Effect of antihypertensive therapy on calcium transport by cardiac sarcoplasmic reticulum of SHRs.
Cardiac hypertrophy develops during the course of blood pressure elevation in spontaneously hypertensive rats (SHRs) and is associated with defective calcium transport by cardiac sarcoplasmic reticulum (SR). AT 20 weeks of age, calcium uptake is reduced in SHRs (42 +/- 1.3 vs 64 +/- 1.6 nmol X mg-1 X min-1 in age-matched normotensive Wistar-Kyoto rats, P less than 0.01), while Ca2+ ATPase activity is enhanced (44 +/- 1.1 vs 35 +/- 0.7 nmol X mg-1 X min-1 in WKYs, P = 0.02); this results in low stoichiometry between calcium uptake and ATP hydrolysis in SHRs. The steady-state levels of the phosphoprotein intermediate [EP] of the transport ATPase are higher in normotensive rats (0.97 +/- 0.1 vs 0.67 +/- 0.08 nmol X mg-1 in SHRs, P less than 0.01) but the Ca2+- and ATP-dependency are similar in the two groups. In order to study the relative roles of hypertension and cardiac hypertrophy in the depression of SHR function, 20-week old SHRs and normotensive rats were treated for 10 weeks with either hydralazine (100 mg X litre-1) or alpha-methyldopa (8 g X litre-1). Both therapeutic regimens resulted in near normalisation of blood pressure of SHRs (hydralazine: 18.1 +/- 0.5 kPa [136 +/- 4 mmHg]; alpha-methyldopa 17.6 +/- kPa [132 +/- 3 mmHg]). Regression of cardiac hypertrophy, however, was seen only in the alpha-methyldopa-treated group, as judged by changes in left ventricular weight, RNA/DNA ratio, and hydroxyproline content. Furthermore, improvement in calcium transport capacity by the SHR, as reflected in higher calcium uptake and stoichiometric ratio between uptake and ATP hydrolysis, was found after alpha-methyldopa, but not hydralazine treatment. These results indicate that reversal of cardiac hypertrophy is required for improvement in calcium transport by cardiac SR after antihypertensive therapy of SHRs.


Biofilm compressibility in ultrafiltration: A relation between biofilm morphology, mechanics and hydraulic resistance.
Poroelastic fluid-structure interaction models were coupled to experimental data to determine the effects of biofilm spatial distribution of mechanical and hydraulic properties on the biofilm hydraulic resistance and compressibility in membrane filtration processes. Biofilms were cultivated on ultrafiltration membranes for 20 and 30 days under high (0.28 bar) and low (0.06 bar) transmembrane pressure (TMP), in dead-end filtration mode. Subsequently, biofilms were subjected to a compression/relaxation cycles by step-wise TMP changes. Structural deformation of biofilms during compression was observed in-situ using optical coherence tomography. Experimental results show that the observed increase in the biofilm hydraulic resistance during compression is not necessarily accompanied by a detectable biofilm thickness reduction. A dual-layer biofilm model with a dense base and porous top layer could explain these observed results. Because porosity controls indirectly the mechanical response of biofilms under compression, results could be described without assuming a gradient in mechanical properties within the biofilm. The biofilm surface roughness did not significantly influence the water flux in this study. However, the fraction of biofilm base layer directly exposed to bulk liquid could be a good indicator in the determination of water flux. The main implications of this study for the design and operation of low-pressure membrane systems (e.g., MF and UF with fouling layer being the main filtration resistance) lays in the selection of favorable operational TMP and biofilm morphology.


In vitro removal of polycyclic aromatic hydrocarbons by lactic acid bacteria.
The current study aimed to investigate the ability of lactic acid bacteria (LABs) in removing four polycyclic aromatic hydrocarbons (PAHs) namely, benzo(a)pyrene (BaP), benz(a)anthracene (BaA), chrysene (Chr) and benzo(b)fluoranthene (BbF) from contaminated phosphate buffer saline (PBS). The effect of initial PAH concentrations (5, 10, 15, 20 μg ml-1 ), bacterial population (107 , 108 , 109 , 1010 CFU per ml) and pH (3, 5, 7) was studied to evaluate bacterial binding ability. All the tested bacteria could remove BaA, Chr, BbF and BaP from phosphate buffer solution and in almost all assays, removing of PAHs was as follows: BaP>Chr>BaA>BaF. Bifidobacterium lactis BB-12 had the lowest binding rate for all four PAHs, while the highest binding ability was related to Lactobacillus acidophilus LA-5. Moreover, cell viability was not required for the binding ability and even acid-treated, heat-treated and ultrasonic-treated bacterial cells showed more binding ability. The results showed that the bacteria-PAH complex was irreversible after washing with PBS. The removal of PAHs was significantly related to pH of media, strains of bacteria, type and concentration of PAHs SIGNIFICANCE AND IMPACT OF THE STUDY: This study has been focused on the reduction of polycyclic aromatic hydrocarbons using LABs and probiotics. Our results showed that not only live strains but also inactivated tested strains are able to remove PAHs from aqueous media, presenting new methods to diminish the amount of these contaminants in foods. Furthermore, the results of this study can be used in future research on evaluating the effects of oral administration of probiotic supplements and even dead probiotic strains on reducing PAHs in humans.


DNA ligase IV from HeLa cell nuclei.
A human cDNA encoding a previously unrecognized DNA ligase IV has been identified (Wei, Y.-F., Robins, P., Carter, K., Caldecott, K., Pappin, D. J. C., Yu, G.-L., Wang, R.-P., Shell, B. K., Nash, R. A., Schär, P., Barnes, D. E., Haseltine, W. A., and Lindahl, T. (1995) Mol. Cell. Biol. 15, 3206-3216). Antibodies have been raised against predicted peptide sequences of DNA ligase IV and used to identify the enzyme during purification from HeLa cell nuclei. The 96-kDa DNA ligase IV and the 103-kDa DNA ligase III co-migrate during SDS-polyacrylamide gel electrophoresis and have similar column fractionation properties, which complicates the distinction between the two enzymes, but they have been separated by Mono S liquid chromatography. During initial size fractionation by gel chromatography in 1 M NaCl, DNA ligase IV elutes in the same position as the DNA ligase III-XRCC1 protein complex, indicating that DNA ligase IV is also bound to another protein or occurs as a dimer. DNA ligase IV has been purified free from other DNA ligases, and its enzymatic properties have been examined. The purified protein effectively joins single-strand breaks in a double-stranded polydeoxynucleotide in an ATP-dependent reaction. The substrate specificity of DNA ligase IV differs from those of the other two cloned human DNA ligases, I and III, with regard to their ability to join the hybrid substrates oligo(dT).poly(rA) and oligo(rA).poly(dT). DNA ligase IV occurs in part as an enzyme-adenylate complex in HeLa cell nuclear extracts.


Analysis of Human Mitochondrial DNA Content by Southern Blotting and Nonradioactive Probe Hybridization.
A single cell can contain several thousand copies of the mitochondrial DNA genome or mtDNA. Tools for assessing mtDNA content are necessary for clinical and toxicological research, as mtDNA depletion is linked to genetic disease and drug toxicity. For instance, mtDNA depletion syndromes are typically fatal childhood disorders that are characterized by severe declines in mtDNA content in affected tissues. Mitochondrial toxicity and mtDNA depletion have also been reported in human immunodeficiency virus-infected patients treated with certain nucleoside reverse transcriptase inhibitors. Further, cell culture studies have demonstrated that exposure to oxidative stress stimulates mtDNA degradation. Here we outline a Southern blot and nonradioactive digoxigenin-labeled probe hybridization method to estimate mtDNA content in human genomic DNA samples. © 2019 by John Wiley & Sons, Inc.


The failure of ascorbic acid therapy to alter the induction or remission of murine amyloidosis.
It has been claimed that ascorbic acid enhances the in vitro degradation of AA amyloid fibrils. This raises the possibility that ascorbic acid may be of benefit in systemic AA amyloidosis, a condition with serious morbidity and mortality for which there is as yet no specific treatment. The effect was therefore tested of oral or injected supplements of ascorbic acid on the induction of AA amyloidosis in mice. Amyloid was induced either by repeated injections of casein or by injection of 'amyloid enhancing factor' and silver nitrate. Mice with established amyloidosis were also treated with additional ascorbic acid. Despite the fact that plasma ascorbic acid levels were significantly higher in orally supplemented mice than in controls there was no demonstrable effect on the induction, the extent and distribution or the progression of amyloidosis.


Two worlds collide: image analysis methods for quantifying structural variation in cluster molecular dynamics.
Inspired by methods of remote sensing image analysis, we analyze structural variation in cluster molecular dynamics (MD) simulations through a unique application of the principal component analysis (PCA) and Pearson Correlation Coefficient (PCC). The PCA analysis characterizes the geometric shape of the cluster structure at each time step, yielding a detailed and quantitative measure of structural stability and variation at finite temperature. Our PCC analysis captures bond structure variation in MD, which can be used to both supplement the PCA analysis as well as compare bond patterns between different cluster sizes. Relying only on atomic position data, without requirement for a priori structural input, PCA and PCC can be used to analyze both classical and ab initio MD simulations for any cluster composition or electronic configuration. Taken together, these statistical tools represent powerful new techniques for quantitative structural characterization and isomer identification in cluster MD.


The prevalence of histologic acute chorioamnionitis among HIV infected pregnant women in Uganda and its association with adverse birth outcomes.
Preterm birth (PTB) is a leading cause of neonatal mortality and longer-term morbidity. Acute chorioamnionitis (ACA) is a common cause of PTB, however, there are limited data on the prevalence of ACA and its association with PTB in resource limited settings. Data and samples came from a clinical trial evaluating novel strategies for the prevention of malaria in HIV infected pregnant women in Uganda. Women were enrolled between 12-28 weeks of gestation and followed through delivery. For each placenta delivered, three placental tissue types (membrane roll, umbilical cord and chorionic plate/villous parenchyma) were collected. Slides were assessed for diagnosis of maternal and fetal ACA by microscopic evaluation of neutrophilic infiltration using a standardized grading scale. The primary outcomes were PTB (<37 weeks), low birth weight (LBW, <2500 grams), and small-for-gestational age (SGA, birth weight <10th percentile for age). Univariate and multivariate logistic regression were used to estimate associations between 1) maternal characteristics (age, education, wealth, gravidity, gestational age at enrollment, placental malaria, anti-malarial prophylaxis treatment regimen, HIV disease parameters) and ACA, and 2) associations between ACA and adverse birth outcomes. A total of 193 placentas were included in the analysis. The prevalence of maternal and fetal ACA was 44.5% and 28.0%, respectively. HIV infected women between 28-43 years of age had a higher risk of maternal ACA compared to those between 17-21 years of age (50.9% vs. 19.1%; aOR = 4.00 (1.10-14.5), p = 0.04) and the diagnosis of severe maternal ACA was associated with a significantly higher risk of PTB (28.6% vs. 6.0%; aOR = 6.04 (1.87-19.5), p = 0.003), LBW (33.3% vs. 9.4%; aOR = 4.86 (1.65-14.3); p = 0.004), and SGA (28.6% vs. 10.1%; aOR = 3.70 (1.20-11.4), p = 0.02). No maternal characteristics were significantly associated with fetal ACA and the diagnosis of fetal ACA was not associated with adverse birth outcomes. Histological evidence of severe maternal ACA was associated with an increased risk of PTB, LBW, and SGA in HIV infected, pregnant Ugandan women.


[Hemichorea with Contralateral High Signal Intensity Putaminal Lesion on T1-Weighted Images in Non-Ketotic Hyperglycemia].
A 64-year-old diabetic female patient presented with involuntary unilateral hyperkinetic movements of the left limbs. Cranial MRI showed a contralateral high signal intensity putaminal lesion on T1-weighted images without any signal changes in the T2-weighted images. This finding is characteristic for hemichorea-hemiballism associated with insufficiently treated diabetes mellitus. Additionally, proton MR spectroscopy was performed and revealed a decreased N-acetylaspartate/creatine and N-acetylaspartate/choline ratio, indicating neuronal damage of the contralateral putamen.


Bronisława Fejgin (1883-1943): Forgotten Important Contributor to International Microbiology and Phage Therapy.
Bronisława Brandla Fejgin was a Polish-born Jewish female physician. Among Fejgin's numerous articles in the field of microbiology, her later work was almost entirely devoted to phage research. Although not equally famous as the phage pioneers from Western Europe, F.W. Twort and F. d'Herelle, Fejgin's contribution to phage research deserves proper recognition. Her studies on phages resulted in the publication of numerous original scientific reports. These articles, published mostly in French, constitute an important source of information and expertise on early attempts towards therapeutic use of phages in humans. The interwar period marks the most intense years in Bronisława Fejgin's research activity, brutally interrupted by her death in the Warsaw Ghetto in 1943. Her microbiology contributions have not been analyzed so far. Thus, the aim of this article is to fill the existing gap in the history of microbiology and phage therapy.


Circular RNA CDR1as Alleviates Cisplatin-Based Chemoresistance by Suppressing MiR-1299 in Ovarian Cancer.
Cisplatin (CDDP) chemoresistance seriously affects the prognosis and survival of patients with ovarian cancer (OC). Previous research has shown that circular RNA CDR1as is biologically associated with a large number of cancers. However, the molecular mechanism underlying the role of CDR1as in CDDP chemoresistance in OC remains unclear. Here, we investigated the mechanism of CDR1as in CDDP-resistant OC. First, we employed bioinformatics analysis and quantitative real-time PCR (qRT-PCR) to determine the expression of CDR1as and related RNAs in CDDP-sensitive and -resistant OC tissues and cells. Then, functional experiments were used to determine cell proliferation, invasion, migration, and apoptosis in CDDP chemoresistance and parent OC cells in vitro. The effect of CDR1as in CDDP chemoresistance OC progression was tested in nude mice in vivo. Moreover, dual-luciferase assays and RNA immunoprecipitation (RIP) were performed to confirm the interactions of CDR1as and related RNAs. Finally, we used Western blotting to determine protein expression levels. Our findings interpret the underlying mechanisms of the CDR1as/miR-1299/PPP1R12B axis and shed light on the clinical applications for CDDP-chemoresistant OC.


Effects of low abdominal blood flow and dobutamine on blood flow distribution and on the hepatic arterial buffer response in anaesthetized pigs.
Low cardiac output impairs the hepatic arterial buffer response (HABR). Whether this is due to low abdominal blood flow per se is not known. Dobutamine is commonly used to increase cardiac output, and it may further modify hepatosplanchnic and renal vasoregulation. We assessed the effects of isolated abdominal aortic blood flow changes and dobutamine on hepatosplanchnic and renal blood flow. Twenty-five anesthetized pigs with an abdominal aorto-aortic shunt were randomized to 2 control groups [zero (n = 6) and minimal (n = 6) shunt flow], and 2 groups with 50% reduction of abdominal blood flow and either subsequent increased abdominal blood flow by shunt reduction (n = 6) or dobutamine infusion at 5 and 10 microg kg(-1) min(-1) with constant shunt flow (n = 7). Regional (ultrasound) and local (laser Doppler) intra-abdominal blood flows were measured. The HABR was assessed during acute portal vein occlusion. Sustained low abdominal blood flow, by means of shunt activation, decreased liver, gut, and kidney blood flow similarly and reduced local microcirculatory blood flow in the jejunum. Shunt flow reduction partially restored regional blood flows but not jejunal microcirculatory blood flow. Low-but not high-dose dobutamine increased gut and celiac trunk flow whereas hepatic artery and renal blood flows remained unchanged. Neither intervention altered local blood flows. The HABR was not abolished during sustained low abdominal blood flow despite substantially reduced hepatic arterial blood flow and was not modified by dobutamine. Low-but not high-dose dobutamine redistributes blood flow toward the gut and celiac trunk. The jejunal microcirculatory flow, once impaired, is difficult to restore.


Invertases in Oat Seedlings: SEPARATION, PROPERTIES, AND CHANGES IN ACTIVITIES IN SEEDLING SEGMENTS.
The soluble invertase activity in etiolated Avena seedlings was highest at the apex of the coleoptile and much lower in the primary leaf, mesocotyl, and root. The activity in all parts of the seedling consisted of two invertases (I and II) which were separated by chromatography on diethylaminoethylcellulose. Both enzymes appeared to be acid invertases, but they differed in molecular size, pH optimum, and the kinetic parameters K(m) and V(max) of their action on sucrose, raffinose, and stachyose. Invertase II had low stability at pH 3.5 and below, and exhibited high sensitivity to Hg(2+), with complete inhibition by 2 micromolar HgCl(2). Segments of coleoptiles incubated in water lost about two-thirds of the total invertase activity after 16 hours. The loss of activity was due primarily to a decrease in the level of invertase II. The loss of invertase was decreased by indoleacetic acid, 2,4-dichlorophenoxyacetic acid, and alpha-naphthaleneacetic acid but not by beta-naphthaleneacetic acid and p-chlorophenoxyisobutyric acid. Conditions that inhibited auxin-induced growth of the segments (20 millimolar CaCl(2) and 200 millimolar mannitol) also blocked the auxin effect on invertase loss.


The relationship of various measures of time urgency to indices of physical health.
The degree of association with two general health indices was assessed for three separate measures of time urgency. The Speed and Impatience subscale of the Jenkins Activity Survey was found to have no significant relationships with the health indices. The Time Urgency/Perpetual Activation (TUPA) scale, as well as the Irritability and Impatience scale, did correlate in comparable ways with a majority of the health indicators. A very brief, 2-item impatience subscale of the Irritability and Impatience Scale also correlated with health indices in essentially the same manner as the complete Irritability and Impatience Scale and the TUPA Scale. It was concluded that because of its convenience of administration, the very brief 2-item impatience subscale of the Irritability and Impatience Scale may constitute the instrument of choice for assessing time urgency as it relates to noncardiovascular health. A question is raised regarding whether anger and time urgency constitute separate factors or are aspects of a single behavioral trait.


Learning from soil gas change and isotopic signatures during 2012 Emilia seismic sequence.
Soil surveys were performed in Medolla (Italy), a peculiar area characterized by spotty high soil temperature, gas vent, and lack of vegetation, to determine the migration mechanisms and spatial behavior of gas species. Hereby we present soil gas measurements and their isotopic ratios measured between 2008 and 2015, including the 2012 Emilia-Romagna seismic sequence. We found that soil gas concentrations markedly changed during the main shocks of May 20 and 29, 2012 (Mw 6.1 and 6.0, respectively), highlighting the presence of a buried fault intersecting the gas vents. We suggest that crustal dilation associated with seismic activity favored the uprising of geogas towards the surface. Changes in the isotopic signature highlight the contribution of two distinct sources, one deeper, thermogenic and another superficial related to organic-rich layer, whose relative contribution varied before, during and after the earthquake. We suppose an increase of microbial component likely due to the ground shaking of shallower layers linked to seismic sequence, which masks the thermogenic contribution. Although the changes we detect are specific for an alluvial plain, we deduce that analogous processes may be active elsewhere, and that soil gas geochemistry represents an useful tool to discriminate the gas migration related to seismic activity.


The mycobiome of Australian tree hollows in relation to the Cryptococcus gattii and C. neoformans species complexes.
Cryptococcosis is a fungal infection caused by members of the Cryptococcus gattii and C. neoformans species complexes. The C. gattii species complex has a strong environmental association with eucalypt hollows (particularly Eucalyptus camaldulensis), which may present a source of infection. It remains unclear whether a specific mycobiome is required to support its environmental survival and growth. Conventional detection of environmental Cryptococcus spp. involves culture on differential media, such as Guizotia abyssinica seed agar. Next-generation sequencing (NGS)-based culture-independent identification aids in contextualising these species in the environmental mycobiome. Samples from 23 Australian tree hollows were subjected to both culture- and amplicon-based metagenomic analysis to characterize the mycobiome and assess relationships between Cryptococcus spp. and other fungal taxa. The most abundant genera detected were Coniochaeta, Aspergillus, and Penicillium, all being commonly isolated from decaying wood. There was no correlation between the presence of Cryptococcus spp. in a tree hollow and the presence of any other fungal genus. Some differences in the abundance of numerous taxa were noted in a differential heat tree comparing samples with or without Cryptococcus-NGS reads. The study expanded the known environmental niche of the C. gattii and C. neoformans species complexes in Australia with detections from a further five tree species. Discrepancies between the detection of Cryptococcus spp. using culture or NGS suggest that neither is superior per se and that, rather, these methodologies are complementary. The inherent biases of amplicon-based metagenomics require cautious interpretation of data through consideration of its biological relevance.


Theoretical Study of Actinide Complexes with Macropa.
The complex formation of actinium (Ac3+) and californium (Cf3+) ions with macropa (a promising ligand for medical applications, e.g., in targeted α therapy) has been studied by means of density functional theory (DFT) calculations. This work is focused on the structural and bonding properties, the latter on the basis of charge transfer data and topological properties of the electron density distribution. The effect of water solvent on the energetics has been investigated using the SMD model. A comparative analysis with the related properties of two representative lanthanide (La, Lu) complexes has been performed.


The efficacy and safety of QVAR (hydrofluoroalkane-beclometasone diproprionate extrafine aerosol) in asthma (Part 2): Clinical experience in children.
QVAR [hydrofluoroalkane-134a beclometasone dipropionate (BDP)] produces equivalent asthma control to chlorofluorocarbon-based BDP inhalers, at approximately half the daily dose in adults, a probable consequence of the increased lung deposition of QVAR that results from its greater fine particle fraction. Recent studies have relied on the clinical experience with QVAR in adults as a basis for investigations in childhood asthma. Design considerations, such as the use of the breath-actuated Autohaler delivery device and measurement of direct health benefits, account for problems of variation in inspiratory flow, handling difficulties and low airways resistance that are associated with children. QVAR appears to be well tolerated in children with no clinically relevant adverse effects on adrenal function, bone metabolism or growth at recommended doses.


Mode crystallography of distorted structures.
The description of displacive distorted structures in terms of symmetry-adapted modes is reviewed. A specific parameterization of the symmetry-mode decomposition of these pseudosymmetric structures defined on the setting of the experimental space group is proposed. This approach closely follows crystallographic conventions and permits a straightforward transformation between symmetry-mode and conventional descriptions of the structures. Multiple examples are presented showing the insight provided by the symmetry-mode approach. The methodology is shown at work, illustrating its various possibilities for improving the characterization of distorted structures, for example: detection of hidden structural correlations, identification of fundamental and marginal degrees of freedom, reduction of the effective number of atomic positional parameters, quantitative comparison of structures with the same or different space group, detection of false refinement minima, systematic characterization of thermal behavior, rationalization of phase diagrams and various symmetries in families of compounds etc. The close relation of the symmetry-mode description with the superspace formalism applied to commensurate superstructures is also discussed. Finally, the application of this methodology in the field of ab initio or first-principles calculations is outlined. At present, there are several freely available user-friendly computer tools for performing automatic symmetry-mode analyses. The use of these programs does not require a deep knowledge of group theory and can be applied either a posteriori to analyze a given distorted structure or a priori to parameterize the structure to be determined. It is hoped that this article will encourage the use of these tools. All the examples presented here have been worked out using the program AMPLIMODES [Orobengoa et al. (2009). J. Appl. Cryst. 42, 820-833].


Ligand-controlled regioselectivity in palladium-catalyzed cross coupling reactions.
The reversal of regioselectivity in a Pd-catalyzed cross-coupling reaction of an aryl chloro triflate with different ligands, established by Fu and co-workers, has been studied computationally. C-O insertion was found to be controlled by Pd-HOMO ArO-LUMO interaction, where C-Cl insertion is facilitated by the lower C-Cl TS distortion energy. The greater reactivities of monoligated Pd species are due primarily to the lack of distortion of the Pd species.


The role of p53 mutation in BRCA1-associated ovarian cancer.
Ovarian cancer remains the most deadly gynecologic malignancy, resulting in an estimated 23,300 new cases and 13,900 deaths in the United States in the year 2002. The discovery of the BRCA1 gene in 1994 has proven to be of great interest to the study of hereditary ovarian cancer. BRCA1 gene mutation confers a 16-42% lifetime risk of the development of ovarian cancer in those affected. Although BRCA1 functions as a tumor suppressor gene, conflicting studies have shown that BRCA1 dysfunction alone may not be sufficient for tumorigenesis. p53 is a tumor suppressor gene found to be dysfunctional in nearly 50% of all human cancers and in up to 80% of ovarian malignancies. The p53 protein product plays a crucial role in DNA surveillance and repair at the Gap 1-synthesis (G1-S) cell cycle checkpoint. Studies exhibiting the interaction of BRCA1 and p53 and the role of this interaction in DNA damage response led many investigators to suggest that p53 gene mutation is required for BRCA1-associated tumor development. This review explores the evidence for BRCA1 and p53 interplay, and outlines the crucial role p53 may play in BRCA1-related ovarian cancer.


Activation and function of the Rap1 GTPase in B lymphocytes.
Rap1 is a monomeric GTPase that is closely related to Ras. In this review, we summarize our recent work showing that the B cell antigen receptor (BCR), as well as chemokine receptors, activate Rap1 via a pathway that involves phospholipase C-dependent production of diacylglycerol (DAG). The possible identities of the DAG-regulated guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) that regulate the activation of Rap1 by the BCR and chemokine receptors will be discussed. Although initially thought to be an antagonist of Ras-mediated signaling, Rap1 does not appear to modulate the ability of the BCR to activate downstream targets of Ras. Instead, activation of Rap1 promotes B cell adhesion as well as B cell migration toward chemokines. Thus, Rap1 may play a key role in a number of processes that are essential for B cell development and activation.


Constituents of Passiflora incarnata, but Not of Valeriana officinalis, Interact with the Organic Anion Transporting Polypeptides (OATP)2B1 and OATP1A2.
Herbal medication used in the treatment of sleep disorders and anxiety often contain extracts of Valeriana officinalis or Passiflora incarnata. Valerenic acid in V. officinalis and apigenin, orientin, and vitexin in P. incarnata are thought to contribute to their therapeutic effect. It was the aim of this study to test whether these constituents of herbal extracts are interacting with the uptake of estrone 3-sulfate, pregnenolone sulfate, and dehydroepiandrosterone sulfate mediated by the uptake transporters organic anion transporting polypeptide 2B1 (OATP2B1) or organic anion transporting polypeptide 1A2 (OATP1A2). Madin-Darby canine kidney cells overexpressing OATP2B1 or OATP1A2 were used to determine the influence of the constituents on the cellular accumulation of the sulfated steroids. Subsequently, competitive counterflow experiments were applied to test whether identified inhibitors are also substrates of the transporters. Valerenic acid only interacted with OATP2B1, whereas apigenin, orientin, and vitexin interacted with OATP2B1 and OATP1A2. Competitive counterflow revealed that orientin is a substrate of both transporters, while apigenin was transported by OATP1A2 and vitexin by OATP2B1. In a next step, commercially available P. incarnata preparations were assessed for their influence on the transporters, revealing inhibition of transporter-mediated estrone 3-sulfate uptake. HPLC-UV-MS analysis confirmed the presence of orientin and vitexin in these preparations, thereby suggesting that these constituents are involved in the interaction. Our data indicate that constituents of P. incarnata may alter the function of OATP2B1 and OATP1A2, which could affect the uptake of other compounds relying on uptake mediated by the transporters.


Clinical characteristics and pattern of skin test reactivities in shellfish allergy patients in Hong Kong.
Allergens from crustaceans and mollusks exhibit extensive cross-reactivity in vitro. However, the degree and pattern of cross-reactivity between different shellfish species in vivo is still unclear. The objective of this study was to determine the clinical characteristics of shellfish allergic patients in Hong Kong and the pattern of skin test reactivities to the different species. This cohort study involves patients attending the allergy clinic of a large teaching hospital for suspected shellfish allergy. Each subject underwent skin-prick tests to eight species of shellfish and house-dust mites. Eighty-four consecutive patients were tested. Twenty-eight patients reported a history of severe anaphylaxis. Fourteen patients had no positive shellfish skin test and were excluded. There were 183 positive shellfish skin tests, with an average of 2.61 positive tests per subject. Ninety percent of subjects also had positive skin tests to house-dust mites. Overall, 65. 7% of subjects had more than one positive skin test to shellfish. There were strong statistical associations between species belonging to the same order but also between some mollusks and crustaceans. We found a high degree of skin test cross-reactivity between different species of shellfish and between shellfish and house-dust mites. Therefore, patients with a history of shellfish allergy should be cautious with all types of shellfish.


Relationship between cerebral blood flow reduction patterns on scintigraphy and nonmotor symptoms in new-onset Lewy body disease.
This study aimed to investigate the relationship between patterns of reduced cerebral blood flow (CBF) evaluated by means of 123I-N-isopropyl-p-iodoamphetamine ([123I]IMP) scintigraphy and nonmotor symptoms in new-onset Lewy body disease (Parkinson's disease and dementia with Lewy bodies [DLB]). Twenty-four patients diagnosed with new-onset Parkinson's disease or DLB underwent [123I]IMP CBF scintigraphy at St. Marianna Medical University Hospital between January 1, 2010, and March 30, 2018. The reductions in CBF in various brain regions were analyzed using the three-dimensional stereotactic surface projection method and were compared to standard database values, yielding extent values (%). The extent values were evaluated in relation to the presence/absence of motor or nonmotor symptoms such as visual hallucinations, auditory hallucinations, delirium, depression, delusions, and dementia. The extent value was 100% in the angular, supramarginal, and lingual gyri; 95% in the orbital gyri; and 92.6% in the fusiform gyri. The extent value in patients without hallucinations and those with visual hallucinations was 41.2% and 54.3%, respectively, in the frontal lobe (p = 0.02) and 33.3% and 51.0%, respectively, in the medial prefrontal gyri (p = 0.02). Age-adjusted multivariate analysis showed that extent values in the frontal lobe were associated with visual hallucinations (odds ratio: 1.09, 95% confidence interval 1.00-1.18, p = 0.04). The above results show that the CBF is reduced in several areas of the cerebral cortex and suggest an association between reduced blood flow in the frontal lobe and the appearance of visual hallucinations in patients with new-onset DLB.


Paradoxical temperature dependence of sodium and potassium fluxes in human red cells.
1. The effect of temperature on passive movements of sodium and potassium through the red cell membrane has been determined in the presence of various monovalent anions.2. Passive sodium and potassium fluxes varied in a complex way with temperature, when the isotonic electrolyte media contained 120 mM thiocyanate or salicylate. Between 0 and 18 degrees C the fluxes decreased with increasing temperature. Above 18 degrees C the rate of permeation increased when temperature was increased.3. The ability of anions to induce an increased sodium influx at 0 degrees C was gradually intensified through the following sequence of anions:HCO(3) (-) < Cl(-) = Br(-) < NO(3) (-) < I(-) << SCN(-) << salicylate.4. It is proposed that the anion induced effects on the cation permeability are secondary to binding of anions to fixed cations in the red cell membrane. The temperature dependence of the cation fluxes is assumed to reflect the binding on anions to fixed charges at temperatures between 0 and 18 degrees C.


Ligamentum flavum hematoma presenting as progressive root compression in the lumbar spine.
This is a case report. To provide a better understanding of a rare entity, ligamentum flavum hematoma, based on a successfully treated patient. Lumbar root compression is frequently caused by disc herniation. Canal stenosis, epidural hematoma, or tumors are less common. Few cases of hematoma in the ligamentum flavum causing lumbar root compression have been described. A patient was treated for ligamentum flavum hematoma causing progressive lumbar root symptoms. Clinical and radiologic features, including magnetic resonance images, were recorded. Symptoms consisted of progressive lumbar root deficit after mild physical exertion. On magnetic resonance images, a mass continuous with the ligamentum flavum, compressing the dural sac and roots, was found. Areas of high signal in T1 were present in it. In this patient, removal of the ligamentum flavum (degenerated tissue containing hematoma) resolved all of the symptoms. The diagnosis could have been suspected based on clinical history and magnetic resonance imaging. Magnetic resonance imaging can provide a basis for diagnosing ligamentum flavum hematoma. Removal of ligamentum flavum is the treatment of choice.


A study to compare the use of fusidic acid viscous eye drops and chloramphenicol eye ointment in an accident and emergency department.
A total of 300 patients attending an Accident and Emergency department with ophthalmic complaints needing topical antibiotic treatment were treated with fucithalmic or chloramphenicol (chloromycetin). Their compliance and the incidence of side effects were assessed. There was a 70.3% response rate to the questionnaire. Of the patients 51.3% using fucithalmic completed the 5 day course compared with 37.2% of those taking chloramphenicol. However, no patients were found to have suffered as a result of failing to complete the course. The incidence of side effects was similar in both groups.


Gallstone Ileus following Endoscopic Stone Extraction.
An 85-year-old woman was an outpatient treated at Tokyo Rosai Hospital for cirrhosis caused by hepatitis B. She had previously been diagnosed as having common bile duct stones, for which she underwent endoscopic retrograde cholangiopancreatography (ERCP). However, as stone removal was unsuccessful, a plastic stent was placed after endoscopic sphincterotomy. In October 2012, the stent was replaced endoscopically because she developed cholangitis due to stent occlusion. Seven days later, we performed ERCP to treat recurring cholangitis. During the procedure, the stone was successfully removed by a balloon catheter when cleaning the common bile duct. The next day, the patient developed abdominal pain, abdominal distension, and nausea and was diagnosed as having gallstone ileus based on abdominal computed tomography (CT) and abdominal ultrasonography findings of an incarcerated stone in the terminal ileum. Although colonoscopy was performed after inserting an ileus tube, no stone was visible. Subsequent CT imaging verified the disappearance of the incarcerated stone from the ileum, suggesting that the stone had been evacuated naturally via the transanal route. Although it is extremely rare for gallstone ileus to develop as a complication of ERCP, physicians should be aware of gallstone ileus and follow patients carefully, especially after removing huge stones.


Migraine Does Not Affect Pain Intensity Perception: A Cross-Sectional Study.
To explore perceived pain intensity (PPI) in three drug-naïve patient groups characterized by homogeneous migraine phenotypes-migraine without aura without cutaneous allodynia (MwoA CA-), MwoA with ictal CA (MwoA CA+), and migraine with aura without cutaneous allodynia (MwA CA-)-compared with age- and sex-matched healthy controls (HCs). Using trigeminal heat stimulation (THS) at three different predefined intensities (41 °C, 51 °C, and 53 °C) performed by the contact heat-evoked potential stimulator (CHEPS), PPI was investigated in 34 patients with MwoA CA-, 30 patients with MwoA CA+, and 30 patients with MwA CA- compared with 30 age- and sex-matched HCs. The patients had never taken migraine-preventive drugs, and they were investigated during an interictal period to avoid confounds associated with migraine attack. Secondary analyses evaluated associations between PPI and clinical features of migraine in patients. No significant differences were observed between the four groups for each experimentally induced stimulus. Moreover, no significant correlations were found between clinical variables and the PPI of the THS at any level of experimental stimulus. Despite the converging evidence of pain threshold abnormalities in migraine patients, our findings suggest that migraine patients did not exhibit differences in the PPI of THS when compared with HCs, independent of phenotype and migraine severity, as well as somatic, psychiatric, or pharmacological interferences. This may depend on both the nature of the pain stimulus experienced and the involvement of selective regions or specific pain processing pathways.


Protoplast Fusion: EFFECT OF LOW TEMPERATURE ON THE MEMBRANE FLUIDITY OF CULTURED CELLS.
The relation between the composition of the phospholipid molecular species in a cell membrane and the velocity of protoplast fusion was studied using cells cultured at a low temperature (10 C). Cells cultured at a low temperature contained larger proportions of phospholipids of low phase transition point, the 1,2-dilinoleoyl-type, than those cultured at a normal temperature (25 C). When treated with polyethylene glycol 6000, protoplasts from cells cultured at 10 C fused and progressed to the fused sphere stage more rapidly than did those from cells cultured at 25 C.


Transfusion requirements in conservative nonoperative management of blunt splenic and hepatic injuries during childhood.
Nonoperative management of splenic and hepatic injuries in children is safe, and the majority of those with isolated injuries do not require blood transfusion. Thirty-seven children were treated for blunt splenic or hepatic trauma from November 1983 to September 1989. There was one death in a patient with a lethal head injury. No operations were performed on those with isolated splenic or hepatic injuries. Three of those with multiple injuries underwent delayed laparotomy. Two had perirenal and retroperitoneal hematomas without active bleeding, and one had a bowel obstruction secondary to an intramural jejunal hematoma. There were no late complications related to the splenic or hepatic injuries. Eight children (22%) required surgery for other injuries. Twelve children were not transfused, including the majority (8/11) of those with isolated splenic or hepatic injury. The hematocrit of four of these children fell to below 28% and this anemia was well-tolerated. Two children with bleeding disorders (factor VIII [antihemophilic factor] and factor XII [Hageman factor] deficiency) did not require packed red blood cells transfusion. Two clinically distinct groups of children received blood transfusions: (1) eight patients with multiple injuries were transfused during initial resuscitation when unstable or during early operation for other system trauma (mean, 62.0 mL blood/kg body weight); and (2) three hemodynamically stable patients with isolated injuries and 14 stable patients with multiple injuries were transfused empirically after initial resuscitation solely because of decreasing blood counts. They received an average of 16.5 and 21.1 mL blood/kg body weight, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)


Increasing New Delhi metallo-β-lactamase-positive Escherichia coli among carbapenem non-susceptible Enterobacteriaceae in Taiwan during 2016 to 2018.
New Delhi metallo-β-lactamase (NDM) had been reported to be the predominant carbapenemase among Escherichia coli in Taiwan. However, studies focusing on the clonal background and epidemiology of plasmids carrying NDM genes were limited. Between 2016 and 2018, all clinical E. coli and Klebsiella pneumoniae isolates that were non-susceptible to ertapenem, meropenem, and imipenem were tested for carbapenemase-encoding genes (CEGs) and antimicrobial susceptibilities. Molecular typing was performed on all carbapenemase-producing isolates. Whole genome sequencing (WGS) was performed on all NDM-positive E. coli isolates. Twenty-three (29.5%) of 78 carbapenem non-susceptible E. coli and 108 (35.3%) of 306 carbapenem non-susceptible K. pneumoniae isolates carried CEGs. The most prevalent CEGs in carbapenemase-producing E. coli (CPEc) were blaNDM (39.1%) and blaIMP-8 (30.4%), while that in carbapenemase-producing K. pneumoniae was Klebsiella pneumoniae carbapenemase (KPC) (72.2%). Fifteen sequence types were identified among 23 CPEc, and 55.6% of NDM-positive E. coli isolates belonged to ST410. WGS showed ST410 isolates were highly clonal and similar to those from other countries. All NDM-5-positive E. coli isolates carried identical IncX3 plasmid harboring blaNDM-5 but no other antimicrobial resistance (AMR) genes. In each of the four NDM-1-positive E. coli isolates, the blaNDM-1 was present in a ∼ 300 kb IncHI2/IncHI2A plasmid which carried an array of AMR genes. NDMs are the most prevalent carbapenemase among CPEc in Taiwan. Awareness should be raised as the prevalence of NDM-positive E. coli might increase rapidly with IncX3 plasmid and globally distributed strain ST410 being the potential vectors for wide dissemination.


Sequence-specific cleavage of RNA by Type II restriction enzymes.
The ability of 223 Type II restriction endonucleases to hydrolyze RNA-DNA heteroduplex oligonucleotide substrates was assessed. Despite the significant topological and sequence asymmetry introduced when one strand of a DNA duplex is substituted by RNA we find that six restriction enzymes (AvaII, AvrII, BanI, HaeIII, HinfI and TaqI), exclusively of the Type IIP class that recognize palindromic or interrupted-palindromic DNA sequences, catalyze robust and specific cleavage of both RNA and DNA strands of such a substrate. Time-course analyses indicate that some endonucleases hydrolyze phosphodiester bonds in both strands simultaneously whereas others appear to catalyze sequential reactions in which either the DNA or RNA product accumulates more rapidly. Such strand-specific variation in cleavage susceptibility is both significant (up to orders of magnitude difference) and somewhat sequence dependent, notably in relation to the presence or absence of uracil residues in the RNA strand. Hybridization to DNA oligonucleotides that contain endonuclease recognition sites can be used to achieve targeted hydrolysis of extended RNA substrates produced by in vitro transcription. The ability to 'restrict' an RNA-DNA hybrid, albeit with a limited number of restriction endonucleases, provides a method whereby individual RNA molecules can be targeted for site-specific cleavage in vitro.


Hexapeptide analogue of somatostatin, Sandoz 201-456. Conformational study in dimethylsulfoxide by 1D and 2D n.m.r. methods.
The conformational properties of the somatostatin analogue 201-456 (1) have been studied by high field n.m.r. in DMSO. This analogue is the base structure of nine derivates synthesized by Bauer et al. and shows a very low biological activity, although derived structures such as SMS 201-995 (2) are very potent. Our study has shown an important difference between the most stable conformation of the two compounds: although the beta turn type II' structure at the Phe3-Trp4-Lys5 level is present in both analogues, an important conformational change appears at the cystine bridge. In SMS 201-995 the beta turn/beta sheet conformation is stabilized by the additional amino-acids D-Phe1 and Thr8 (ol) through intramolecular H-bonds.


Anharmonic frequencies of CX2Y2 (X, Y = O, N, F, H, D) isomers and related systems obtained from vibrational multiconfiguration self-consistent field theory.
Accurate anharmonic frequencies are provided for molecules of current research, i.e., diazirines, diazomethane, the corresponding fluorinated and deuterated compounds, their dioxygen analogs, and others. Vibrational-state energies were obtained from state-specific vibrational multiconfiguration self-consistent field theory (VMCSCF) based on multilevel potential energy surfaces (PES) generated from explicitly correlated coupled cluster, CCSD(T)-F12a, and double-hybrid density functional calculations, B2PLYP. To accelerate the vibrational structure calculations, a configuration selection scheme as well as a polynomial representation of the PES have been exploited. Because experimental data are scarce for these systems, many calculated frequencies of this study are predictions and may guide experiments to come.


Diffusion in disordered media with long-range correlations: anomalous, Fickian, and superdiffusive transport and log-periodic oscillations.
We present the results of extensive Monte Carlo simulation of diffusion in disordered media with long-range correlations, a problem which is relevant to transport of contaminants in field-scale porous media, such as aquifers, gas transport in soils, and transport in composite materials. The correlations are generated by a fractional Brownian motion characterized by a Hurst exponent H. For H>1/2 the correlations appear to have no effect, and the transport process is diffusive. However, for H<1/2 and depending on the morphology of the medium, three distinct types of transport processes, namely, anomalous, Fickian, and superdiffusive transport may emerge. Moreover, if the medium is anisotropic and stratified, biased diffusion in it is characterized by power-law growth of the mean square displacements with the time in which the effective exponents characterizing the power-law oscillates log periodically with the time. This result cannot be predicted by any of the currently available continuum theories of transport in disordered media.


Familial Adenomatous Polyposis Manifesting as Lactococcus Endocarditis: A Case Report and Review of the Association of Lactococcus with Underlying Gastrointestinal Disease.
A 45-year-old male with a prosthetic aortic valve presented to the hospital with several months of generalized malaise. On admission, he was noted to have anemia of unclear etiology and subsequently became febrile with multiple blood cultures growing Lactococcus garvieae. Inpatient workup was concerning for infectious endocarditis (IE) secondary to Lactococcus. The patient was discharged home with appropriate antimicrobial therapy; however, he was readmitted for persistent, symptomatic anemia and underwent colonoscopy, which revealed innumerable colonic polyps consistent with Familial Adenomatous Polyposis (FAP) that was later confirmed with genetic testing. Surveillance computed tomography (CT) imaging of the aortic repair later demonstrated valve dehiscence with surrounding fluid collection; he underwent redo surgery and was found to have destruction of the aortic annulus and a large pseudoaneurysm. Histopathology of the valve prosthesis confirmed IE. It is suspected that the patient developed Lactococcus IE from enteric translocation. Review of the literature provides several reports of Lactococcus infections in association with underlying gastrointestinal disease, including colorectal cancer. Given this association, we raise the question of whether the diagnosis of Lactococcus IE should evoke suspicion and encourage evaluation for gastrointestinal pathology, as occurs with Streptococcus bovis.


Exploring the Link Between Completion of Accreditation Prerequisites and Local Health Departments' Decision to Collaborate With Tax-Exempt Hospitals Around the Community Health Assessment.
Community health assessments (CHAs) are a core function of local health departments (LHDs). Recently, completing a CHA has become a prerequisite for LHDs seeking accreditation by the Public Health Accreditation Board (PHAB). Similarly, under the Affordable Care Act, nonprofit hospitals are required to conduct periodic community health needs assessments (CHNAs). Opportunities thus exist for LHDs and hospitals to jointly complete CHAs/CHNAs. This study examined existing LHD-hospital collaborations around CHAs/CHNAs, focusing specifically on the relationship between LHDs' level of engagement with PHAB accreditation activities and their collaboration with hospitals around CHAs/CHNAs. Data came from the 2013 NACCHO (National Association of County & City Health Officials) Profile Study and the Area Health Resource File. Complete data were available for 1332 LHDs that participated in the 2013 NACCHO Profile Study. Logistic regression explored the relationship between LHDs' completion of accreditation prerequisites, in particular completion of a CHA, community health improvement plan, and strategic plan, and their involvement in collaborations with tax-exempt hospitals around CHAs/CHNAs. LHDs that collaborated with tax-exempt hospitals on CHAs/CHNAs were larger, more likely to be locally governed, and more likely to have a local board of health. Bivariate analysis showed that CHA/CHNA-related collaboration with hospitals was significantly correlated (P < .01) with an LHD's completion of accreditation prerequisites. In multivariate regression analysis, completion of all 3 PHAB accreditation prerequisites significantly increased the odds of LHDs collaborating with hospitals when controlling for other LHD and community-level characteristics. PHAB accreditation prerequisites together with IRS requirements for hospitals foster potential for collaboration around CHAs/CHNAs. Joint completion of CHAs/CHNAs not only allows partners to complete the assessment more efficiently but has also been shown to produce higher-quality assessments, thus building a strong foundation for continued collaboration to improve community health.


Integrative Analysis of the Metabolome and Transcriptome of a Cultivated Pepper and Its Wild Progenitor Chiltepin (Capsicum annuum L. var. glabriusculum) Revealed the Loss of Pungency During Capsicum Domestication.
Pungency is a unique characteristic of chili peppers (Capsicum spp.) caused by capsaicinoids. The evolutionary emergence of pungency is thought to be a derived trait within the genus Capsicum. However, it is not well-known how pungency has varied during Capsicum domestication and specialization. In this study, we applied a comparative metabolomics along with transcriptomics analysis to assess various changes between two peppers (a mildly pungent cultivated pepper BB3 and its hot progenitor chiltepin) at four stages of fruit development, focusing on pungency variation. A total of 558 metabolites were detected in two peppers. In comparison with chiltepin, capsaicinoid accumulation in BB3 was almost negligible at the early stage. Next, 412 DEGs associated with the capsaicinoid accumulation pathway were identified through coexpression analysis, of which 18 genes (14 TFs, 3 CBGs, and 1 UGT) were deemed key regulators due to their high coefficients. Based on these data, we speculated that downregulation of these hub genes during the early fruit developmental stage leads to a loss in pungency during Capsicum domestication (from chiltepin to BB3). Of note, a putative UDP-glycosyltransferase, GT86A1, is thought to affect the stabilization of capsaicinoids. Our results lay the foundation for further research on the genetic diversity of pungency traits during Capsicum domestication and specialization.


Modifications in the Topological Structure of EEG Functional Connectivity Networks during Listening Tonal and Atonal Concert Music in Musicians and Non-Musicians.
The present work aims to demonstrate the hypothesis that atonal music modifies the topological structure of electroencephalographic (EEG) connectivity networks in relation to tonal music. To this, EEG monopolar records were taken in musicians and non-musicians while listening to tonal, atonal, and pink noise sound excerpts. EEG functional connectivities (FC) among channels assessed by a phase synchronization index previously thresholded using surrogate data test were computed. Sound effects, on the topological structure of graph-based networks assembled with the EEG-FCs at different frequency-bands, were analyzed throughout graph metric and network-based statistic (NBS). Local and global efficiency normalized (vs. random-network) measurements (NLE|NGE) assessing network information exchanges were able to discriminate both music styles irrespective of groups and frequency-bands. During tonal audition, NLE and NGE values in the beta-band network get close to that of a small-world network, while during atonal and even more during noise its structure moved away from small-world. These effects were attributed to the different timbre characteristics (sounds spectral centroid and entropy) and different musical structure. Results from networks topographic maps for strength and NLE of the nodes, and for FC subnets obtained from the NBS, allowed discriminating the musical styles and verifying the different strength, NLE, and FC of musicians compared to non-musicians.


Pharmacokinetics of imidocarb dipropionate in horses after intramuscular administration.
The objective of this study was to determine the pharmacokinetic behaviour of imidocarb in horses following a single i.m. injection at the dose commonly administered to treat Babesia caballi infections or to prevent babesiosis. Eight horses were injected i.m. with a single dose of 2.4 mg imidocarb dipropionate/kg bwt and blood, faecal, urine and milk samples were collected. For imidocarb determination, a high-performance liquid chromatographic method (HPLC) was used after weak cation-exchange solid phase, or liquid-liquid, extraction procedures. Twelve hours after treatment, no detectable plasma concentrations were recorded in any of the treated animals. The distribution and elimination patterns of the drug suggested that it is quickly sequestrated in some storage tissues and remains in the body for a long time. Its prolonged presence in the body may confer a reservoir effect to imidocarb in some tissues, therefore making it undetectable in the plasma of animals but sufficient to produce its described therapeutic and prophylactic activities.


Zonisamide in the treatment of bulimia nervosa: an open-label, pilot, prospective study.
To assess preliminarily the effectiveness of zonisamide in bulimia nervosa. This was an open-label, prospective, 12-week, flexible dose study of zonisamide in bulimia nervosa. The primary outcome was binge-purge episode frequency. Twelve individuals received zonisamide, 10 completed at least one post-baseline evaluation, and six completed the study. Mean dose at endpoint was 420 (SD = 215) mg/day. Zonisamide was associated with significant reductions in frequency of binge-purge episodes and binge-purge days as well as measures of binge eating behavior, purging behavior, clinical severity, obsessive-compulsive features, and depressive symptoms. Weight was unchanged. In this open-label trial, zonisamide was effective in bulimia nervosa, but associated with a high discontinuation rate.


Orientation of the Atrial Septum to the Inferior Vena Cava May Contribute to the Persistent Patency of the Foramen Ovale.
There is growing evidence that paradoxical embolism through patent foramen ovale (PFO) is a cause for cryptogenic stroke. However, it is still unclear why the foramen ovale fails to close after birth. We studied whether the 3D relations between the atrial septum (AS) and the inferior vena cava (IVC) are associated with PFO. We recruited 30 patients (18-49 years) with a first-ever cryptogenic stroke and 30 age- and sex-matched stroke-free controls. Using cardiac magnetic resonance, an approach to evaluate the 3D relations between the AS and the IVC was developed. The presence of interatrial right-to-left shunt was evaluated with transesophageal echocardiography (TEE) in patients and transcranial Doppler in controls. Of 30 patients, 29 underwent successful TEE, of which 12 (41%) had a shunt. Patients with a shunt had a greater mean 3D angle (γ) between the atrial septal plane and the vector from the orifice of the IVC to the middle of the AS compared with patients without a shunt (45 ± 9° vs. 36 ± 8°, p = 0.017). Of 30 controls, 12 (40%) had a shunt and a greater mean γ compared with controls without a shunt (47 ± 8° vs. 37 ± 10°, p = 0.007). In a pooled analysis, 24 (41%) of 59 subjects with a shunt had a mean γ of 46 ± 9° compared with subjects without a shunt of 37 ± 9° (p < 0.001). More perpendicular orientation of the atrial septal plane to the orifice of the IVC is associated with PFO, possibly by directing the IVC flow to PFO.


Current concepts of the etiology and pathogenesis of ulcerative colitis and Crohn's disease.
Although the causes, events initiating and triggering inflammation, and the precise immunoregulatory defects of IBD are still not known, investigations have provided a better understanding of the mechanisms of perpetuation of inflammation, genetic susceptibility, tissue injury, and symptoms. Ulcerative colitis and Crohn's disease are related disorders that probably share susceptibility genes and have similar nonspecific inflammatory mediator profiles. These diseases, however, almost certainly have different causes and respond to different antigenic stimuli. It is probable that both ulcerative colitis and Crohn's disease represent heterogenic groups of diseases that share similar mechanisms of tissue damage but have different initiating events and immunoregulatory abnormalities. Rodent models demonstrate that a wide variety of initial injuries or perturbations of immunoregulatory pathways can lead to similar phenotypes of intestinal injury, and human studies show evidence of genetic heterogeneity. It is equally apparent from these models that initiating and perpetuating mechanisms are entirely distinct and that the intestine has a remarkable ability to heal. Chronicity of disease depends on continued exposure to toxic luminal components, most commonly of bacterial origin, and genetically determined host susceptibility. Precise mechanisms of differential genetic susceptibility remain unclear, but defective down-regulation of inflammation is consistent with clinical and experimental observations. The author proposes the following sequence of events (Fig. 9). Nonspecific intestinal inflammation can be induced by a wide variety of enteric infections or ingested toxins. Resultant increased mucosal permeability leads to enhanced uptake of toxic luminal bacterial products, which potentiate local injury. The vast majority of hosts respond to these injurious events by promptly down-regulating the inflammatory response and rapidly healing the mucosal damage without residual scarring. The genetically susceptible host, however, who lacks the ability to suppress the inflammatory response efficiently, has inappropriate amplification of the immune cascade. In response to constant exposure to phlogistic luminal constituents, these patients develop an unrestrained inflammatory response, leading to tissue destruction, chronic inflammation, and fibrosis. Thus, IBD is caused by a genetically determined defective down-regulation of inflammation driven by ubiquitous antigens. Luminal anaerobic bacterial antigens are the stimuli in Crohn's disease, but ulcerative colitis may be caused by functionally abnormal aerobic bacteria or primary defects in epithelial cell physiology. Spontaneous or therapy-induced remissions can be achieved, but the risk of reactivation of inflammation is high because of the frequent exposure to triggering episodes that can reignite the inflammatory cascade. [formula: see text] This theory suggests that the intestine is in a constant state of controlled inflammation, mediated by a balance between aggressive luminal forces and host protective mechanisms (Fig. 10). This delicate balance can be deranged by any number of environmental triggering events and is in dysequilibrium in IBD. Amplification of the inflammatory response activates effector cells and cascades of soluble inflammatory molecules, which mediate tissue injury and physiologic responses leading to symptoms of IBD. These relatively nonspecific events are the target of most current therapeutic agents, which can inhibit but not completely block intestinal inflammation because of the overwhelming number of parallel pathways involved. Specific inhibition of selected effector molecules is intellectually intriguing but is less likely to paralyze the inflammatory response during clinically apparent inflammation than is blockade of key immunoregulatory cells and molecules. Better understanding of initiating, perpetuating, and immunoregulatory mechanisms should provide more


Erosive cheilitis as an early manifestation in DRESS syndrome.
Drug reaction with eosinophilia and systemic symptoms (DRESS) is a distinct part of severe cutaneous adverse reactions (SCARs). It is characterized by fever, rash, hematologic abnormalities, lymphadenopathy, or/and different degrees of visceral organ involvement. Its diagnosis is particularly challenging due to the variability of its clinical presentations and its long latency period (2-6 weeks). Allopurinol, an uric acid-lowering drug, has been incriminated in several cases of allopurinol-induced DRESS syndrome. Through this paper, we present a case of allopurinol-induced DRESS syndrome with initial oral mucosal involvement. A 69-year-old female patient presented with an erosive cheilitis that started 1 week prior to his presentation. The cheilitis was associated with maculopapular rash and fever. She started taking allopurinol, as treatment of Gout, 6 weeks before hospitalization. The histologic findings obtained from skin biopsy were consistent with a toxic drug reaction. A complete blood count (CBC) showed a moderate eosinophilia. Alteration of renal function was also noted, and the diagnosis of allopurinol-induced DRESS syndrome was made. Systemic corticosteroid therapy was therefore started. The patient completely recovered and had been healthy for 3 years before developing a recurrence after re-challenge with allopurinol.


In Vivo Blue-Light Activation of Chlamydomonas reinhardii Nitrate Reductase.
Chlamydomonas reinhardii cells, growing photoautotrophically under air, excreted to the culture medium much higher amounts of NO(2) (-) and NH(4) (+) under blue than under red light. Under similar conditions, but with NO(2) (-) as the only nitrogen source, the cells consumed NO(2) (-) and excreted NH(4) (+) at similar rates under blue and red light. In the presence of NO(3) (-) and air with 2% CO(2) (v/v), no excretion of NO(2) (-) and NH(4) (+) occurred and, moreover, if the bubbling air of the cells that were currently excreting NO(2) (-) and NH(4) (+) was enriched with 2% CO(2) (v/v), the previously excreted reduced nitrogen ions were rapidly reassimilated. The levels of total nitrate reductase and active nitrate reductase increased several times in the blue-light-irradiated cells growing on NO(3) (-) under air. When tungstate replaced molybdate in the medium (conditions that do not allow the formation of functional nitrate reductase), blue light activated most of the preformed inactive enzyme of the cells. Furthermore, nitrate reductase extracted from the cells in its inactive form was readily activated in vitro by blue light. It appears that under high irradiance (90 w m(-2)) and low CO(2) tensions, cells growing on NO(3) (-) or NO(2) (-) may not have sufficient carbon skeletons to incorporate all the photogenerated NH(4) (+). Because these cells should have high levels of reducing power, they might use NO(3) (-) or, in its absence, NO(2) (-) as terminal electron acceptors. The excretion of the products of NO(2) (-) and NH(4) (+) to the medium may provide a mechanism to control reductant level in the cells. Blue light is suggested as an important regulatory factor of this photorespiratory consumption of NO(3) (-) and possibly of the whole nitrogen metabolism in green algae.


Organic pollutants in microplastics from two beaches of the Portuguese coast.
Microplastics pose a threat to coastal environments due to their capacity to adsorb persistent organic pollutants (POPs). These particles (less than 5 mm in size) are potentially dangerous to marine species due to magnification risk over the food chain. Samples were collected from two Portuguese beaches and sorted in four classes to relate the adsorption capacity of pollutants with color and age. Polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs) and DDTs were analysed on pellets through gas chromatography mass spectrometry (GC-MS), and types of plastic were identified using Fourier transformed infra-red spectroscopy (micro-FTIR). Microplastics were mostly polyethylene and polypropylene. Regarding sizes, some fibres ranged from 1 to 5 μm in diameter and were 500 μm in length. The majority of samples collected had sizes above 200 μm. Black pellets, unlike aged pellets, had the highest concentrations of POPs except for PAHs in Fonte da Telha beach. PAHs with higher concentrations were pyrene, phenantrene, chrysene and fluoranthene. Higher concentrations of PCBs were found for congeners 18, 31, 138 and 187. Further investigation is necessary to understand the relationship between plastic degradation and adsorption for different pollutants.


Estimating HIV incidence based on combined prevalence testing.
Knowledge of incidence rates of HIV and other infectious diseases is important in evaluating the state of an epidemic as well as for designing interventional studies. Estimation of disease incidence from longitudinal studies can be expensive and time consuming. Alternatively, Janssen et al. (1998, Journal of the American Medical Association 280, 42-48) proposed the estimation of HIV incidence at a single point in time based on the combined use of a standard and "detuned" antibody assay. This article frames the problem from a longitudinal perspective, from which the maximum likelihood estimator of incidence is determined and compared with the Janssen estimator. The formulation also allows estimation for general situations, including different batteries of tests among subjects, inclusion of covariates, and a comparative evaluation of different test batteries to help guide study design. The methods are illustrated with data from an HIV interventional trial and a seroprevalence survey recently conducted in Botswana.


Influences of Interface Properties on the Performance of Fiber-Reinforced Asphalt Binder.
This paper presents an experimental study about the influence of interfacial properties on the performance of fiber-reinforced asphalt. In this study, four types of fiber including one fiber-reinforced plastic (FRP), two lignin fibers, and one basalt fiber are used, and also four types of asphalt: Asphalt No. 90, asphalt No. 70, one styrene-butadiene-styrene (SBS) modified asphalt, and asphalt rubber are used. The surface energy parameters of various asphalts and fibers and the shear strength of various fiber-reinforced asphalts are measured. On the basis of these measurements, the influences of surface properties of asphalt and fiber on the performance of fiber-reinforced asphalt are analyzed. The results show that the shear strength of asphalt binder can be significantly increased by adding fibers, and the reinforcement effect is closely related to the types of asphalt and fiber. It was discovered, for the same asphalt, that the basalt fiber has the best reinforcement effect, followed by the two lignin fibers, and the FRP. For the same fiber, asphalt rubber was the most reinforced, followed by the SBS modified asphalt, asphalt No. 70 and asphalt No. 90. It was also discovered, for the same asphalt, the higher the surface energy of the fiber, the better the fiber reinforcement effect. The analysis indicates a good correlation between the work of adhesion between asphalt and fiber and the effect of fiber reinforcement. The results can be used as a basis for the selection of the proper fiber-asphalt combination to improve fiber reinforcement effects.


Diagnostic accuracy of the Patient Health Questionnaire 2 (PHQ-2) in Qatar's primary care settings.
This cross-sectional study was designed to establish diagnostic accuracy of the Patient Health Questionnaire 2 in Qatar's primary care population. The data required for the study were anonymously extracted from Qatar's primary care electronic medical record system. The sensitivity, specificity, predictive values, negative values and optimal cut-off points were calculated for the tool. A total of 6921 individuals met the study's inclusion criteria. The diagnostic accuracy of cut-off values was calculated for scores 1-6. Based on the Youden's index (0.58), a score of 2 was identified as the most optimal cut-off. It offers a sensitivity of 88.73% and specificity of 69.31%. Further studies should aim to confirm the results using alternative study designs and to report them in accordance to population characteristics both in Qatar and internationally.


The insertion-deletion polymorphism of the ACE gene is associated with increased blood pressure in women at the end of pregnancy.
Malfunctioning of the cardiovascular system during pregnancy may be responsible for adverse effects on the 'mother-fetus' system. The cardiovascular system of a pregnant woman develops adaptation to the increased load. Angiotensin-converting enzyme (ACE) is known to play an important role in the adaptation. The present study was designed to investigate whether the insertion-deletion (I/D) polymorphism of the ACE gene is associated with the level of arterial blood pressure in women before and during pregnancy. The level of blood pressure was measured in 591 Russian women (Central Russia) before and during (37-40 weeks term) pregnancy. The women were divided into three groups which were hypertensive, hypotensive, and normotensive according to blood pressure level. Genotyping of the ACE I/D polymorphism was performed using polymerase chain reaction (PCR) and amplified fragment length polymorphism assay. Women with genotype DD showed the highest blood pressure level both during and at the end of pregnancy (p<0.05). The highest frequencies of allele D and genotype DD were found in pregnant women in the hypertensive group. The deletion variant of the ACE gene is associated with high blood pressure level at the end of pregnancy.


Nosocomial pneumonia in the intubated patient.
The intubated patient receiving mechanical ventilation is at high risk for nosocomial pneumonia. Epidemiologic data, pathogenic mechanisms, and risk factors for the development of nosocomial pneumonia are reviewed in this subset of patients. Exogenous and endogenous factors for bacterial colonization of the oropharynx are summarized with particular emphasis on the effects of bacterial overgrowth in the stomach. In addition, we review the role of respiratory therapy equipment in the pathogenesis of pneumonia. Overall fatality rates for patients receiving mechanical ventilation in an intensive care unit is approximately 40%. Patients who develop ventilator-associated pneumonia have fatality rates that exceed 50% and are more than two-fold higher than intubated patients without pneumonia. Measures for altering oropharyngeal colonization, reducing gastric colonization, and the use of sound infection control practices are cornerstones for the prevention of ventilator-associated pneumonia.


Co-Inoculation of an Endophytic and Arbuscular Mycorrhizal Fungus Improve Growth and Yield of Helianthus tuberosus L. under Field Condition.
Endophytic fungi (EPF) and arbuscular mycorrhizal fungi (AMF) symbioses can promote the growth and productivity of several types of plants. This work aimed to investigate the effect of co-inoculation of an EPF Exserohilum rostratum NMS1.5 and an AMF Glomus etunicatum UDCN52867 g.5 on the growth and yields of sunchoke (Helianthus tuberosus L.) compared to the effects of full-dose and half-dose chemical fertilizer (15-15-15) under field conditions. Several plant growth parameters of the co-inoculated plants were significantly higher than the other treatments. Remarkably, such an effect was relatively equal to that of the full-dose chemical fertilizers. Moreover, the co-inoculation of EPF and AMF significantly improved the tuber yield production, even better than the use of a chemical fertilizer. This is the first report to show that plant growth promoting effects of the co-inoculation of EPF and AMF were exceptionally greater than those of the chemical fertilizer. Therefore, our EPF and AMF could potentially be used as a biofertilizer for promoting the growth and yield of sunchoke in the fields.


Subzero nonfreezing storage of the mammalian cardiac explant. I. Methanol, ethanol, ethylene glycol, and propylene glycol as colligative cryoprotectants.
We employed hyperosmotic concentrations of penetrating cryoprotective agents (CPA) to store the isolated rat hearts unfrozen at subzero temperatures. The effect of acute exposure to CPA was assessed by flushing the hearts with CP-14, a cardioplegic solution, containing methanol (MeOH), ethanol (EtOH), ethylene glycol (EG), or propylene glycol (PG) for 2 min and reperfusing immediately with Krebs-Henseleit buffer in a working-heart model. The maximal doses that did not cause irreversible suppression of heart function were: MeOH, 1.78 M; EtOH, 1.27 M; EG, 0.84 M; and PG, 0.87 M. For nonfreezing storage, the hearts were flushed with CP-14 containing the highest tolerable concentrations of MeOH, EtOH, EG, or PG, stored for 6 h at -3.7, -2.8, and -1.4 degrees C, respectively, and then reperfused. Control cardiac output (CO) was 76.2 +/- 1.8 ml/min. Post-reperfusional recovery of CO was 86% in MeOH hearts, 82% in EtOH hearts, 76% in EG hearts, and 79% in PG hearts. Thus MeOH offered not only the least cardiac-suppressing effect but the lowest nonfreezing storage temperature. When storage time was extended, recovery and myocardial ATP level decreased with time in hearts flushed with CP-14 + 1.78 M MeOH and stored at -3.7 degrees C. The decay of function was faster than the decay of ATP level, suggesting energy was better preserved than function. The low return of function, however, may be related to CPA toxicity, osmotic stress, and ischemia/reperfusion injury. Nonfreezing storage at subzero temperatures using these CPAs may provide a novel approach to long-term cardiac preservation.


[Evaluation of municipal management of the Brazilian National School Nutrition Program in the largest cities of Santa Catarina State, Brazil].
This article reports on an evaluative study of municipal management of the Brazilian National School Nutrition Program in the largest cities in Santa Catarina State, Brazil. The matrix of indicators included two dimensions: political-organizational, with the sub-dimensions resources, inter-sector action, and social control, and operational-technical, organized in nutritional and feeding efficacy, nutritional monitoring, and educational activities for a healthy diet. A total of 22 indicators were determined, and data were collected through interviews with nutritionists. The political-organizational dimension showed 60% of fair cases and 40% of poor cases, while the operational-technical dimension showed 90% of poor cases, resulting from low performance in monitoring and educational activities. Although the cases showed unsatisfactory results, the evaluation provides important data on the management of the Brazilian National School Nutrition Program. The study emphasizes the importance of evaluation for alerting managers to the relevance of reviewing and upgrading activities.


Calibration and validation of a dynamic water model in agricultural scenarios.
A dynamic aquatic model (DynA model) was previously developed to predict the fate of a chemical in aquatic scenarios characterized by daily or periodic changes in several input parameters. DynA model is here calibrated with data obtained from the literature in specific unsteady state scenarios, such as those of rice fields. The results obtained for two herbicides (cinosulfuron and pretilachlor) in rice paddy scenarios revealed the capability of the model to accurately predict water and sediment concentrations, as shown by some statistical indicators. Modelling efficiency (EF) values of 0.86-0.99 for the water compartment and of 0.77-0.84 for sediment show the good agreement between predicted and measured concentrations. An "external validation" was performed using measured data for a different herbicide (molinate) applied in a Portuguese paddy rice scenario. A sensitivity analysis for this volatile chemical revealed the influence of some climatic parameters (e.g. temperature) to the model outcomes, such as water and sediment concentrations. This confirmed the capability of DynA model as an efficient tool for the pesticide risk assessment in dynamic scenarios.


Pharmacokinetics, metabolism, and excretion of irinotecan (CPT-11) following I.V. infusion of [(14)C]CPT-11 in cancer patients.
This study determined the disposition of irinotecan hydrochloride trihydrate (CPT-11) after i.v. infusion of 125 mg/m(2) (100 microCi) [(14)C]CPT-11 in eight patients with solid tumors. Mean +/- S.D. recovery of radioactivity in urine and feces was 95.8 +/- 2.7% (range 92.2-100.3%, n = 7) of dose. Radioactivity in blood, plasma, urine, and feces was determined for at least 168 h after dosing. Fecal excretion accounted for 63.7 +/- 6.8 (range 54.2-74.9%, n = 7) of dose, whereas urinary excretion accounted for 32.1 +/- 6.9% (range 21.7-43.8%; n = 7) of dose. One patient with a biliary T-tube excreted 30.1% of dose in bile, 14.2% in feces, and 48.2% in urine. Quantitative radiometric HPLC revealed that CPT-11 was the major excretion product in urine, bile, and feces. Aminopentane carboxylic acid (APC) and SN-38 glucuronide (SN-38G) were the most significant metabolites in urine and bile, whereas SN-38 and NPC, a primary amine metabolite, were relatively minor excretion products. SN-38 and APC were the most significant metabolites in feces. The relatively higher amount of SN-38 in feces compared with bile is presumably due to hydrolysis of SN-38G to SN-38 by enteric bacterial beta-glucuronidases. There was close correspondence between quantitative fluorescence HPLC and mass balance findings. CPT-11 was the major circulating component in plasma (55% of the mean radiochemical area under the curve), and CPT-11, SN-38, SN-38G, and APC accounted for 93% of the mean radiochemical AUC. These results show that the parent drug and its three major metabolites account for virtually all CPT-11 disposition, with fecal excretion representing the major elimination pathway.


New rice mutants lacking glutelin alpha-1 subunit.
Four rice (Oryza sativa L.) mutant lines lacking glutelin alpha-1 subunit were obtained by screening the progenies of fertilized egg treatment with MNU. SDS-PAGE and IEF analyses showed that the mutants without pI6.82 polypeptide in common while forming/increasing other polypeptide indicating that the mutants were controlled by structural genes. IEF analysis also suggested that the polypeptides of pI6.82 and pI8.58 derived from the same glutelin precursor. The mutants are considered to be useful material for glutelin quality improvement and for genetic regulatory mechanism study of glutelin biosynthesis.


Nitric oxide and prostaglandin inhibition during acetylcholine-mediated cutaneous vasodilation in humans.
Acetylcholine-induced endothelium-dependent vasodilation in conduit arteries primarily depends on nitric oxide (NO). However, the biochemical mediators in the microvasculature remain less well defined. We tested whether prostaglandins and NO are responsible for cutaneous acetylcholine-mediated vasodilation and if they interact to modulate vasodilation. We measured skin blood flow (SBF) using laser Doppler flow (LDF) with intradermal microdialysis in the calves of 23 healthy volunteers. We examined the response of SBF to different doses of acetylcholine (0.01-100 mM), the nonisoform-specific NO synthase inhibitor, nitro-L-arginine (NLA, 10 mM), the nonspecific cyclo-oxygenase (COX) inhibitor, ketorolac (Keto, 10 mM), and combined NLA + Keto. NLA had no effect on baseline SBF, while Keto increased baseline SBF by approximately 150%. The increase was blunted with combined NLA + Keto. SBF increased by approximately 700% with the highest acetylcholine concentration and reduced by approximately 60% by NLA. Ketorolac alone also reduced the response to acetylcholine, although the reduction varied between 10 and 20% at differing acetylcholine doses. NLA plus ketorolac reduced the responses to different doses of acetylcholine by some 30%, which was intermediate to NOS or COX inhibition alone. These data suggest that cutaneous acetylcholine-mediated endothelium-dependent vasodilation is highly NO-dependent and is also strongly related to the interactions of NO with prostaglandins.


Risk factors for negative experiences during psychotherapy.
It is estimated that between 3% and 15% of patients have a negative experience of psychotherapy, but little is understood about this. The aim of this study was to investigate the factors associated with patients' negative therapy experiences. The data comprised 185 patient and 304 therapist questionnaires, 20 patient and 20 therapist interviews. Patients reported on an unhelpful or harmful experience of therapy, and therapists on a therapy where they thought the patient they were working with had a poor or harmful experience. These were transcribed and analysed using thematic analysis. There was a Lack of fit between Patient needs, Therapist skills, and Service structures. This could result in Fault Lines, a tension between Safety and containment and Power and control. This tension led to Strain and Poor Engagement, which led to Consequences following the negative therapy experience. Patients require clear information, choice, involvement in decision-making, explicit contracting and clarity about sessions and progress. Opportunities for patient feedback should be the norm, where the therapist and service are vigilant for signs of deterioration and solutions considered. Clinical and methodological significance of this article: Estimates of "unwanted effects," including long-lasting effects, of psychotherapy have ranged from 3% to 15%. Few empirical studies have been conducted in this area. This study aimed to address this gap and provide clinicians with a model of risk factors for negative therapy effects. The findings of this study indicate the importance of providing patients with a supportive service structure that offers clear information, choice and involvement in decision-making. Explicit contracting at the beginning of therapy and clarity about sessions and progress are also important in managing patient expectations throughout. Opportunities for patient feedback should be provided.


Effectiveness of Diabetes Community Sharp Disposal Education Module in Primary Care: An Experimental Study in North-East Peninsular Malaysia.
Background: Structured education is needed to cultivate safe sharp disposal behavior among diabetic patients. Thus, this study aimed to assess the effectiveness of the Diabetes Community Sharp Disposal Education Module in improving knowledge and sharp disposal practice among Malaysian Type 2 diabetic patients. Methods: This quasi-experimental study was conducted at primary health clinics in two districts in Kelantan, a state in the North-East Region of Peninsular Malaysia. A total of 132 Type 2 diabetic patients on insulin therapy were involved, with 68 participants in each control and intervention group. The health education intervention was based on the validated Diabetes Community Sharp Disposal Education Module. The knowledge and practices were measured using a validated questionnaire at baseline, one month, and three months after the intervention. Results: There was a significant increment in the mean knowledge score for intervention group; from baseline to one month follow up and from baseline to three months follow up [Greenhouse-Geisser; F(1.5, 199.7) = 62.38, p < 0.001; effect size (η2) = 0.318]. Intervention group had significantly higher mean knowledge score as compared to control group; at one month and three months follow up [F(1, 134) = 17.38, p < 0.001; effect size (η2) = 0.115]. There was a statistically significant increment in the proportion of participants in the intervention group who practiced the proper community sharp disposal method over time, X2(2) = 52.061, p < 0.001. Conclusions: The Diabetes Community Sharp Disposal Education Module was an effective health education tool to improve knowledge and encourage Malaysian diabetic patients to engage with proper sharp disposal practices.


Apoptosis in cultured rat islets of langerhans and occurrence of Bcl-2, Bak, Bax, Fas and Fas ligand.
Isolated Langerhans islets are widely used for diabetic transplantation experiments and investigations of the mechanisms leading to the death or survival of insulin-producing cells in cultured islets. The present study was aimed at investigating programmed cell death and the role of apoptosis-associated peptides in insulin and glucagon cells of islets isolated from untreated rats and held in cultured suspension. Islets were removed from medium on days 0, 7, 14, 21 and 29, embedded in Epon, and semi-thin serial sections were prepared. At designated intervals, histologic sections were treated with the direct fluorescein-labelled TUNEL method and immunostained for pancreatic hormones (glucagon, insulin) and apoptotic peptides [Bak, Bax, Fas, Fas ligand (FasL)], as well as for the anti-apoptotic peptide Bcl-2. All tissue sections were investigated using confocal laser scanning microscopy under identical setting for semiquantitative estimation of staining intensity. The percentage of apoptotic cells was between 1.6 and 2.1% and most apoptotic cells were beta-cells. Corresponding cells often contained Bak and Bax. Fas and FasL were mostly detected in islet cells within the first week after preparing the cultured suspension. The insulin content was low (1.1 +/- 0.22 ng per islet) directly after isolation. It then increased progressively up to day 14, after which it began to decrease. Glucagon expression, on the other hand, remained high for the entire duration of the investigation. In conclusion, the islet beta-cells may recover after the isolation procedure, but after 4 weeks in culture, both the insulin content and Bcl-2 staining decrease. Moreover, apoptosis is mediated by different mechanisms after the isolation procedure and after culturing the islets for 1 month. The present data may be important for further studies on isolated, cultivated or transplanted islets.


Cardiac autonomic neuropathy in patients with diabetes mellitus: current perspectives.
Cardiac autonomic neuropathy (CAN) is a common and often-underdiagnosed complication of diabetes mellitus (DM). CAN is associated with increased mortality, cardiovascular disease, chronic kidney disease, and morbidity in patients with DM, but despite these significant consequences CAN often remains undiagnosed for a prolonged period. This is commonly due to the disease being asymptomatic until the later stages, as well as a lack of easily available screening strategies. In this article, we review the latest developments in the epidemiology, pathogenesis, diagnosis, consequences, and treatments of CAN in patients with DM.


Extracting hydrophobicity parameters from solute partition and protein mutation/unfolding experiments.
Hydrophobicity values for amino acids obtained from protein unfolding experiments are about twice as large as those obtained from data on the partitioning of amino acids between water and octanol. Quantitative analyses of several data sets, presented here, indicate that the difference is best explained by the most direct hypothesis, i.e. that the environment of hydrophobic groups in the interior of a protein is poorly modeled by octanol. Instead, we propose--and provide supporting evidence--that hydrocarbons are a more suitable model. First, we reanalyze data from both solute partitioning and protein unfolding experiments, taking account of the effects that were omitted previously, by introducing a volume dependence in the former and a full free energy analysis in the latter. Both changes in evaluation methodology decrease the discrepancy, but the differences remain substantial. The hydrophobicity parameter obtained from side-chain transfers between octanol and water increases from 16.7 to 22 cal/mol/Angstrom2, while that obtained from protein unfolding decreases from 34.9 to 31.2 cal/mol/Angstrom2. On the other hand, our analysis of the solubilities of pure hydrocarbons in water provides a hydrophobicity parameter of 30.8 cal/mol/Angstrom2. This apparent hydrocarbon-like environment of a protein's interior is also suggested more directly by an analysis of the contact environment of hydrophobic side chains in mutation/unfolding experiments, which have polar contact areas that are <2% of the total.


Evaluation of aortic root and valve calcifications by multi-detector computed tomography.
In percutaneous aortic valve replacement (AVR), whilst calcifications are used as landmarks in fluoroscopic placement of the stent, they may also complicate stent placement. In response to this problem, the study aim was to examine severe aortic root calcification by using multi-detector computed tomography (MDCT), to better understand the pathology complicating percutaneous valve placement. In 33 patients with severe aortic stenosis and scheduled for surgery, the 'inner orifice' and 'outer fibrous' annulus diameter and area (with and without calcification) were measured, in addition to the distances of the calcifications and coronary ostia from the annulus, using by ECG-gated 64-slice MDCT. Aortic root calcification was evaluated as minimal (< 25% of total circumference), mild (25-50%), moderate (50-75%), and severe (75-100%). The inner orifice annulus area was 5.9 +/- 1.9 cm2 (range: 1.4-10.1 cm2), while the outer fibrous area was 7.5 +/- 1.8 cm2 (range: 4.7-11.5 cm2). The proximal-to-distal extent of valve calcification from the annulus in the mid-center of leaflets was 0.8 +/- 0.26 cm. In 36% of patients, valvular calcification extended +/- 3 mm within the coronary-ostium level. The distance of the coronary ostia from the annulus was variable, with a mean of 1.3 +/- 0.35 cm (range: 0.6-2.4 cm) for the left coronary artery. In 42% of patients, a 'low coronary ostium' (< or = 1.1 cm), and in 6% a 'critical-low-coronary ostium' (< or = 8 mm) was identified. Annulus calcification was present in 100% of cases, but the severity varied widely (severe 50%, moderate 35%, mild 15%). In 36% of cases, the aortic annulus calcification extended caudally into the membranous part of the interventricular septum (and thus into the left ventricular outflow tract), and in 42% of cases (n = 14) into the anterior mitral valve leaflet. The present results indicated that cardiac MDCT may qualify as a primary pre-procedural imaging modality to select patients for percutaneous AVR, based on the measurement and characterization of the aortic root and valve calcification. In comparison to echocardiography, CT will reduce--if not eliminate--difficulties in visualizing the aortic orifice area in heavily calcified valves. Furthermore, knowledge of the exact location of calcific deposits provides a distinct advantage to the fluroscopist for precise placement of the percutaneous aortic valve. Likewise, knowledge of the coronary arteries orifice in relation to the valve plane is critical to prevent inadvertent coronary artery occlusion, and would clearly be beneficial when planning future valve designs.


The safety profile of nefazodone.
Comprehensive review of safety data from approximately 3500 patients who received nefazodone in premarketing clinical trials demonstrates the drug to be very well tolerated, with a favorable side effect profile compared with other antidepressant drugs. Nefazodone treatment was associated with fewer side effects than were the control drugs. The incidence of side effects was generally low, and treatment discontinuations for adverse effects were less frequent with nefazodone than with imipramine and comparable with fluoxetine. No late-appearing side effects or toxicity emerged during the long-term treatment (1 year or longer) of several hundred patients. There were no drug-related fatalities and no evidence that nefazodone caused specific organ toxicity, although some cardiovascular side effects were noted (e.g., asymptomatic reduced systolic blood pressure, asymptomatic sinus bradycardia). Experience in 488 elderly patients treated with nefazodone yielded no evidence of increased susceptibility of older patients to nefazodone-associated adverse experiences, including those pertaining to the cardiovascular system. However, treatment should be initiated at a reduced dose in elderly patients because of reduced hepatic clearance of nefazodone in this age group. Final dose range may be similar in healthy younger and older patients. Although nefazodone may interact with some other medications (e.g., increases at steady state in AUC: alprazolam, twofold; triazolam, fourfold), drug-drug interactions involving patients have been clinically minor. On the basis of the inhibition of cytochrome P450 3A4 isoenzyme by nefazodone in vitro, coadministration of terfenadine or astemizole with nefazodone is contraindicated because nefazodone can increase the plasma levels of these two drugs. Extensive clinical experience provides substantial evidence that nefazodone is an extremely safe and effective treatment for depression, with important advantages over existing therapies. Therapeutic benefits include a low incidence of clinically troublesome side effects and lack of unwanted psychic activation, sexual dysfunction, weight change, and the cardiotoxicity of other antidepressants.


The contribution of modern EPR to structural biology.
Electron paramagnetic resonance (EPR) spectroscopy combined with site-directed spin labelling is applicable to biomolecules and their complexes irrespective of system size and in a broad range of environments. Neither short-range nor long-range order is required to obtain structural restraints on accessibility of sites to water or oxygen, on secondary structure, and on distances between sites. Many of the experiments characterize a static ensemble obtained by shock-freezing. Compared with characterizing the dynamic ensemble at ambient temperature, analysis is simplified and information loss due to overlapping timescales of measurement and system dynamics is avoided. The necessity for labelling leads to sparse restraint sets that require integration with data from other methodologies for building models. The double electron-electron resonance experiment provides distance distributions in the nanometre range that carry information not only on the mean conformation but also on the width of the native ensemble. The distribution widths are often inconsistent with Anfinsen's concept that a sequence encodes a single native conformation defined at atomic resolution under physiological conditions.