophageal sphincter (UES) tonic pressures measured with the catheter-mounted assembly were lower and more reproducible than pressures measured with the sleeve system. Compared with water, bread swallows showed greater pharyngeal and sphincter after-contraction pressures, while semisolid swallows had less complete sphincter relaxation. Duration of pharyngoesophageal contractions was greater with bread or semisolid than water. The observations have established normal values for measurements of UES function and, in addition, have shown that (1) catheter variables significantly influence the measurement of upper sphincter tonic pressure, (2) pressures recorded with the catheter-mounted transducer are most reproducible, and (3) pharyngoesophageal motility patterns vary significantly according to the substance swallowed.

Protective role of Melissa officinalis L. extract on liver of hyperlipidemic rats: a morphological and biochemical study. In this study, the effects of Melissa officinalis L. extract on hyperlipidemic rats were investigated, morphologically and biochemically. The animals were fed a lipogenic diet consisting of 2% cholesterol, 20% sunflower oil and 0.5% cholic acid added to normal chow and were given 3% ethanol for 42 days. The plant extract was given by gavage technique to rats to a dose of 2 g/kg every day for 28, 14 days after experimental animals done hyperlipidemia. The degenerative changes were observed in hyperlipidemic rats, light and electron microscopically. There was a significant increase in the levels of serum cholesterol, total lipid, alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP), a significant decrease in the levels of liver tissue glutathione (GSH), a significant increase in the levels of tissue lipid peroxidation (LPO) in this group. On the other hand, the administration of Melissa officinalis L. extract reduced total cholesterol, total lipid, ALT, AST and ALP levels in serum, and LPO levels in liver tissue, moreover increased glutathione levels in the tissue. As a result, it was suggested that Melissa officinalis L. extract exerted an hypolipidemic effect and showed a protective effect on the liver of hyperlipidemic rats.

Post-caesarean delivery analgesia in resource-limited settings: a narrative review. Post-caesarean pain is an important and often neglected outcome. It causes suffering, affects breastfeeding and is associated with postpartum depression and the development of chronic pain syndromes. Pain control is often difficult even in resource-rich environments; it is likely far worse in resource-limited settings, where emphasis is on reducing the high maternal mortality rate. Lack of adequate staffing, education, and postoperative monitoring severely limit the options in resource-limited settings. Resource-limited settings are further compromised by limited access to essential analgesic drugs and equipment for their administration. Solutions using affordable and accessible medications as part of a multimodal analgesic strategy are possible, supplemented by education and training programmes. More research is required, both to establish current practice and to test methods for improving maternal pain control. While government involvement is necessary to improve infrastructure and resources in individual countries, other solutions should also be sought, empowering local institutions and harnessing individual cultural characteristics.

Fulminant endocarditis due to infection with penicillinase-producing Neisseria gonorrhoeae. Endocarditis is a rare but potentially lethal manifestation of gonococcal infection. We report the case of a patient with fulminant endocarditis secondary to infection with penicillinase-producing Neisseria gonorrhoeae (PPNG). The patient had rapid deterioration from extensive destruction of the aortic valve with abscess and fistula formation. Lifesaving emergency surgery was performed. To our knowledge this is the first reported case of gonococcal endocarditis secondary to infection with a penicillinase-producing organism.

Measurement of specific airway conductance in guinea pigs. A noninvasive method. A constant volume plethysmographic technique has been developed to measure specific airway conductance (sGaw) in unanesthetized spontaneously breathing guinea pigs. The technique utilizes a specially designed animal restraining device and mask piece. sGaw is measured at end-expiration and does not require knowledge of thoracic gas volume. Control values are within the range reported previously for this species. The method is noninvasive with minimum stress to the animals. Exposure of guinea pigs to an aerosol of cotton dust extract produces similar qualitative changes (a fall) in sGaw to those observed in human volunteers exposed to the same aerosol. The method is proposed as a suitable model for the study of byssinosis (the occupational lung disease associated with chronic exposure to cotton dust). The technique may also be applied to the acute and chronic study of the airway response to other airborne pharmacological and toxicological agents.

Outcome of women referred to colposcopy for persistently inadequate smears. The outcome of referral to colposcopy of 240 women who had persistently inadequate smears was investigated. Of 232 women who attended colposcopy, 214 (92.2%) had a normal outcome, 12 (5.2%) had low grade abnormalities, and six (2.6%) had high grade abnormalities. This group of women therefore has a negligibly increased risk of harbouring cervical neoplasia. Although not directly comparable, women with a history of previous abnormal cytology did not have a higher risk than those without such a history. Unnecessary colposcopy could have been avoided in the majority of cases if a good quality repeat smear had been taken. Improved smear taker training could decrease the number of referrals. A hospital cytology clinic is proposed as a cost-effective alternative to colposcopy at the first attendance.

Challenges to achieving appropriate and equitable access to Caesarean section: ethnographic insights from rural Pakistan. Access to Caesarean section (C-section) remains inadequate for some groups of women while others have worryingly high rates. Understanding differential receipt demands exploration of the socio-cultural, and political economic, characteristics of the health systems that produce them. This extensive institutional ethnography investigated under- and over-receipt of C-section in two rural districts in Pakistan - Jhelum and Layyah. Data were collected between November and July 2013 using semi-structured interviews from a randomly selected sample of 11 physicians, 38 community midwives, 18 Lady Health Visitors and nurses and 15 Traditional Birth Attendants. In addition, 78 mothers, 35 husbands and 23 older women were interviewed. The understandings of birth by C-section held by women and their family members were heavily shaped by gendered constructions of womanhood, patient-provider power differentials and financial constraints. They considered C-section an expensive and risky procedure, which often lacked medical justification, and was instead driven by profit motive. Physicians saw C-section as symbolizing obstetric skill and status and a source of legitimate income. Physician views and practices were also shaped by the wider health care system characterized by private practice, competition between providers and a lack of regulation and supervision. These multi-layered factors have resulted in both unnecessary intervention, and missed opportunities for appropriate C-sections. The data indicate a need for synergistic action at patient, provider and system levels. Recommendations include: improving physician communication with patients and family so that the need for C-section is better understood as a life-saving procedure, challenging negative attitudes and promoting informed decision-making by mothers and their families, holding physicians accountable for their practice and introducing price caps and regulations to limit financial incentives associated with C-sections. The current push for privatization of health care in low-income countries also needs scrutiny given its potential to encourage unnecessary intervention.

Heterogeneous cytokine production by acutely stimulated bronchoalveolar T lymphocytes in reovirus 1/Lang-infected mice. While the in vitro properties of CD4(+) and CD8(+) cytokine-producing lymphocytes have been well studied, the in vivo cytokine production patterns and relative roles of CD4(+) and CD8(+) T lymphocytes during a primary in vivo immune response remain unclear. In this study, mice were inoculated intranasally with reovirus 1/L, and respiratory T lymphocyte populations were analyzed using multicolor flow cytometric analysis for the production of cytokine within and between classical type 1/type 2 patterns. Cytokine production observed in vivo following infection did not correlate with classical T cell cytokine expression patterns; instead, multiple types of lymphocyte populations that produced one of several possible cytokine combinations were present. Cytokine production by CD4(+) lymphocytes appears in the early and middle stages of the immune response, while CD8(+) lymphocytes produce more cytokine in the later stages. Early cytokine responses occurred predominantly in the whole lung and lung-associated lymph node populations. The complex patterns of cytokine expression seen in this study likely influence local cell-mediated immunity as well as the complex interaction of T cell subsets and the interaction of T cells with B cells which are necessary for the generation of cell-mediated and humoral immune responses required for effective broad-spectrum immunity.

Successful use of calcium channel blocker for management of arterio-venous malformations following Fontan procedure. In diffuse forms of arteriovenous malformation following Fontan procedure, "classical" medical therapy, inhaled nitric oxide and sildenafil, may play a role, until re-direction of hepatic flow to pulmonary circulation cures it. However, in refractory cases, as reported in our 2-year-old patient, unusual medications such as calcium channel blockers can be tried and continued if patients respond adequately.

Uses of enthalpy-entropy compensation in protein research. Cooperative systems of proteins and small molecules form most of biology but are so weakly linked that conventional mass-law formalism requiring exact stoichiometry is inapplicable. The weaknesses cannot be eliminated but using selected families of reactions useful fragmentation of those quantities is often possible. Extra-thermodynamic treatments based on linear-free-energy relationships (LFE) are developed to utilize enthalpy, entropy and volume information not otherwise reliable Linkage systems build around mesophilic proteins are well suited to enforced marriage of linear equations and scaled molecule detail because the ratio of substructure sizes on which folded stability depends is independent of total number of amino-acid residues. Conformational changes in physiological function usually no greater than 0.5 A closely scale to linear thermodynamic changes. The formalisms for use of LFE and compensation relationships are modified to eliminate complications that have previously arisen from incorrect inclusion of the thermal parts of enthalpy and entropy changes in free energy changes. The results are used to remove current confusion about the basis of folded stability in proteins and to minimize the quantitative errors arising from classical treatments of denaturation data. The enthalpy to entropy ratio given by the slope of a compensation plot (its 'compensation temperature') is used to characterize protein construction and function so as to extract machine descriptions of protein linkage systems. In this way the 'fragile' nature of the free-energy surfaces of the myoglobin proteins and the 'strong' character of those surfaces of most other mesophiles can be deduced very simply from the Debye-Waller factors obtained in diffraction studies. The major evolutionary achievement in making proteins big is their crystallike phase behavior. That makes entropy exactly as important as enthalpy so the scalar quantities of small-molecule chemistry can be replaced by the vector quantities that appear necessary to make biology possible.

Proton facility economics: the importance of "simple" treatments. Given the cost and debt incurred to build a modern proton facility, impetus exists to minimize treatment of patients with complex setups because of their slower throughput. The aim of this study was to determine how many "simple" cases are necessary given different patient loads simply to recoup construction costs and debt service, without beginning to cover salaries, utilities, beam costs, and so on. Simple cases are ones that can be performed quickly because of an easy setup for the patient or because the patient is to receive treatment to just one or two fields. A "standard" construction cost and debt for 1, 3, and 4 gantry facilities were calculated from public documents of facilities built in the United States, with 100% of the construction funded through standard 15-year financing at 5% interest. Clinical best case (that each room was completely scheduled with patients over a 14-hour workday) was assumed, and a statistical analysis was modeled with debt, case mix, and payer mix moving independently. Treatment times and reimbursement data from the investigators' facility for varying complexities of patients were extrapolated for varying numbers treated daily. Revenue assumptions of $X per treatment were assumed both for pediatric cases (a mix of Medicaid and private payer) and state Medicare simple case rates. Private payer reimbursement averages $1.75X per treatment. The number of simple patients required daily to cover construction and debt service costs was then derived. A single gantry treating only complex or pediatric patients would need to apply 85% of its treatment slots simply to service debt. However, that same room could cover its debt treating 4 hours of simple patients, thus opening more slots for complex and pediatric patients. A 3-gantry facility treating only complex and pediatric cases would not have enough treatment slots to recoup construction and debt service costs at all. For a 4-gantry center, focusing on complex and pediatric cases alone, there would not be enough treatment slots to cover even 60% of debt service. Personnel and recurring costs and profit further reduce the business case for performing more complex patients. Debt is not variable with capacity. Absent philanthropy, financing a modern proton center requires treating a case load emphasizing simple patients even before operating costs and any profit are achieved.

5-HT1A/7 receptor agonist excites cardiac vagal neurons via inhibition of both GABAergic and glycinergic inputs. To study the synaptic mechanisms involved in the 5-hydroxytryptamine1A/7 (5-HT1A/7) receptor-mediated reflex control of cardiac vagal preganglionic neurons (CVPN). CVPN were retrogradely labeled and identified in brain stem slices of newborn rats, and their synaptic activity was examined using whole-cell patch-clamp. 8-Hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT), an agonist of 5-HT1A/7 receptors, had no effect on the glutamatergic inputs of CVPN. In contrast, it significantly decreased the frequency and the amplitude of both the GABAergic and the glycinergic spontaneous inhibitory postsynaptic currents (sIPSC). 8-OH-DPAT also caused significant amplitude decrease of the GABAergic currents evoked by stimulation of the nucleus tractus solitarius. Both the frequency inhibition and the amplitude inhibition of the GABAergic and the glycinergic sIPSC by 8-OH-DPAT had dose-dependent tendencies and could be reversed by WAY-100635, an antagonist of 5-HT1A/7 receptors. In the pre-existence of tetrodotoxin, 8-OH-DPAT had no effect on the GABAergic or the glycinergic miniature inhibitory postsynaptic currents, and had no effect on the GABAergic or the glycinergic currents evoked by exogenous GABA or glycine. The 5-HT1A/7 receptor agonist excites CVPN indirectly via the inhibition of both the GABAergic and glycinergic inputs. These findings have at least in part revealed the synaptic mechanisms involved in the 5-HT1A/7 receptor-mediated reflex control of cardiac vagal nerves in intact animals.

Serologic assay based on gliadin-related nonapeptides as a highly sensitive and specific diagnostic aid in celiac disease. Celiac disease (CD) is induced by wheat gliadins and related cereal proteins. Anti-gliadin antibodies (AGAs) are present in the serum of CD patients, but these antibodies have lower diagnostic specificity and sensitivity than autoantibodies [anti-endomysium antibodies (AEmAs) and anti-tissue transglutaminase antibodies (AtTGAs)]. Recently, AGAs from CD patients were found to recognize deamidated gliadin peptides, probably formed by the action of tissue transglutaminase. We synthesized several gliadin peptides and their glutamine-glutamic acid-substituted counterparts on cellulose membranes and tested their recognition by IgA in sera of 52 AEmA-positive CD patients and 76 AEmA-negative controls in a luminescence assay. For comparison, we assayed IgA concentrations of AGAs, AtTGAs, and AEmAs. For measurement of AtTGAs, we used the human recombinant antigen. We identified several nonapeptides that were detected with high specificity by IgA in CD patients. Diagnostic accuracy of the peptide antibody assay was highest when peptide PLQPEQPFP was used in combination with peptide PEQLPQFEE within one assay. AGAs were above the cutoff in 14 of the controls, but only 5 of the controls were positive for peptide antibodies. For comparison, 82% and 94% of samples were correctly classified by AGAs and the combination nonapeptide assay, respectively (P = 0.007), and the AtTGAs correctly classified 98%. The peptide antibody assay has higher diagnostic accuracy than AGAs for distinguishing patients with CD from controls, and has diagnostic accuracy similar to that of AtTGAs.

Functional in vivo interaction between growth hormone and dopamine systems are correlated to changes in striatal somatostatin levels as detected by voltammetry. The effects of growth hormone (GH) and somatomedin C (SmC), as well as those of apomorphine, dopamine (DA) agonist, or haloperidol (DA antagonist), upon the size of striatal voltammetric peaks 2 and 5 were investigated. Local intrastriatal injections of GH or SmC were followed by an increase in the height of both peak 2 (corresponding to the oxidation of extracellular dihydrophenylacetic acid, DOPAC, a metabolite of DA) and peak 5 (which may represent the oxidation of striatal extracellular somatostatin, SRIF). Treatment with haloperidol also increased the size of the striatal catechol peak but was responsible for a reduction of the neuropeptidergic signal. By contrast, apomorphine determined a decrease in striatal peak 2 (DOPAC) while increasing the levels of peak 5 (SRIF). The data further support the chemical identification of peak 5 at +800 mV as related to the in vivo oxidation of SRIF; in addition they indicate the presence of a functional relationship between this neuropeptide and the GH and DA systems in the striatum of anaesthetised rats.

Global Scientific Outputs of Brain Death Publications and Evaluation According to the Religions of Countries. In 1950s, the concept of brain death, which began to be discussed primarily in terms of medicine and then in terms of religion, law, and ethics, became a central topic in all world countries as it was an early diagnosis of death. Despite the fact that brain death (BD) diagnosis is of importance for benefitting from organ and tissue transplantation of patients in the world, the literature still involves no bibliometric studies that made a holistic evaluation of the publications about this issue. The present study aims to investigate the top-cited articles about BD published between 1980 and 2018, identify the citation collaboration of the journals, demonstrate the collaboration between the countries, define the relationship between organ transplantation and BD, and reveal the latest developments and trend topics about this issue. In addition, this study aims to investigate the relationship between religions of countries and brain death publication productivity. Documents for bibliometric analysis were downloaded from Web of Science. The literature search was performed using the keywords "brain death/dead" during 1980-2018. The correlations between gross domestic product (GDP), Human Development Index (HDI) and publication productivity of the countries on BD were investigated with Spearman's correlation coefficient. There was a high-level, statistically significant correlation between the number of publications and GDP, and HDI and the number of publications about BD (r = 0.761, p < 0.001; r = 0.703, p < 0.001). The USA was the top country in terms of publication productivity, which was followed by developed countries such as Germany, Japan, France, and Spain. However, the contribution of the undeveloped or developing countries such as China, Brazil, Turkey, Iran, and South Africa was found to be considerably important. While many people in the world die with undamaged organs, many other people die needing those organs. Therefore, it is considered that the collaborations and thus multidisciplinary studies about BD should be increased in the world countries, and the countries should be involved in bigger collaborations instead of little clusters. Especially, Muslim countries should be encouraged to do research and publish studies about the issues of brain death and organ transplantation.

Radical retropubic prostatectomy--report on 41 cases. Anatomic radical retropubic prostatectomy is an effective method for long-term control of the prostatic carcinoma. In the current era of the anatomic prostatic surgery, blood loss is reduced, complication rate is low and control of the disease may be excellent. Some authors reported cancer-specific survival rate after the radical retropubic prostatectomy of 85-90% over the 10-year period and 82% over the 15-year period. The survival may be more favorable in the patients with lower Gleason scores. The former indicates that radical retropubic prostatectomy is an excellent therapeutic option for treatment of the localized prostatic carcinoma, while selection of patients is a crucial factor for true success of therapy based on this method.

Autologous blood transfusion: standard of care for the 1990s. The risks of transmission of devastating and sometimes fatal viral infections from homologous blood transfusion have caused concern among patients undergoing elective major surgical procedures. Autologous blood transfusions eliminate the potential risk posed by these viruses. A well-informed primary care physician can help patients undergoing elective surgical procedures to determine whether autologous blood transfusion is an appropriate therapeutic alternative. A well-equipped and certified blood bank will allow patients to donate autologous units while keeping patient risk at a minimum.

Genetic counseling in families with inherited balanced translocations: experience with 36 families. We report on genetic counseling and investigations in 36 families with inherited balanced translocations ascertained in different ways, with special regard to the completeness and reasons for incompleteness of family investigation. Quantitative evaluation of the results of cytogenetic investigations shows that non-directive genetic counseling was very effective in many families. Yet, in most of the families (34) genetic counseling and investigation remained incomplete in the sense that not all living potential translocation carriers could be counseled or investigated or that the origin of a fresh mutation could not be established by a normal karyotype in the parents of a carrier. Only in seven families could nearly all living potential carriers be counseled and investigated. The most frequent reason for incompleteness was the impossibility of transmitting or refusal to transmit information about the genetic risks to relatives (21 families), whereas direct rejection of investigation by a counseled individual was a rather rare event (18 adults). Families ascertained because of an unbalanced child seem to be more willing to transmit genetic information to relatives than families ascertained in other ways. Non-directive genetic counseling gave us an insight into the emotional problems arising during counseling of translocation families.

A simplified method of total contact casting for diabetic foot ulcers. A simplified method of total contact casting for diabetic plantar ulcerations is described in which a standard, well-molded short-leg walking cast is applied. Weekly cast changes are performed initially, followed by longer cast change intervals. Either fiberglass or plaster casting tape appears equally efficacious. Healing of all ulcers was demonstrated in 12 patients treated with this technique.

E2F - at the crossroads of life and death. The retinoblastoma tumor suppressor, pRb, restricts cell-cycle progression mainly by regulating members of the E2F-transcription-factor family. The Rb pathway is often inactivated in human tumors, resulting in deregulated-E2F activity that promotes proliferation or cell death, depending on the cellular context. Specifically, the outcome of deregulated-E2F activity is determined by integration of signals coming from the cellular DNA and the external environment. Alterations in cell proliferation and cell-death pathways are key features of transformed cells and, therefore, an understanding of the variables that determine the outcome of E2F activation is pivotal for cancer research and treatment. In this review, we discuss recent studies that have elucidated some of the signals affecting E2F activity and that have revealed additional E2F targets and functions, thereby enriching the understanding of this versatile transcription-factor family.

Effect of histamine on human placental chorionic veins: interaction with serotonin. The vasomotor effects of histamine and its interaction with serotonin were studied in isolated human placental chorionic veins. Histamine induced concentration-dependent contractions with an EC50 of 8.7 +/- 1.2 x 10(-6) mol/l. The H1 antagonist, pyrilamine (10(-9) to 10(-7) mol/l), inhibited histamine-induced contractions, with a pA2 of 8.33 +/- 0.32 at a slope of 0.635. Cimetidine (H2 antagonist) had no effect on histamine-induced contractions. Serotonin (10(-9) to 10(-8) mol/l) significantly potentiated the contractile effect of histamine. The possible implications of the interaction between both amines in the regulation of placental blood flow is discussed.

Quantum Statistical Mechanical Derivation of the Second Law of Thermodynamics: A Hybrid Setting Approach. Based on quantum statistical mechanics and microscopic quantum dynamics, we prove Planck's and Kelvin's principles for macroscopic systems in a general and realistic setting. We consider a hybrid quantum system that consists of the thermodynamic system, which is initially in thermal equilibrium, and the "apparatus" which operates on the former, and assume that the whole system evolves autonomously. This provides a satisfactory derivation of the second law for macroscopic systems.

Parkinsonism with basal ganglia lesions in a patient with uremia: Evidence of vasogenic edema. Parkinsonian syndromes associated with basal ganglia pathology have very rarely been reported in patients with end-stage renal failure. The nature and pathophysiology of the basal ganglia lesion responsible for parkinsonism were unknown. A 48-year-old man who had advanced renal failure developed disturbance of balance and gait and decreased spontaneity. Brain magnetic resonance (MR) imaging disclosed bilateral basal ganglia lesions. By the finding of diffusion-weighted image, the apparent diffusion coefficient map, MR angiography, and SPECT, we suggest that the basal ganglia lesions may be the result of vasogenic edema attributable to focal hyperemia secondary to abnormal dilatation of small vessels.

Therapeutic proposals for the treatment of idiopathic constipation. The objectives to be achieved by a medical therapy of constipation are: 1) to protect the patient from excessive use of dangerous drugs (laxatives), 2) to help the patient to understand what is a "normal" intestinal function, 3) to reduce or eliminate pain and 4) to avoid complications. The first step consists in general measures (reduced stress, regular meals and physical exercise) and some modifications in diet habits (greater than 1.5 1 of water a day, vegetables, fruits, whole wheat bread). The pharmacological therapy is based on drugs which act in different ways: a) some contain unabsorbable substances (i.e. cellulose, emicellulose) that increase the volume of the stools: b) unabsorbable sugars (i.e. lactulose, lactose) or salts (Mg-sulphate, citrate and Na-sulphate) that provoke an osmotic effect and stimulate the colonic motility; c) suppositories that stimulate the defecation reflex; d) drugs able to stimulate colonic secretion and propulsive motility (i.e. anthraquinones, oral bisacodyl, phenolphthalein, castor oil, prokinetics). There are many conditions in which medical therapy fails its objective: in these cases it is important to exclude other causes of constipation (i.e. drug-related constipation, endocrine disorders, metabolic diseases, systemic illnesses or lesion of the enteric plexus) in order to obtain an improvement of this symptom.

Race and risk of maternal vascular malperfusion lesions in the placenta. The biological mechanisms that underlie racial disparities in placenta-mediated pregnancy complications remain unknown. Placental evidence of maternal vascular malperfusion (MVM), a common pathologic feature of these outcomes, represents hypoxic-ischemic damage to the placenta. We sought to separately estimate the risk of MVM and individual lesions associated with maternal race. This was a retrospective cohort study of black and white women with singleton live births and placental pathology data at Magee-Womens Hospital during 2008-2012 (n = 15,581). MVM consisted of ≥1 individual lesions: low placental weight, decidual vasculopathy, accelerated villous maturation, infarcts, and fibrinoid deposition. We separately compared the incidence of MVM and individual lesions in black and white women using logistic regression with generalized estimating equations. After adjusting for covariates, black women had increased risks of MVM (aOR 1.14, 95% CI 1.05-1.23), low placental weight (aOR 1.41, 95% CI 1.28-1.55), and decidual vasculopathy (aOR 1.58, 95% CI 1.36-1.83), also observed in uncomplicated, preterm, and term births. Conversely, black women had decreased risk of infarcts (aOR 0.84, 95% CI 0.75-0.95) compared with white women, also observed in uncomplicated and full-term births. Race was not associated with accelerated villous maturation or fibrinoid deposition. Inverse probability weighting to account for potential selection bias generated similar results. Our findings suggest that excess risks of MVM, specifically low placental weight and decidual vasculopathy in black women may be due to a pathological susceptibility to an underlying high-risk vascular phenotype. The clinical significance of race differences in the occurrence of infarcts warrants further investigation.

[Hypothalamic factors in the human fetal brain: their role in the ontogeny of fetal hypophyseal functions]. The anterior pituitary gland of the human fetus has the ability of synthetizing, storing and secreting hormones early during gestation. The patterns of plasma concentrations of hGH, ACTH, LH and FSH during gestation indicate a maximum of secretion at mid-gestation followed by a progressive decrease of these concentrations until term. In contrast, the secretions of PRL and TSH are moderate at mid-gestation and only increase in the last trimester of gestation. Effective control by the central nervous system (CNS) of the pituitary secretions is still immature at mid-gestation. The presence of releasing factors in the fetal hypothalamus has been established (TRF, LRF, somatostatine) and it was postulated that early in life, relatively autonomous and unrestrained secretion of hypothalamic hypophysiotropic releasing factors occurs and, later in development, there was a maturation of inhibitory or restraining influences mediated via the CNS that modulate the secretion of the fetal adenohypophyseal hormones. Observations made with anencephalic newborns confirm that a functional hypothalamus is necessary for the secretions of each of the hormones of the anterior pituitary gland with the exceptiion of PRL, the secretion of which is normal in anencephaly. Although somatostatin probably participates in the regulation of hGH during fetal life, it appears evident that this regulation can only be fully understood with the existence of a GRF (Growth Hormone Releasing Factor).

Donor buffy-coat infusion and chemotherapy for leukemia in relapse after marrow transplantation. A patient relapsing with blastic lymphoid transformation of chronic myeloid leukemia after bone marrow transplantation received donor buffy-coat infusion. Low-dose chemotherapy was added because of a rapid WBC increase. Complete hematologic and cytogenetic remission was obtained. The patient remained in complete hematologic and cytogenetic remission for four months until he died in an accident. Two patients with acute leukemia failed to respond to a similar treatment.

The role of videothoracoscopy in the diagnosis and treatment of chest diseases. Recent developments in video camera techniques, new instruments and advanced surgical techniques have increased the importance of thoracoscopy in both the diagnosis and therapy of diseases of the chest. Many diseases previously demanding open thoracotomy (i.e. spontaneous pneumothorax, biopsies of lung, pleura and mediastinum, several benign intrathoracic tumours, achalasia and reflux disease of the esophagus) can, today, be treated by video-assisted thoracic surgery with the same results as by using open procedures. The advantages of this technique compared to open thoracotomy include less operative trauma, less postoperative pain, good cosmetic results and shorter hospital stay. The drawbacks are the more difficult technique, demanding special education, the possibility of inadequate radicality in the treatment of malignant diseases and the necessity of longer operating time. The physician performing thoracoscopic surgery must also master the techniques of open procedures.

Purification, Characterization of Amylase from Indigenously Isolated Aureobasidium pullulans Cau 19 and Its Bioconjugates with Gold Nanoparticles. The amylase from Aureobasidium pullulans Cau 19 was purified by ammonium sulfate precipitation and Sephadex G-100 chromatography with a 9.25-fold increase in specific activity as compared to crude enzyme. Km and turn over values of the enzyme were 6.25 mg/mL and 5.0 × 102/min, respectively. Effect of different metal ions on the purified enzyme was investigated; 1 mM calcium (Ca) and cobalt (Co) enhanced enzyme activity by twofold; copper (Cu) had no effect on the activity of the enzyme. Mercury (Hg) 1 mM caused 90% inactivation whereas iron (Fe) and manganese (Mn) caused 10 to 16% inhibition. Amylase from A. pullulans Cau 19 was bioconjugated to gold nanoparticles synthesized using the biomass of A. pullulans Cau 19. Fourier transform infrared spectroscopy confirmed the conjugation of the enzyme to the gold nanoparticles. Though, only 20% of the added enzyme was adsorbed/conjugated on gold nanoparticles, 80% of the adsorbed activity could be estimated in the assay. The conjugated enzyme exhibited better tolerance to a broad pH range of 3.0-9.0 and higher temperatures compared with native enzyme.

Presence of the di-leucine motif in the cytoplasmic tail of the pig FcRn alpha chain. The sequence of the pig FcRn alpha chain was recently published. The lack of a conserved di-leucine motif in the cytoplasmic tail suggests a rare polymorphism in the described animal, alternatively, a sequencing error. We therefore cloned and sequenced the pig FcRn alpha chain. Our sequence, along with a previous NCBI GenBank submission and five pig derived EST clones clearly demonstrate the presence of di-leucine motif in the cytoplasmic tail of the pig FcRn. No polymorphism in the cytoplasmic tail-encoding region was found in 25 animals from six pig breeds based on single-stranded conformation polymorphism and sequencing analysis, suggesting that the previously described pig FcRn alpha chain may represent a sequencing error in the 3' portion of the gene.

[Objective evaluation of vocal pathology in childhood]. Voice disorders in children are often described as existing on a continuum with anatomic or physiologic causes at one end and functional or psychogenic causes at the other. In this study we report the objective evaluation of the voice disorders on 48 school children. The evaluation was made by means of laryngostroboscopy, acoustic analysis of the voice and narrow-band spectrography. The stroboscopic examination was performed on more than a half of the patients, resulting in the change of diagnose in six cases. The severity of the hoarseness was classified in four groups according Yanagihara method. A multivariate analysis was carried out using jitter, shimmer and harmonic-to-noise ratio as variables. Only the harmonic-to-noise ratio predicts the severity of the spectrographic record. Classification of degrees of hoarseness is found to be clinically useful in two respects: the degree of hoarseness can be numerically expressed and the objective acoustic degree of hoarseness based on this method closely agrees with subjective perceived degree of hoarseness.

Exploiting quartz spectral signature for the detection of cloud-affected satellite infrared observations over African desert areas. It is shown that IMG (interferometric monitoring of greenhouse gases) spectra recorded over African and Arabian deserts clearly contain the fingerprint of quartz-rich soils. We illustrate how this spectral signature can be exploited to devise a suitable cloud-detection scheme to identify which infrared observations are affected by clouds. As a by-product, the scheme also allows one to identify the most likely underlying emitting surface type and provides a suitable first guess for the surface emissivity to be used, e.g., for the retrieval of geophysical parameters from high-spectral-resolution infrared radiance from space. The analysis has focused on African deserts because of their intrinsic relevance to numerical weather prediction and Earth's climate. Desert areas, like oceans, are poorly covered by the world meteorological radiosonde network and therefore are geographical regions for which the global coverage capability of satellites soundings is expected to provide better initializations for numerical weather prediction than are now available. Application of the cloud-detection scheme to IMG spectra has been considered, which demonstrates the good performance of the method.

A Better Pathway? Building Consensus and Engaging Providers with Feedback to Improve and Standardize Cancer Care. Unwanted clinical variation is common across the United States health care system and is particularly vexing in oncology owing to the complexity, morbidity, and high cost of the disease. Efforts to standardize care including guidelines and continuing medical education have had only limited impact. Disease-specific oncology clinical pathways hold the promise of reducing variation but have been hampered by a lack of ownership and accountability among oncology providers. We describe the utility of combining a patient simulation-based clinical variation measurement with the in-house development of multidisciplinary breast cancer pathways at a National Cancer Institute-designated cancer center. At baseline, we found high variation in care decisions across the multidisciplinary team and within individual specialties in the management of simulated patients. Development and introduction of breast cancer clinical pathways combined with individual and group feedback on pathway adherence led to significant increases in pathway-aligned care decisions and decreases in measured variation. Overall quality scores increased from 47.5% to 61.1% (P < .001), with the largest improvement in diagnostic accuracy (+22.1%). Providers also ordered fewer unnecessary tests, saving an estimated $305 per patient case. Adherence to preferred chemotherapy regimens increased for both medical oncologists (+16%) and other members of the multidisciplinary team (+19%). Our work shows that a structured process to measure clinical variation and provide personalized feedback to an oncology multidisciplinary team drives adoption of evidence-based pathways, less unneeded spending, and higher quality care for patients.

Further evidence that rats use ordinal timing in a daily time-place learning task. Rats received morning, midday, and afternoon sessions each day in a chamber located in a room containing distal spatial cues. A lever was mounted on each of the four walls. The rats could work for food on a different lever during each of the three sessions. The rats were able to learn the location of food availability during morning, midday, and afternoon sessions. Results obtained after skipped morning, midday, and afternoon sessions support our contention that rats solve this time-place task using ordinal timing, or knowledge of the daily spatiotemporal sequence of food availability. However, during probe sessions when the predicted location of food availability based on ordinal information conflicted with the predictions based on other types of information, behavioural compromise was evident. It appears that rats use multiple types of information, one of which is ordinal timing, to track the location of food availability in the daily time-place task.

Kinesins in the spindle: an update. Eukaryotes contain a superfamily of microtubule-based motor proteins comprising kinesin and a number of related proteins that are thought to participate in various forms of intracellular motility, including cell division and organelle transport. The role of various members of the kinesin superfamily in chromosome segregation and spindle morphogenesis was described in TCB last year in parts of a series on cytoplasmic motor proteins. In this brief update, Helen Epstein and Jon Scholey comment on new findings that have improved our understanding of the functions of kinesin-related proteins in mitosis and meiosis.

The safe introduction of new technologies into neonatal medicine. In neonatal medicine, there is a technologic revolution in progress. During the past 10 years, we witnessed the introduction and improvement of monitoring equipment, the development of new modes of assisted ventilation, and the proliferation of extracorporeal membrane oxygenation. This article reviews how we might improve the process of the safe introduction of new technologies into neonatal medicine.

Assessment of Suny Upstate Medical University's child telepsychiatry consultation program. The project assesses the child telepsychiatry services provided by SUNY Upstate psychiatrists to several county mental health clinics in central New York State. Data for 45 patients was extracted from pre-consultation forms completed by the referring clinic and postconsultation summaries completed by the Upstate psychiatrists that occurred between July 13, 2009 and May 12, 2010. The study identified characteristics of patients for whom telepsychiatry consultations were sought, why they were sought, and reviewed recommended changes in therapy and medication provided by the telepsychiatry consultant. Analysis of the data showed that there was a large variation in patient characteristics such as age (from age 3 to 17), current living situation, and psychological symptoms. In addition to a family history of mental illness (80%), the most common symptoms were physical aggression (60.0%), defiant/oppositional behavior (57.8%), and attentional problems (55.6%). The most common reason for referral was diagnostic clarification (67%). The child telepsychiatrist recommended a change in medication for most (80.8%) of the patients who were on medications, and to begin medications for most (63.2%) who were not receiving medication at the time of consult. Further, the telepsychiatrist often recommended the addition of family therapy (71.1%) and counseling at school (17.8%). The child telepsychiatric program at Upstate seemed effective. It reached a large variety of children with significant mental disorders. The consultants provided diagnostic clarification and recommended modification of treatment for most. However, this assessment is limited as examined as it did not include follow-up information on whether consultant recommendations were followed and, if they were, whether they were effective.

Soluble IgA and IgG aggregates are catabolized by cultured rat mesangial cells and induce production of TNF-alpha and IL-6, and proliferation. IgA nephropathy, a primary glomerulonephritis, is principally characterized by mesangial deposits of IgA immune complexes. Recently, it has been demonstrated that cultured glomerular mesangial cells (MC) express Fc alpha and Fc gamma receptors. In this work, we studied whether the interaction of soluble aggregates of IgA and IgG (AIgA and AIgG) with MC triggers a number of responses, including generation and release of inflammatory mediators, cell proliferation, and catabolism of the complexes. Aggregates bound to MC and were catabolized in a time-dependent manner. The percentage of cell-associated or -degraded proteins decreased in the presence of Fc, but not with Fab fragments. Both AIgA and AIgG elicited the synthesis and release of TNF-alpha and IL-6 in a dose-dependent manner, reaching a maximum between 6 and 12 h, respectively. Northern blot analysis showed that both aggregates induced the expression of mRNA encoding TNF-alpha and IL-6. Because MC proliferation is a morphologic feature commonly observed in patients with IgA nephropathy, we examined whether immune aggregates could be involved in this phenomenon. Both AIgA and AIgG induced an increase in MC number, assessed by [3H]thymidine and methylene blue uptake. The presence of anti-TNF-alpha or anti-IL-6 Abs in the medium decreased the proliferative effect triggered by aggregates. These results show that Fc alpha and Fc gamma receptor occupancy of MC induces the synthesis and release of inflammatory cytokines and proliferation, as well as the phagocytosis of stimulatory proteins. These findings could have implications for the understanding of inflammation and repair in IgA nephropathy.

Sleep problems in young infants and maternal mental and physical health. Sleep problems in the second 6 months of life are common and associated with maternal depression. This paper extends previous research to (i) establish the prevalence of sleep problems in younger infants from a broader socio-economic spectrum, (ii) examine the relationship between infant sleep problems and maternal physical, as well as mental, health, and (iii) explore mothers' sleep quality as a potential mediator of this relationship. Cross-sectional, community survey in Melbourne, Australia. Mothers of 3- to 6-month-old infants (mean 4.6 months) recruited from well-child clinics in six sociodemographically diverse metropolitan local government areas. Maternal mental and physical health; standardised questionnaire on infant sleep patterns; maternal report of an infant sleep problem (yes/no). The survey was completed by 692 mothers; 237 (34%) reported an infant sleep problem, of whom 73 (31%) rated the problem as severe. Sleep patterns characterising a problem included the infant waking seven nights per week, nursing the infant to sleep at the beginning of the night, the infant sleeping in the parent's room, and parental disagreement regarding managing infant sleep. There was no relationship between sleep problems and socio-economic levels. Mothers reporting infant sleep problems had poorer mental and physical health compared with those not reporting sleep problems. Sleep problems are common in early infancy across metropolitan socio-economic levels and are associated with poorer maternal health and well-being. Preventive strategies for infant sleep problems need to begin early in primary care to improve mothers' health.

Growth rate distribution of NH4Cl dendrite and its scaling structure. Scaling structure of the growth rate distribution on the interface of a dendritic pattern is investigated. The distribution is evaluated for an NH4Cl quasi-two-dimensional crystal by numerically solving the Laplace equation with the boundary condition taking account of the surface tension effect. It is found that the distribution has multifractality and the surface tension effect is almost ineffective in the unscreened large growth region. The values of the minimum singular exponent and the fractal dimension are smaller than those for the diffusion-limited aggregation pattern. The Makarov's theorem, the information dimension equals one, and the Turkevich-Scher conjecture between the fractal dimension and the minimum singularity exponent hold.

Genetic population structure of Natterer's bats explained by mating at swarming sites and philopatry. During autumn 'swarming', large numbers of temperate bats chase each other in and around underground sites. Swarming has been proposed to be a mating event, allowing interbreeding between bats from otherwise isolated summer colonies. We studied the population structure of the Natterer's bat (Myotis nattereri), a swarming species in northern England, by sampling bats at seven sites in two swarming areas and at 11 summer colonies. Analysis of molecular variance (amova) and genetic assignment analyses showed that the swarming areas (60 km apart) support significantly different populations. A negative correlation was found between the distance of a summer colony from a swarming area and the assignment of bats to that area. High gene diversity was found at all sites (HE = 0.79) suggesting high gene flow. This was supported by a low FST (0.017) among summer colonies and the absence of isolation by distance or substructure among colonies which visit one swarming area. The FST, although low, was significantly different from zero, which could be explained by a combination of female philopatry and male-mediated gene flow through mating at swarming sites with bats from other colonies. Modelling suggested that if effective size of the summer colonies (Ne) was low to moderate (10-30), all mating must occur at the swarming sites to account for the observed FST. If the Ne was higher (50), in addition to random mating during swarming, there may be nonrandom mating at swarming sites or some within-colony mating. Conservation of swarming sites that support potentially large populations is discussed.

Heterotopic ossification of the shoulder after central nervous system lesion: indications for surgery and results. Heterotopic ossification (HO) of the shoulder after central nervous system damage has seldom been studied. We performed a single-center retrospective study from 1993 to 2009 including patients who underwent surgery for troublesome shoulder HO. Demographic data, HO location, surgical approach, preoperative and postoperative shoulder range of motion, etiologies, and postoperative complications were collected from patients' files. We found 19 shoulder HOs in 16 patients (traumatic brain injury in 11, spinal cord injury in 2, stroke in 1, and cerebral anoxia in 2). The data in 2 files were incomplete and were therefore not used. HO locations around the joint were anteroinferomedial in 4 (21.1%), posteroinferomedial in 5 (26.3%), encircling in 3 (15.8%), superior in 1 (5.3%), and mixed (2 associated HOs that are not encircling) in 6 (31.6%). The surgical approaches were as follows: deltopectoral, 5 (26.3%); Neer, 3 (15.8%); posterior, 5 (26.3%); axillary, 1 (5.3%); Martini, 2 (10.5%); posterior associated with deltopectoral, 2 (10.5%); and Neer (superolateral) associated with deltopectoral, 1 (5.3%). The mean range of motion increased significantly (gain at follow-up of 69°, 60°, and 13° in forward elevation, abduction, and lateral rotation, respectively). Regarding postoperative complications, there was 1 case of capsulitis and 1 reoperation for insufficient excision (because of hemorrhage during surgery). There were no other side effects. Anatomic relations with nerves and vessels, as well as limited range of motion, require a case-by-case surgical approach, a preoperative scan (looking for a gutter), and sometimes, electromyography. Surgical indications depend on the degree of loss of function or hygiene, control of comorbid factors, and discussion with the patient and his or her family.

Super-resolution Microscopical Localization of Dopamine Receptors 1 and 2 in Rat Hippocampal Synaptosomes. Although dopamine receptors D1 and D2 play key roles in hippocampal function, their synaptic localization within the hippocampus has not been fully elucidated. In order to understand precise functions of pre- or postsynaptic dopamine receptors (DRs), the development of protocols to differentiate pre- and postsynaptic DRs is essential. So far, most studies on determination and quantification of DRs did not discriminate between subsynaptic localization. Therefore, the aim of the study was to generate a robust workflow for the localization of DRs. This work provides the basis for future work on hippocampal DRs, in light that DRs may have different functions at pre- or postsynaptic sites. Synaptosomes from rat hippocampi isolated by a sucrose gradient protocol were prepared for super-resolution direct stochastic optical reconstruction microscopy (dSTORM) using Bassoon as a presynaptic zone and Homer1 as postsynaptic density marker. Direct labeling of primary validated antibodies against dopamine receptors D1 (D1R) and D2 (D2R) with Alexa Fluor 594 enabled unequivocal assignment of D1R and D2R to both, pre- and postsynaptic sites. D1R immunoreactivity clusters were observed within the presynaptic active zone as well as at perisynaptic sites at the edge of the presynaptic active zone. The results may be useful for the interpretation of previous studies and the design of future work on DRs in the hippocampus. Moreover, the reduction of the complexity of brain tissue by the use of synaptosomal preparations and dSTORM technology may represent a useful tool for synaptic localization of brain proteins.

Chloroquine and Hydroxychloroquine Increase Retinal Pigment Epithelial Layer Permeability. Antimalarials chloroquine (CQ) and hydroxychloroquine (HCQ) are widely used as antiinflammatory drugs, but side effects include retinopathy and vision loss. The objective of this study was to examine the effect of CQ and HCQ on the barrier integrity of retinal pigment epithelial (RPE) cell monolayers in vitro. Permeability of ARPE-19 cell monolayers was determined using Fluorescein isothiocyanate (FITC)-labeled dextran. The influence of CQ and HCQ on cell death and the expression tight junction molecules was examined. CQ and HCQ significantly increased ARPE-19 monolayer permeability after 3 and 18 h, respectively, and enhanced mRNA levels for claudin-1 and occludin. Cytotoxicity was only observed after 18 h exposure. Thus, CQ and HCQ rapidly enhance RPE barrier permeability in vitro, independent of cytotoxicity or loss of zonula occludens-1, claudin-1, and occludin expression. Our findings suggest that CQ/HCQ-induced permeability of the RPE layer may contribute to blood-retinal barrier breakdown in case of CQ/HCQ-induced retinopathy.

Prevalence and risk factors of anxiety and depression in patients with systemic lupus erythematosus in Southwest China. Systemic lupus erythematosus (SLE) patients have high risk for anxiety and depression. We aimed to investigate the prevalence and risk factors of anxiety and depression in SLE patients in Southwest China. Participants were recruited by convenience sampling from Rheumatic Outpatient Clinic of West China Hospital Sichuan University between August and October 2014. The prevalence of anxiety and depression was evaluated using Hospital Anxiety and Depression Scale (HADS). Risk factors were explored by multiple logistic regression analyses. A total of 352 participants were enrolled, of who 64 (18.2 %) met the HADS criteria for anxiety and 82 (23.3 %) for depression. In multivariable analysis, higher levels of pain (OR = 1.17, P = 0.02) and fatigue (OR = 1.19, P < 0.01) predicted a higher risk of anxiety. Similarly, a higher level of fatigue (OR = 1.2, P < 0.01) was associated with a higher risk of depression. The results suggest that anxiety and depression are common in patients with SLE in Southwest China. Health care providers and SLE patients should take some measures to cope with them as early as possible. Strengthening management of pain and fatigue may be useful. But further studies are needed to verify these findings.

Intranasal nicotine increases postoperative nausea and is ineffective in reducing pain following laparoscopic bariatric surgery in tobacco-Naïve females: a randomized, double blind trial. Nicotine is a known analgesic. Our primary aim was to test the hypothesis that intranasal nicotine administered intraoperatively reduces the need for postoperative opioids. The secondary outcomes included evaluation of both postoperative pain and nausea and vomiting (PONV). Nonsmoking female patients undergoing laparoscopic bariatric operations were randomized to receive either 3 mg intranasal nicotine (N = 42) or placebo spray (N = 47) at the conclusion of surgery. Postoperative opioid use converted to intravenous morphine equivalents (iv MEQ) and PONV rates were recorded during both the recovery room postanesthesia care unit (PACU) stay and the first 24 postoperative hours. All patients received multimodal antiemetic prophylaxis. Total iv MEQ were not significantly reduced during the PACU stay in patients receiving nicotine (median [interquartile range (IQR)], 5.3 [0, 10.0] mg for nicotine vs. 5.2 [0, 12.7] mg for placebo, one-tailed P = 0.414) or for the first 24 h following PACU discharge (39.6 [20.0, 52.5] mg for nicotine vs. 32.7 [20.3, 51.3] mg for placebo, one-tailed P = 0.752). For the combined period (PACU + 24-h post-PACU discharge), iv MEQ were 45.8 [27.0, 58.6] mg for nicotine and 39.4 [23.5, 60.0] mg for placebo, one-tailed P = 0.801. Compared to placebo, a higher percentage of patients administered nicotine received antiemetics in the PACU (57.1 vs. 25.5 %, P = 0.002). Intraoperative intranasal nicotine did not exhibit opioid-sparing effect in nonsmoking bariatric female patients. Despite antiemetic prophylaxis, the use of nicotine was associated with the higher frequency of the use of rescue antiemetics in PACU.

Relevance of Breast Cancer Resistance Protein to Brain Distribution and Central Acting Drugs: A Pharmacokinetic Perspective. Breast Cancer Resistance Protein (BCRP, also known as ABCG2) is gaining momentum as a key transporter that restricts the permeability of a large number of therapeutic agents through the Blood-brain Barrier (BBB). BCRP is highly expressed in the apical membranes of epithelial cells of the small and large intestine, renal proximal tubules and canalicular membrane of hepatocytes, determining the gastrointestinal absorption and biodisposition of its substrates. It is also expressed in the luminal surface of endothelial cells of the BBB and Bloodspinal Cord Barrier (BSCB), where it undoubtedly limits the entry of a wide range of therapeutics into the CNS, potentially contributing to the therapeutic failure of CNS-acting drugs. As the U.S. Food and Drug Administration and the European Medicines Agency recommend pre-clinical evaluation and clinical assessment of BCRP-mediated drug-drug interactions, compounds that are currently recognized as BCRP substrates, inhibitors or inducers will be addressed, focusing on their pharmacokinetic behaviour in plasma and brain. Recent studies indicated a strong BCRP expression in the microvasculature of the BBB in brain tumors, hypothesizing that this phenomenon critically influences the penetration of drugs in these tumors and potentially contributes to the failure of antitumor therapy. BCRP expression in brain tissue from patients or animal models of neurological and neurodegenerative diseases has also been investigated, and the role of BCRP and its implications for novel therapeutic interventions was also herein demonstrated. The clinical significance of BCRP in drugs disposition is currently undeniable.

Attitudes of Ohio hospital pharmacy directors toward national voluntary pharmacy technician certification. Ohio pharmacy directors' attitudes about national voluntary pharmacy technician certification were surveyed. In May 1996 a questionnaire was mailed to all 224 hospitals in Ohio. The questionnaire contained 29 attitudinal statements constructed as forecasts of the effects of certification; pharmacy directors were asked to rate their level of agreement or disagreement with each statement using a 7-point Likert scale. The response rate was 61.4% (137 questionnaires returned). Respondents indicated modest agreement with 21 of 27 attitudinal statements and therefore had a generally positive view of certification. For example, they agreed that certification will improve technicians' knowledge, image, confidence, skills, and job satisfaction. They disagreed that certification will allow technicians to function independently, result in the replacement of pharmacist positions with technicians, or eliminate the need for on-the-job training of technicians. There were significant differences in scores between directors working at hospitals employing certified technicians and directors working at hospitals not employing certified technicians for only three statements. Overall, Ohio hospital pharmacy directors had positive attitudes about pharmacy technician certification.

Prolactin, psychological stress and environment in humans: adaptation and maladaptation. Non-puerperal lactation and/or hyperprolactinemia in humans have been related to psychological variables in a variety of ways: (1) Non-puerperal nursing; (2) Pseudopregnancy; (3) Rapid weight gain; (4) Psychogenic galactorrhea; (5) Acute prolactin responses to psychological stress; (6) High prolactin levels in persons who cope passively in real life stress situations; (7) Paternal deprivation in women with pathological hyperprolactinemia; (8) Clinical onset of prolactinomas following life-events. Publications on the above subjects are scattered in the literature as curiosities, anecdotal case-reports or unexplained associations, as there is no theoretical frame of reference to accommodate them. We propose that prolactin is a component of a biological, "maternal", subroutine, adaptive to the care of the young, which promotes accumulation of fat for the extraordinary expenses of pregnancy and lactation, the production of milk and maternal behavior. In an attempt to characterize the stimuli responsible for the activation of the maternal subroutine in the absence of pregnancy we studied the hormonal profiles of female volunteers during three types of sessions under hypnosis: (1) Relaxation-only, control sessions; (2) Sessions in which a fantasy of "nursing" was induced; (3) Sessions of evocations of memories. Prolactin surges were related to the evocation, with rage, of humiliating experiences, but not with the fantasy of nursing. Cortisol surges were related to surprise and shock and were negatively associated with prolactin. In conclusion--Prolactin and cortisol are measurable markers of two different, and alternative, coping strategies to "psychological stress".

Potential health benefits of child day care attendance. Despite fears that child day care attendance enhances the transmission of infection among attending children, there are positive aspects of the day care experience that, from the standpoint of infectious diseases, directly and indirectly contribute to the child's well-being. Quality child day care first requires a preadmission physical examination and then requires that the child begin the series of prescribed immunizations, which might not have been received if care were provided at home by a care giver who was not knowledgeable of available mechanisms for the prevention of disease. Once enrolled, the child and parents can be exposed to health education, which benefits them in terms of overall good health for the entire family. The child day care environment, like every other place where children congregate, is subject to the transmission of infectious agents among child and staff. But the risk of infection can be minimized and the health benefits maximized, and child day care can make positive contributions toward the social and physical development of the child.

Changes of perfusion patterns of surgical wounds under application of closed incision negative pressure wound therapy in postbariatric patients1. Negative pressure wound therapy applied over closed incisions (ciNPT) has been shown to influence wound healing. Therefore, the aim of this study was to examine the short-term effects of ciNPT on skin perfusion patterns in postbariatric wounds. 17 patients were included. Patients from the study group received a ciNPT dressing with a continuous negative pressure of - 125 mmHg for five days. Two intra- and two postoperative measurements were performed using both a combined laser Doppler spectrophotometry and an ICG angiography system to determine oxygen saturation (sO2), hemoglobin content (rHb) and perfusion patterns. Three days postoperatively the sO2 was significantly higher in the study group compared to the control group and also compared to the end of the operation. Concerning the rHb, there was no statistical significant alteration in or between the groups, but a trend towards a correlated alteration of sO2 and rHb. ICG angiography showed an earlier and stronger enhancement of perfusion parameters in the study group. CiNPT has a positive effect on oxygen saturation and tissue perfusion, which are both associated with the wound healing process. The use of ciNPT could therefore possibly reduce the risk of wound healing complications in this high-risk patient group.

Multiresidue determination of 160 pesticides in wines employing mixed-mode dispersive-solid phase extraction and gas chromatography-tandem mass spectrometry. A new multiresidue method for the efficient screening, identification and quantification of over 160 pesticides belonging to different chemical classes in red, rose and white wines have been developed. The analysis was based on gas chromatographic-tandem quadrupole mass spectrometric determination (GC-QqQ-MS/MS). An optimization strategy involved the selection of buffering conditions and sorbents for dispersive-solid phase extraction (dispersive-SPE) in order to achieve acceptably high recoveries and reduce co-extractives in the final extracts. As a result, the optimized procedure allowed us to obtain consistent recoveries of the target pesticides including problematic ones such as captan, chlorothalonil, dichlofluanid, folpet and tolylfluanid. The attained recoveries were typically between 80 and 110% (89% on average) with RSD values typically lower than 10% (8% on average) at three spiking levels of 0.01, 0.05 and 0.2 mg kg(-1). Linearity was studied in the range between 0.005 and 0.2 mg kg(-1) using pesticide standards prepared both in pure solvent and in the presence of matrix, showing coefficients of determination (R(2)) higher than 0.99 for all the pesticides except for desmedipham, thiabendazole and thiamethoxam in pure solvent. The study of the ratio of the slopes obtained in solvent and in matrix provided information about the matrix effects, which was <10%, 10-20% and >20% for 33, 36 and 31% of the studied pesticides, respectively. To improve accuracy, matrix matched standards were always used for calculation of the quantification results. The expanded uncertainties were estimated by using a "top-down" approach as being 17% on average (coverage factor k=2, confidence level 95%). Finally, the method was used with success to detect and quantify pesticide residues in commercial wines.

Objective measurement of synergistic movement patterns of the upper extremity following stroke: an explorative study. The majority of stroke survivors have to cope with deficits in arm function, which is often monitored with subjective clinical scales during stroke rehabilitation. The aim of this study is to examine whether robotic outcome measures obtained during circle drawing are suitable to objectively measure upper extremity function of stroke survivors, especially regarding synergistic movement patterns. Stroke survivors (n = 16) and healthy subjects (n = 20) drew circles, as big and as round as possible, above a table top. Joint angles and positions of the shoulder and elbow were measured. Synergistic movement patterns were identified based on simultaneous changes of the shoulder elevation angle and elbow angle. Stroke survivors moved significantly more within synergistic movement patterns, compared to healthy subjects. Strong correlations between the proximal upper extremity part of the Fugl-Meyer (FM) scale and the use of synergistic movement patterns were found. The proposed outcome measures seem to be suitable measures to objectively quantify the occurrence of synergistic movement patterns of the upper extremity following stroke.

P53 gene protein overexpression predicts results of trimodality therapy in esophageal cancer patients. P53 protein overexpression in esophageal cancer and its correlation with response and survival after chemoradiation was retrospectively investigated. Pretreatment and resection specimens were stained by automatic p53 immunohistochemical staining technique. P53 was expressed in 84.0% of esophagoscopy (EGD) biopsies; 71.4% of patients with metastasis of thoracoscopy/laparoscopy lymph nodes (TS/LS LN) identified by hematoxylin/eosin (H/E) were p53 (+); 14.2% of patients with negative TS/LS LN by H/E were p53 (+). Eleven out of 18 patients with p53 (+) in pretreatment EGD remained p53 (+) after chemoradiation; 38.8% of these patients had a pathological complete response (pCR). The median survival of this group was 15 months. Of 4 patients with p53 (-) pretreatment EGD, all of those were still p53 (-) after chemoradiation; 75% of these patients had pCR. The median survival was 30 months. In patients with p53 (+) TS/LS LN, 23% had a pCR after chemoradiation with a median survival of 16 months. In patients with p53 (-) TS/LS LN, 50.0% had a pCR with a median survival of 31.5 months. P53 protein overexpression in pretreatment EGD and TS/LS LN may predict response to chemoradiation and survival in esophageal cancer patients.

Deterministic Coupling of Quantum Emitters in 2D Materials to Plasmonic Nanocavity Arrays. Quantum emitters in two-dimensional materials are promising candidates for studies of light-matter interaction and next generation, integrated on-chip quantum nanophotonics. However, the realization of integrated nanophotonic systems requires the coupling of emitters to optical cavities and resonators. In this work, we demonstrate hybrid systems in which quantum emitters in 2D hexagonal boron nitride (hBN) are deterministically coupled to high-quality plasmonic nanocavity arrays. The plasmonic nanoparticle arrays offer a high-quality, low-loss cavity in the same spectral range as the quantum emitters in hBN. The coupled emitters exhibit enhanced emission rates and reduced fluorescence lifetimes, consistent with Purcell enhancement in the weak coupling regime. Our results provide the foundation for a versatile approach for achieving scalable, integrated hybrid systems based on low-loss plasmonic nanoparticle arrays and 2D materials.

Genetic dissection of optomotor behavior in Drosophila melanogaster. Studies on wild-type and the mutant optomotor-blindH31. In stationary flight Drosophila melanogaster produces yaw torque in response to visual movement stimuli. The residual optomotor yaw torque response of the mutant optomotor-blindH31 (omb), which lacks the horizontal (HS) and vertical (VS) giant fibers in the lobula plate, differs from that of wild-type in several aspects: it is restricted to the frontal visual field, it is only elicited by front-to-back motion and appears to be mediated by a different set of elementary movement detectors (EMDs). Using a single black stripe as motion stimulus the torque response is, even in wild-type flies, dominated by the frontal visual field and by front-to-back motion. We thus propose that Drosophila's optomotor yaw control is organized as two partially parallel subunits. The component still displayed by omb is called "object response"; the component missing in the mutant (which is presumably mediated by the giant HS-cells in the wild-type) is called "large field response". Several properties of the object response are described.

Localization of cytochrome P450 cholesterol side-chain cleavage, cytochrome P450 17 alpha-hydroxylase/17, 20-lyase, and 3 beta-hydroxysteroid dehydrogenase isomerase steroidogenic enzymes in human and rhesus monkey fetal adrenal glands: reappraisal of functional zonation. We examined the in situ localization of key steroidogenic enzymes in adrenal gland sections from midgestation (17-24 weeks) human fetuses and late gestation (130-142 days; term = 165 days) rhesus monkey fetuses. The rhesus monkey fetal adrenals were used as a model for the late gestation human fetal adrenal. The enzymes examined were cytochrome P450 cholesterol side-chain cleavage (P450scc), cytochrome P450 17 alpha-hydroxylase/17,20-lyase (P450c17), and 3 beta-hydroxysteroid dehydrogenase/isomerase (3 beta HSD). In human fetal adrenals, P450scc and P450c17 proteins and mRNAs were detected only in fetal zone (innermost cortical zone) and transitional zone (between the fetal and definitive zone) cells, not in definitive zone cells. Expression of 3 beta HSD was not detected in any cortical zone cells in midgestation human fetal adrenals. In rhesus monkey fetal adrenals, a similar pattern of P450scc and P450c17 expression was observed in the fetal and transitional zones. In the definitive zone cells of rhesus monkey fetal adrenals, expression of both P450scc and 3 beta HSD was detected. In addition, low levels of 3 beta HSD expression could be detected in some transitional zone cells. P450c17 expression was lacking in definitive zone cells from rhesus monkey fetal adrenals. These data suggest that early in gestation, cortisol is not produced by the human fetal adrenal cortex in vivo (because it does not express 3 beta HSD), whereas androgen production occurs in the transitional and fetal zones (which express P450scc and P450c17). Later in gestation, the definitive zone may produce minearlocorticoids (because it expresses P450scc and 3 beta HSD, but lacks P450c17), and the transitional zone may produce glucocorticoids (it expresses P450scc, P450c17, and 3 beta HSD), whereas the fetal zone continues to produce androgens. Thus, late in gestation the functional zonation of the human fetal adrenal cortex may be similar to that of the adult, with the definitive zone being analogous to the nascent zona glomerulosa, the transitional zone analogous to the zona fasciculata, and the fetal zone analogous to the zona reticularis.

6-phenyl-3-(4-pyridyl)-1,2,4-triazolo[3,4-b][1,3,4]thiadiazole. The title compound, C(14)H(9)N(5)S, has been synthesized and characterized both spectroscopically and structurally. The triazolo-thiadiazole system, the pyridine ring and the phenyl ring are all planar. The plane of the triazolo-thiadiazole system forms dihedral angles of 1.53 (13) and 7.55 (12) degrees with the planes of the pyridine and phenyl rings, respectively. In the molecule, there are two intramolecular interactions of types C-H...N and C-H...S. Intermolecular C-H...N interactions involving a phenyl CH group and a triazole N atom lead to the formation of a one-dimensional chain. In the crystal structure, two types of pi-pi interactions affect the packing of the molecules. In addition, there are intermolecular non-bonded S...N contacts of 2.870 (2) A, which may cause steric hindrance.

Myb-independent macrophages: a family of cells that develops with their tissue of residence and is involved in its homeostasis. In most metazoans, all tissues contain phagocytes "in residence," generally termed "macrophages" in vertebrates. In contrast to myeloid cells produced continuously by the bone marrow (BM), tissue-resident macrophages develop during embryogenesis together with their tissue of residence, and persist in adulthood, independently of hematopoietic stem cells and the transcription factor Myb. They therefore represent an independent lineage from blood monocytes, dendritic cells, and monocytes/macrophages that are recruited to tissues during inflammation. Tissue-resident macrophage functions are yet to be completely defined. They all share the ability to scavenge toxic compounds, lipids, microorganisms, and dead cells and contribute to tissue remodeling, via phagocytosis and the production of growth factors. In contrast, the production of inflammatory mediators seems to be more associated with BM-derived cells. Tissue-resident macrophages and BM-derived myeloid cells thus differ in developmental origin and functions; the term "macrophages" could be reserved for Myb-independent-resident macrophages to avoid confusion. A genetic and molecular dissection of resident macrophage functions will reveal their roles in tissue metabolism and the maintenance of homeostasis independently of the extravasation of inflammatory leukocytes, and in the control of the recruitment of BM-derived cells in overt inflammation.

[Present status and problems of the normal values (clinical reference range) of the laboratory tests--results of a questionnaire survey in university hospitals in Japan]. The normal values (clinical references range) of the laboratory tests differs among hospitals due to the differences in: (1) the kinds of instruments and reagents used, (2) how the population for study was selected and the size of the population was, (3) when the specimens were taken, (4) how they were stored until use, and (5) how the data obtained were calculated and (6) who evaluated the results. In this study, questionnaires regarding the above-mentioned points were sent to the heads of the clinical laboratories in 80 university hospitals in Japan. Answers were received from 71 laboratories (the rate of recovery was 88.8%). The normal range of potassium, uric acid, total cholesterol, enzyme activities [ALP, LDH, CHE, AST (GOT) and ALT (GPT)] in the university hospitals in Japan varied. It is not ideal to use different reference values in different hospitals. However, it is impossible to prepare a standard manual to obtain the normal range at present. When the inter-hospital differences become small enough to obtain one normal range for the Japanese peoples, a standard manual for normal values should be made.

Boron cluster-based development of potent nonsecosteroidal vitamin D receptor ligands: direct observation of hydrophobic interaction between protein surface and carborane. We report here the design and synthesis of a novel vitamin D receptor (VDR) agonist whose hydrophobic core structure is p-carborane (1,12-dicarba-closo-dodecaborane, an icosahedral carbon-containing boron cluster having remarkable thermal and chemical stability and a characteristically hydrophobic B-H surface). This carborane-based VDR ligand exhibited moderate vitamin D activity, comparable to that of the natural hormone, despite its simple and flexible structure. X-ray structure analysis provided direct evidence that the carborane cage binds to the hydrophobic surface of the ligand-binding pocket of the receptor, promoting transition to the active conformation. These results indicate that the spherical B-H surface of carborane can function efficiently as a hydrophobic anchor in binding to the receptor surface, thereby allowing induced fitting of the three essential hydroxyl groups on the alkyl chains to the appropriate positions for interaction with the VDR binding site, despite the entropic disadvantage of the flexible structure. We suggest that carborane structure is a promising option in the design of novel drug candidates.

Gastrointestinal lymphoma in Chinese: a retrospective analysis. Eighty-four Chinese patients with gastrointestinal lymphoma were reviewed. There were 45 gastric and 39 intestinal lymphomas. The median age was 45 years and the male to female ratio 1.14:1. Diffuse histiocytic (60 per cent) or diffuse large cell (53.5 per cent) lymphoma comprised a majority of the cases. A high incidence of gastrointestinal bleeding at presentation was observed in our patients. According to a modified staging classification, a larger proportion of patients with intestinal lymphoma had advanced disease (Stage III and IV) than those with gastric lymphoma (82 per cent versus 55 per cent, p less than 0.02) and gastric lymphoma carried a better prognosis. The modified staging classification used in this study appeared to stratify better the patients into 2 sub-groups of localized (Stage I and II) and advanced (Stage III and IV) disease, which correlated very well with the prognosis. Good treatment results were obtained following intensive therapy in our patients with localized disease (Stage I and II). The poorer treatment results of patients with advanced disease (Stage III and IV) call for better chemotherapy regimens and earlier diagnosis. Surgical resection of the primary gastrointestinal lesion is recommended to prevent haemorrhage and perforation following chemotherapy, which occurred in 38 per cent of our patients whose gastrointestinal lesions were not resected.

Mycotoxicoses of domestic animals and their diagnosis. Mycotoxins have been named "agents in search of a disease," and the considerable progress in analytical methodology over the last 10 years has not changed this very much. The following are factors that contribute to the difficulty of making a diagnosis: (1) nonspecificity of lesions; (2) masking of mycotoxic effects by secondary effects, e.g., through immunosuppression; (3) late appearance of a lesion, e.g., bone marrow damage or neoplasia; (4) interaction of several mycotoxins or presence of other toxicants or deficiency states; (5) species variation in the response to the mycotoxin(s); (6) difficulty of linking a late appearing effect with a demonstrable cause; (7) low doses of mycotoxins may cause stimulating effects; and (8) not being aware of the potential of a mycotoxin as a causative factor in disease. The mycotoxins of major importance in Canada are trichothecenes, ochratoxin, zearalenone, and ergot. It is concluded that the significance of mycotoxins for animals in Canada is likely generally underestimated.

Diastereoselective synthesis of octahydro-14H-benzo[g]quinolino-[2,3-a]quinolidines. Improved cytotoxic activity against human brain tumor cell lines as a result of the increased rigidity of the molecular backbone. Cis-Octahydro-14H-benzo[g]quinolino[2,3-a]quinolidines 6 were obtained in 6 steps from L-phenylalanine. The key step utilizes a diastereoselective intramolecular EtAlCl2-catalyzed hetero-Diels-Alder reaction. Compounds 6a-f were tested in vitro against human medulloblastoma D283 Med and glioblastoma A-172 and T98G cell lines and showed improved cytotoxicity compared to the corresponding, less rigid pyrido[1,2-b]isoquinolines 1.

Cold- and cryopreservation of dog liver and kidney slices. The use of tissue slices in culture could decrease the number of animals used in health-related research and decrease experimental variation. This reduction may come about particularly if the methods of cold- and cryopreserving tissue slices are perfected, and one can conduct sequential in vitro experiments into xenobiotic metabolism, organ-specific toxicity, or organ-specific biochemical processes with tissue slices. With this goal in mind, dog liver and kidney slices were placed in cold storage at 0 degrees C using Viaspan (UW), Euro-Collins (EC), Sacks + prostacyclin (SP), and V-7 (V7) cold-preservation solutions for 10 days. Viability was assessed each day by measuring K+ content and protein synthesis after 4 h of incubation in Waymouth + 10% fetal calf serum (FCS). Dog liver slices can be cold-preserved in V7 for up to 7 days using K+ retention as the viability criterion but only up to 4 days using protein synthesis. Dog kidney slices can be cold-preserved in UW, EC, and V7 for up to 10 days using K+ retention, but only V7 could maintain protein synthesis for 10 days. Cryopreserved dog liver and kidney slices retained 63-68% of control viability after 4 h of incubation in FCS. The cryopreservation regimen included using 10% dimethyl sulfoxide in FCS as the cryoprotectant, a freezing rate of 0.5 degrees C/min for liver slices and 12 degrees C/min for kidney slices, and thawing in 37 degrees C FCS. Continued development of cold- and cryopreserving tissue slices could reduce the numbers of animals used and provide accurate and reproducible data.

Monoclonal antibodies directed to different tumor-associated antigens on a murine mammary tumor cell line, MM46. Seven monoclonal antibodies to a murine mammary carcinoma MM46 were produced by fusing a mouse hybridoma cell line Sp2/O-Ag14 or a myeloma cell line P3-X63-Ag8-U1 with spleen cells from C3H/He mice immunized with MM46. Their specificities were investigated by the complement-dependent cytotoxicity test and binding inhibition assay using 125I-labeled monoclonal antibodies. The complement-dependent cytotoxicity test showed that all of them reacted with MM antigen-positive tumor cells such as MM46 and FM3A/R. Three of them reacted with both C57BL/6 lymph node cells and EL4 tumor cells, suggesting that these 3 antibodies recognize Ly-6.2 antigen. One reacted with all tumor cells so far tested (MM46, FM3A/R, MM48, MH134, and Meth A) except EL4. One antibody that cross-reacted with MH134 was also obtained. Binding inhibition assay confirmed hat the 7 monoclonal antibodies detected at least 4 different epitopes on MM46. These results suggest that there are at least 4 different molecules on the cell surface of MM46: namely, molecules that are 1) restricted to MM antigen-positive tumor cells, 2) present on several tumor cells, 3) broadly distributed on tumor cells, and 4) cross-reactive with Ly antigen.

Functional changes following combined intravitreal bevacizumab and photodynamic therapy for polypoidal choroidal vasculopathy. To assess the functional changes of retina in patients affected by polypoidal choroidal vasculopathy (PCV) after combined intravitreal bevacizumab and photodynamic therapy (PDT) by means of contrast sensitivity (CS) test and color vision test. Twelve eyes of 12 patients were included in the study. The CS and color vision were measured and compared before the combined treatment and 1, 3 and 6 months after the treatment. The patients had an improvement in CS over pre-treatment values at the all of the five spatial frequencies. And the differences at 1.5 cycle per degree (cpd) at 1 and 3 months after treatment (p = 0.04 and 0.007 respectively) were statistically significant. The mean square root of total error score for color vision of the FM 100-hue test decreased after treatment and the change was significant at 3 and 6 months after treatment (p < 0.001 and 0.011 respectively). Combined intravitreal bevacizumab and PDT can improve the CS at low spatial frequency and color vision in patients affected by PCV, although the significant increases of CS were no longer found at 6-month follow-up.

Synthesis, antiviral activity and cytotoxicity evaluation of Schiff bases of some 2-phenyl quinazoline-4(3)H-ones. A new series of 3-(benzylideneamino)-2-phenylquinazoline-4(3H)-ones were prepared through Schiff base formation of 3-amino-2-phenyl quinazoline-4(3)H-one with various substituted carbonyl compounds. Their chemical structures were elucidated by spectral studies. Cytotoxicity and antiviral activity were evaluated against herpes simplex virus-1 (KOS), herpes simplex virus-2 (G), vaccinia virus, vesicular stomatitis virus, herpes simplex virus-1 TK- KOS ACVr, para influenza-3 virus, reovirus-1, Sindbis virus, Coxsackie virus B4, Punta Toro virus, feline corona virus (FIPV), feline herpes virus, respiratory syncytial virus, influenza A H1N1 subtype, influenza A H3N2 subtype, and influenza B virus. Compound 2a showed better antiviral activity against the entire tested virus.

[Sleep-wake cycle in chemotherapy patients: a retrospective study]. Over 50% of cancer patients suffer from insomnia, nearly twice the estimated prevalence in the general population. However, this widespread problem has received far less attention compared to cancer pain and fatigue. The aim of this study was to determine whether certain factors can alter the sleep-wake cycle in this patient subgroup and whether altered nyctohemeral sleep rhythms may negatively impact on quality of life. The medical records of 101 patients treated at the Cancer Center, San Giovanni Battista Hospital, Turin, and who had died of cancer in 2007, were reviewed. Extracted from each record were data on: patient age, sex, primary tumor site, presence of pain, concomitant conditions, concomitant medications, type of therapy, chemotherapeutic (CT) scheme, survival, and side effects. The sample was divided into two subgroups defined as inducers or non-inducers, depending on whether the patient had taken medications or not to treat insomnia. Significant differences between the two groups for these variables were tested using statistical analysis. A statistically significant difference between the two groups emerged for anxiety-depression syndromes (P=0.00001), the number of sleeping pills taken in association with a concurrent anxiety-depression syndrome (P=0.01463), and side effects (P=0.0015). There was a statistically significant difference between the inducer and the non-inducer groups for female sex (one-tailed Fisher's exact test; P=0.04170) but the difference was marginal on Fisher's two-tailed test (P=0.06121). No statistically significant differences between the two groups were found for mean age (P=0.61281), median age (P=0.9996), primary tumor site, concomitant conditions (P=0.4205), survival (P=0.5704), presence of pain (P=0.53300) or type of therapy (P=0.6466). Sleep disturbances are a common complaint of cancer patients but have only recently attracted greater attention as the diagnosis of cancer has increased. Sleep disturbances are not an isolated problem but rather lead to a vicious circle of insomnia and fatigue where it is not always possible to distinguish between cause and effect. Future studies are needed to gain insight into the underlying mechanisms and a better understanding of what causes alterations in circadian rhythm.

Irritant-induced occupational asthma. A retrospective review was performed on the files of 154 consecutive workers assessed for occupational asthma to clarify the relative frequency of asthma induced by irritants in the workplace and to determine whether such asthma was clearly distinguishable from other forms of occupational asthma. Fifty-nine workers were considered to have occupational asthma. A subset of ten had a history consistent with asthma initiated by exposure to high concentrations of an irritant, had persistent symptoms for an average of five years when seen, demonstrated increased reactivity to methacholine, and gave no prior history of pulmonary complaints. These ten had a lower incidence of atopy (20 percent vs 58 percent) and a more frequent history of smoking (80 percent vs 38 percent) than the other subjects with occupational asthma but did not differ in average latency (5.9 years vs 5.7 years). Our findings suggest that irritant-induced asthma is not uncommon, and those affected may have different baseline characteristics from others with occupational asthma.

Increased probability of repetitive spinal motoneuron activation by transcranial magnetic stimulation after muscle fatigue in healthy subjects. Triple stimulation technique (TST) has previously shown that transcranial magnetic stimulation (TMS) fails to activate a proportion of spinal motoneurons (MNs) during motor fatigue. The depression in size of the TST response, but no attenuation of the conventional motor-evoked potential, suggested increased probability of repetitive spinal MN activation during exercise, even if some MNs failed to discharge by the brain stimulus. Here we used a modified TST [quadruple stimulation (QuadS) and quintuple stimulation (QuintS)] to examine the influence of fatiguing exercise on second and third MN discharges after a single TMS in healthy subjects. This method allows an estimation of the percentage of double and triple discharging MNs. Following a sustained contraction of the abductor digiti minimi muscle at 50% maximal force maintained to exhaustion, the size of QuadS and QuintS responses increased markedly, reflecting that a greater proportion of spinal MNs was activated two or three times by the transcranial stimulus. The size of QuadS responses did not return to precontraction levels during 10-min observation time, indicating long-lasting increase in excitatory input to spinal MNs. In addition, the postexercise behavior of QuadS responses was related to the duration of the contraction, pointing to a correlation between repeated activation of MNs and the subject's ability to maintain force. In conclusion, the study confirmed that an increased fraction of spinal MNs fire more than once in response to TMS when the muscle is fatigued. Repetitive MN firing may provide an adaptive mechanism to maintain motor unit activation and task performance during sustained voluntary activity.

Twelve reasons for considering buprenorphine as a frontline analgesic in the management of pain. Buprenorphine is an opioid that has a complex and unique pharmacology which provides some advantages over other potent mu agonists. We review 12 reasons for considering buprenorphine as a frontline analgesic for moderate to severe pain: (1) Buprenorphine is effective in cancer pain; (2) buprenorphine is effective in treating neuropathic pain; (3) buprenorphine treats a broader array of pain phenotypes than do certain potent mu agonists, is associated with less analgesic tolerance, and can be combined with other mu agonists; (4) buprenorphine produces less constipation than do certain other potent mu agonists, and does not adversely affect the sphincter of Oddi; (5) buprenorphine has a ceiling effect on respiratory depression but not analgesia; (6) buprenorphine causes less cognitive impairment than do certain other opioids; (7) buprenorphine is not immunosuppressive like morphine and fentanyl; (8) buprenorphine does not adversely affect the hypothalamic-pituitary-adrenal axis or cause hypogonadism; (9) buprenorphine does not significantly prolong the QTc interval, and is associated with less sudden death than is methadone; (10) buprenorphine is a safe and effective analgesic for the elderly; (11) buprenorphine is one of the safest opioids to use in patients in renal failure and those on dialysis; and (12) withdrawal symptoms are milder and drug dependence is less with buprenorphine. In light of evidence for efficacy, safety, versatility, and cost, buprenorphine should be considered as a first-line analgesic.

In NIH-3T3 fibroblasts, insulin receptor interaction with specific protein kinase C isoforms controls receptor intracellular routing. Insulin increased protein kinase C (PKC) activity by 2-fold in both membrane preparations and insulin receptor (IR) antibody precipitates from NIH-3T3 cells expressing human IRs (3T3hIR). PKC-alpha, -delta, and -zeta were barely detectable in IR antibody precipitates of unstimulated cells, while increasing by 7-, 3.5-, and 3-fold, respectively, after insulin addition. Preexposure of 3T3hIR cells to staurosporine reduced insulin-induced receptor coprecipitation with PKC-alpha, -delta, and -zeta by 3-, 4-, and 10-fold, respectively, accompanied by a 1.5-fold decrease in insulin degradation and a similar increase in insulin retroendocytosis. Selective depletion of cellular PKC-alpha and -delta, by 24 h of 12-O-tetradecanoylphorbol-13-acetate (TPA) exposure, reduced insulin degradation by 3-fold and similarly increased insulin retroendocytosis, with no change in PKC-zeta. In lysates of NIH-3T3 cells expressing the R1152Q/K1153A IRs (3T3Mut), insulin-induced coprecipitation of PKC-alpha, -delta, and -zeta with the IR was reduced by 10-, 7-, and 3-fold, respectively. Similar to the 3T3hIR cells chronically exposed to TPA, untreated 3T3Mut featured a 3-fold decrease in insulin degradation, with a 3-fold increase in intact insulin retroendocytosis. Thus, in NIH-3T3 cells, insulin elicits receptor interaction with multiple PKC isoforms. Interaction of PKC-alpha and/or -delta with the IR appears to control its intracellular routing.

Adipose tissue remodeling in late-lactation dairy cows during feed-restriction-induced negative energy balance. Excessive rates of demand lipolysis in the adipose tissue (AT) during periods of negative energy balance (NEB) are associated with increased susceptibility to disease and limited lactation performance. Lipolysis induces a remodeling process within AT that is characterized by an inflammatory response, cellular proliferation, and changes in the extracellular matrix (ECMT). The adipose tissue macrophage (ATM) is a key component of the inflammatory response. Infiltration of ATM-forming cellular aggregates was demonstrated in transition cows, suggesting that ATM trafficking and phenotype changes may be associated with disease. However, it is currently unknown if ATM infiltration occurs in dairy cows only during NEB states related to the transition period or also during NEB-induced lipolysis at other stages of lactation. The objective of this study was to evaluate changes in ATM trafficking and inflammatory phenotypes, and the expression of genetic markers of AT remodeling in healthy late-lactation cows during feed restriction-induced NEB. After a 14-d (d -14 to d -1) preliminary period, Holstein cows were randomly assigned to 1 of 2 feeding protocols, ad libitum (AL) or feed restriction (FR), for 4 d (d 1-4). Caloric intake was reduced in FR to achieve a targeted energy balance of -15 Mcal/d of net energy for lactation. Omental and subcutaneous AT samples were collected laparoscopically to harvest stromal vascular fraction (SVF) cells on d -3 and 4. The FR induced a NEB of -14.1±0.62 Mcal/d of net energy for lactation, whereas AL cows remained in positive energy balance (3.2±0.66 Mcal/d of NEL). The FR triggered a lipolytic response reflected in increased plasma nonesterified fatty acids (0.65±0.05 mEq/L on d 4), enhanced phosphorylation of hormone sensitive lipase, and reduced adipocyte diameter. Flow cytometry and immunohistochemistry analysis revealed that on d 4, FR cows had increased numbers of CD172a+, an ATM (M1 and M2) surface marker, cells in SVF that were localized in aggregates. However, FR did not alter the number of SVF cells expressing M1 markers (CD14 and CD11c) or M2 markers (CD11b and CD163). This finding contrasts with the predominately M1 phenotype observed previously in ATM from clinically diseased cows. No changes were observed in the expression of ECMT-related or cell proliferation markers. In summary, an acute 4-d lipolytic stimulus in late-lactation dairy cows led to ATM infiltration with minimal changes in inflammatory phenotype and no changes in ECMT. These results underscore that physiological changes related to parturition, the onset of lactation, extended periods of lipolysis, or a combination of these can induce intense AT remodeling with enhanced ATM inflammatory phenotype expression that may impair the metabolic function of AT in transition dairy cattle.

Risk of Reinfection After Treatment of Infected Total Knee Arthroplasty. The purpose of this study was to determine the incidence of subsequent reinfections after initial treatment of an infected total knee arthroplasty, identify risk factors leading to reinfection, and compare results among the varying treatment modalities. A total of 1,493,924 primary TKA patients were identified from the Medicare data between October 1, 2005, and December 31, 2011. Patients who encountered periprosthetic joint infection (PJI) after TKA were identified using International Classification of Diseases, Ninth Revision, Clinical Modification code 996.66. The risk of subsequent PJI was stratified based on the first-line treatment and compared between the various first-line treatment groups. A total of 16,622 patients (1.1%) were diagnosed with PJI. The Kaplan-Meier risk of PJI was 0.77% at 1 year and 1.58% at 6 years. Age (P < .001), Charlson score (P < .001), hospital control (P < .001), race (P = .036), census region (P = .031), gender (P < .001) were identified as risk factors for PJI. Of the PJI patients, 20.8% (n = 2806) were treated with incision and drainage (I&D), 15.9% (n = 2150) treated with I&D and liner exchange, 22.7% (n = 3069) treated with 1-stage revision, 39.7% (n = 5364) treated with 2-stage revision, and 0.98% (n = 132) treated with amputation. After first-line treatment, 26% of patients with PJI had a subsequent PJI. Patients undergoing I&D as a first-line treatment had the highest risk of reinfection, with risks of 28.2% at 1 year and 43.2% at 6 years. One-stage revision patients had 33.9% greater adjusted risk of reinfection than 2-stage revision patients (P < .001). Two-stage reimplantation, despite 19% recurrence, had the highest success rate. Given the higher failure rates of I&D and single-stage revisions, guidelines need to be established for their specific indications.

The remaining road to classifying personality pathology in the DSM-5: what behavior genetics can add. Replies to comments by C. Hopwood (see record 2013-27219-003), W. Iacono (see record 2013-27219-001) and A. Skodol and R. Krueger (see record 2013-27219-002) on the article by S. C. South and N. J. DeYoung (see record 2012-01744-001). This commentary examines how behavior genetic research can be used to inform the revision of personality disorders (PDs) during the transition from DSM-IV to DSM-5. South and DeYoung address three "meta-themes" that emerged across these responses. First, personality disorders are disorders, and should be defined and diagnosed as such. Second, the DSM is fundamentally a manual for assessment and diagnosis, and thus needs to be usable for those purposes. Third, what can behavior genetics do as we move toward the DSM-5? In summary, there is much work to be done over the coming months to finalize the practical details of the DMS-5 proposal.

Pd-catalyzed C-N bond formation with heteroaromatic tosylates. A protocol for the palladium(0)-catalyzed amidation of heteroaromatic tosylates was successfully developed. The methodology proved to be effective for a variety of heteroaryl tosylates including the pyridine, pyrimidine, quinoline and quinoxaline ring systems. Successful carbon-nitrogen bond formation with these heteroaryl tosylates could be performed with a wide range of primary amides, oxazolidinones, lactams, anilines and indoles, including one cyclic urea. Moreover, this C-N bond forming reaction provided products with high structural diversity. The coupling reaction was also amenable to scale up applications.

[Indications for nailbed capillaroscopy in Raynaud's phenomenon]. 175 patients with Raynaud's phenomenon underwent nailfold capillaroscopy. 22 had suspected connective tissue diseases, 48 idiopathic Raynaud's disease and 105 a variety of other diagnoses. A normal capillaroscopy is fully consistent with Raynaud's disease. A pathological capillaroscopy with megacapillaries prompts suspicion of underlying connective tissue disease. The other abnormal capillaroscopies are suggestive of Raynaud's phenomenon secondary to one of the numerous associated diseases, and do not rule out evolution to connective disease ("waiting group"). The proposed simplified classification seems to offer reasonably good discrimination. The probability of an abnormal capillaroscopy increases with the age of onset of Raynaud's phenomenon but is not insignificant in younger patients. The (53-year-old) Allen's criterion (3 years follow-up without signs of underlying diseases such as scleroderma, etc.) is disappointing and should be discarded. Nailfold capillaroscopy is a non-invasive procedure which is useful at any age.