Discriminative Hierarchical K-Means Tree for Large-Scale Image Classification.
A key challenge in large-scale image classification is how to achieve efficiency in terms of both computation and memory without compromising classification accuracy. The learning-based classifiers achieve the state-of-the-art accuracies, but have been criticized for the computational complexity that grows linearly with the number of classes. The nonparametric nearest neighbor (NN)-based classifiers naturally handle large numbers of categories, but incur prohibitively expensive computation and memory costs. In this brief, we present a novel classification scheme, i.e., discriminative hierarchical K-means tree (D-HKTree), which combines the advantages of both learning-based and NN-based classifiers. The complexity of the D-HKTree only grows sublinearly with the number of categories, which is much better than the recent hierarchical support vector machines-based methods. The memory requirement is the order of magnitude less than the recent Naïve Bayesian NN-based approaches. The proposed D-HKTree classification scheme is evaluated on several challenging benchmark databases and achieves the state-of-the-art accuracies, while with significantly lower computation cost and memory requirement.


Local terminology for medicines to treat fever in Bougouni District, Mali: implications for the introduction and evaluation of malaria treatment policies.
To explore Bambara language terminology and classification for locally available antimicrobial medicines in order to better target promotional messages and improve evaluation measures in Bougouni District, Mali. Mothers (n = 20) and drug vendors (n = 15) were asked to freelist medicines used to treat childhood illnesses, and to identify all medicines that corresponded to each of the listed terms from an array of medicines displayed with their packaging. Each Bambara language medicine term can refer to numerous modern medicines, and each modern medicine has several Bambara names. The term nivakini (Nivaquine), often translated as 'chloroquine', refers to a wide range of medicines commonly used to treat malaria, many with no antimalarial effect. Antibiotics were also identified as common treatments for malaria. Mothers and vendors used slightly different terminology when discussing treatments for malaria, and sometimes employed the same term to refer to different medicines. Neither mothers nor vendors clearly differentiated between antimalarial medicines. Colour, shape and packaging play a large role in their recognition, classification and use. Current household survey methods are likely to provide inaccurate estimates of appropriate treatment of febrile illness, and thus alternative approaches are recommended. In introducing new malaria treatments, malaria control programmes should differentiate recommended treatments from other medications through distinctive packaging, drug appearance and appropriate Bambara language terms.


Glutamate- and GABA-containing neurons in the mouse and rat brain, as demonstrated with a new immunocytochemical technique.
Antisera were raised against gamma-aminobutyric acid (GABA) or glutamate (Glu) conjugated to bovine serum albumin with glutaraldehyde. After purification, these antisera reacted strongly with fixed GABA or Glu, but not significantly with other amino acids fixed with glutaraldehyde to brain macromolecules. The antisera were used to demonstrate the distributions of Glu-like and GABA-like immunoreactivities (Glu-LI and GABA-LI) in parts of the perfusion-fixed mouse and rat brain, including the olfactory bulb, cerebral neocortex, thalamus, basal ganglia, lower brain stem, and cerebellum. The level of GABA-LI varied widely among brain regions, thus it was very high in the globus pallidus and substantia nigra and low in the bulk of the thalamus. The GABA antisera labeled nonpyramidal neurons of the neocortex, most cells of the reticular nucleus of the thalamus, medium-sized cells of the caudatoputamen, and stellate, basket, Golgi, and Purkinje cells of the cerebellum. The distribution of GABA-LI closely matched that of the GABA-synthesizing enzyme, glutamic acid decarboxylase (GAD), as revealed in immunocytochemical studies by others. However, the GABA antisera seem to be better suited than GAD antisera for demonstrating putative GABA-ergic axons. The results suggest that GABA-LI, as displayed by the present method, is a good marker of neurons thought to use GABA as a transmitter. Glutamate-like immunoreactivity was much more evenly distributed among regions than GABA-LI, but was particularly low in globus pallidus and substantia nigra and high in the cerebral cortex. Mitral cells of the olfactory bulb, pyramidal neocortical cells, and other cells assumed to use Glu or aspartate as transmitter were stained for Glu-LI, but so also were neurons that are thought to use other transmitters, such as cells in the substantia nigra pars compacta, in the dorsal raphe nucleus, and in the brain stem motor nuclei. The Glu antisera seem to reveal the "transmitter pool" as well as the "metabolic pool" of Glu in perfusion-fixed material. This report shows that it is possible by means of immunocytochemistry to display reliably the tissue contents of GABA and Glu in material that has been fixed by perfusion with glutaraldehyde.


Glucocorticoid-Induced Fatty Liver Disease.
Glucocorticoids (GCs) are commonly used at high doses and for prolonged periods (weeks to months) in the treatment of a variety of diseases. Among the many side effects are increased insulin resistance with disturbances in glucose/insulin homeostasis and increased deposition of lipids (mostly triglycerides) in the liver. Here, we review the metabolic pathways of lipid deposition and removal from the liver that become altered by excess glucocorticoids. Pathways of lipid deposition stimulated by excess glucocorticoids include 1) increase in appetite and high caloric intake; 2) increased blood glucose levels due to GC-induced stimulation of gluconeogenesis; 3) stimulation of de novo lipogenesis that is augmented by the high glucose and insulin levels and by GC itself; and 4) increased release of free fatty acids from adipose stores and stimulation of their uptake by the liver. Pathways that decrease hepatic lipids affected by glucocorticoids include a modest stimulation of very-low-density lipoprotein synthesis and secretion into the circulation and inhibition of β-oxidation of fatty acids. Role of 11β-hydroxysteroid dehydrogenases-1 and -2 and the reversible conversion of cortisol to cortisone on intracellular levels of cortisol is examined. In addition, GC control of osteocalcin expression and the effect of this bone-derived hormone in increasing insulin sensitivity are discussed. Finally, research focused on gaining a better understanding of the dose and duration of treatment with glucocorticoids, which leads to increased triglyceride deposition in the liver, and the reversibility of the condition is highlighted.


Methanol[1-(methoxymethanimidoyl)-2-(pyridin-2-ylmethyl)guanidine]bis(perchlorato)copper(II).
The title complex, [Cu(ClO(4))(2)(C(9)H(13)N(5)O)(CH(3)OH)], was synthesized from a methanolysis reaction of N-(methylpyridin-2-yl)cyanoguanidine (L(3)) and copper(II) perchlorate hexahydrate in a 1:1 molar ratio. The Cu(II) ion is six-coordinated by an N(3)O(3) donor set which confers a highly distorted and asymmetric octahedral geometry. Three N-donor atoms from the chelating 1-(methoxymethanimidoyl)-2-(pyridin-2-ylmethyl)guanidine (L(3m)) ligand and one O atom from the methanol molecule define the equatorial plane, with two perchlorate O atoms in the apical sites, one of which has a long Cu-O bond of 2.9074 (19) Å. The dihedral angle between the five- and six-membered chelate rings is 8.21 (8)°. Two molecules are associated into a dimeric unit by intermolecular N-H...O(perchlorate) hydrogen bonds. Additionally, the weakly coordinated perchlorate anions also link adjacent [Cu(ClO(4))(2)(L(3m))(CH(3)OH)] dimers by hydrogen-bonding interactions, resulting in a two-dimensional layer in the (100) plane. Further C-H...O hydrogen bonds link the two-dimensional layers along [100] to generate a three-dimensional network.


Effect of acute hypercapnia on diaphragmatic and limb muscle contractility.
The purpose of this study was to determine whether acute hypercapnia depresses limb muscle and diaphragmatic contractility. Twelve subjects breathed 8% CO2 for 20 min on two separate occasions. On one occasion, twitch transdiaphragmatic pressure (Pdi) was obtained during both cervical magnetic and transcutaneous stimulation before and 2, 10, and 30 min after CO2 breathing. In addition, twitch Pdi was obtained during CO2 breathing in five subjects using cervical magnetic stimulation. On the other occasion, adductor pollicis twitch force was measured during transcutaneous supramaximal ulnar nerve stimulation and arterialized venous blood gas determinations were obtained before, during, and after CO2 breathing. Twitch Pdi was not significantly different from baseline at any time after CO2 breathing. Similarly, twitch Pdi did not significantly change from the beginning to the end of the period of CO2 breathing. In contrast, adductor pollicis twitch force was significantly less than baseline 2 min after CO2 breathing (p < 0.01). Furthermore, during CO2 breathing, adductor pollicis twitch force fell significantly, reaching statistical significance at 8 min, decreasing still further by 13 min, and then plateauing. During the final 2 min of CO2 breathing, adductor pollicis twitch force averaged 86.5 +/- 2.7% of the baseline value (p < 0.0007). During CO2 breathing, Pco2 rose to 60.1 +/- 0.5 mm Hg, whereas pH fell to 7.27 +/- 0.004 units. Breathing 8% CO2 elicited a moderate hyperpnea, and minute ventilation during the final minute of CO2 breathing averaged 54.74 +/- 4.90 L/min. To ensure that this hyperpnea did not augment diaphragmatic activity enough to potentiate the twitch, five subjects voluntarily mimicked their CO2 hyperpnea on a separate occasion. Twitch Pdi was not significantly different from baseline at any time after voluntary mimicking. To ensure that changes in diaphragmatic contractility were not missed by our twitch measurements, Pdi was measured during bilateral transcutaneous phrenic nerve stimulation at 10 Hz in four subjects. Again, Pdi during 10 Hz stimulation was not significantly different from baseline at any time after CO2 breathing. In conclusion, (1) acute moderate hypercapnia mildly depresses limb muscle contractility, and (2) acute moderate hypercapnia did not produce significant changes in diaphragmatic contractility.


Microfilament-coordinated adhesion dynamics drives single cell migration and shapes whole tissues.
Cell adhesion to the substratum and/or other cells is a crucial step of cell migration. While essential in the case of solitary migrating cells (for example, immune cells), it becomes particularly important in collective cell migration, in which cells maintain contact with their neighbors while moving directionally. Adhesive coordination is paramount in physiological contexts (for example, during organogenesis) but also in pathology (for example, tumor metastasis). In this review, we address the need for a coordinated regulation of cell-cell and cell-matrix adhesions during collective cell migration. We emphasize the role of the actin cytoskeleton as an intracellular integrator of cadherin- and integrin-based adhesions and the emerging role of mechanics in the maintenance, reinforcement, and turnover of adhesive contacts. Recent advances in understanding the mechanical regulation of several components of cadherin and integrin adhesions allow us to revisit the adhesive clutch hypothesis that controls the degree of adhesive engagement during protrusion. Finally, we provide a brief overview of the major impact of these discoveries when using more physiological three-dimensional models of single and collective cell migration.


Asymmetric synthesis of pochonin E and F, revision of their proposed structure, and their conversion to potent Hsp90 inhibitors.
A concise and modular synthesis of pochonin E and F, and their epimers at C-6 established the correct stereochemistry of these two natural products. Several members of the pochonin family have been shown to bind the heat shock protein 90 (Hsp90), which has been the focus of intense drug discovery efforts. Pochonin E and F as well as their epimers were derivatized into the corresponding pochoximes and further modified at the C-6 position. Molecular dynamics simulations, docking studies, and Hsp90 affinity measurements were performed to evaluate the impact of these modifications.


Effects of raloxifene on body fat distribution and lipid profile in healthy post-menopausal women.
The aim of our prospective, randomised, controlled and open-label clinical study was to evaluate in healthy post-menopausal women the effects of raloxifene (RLX) on body fat distribution and lipids, and the correlations between these parameters. The fat distribution, by dual energy X-ray absorptiometry, and lipids were evaluated at baseline and after 1 yr in 50 post-menopausal women: 25 were treated with RLX 60 mg/die, while 25 served as control group (CG). After 1 yr, we observed in RLX-users a slight reduction of fat mass in trunk and central region and an increase in legs and, in relation to CG, significantly lower values of adiposity in trunk and abdominal region (p < 0.05). At the same time, HDL-cholesterol (HDL-C) and apolipoprotein A1 (ApoA1) were significantly increased in relation to baseline values and CG (p < 0.05) and apolipoprotein B (ApoB), total cholesterol/HDL-C, LDL cholesterol/ HDL-C, and ApoB/ApoA1 ratios significantly decreased compared to baseline values and CG (p < 0.05). No correlation was underlined among lipids and regional fat distribution. These results highlight the positive effect of RLX on lipids and suggest, for the first time, that RLX promotes the shift from android to gynoid fat distribution, and prevents the uptrend of abdominal adiposity and body weight compared with untreated women.


Comparing Serum Levels of Th17 and Treg Cytokines in Women with Unexplained Recurrent Spontaneous Abortion and Fertile Women.
Increased evidences have shown that unexplained recurrent spontaneous abortion (URSA) is associated with inflammatory responses and breakage of immunological autotolerance. Therefore, the balance between Th17 and Treg cells may elucidate the pathophysiology of URSA. To investigate the serum concentration of regulatory and inflammatory cytokines associated with Treg and Th17 in both normal and URSA females. Forty-six women with URSA and 28 non-pregnant control women with at least one successful pregnancy were included. Serum was obtained from both groups and stored at -7º C. The serum concentrations of IL-17, IL-21, IL-22, IL-10, and TGF-β were quantitatively determined by ELISA. The levels of IL-17, IL-21, and IL-22 in sera were significantly higher (P<0.001, P=0.01 and P<0.001, respectively) and TGF-β serum concentration was significantly lower (P=0.02) in URSA women compared with normal controls. Our results suggest that enhancement in Th17-associated cytokine levels and reduction in TGF-β may be one of the factors involved in URSA.


Regional hip blockade in osteoarthrosis. Effects on pain perception.
Eighteen patients with unilateral osteoarthrosis of the hip were investigated in a trial which involved the injection of nine with bupivacaine and nine with normal saline. All the patients completed daily pain analogue charts. Their pain, mobility and functional activity were assessed and gait characteristics analysed, once before the injection and then at three monthly intervals. All the patients recorded a decrease in pain level within two weeks of injection, but it subsequently rose to pre-injection levels. There were no other significant general improvements after the injection. A significant increase in the maximum force at toe-off for the good leg was recorded one month after the injection. However, no further significant differences were found in the gait performance of either group of patients throughout the study. It is concluded that the hip nerve regional blockade offers no useful relief to the pain of osteoarthrosis of the hip joint.


Seminal plasma proteins do not consistently improve fertility after cervical insemination of ewes with non-sorted or sex-sorted frozen-thawed ram spermatozoa.
The effect of supplementation of sex-sorted and non-sorted spermatozoa with seminal plasma protein (SPP) on fertility after cervical insemination was examined in the present study. Spermatozoa were sorted into high purity X and Y chromosome-bearing spermatozoa or not sorted and then either supplemented with SPP (>10 kDa) before freezing and/or after thawing (non-sorted only) or processed without supplementation. Inseminations were performed over 2 days with ewes receiving 100 or 25 million motile non-sorted spermatozoa in the cervix or uterus, respectively, or two cervical inseminations of 3.5 million motile sorted spermatozoa. Pregnancy rates in cervically inseminated ewes were unaffected by supplementation of sorted or non-sorted spermatozoa with SPP before freezing compared with no supplementation. The effect of post-thaw supplementation of non-sorted spermatozoa with SPP on pregnancy rates after cervical insemination varied with the day of insemination (P < 0.05); fertility was similar to laparoscopic insemination on Day 1 (56.0 +/- 10.2% v. 58.6 +/- 10.1%), but not on Day 2 (23.1 +/- 7.4% v. 66.7 +/- 9.2%). In conclusion, under the conditions of the present study, SPP did not consistently improve pregnancy rates after cervical insemination with frozen-thawed ram spermatozoa. This is the first report of pregnancies (5/56 ewes inseminated) after cervical insemination with frozen-thawed sex-sorted ram spermatozoa. Although the success rate is low, the findings are encouraging because ewes inseminated with the sex-sorted spermatozoa received only 7% of the recommended dose (100 million motile) for cervical insemination of frozen-thawed spermatozoa.


A pilot study to determine the effects of skin contact on two commonly used dental impression materials.
Impression materials used in the analysis of bite marks are required to maintain their stability and integrity for extended periods. It has been observed that certain impressions taken of skin lose their properties with time, becoming sticky and unusable as evidence. The objective of this study was to investigate the onset of "stickiness" in two commonly used dental impression materials when brought into contact with skin. The two materials tested were Impregum and President. They were syringed into glass rings positioned on the upper arms of 28 volunteers. Changes in stickiness were monitored over a four-month period using a tensile testing machine. A metal plunger was lowered onto the impression material and then retracted measuring the adhesive force of the material to the lower surface of the plunger. Over the research period 17 of the 28 rings of Impregum became sticky and changed colour from purple to turquoise. The remaining 11 Impregum samples, all the President samples and all control samples remained unchanged over the 120 day period. The results of this study show that certain factors present in or on skin are responsible for the loss of surface integrity of Impregum. The factors responsible for these changes have not been established.


Skin Color and Maternal Near Miss: Exploring a Demographic and Health Survey in Brazil.
Purpose In 2013, it was estimated that 289,000 maternal deaths occurred worldwide. The maternal mortality ratio has decreased in many countries in the past decades, due to early identification and treatment of obstetric complications, despite the dissimilarities observed in diverse locations and populations. Black women, for instance, have always been more susceptible to the occurrence of maternal mortality and severe morbidity. Therefore, the objective of this study is to assess skin color as a predictive factor for maternal near miss (MNM) in a sample of Brazilian women interviewed in the Brazilian National Demographic and Health Survey (DHS) of 2006. Method A secondary analysis of the DHS database, a population-based cross-sectional nationally representative study was conducted. This database is of public domain. The risk of maternal complications according to ethnic group and the associated sociodemographic characteristics were evaluated. For the data analysis, the odds ratios and respective 95% confidence intervals were calculated. Results In the sample interviewed, 59% of women were black or brown (mixed-race). Approximately 23% of women had some complication, and 2% of these women had at least one MNM pragmatic criterion. The MNM rate was 31 per 1,000 live births, and its occurrence was not statistically different among the ethnic groups. The only factors identified that were considered to be associated with the occurrence of MNM were maternal age above 40 and women not currently attending school, but only among white women. Conclusion The 2006 DHS results did not show a higher occurrence of maternal complications, and specifically of MNM associated with black/brown skin color.


Frequency-switchable CO2 laser: design and performance.
A CO(2) laser with an intracavity CdTe modulator is described whose output frequency can be rapidly switched or chirped, while the output intensity remains constant to better than 2%. Currently, frequency switches of up to 20 MHz in 50 nsec can be performed, with the limitation being only the performance of the pulse generator which drives the crystal. The problems which must be addressed in designing such a laser are discussed along with the approaches we have taken to solve them. The laser performance is analyzed and compared with theory, and a novel laser frequency locking scheme is presented which eliminates switching transients in the CO(2) gain medium.


Leukodystrophy in children: a pictorial review of MR imaging features.
Dysmyelinating diseases, or leukodystrophies, encompass a wide spectrum of inherited neurodegenerative disorders affecting the integrity of myelin in the brain and peripheral nerves. Most of these disorders fall into one of three categories-lysosomal storage diseases, peroxisomal disorders, and diseases caused by mitochondrial dysfunction-and each leukodystrophy has distinctive clinical, biochemical, pathologic, and radiologic features. Magnetic resonance (MR) imaging has become the primary imaging modality in patients with leukodystrophy and plays an important role in the identification, localization, and characterization of underlying white matter abnormalities in affected patients. MR imaging has also been extensively used to monitor the natural progression of various white matter disorders and the response to therapy. Although the MR imaging features of leukodystrophy are often nonspecific, systematic analysis of the finer details of disease involvement may permit a narrower differential diagnosis, which the clinician can then further refine with knowledge of patient history, clinical testing, and metabolic analysis.


Effect of thrombin preconditioning on migration of subventricular zone-derived cells after intracerebral hemorrhage in rats.
To investigate the effect of thrombin preconditioning (TPC) on the intracerebral hemorrhage (ICH)-induced proliferation, migration, and function of subventriclular zone (SVZ) cells and to find new strategies that enhance endogenous neurogenesis after ICH. Male Sprague-Dawley rats were randomly divided into 3 groups (ICH, TPC, and control group). Rats of each group were randomly divided into 5 subgroups (3-d, 7-d, 14-d, 21-d, and 28-d subgroup). ICH was caused by intrastrial stereotactic administration of collagenase type IV. Brdu was used to label newborn SVZ cells. Organotypic brain slices were cultured to dynamically observe the migration of SVZ cells at living brain tissue. Migration of Dil-labeled SVZ cells in living brain slices was traced by time-lapse microscopy. To assess whether SVZ cells migrating to injured striatum had the ability to form synapses with other cells, brain slices from each group were double immunolabeled with Brdu and synapsin I. The number of Brdu-positive cells markedly increased in the ipsilateral SVZ and striatum 3 days after TPC, peaked at 14 days (P < 0.01), continued to 21 days, and then gradually decreased at 28 days with significant difference compared to the ICH group at each time point (P < 0.01). Migration of Dil-labeled SVZ cells in brain slices in each group was observed and imaged during a 12-h period. Dil-labeled SVZ cells in the TPC group were observed to migrate laterally toward striatum with time with a faster velocity compared to the ICH group (P < 0.01). Our study also demonstrated that TPC induced strong colocalization of Brdu and synapsin I in the ipsilateral striatum between 3 and 28 days after injury.TPC made colocalization of Brdu and synapsin I appear earlier and continue for a longer time compared to the ICH group. Our results demonstrated that TPC could promote proliferation, migration, and function of SVZ cells after ICH, which may provide a new idea for enhancing endogenous neurogenesis and developing new therapeutic strategies against ICH-induced brain injury.


[Positive feedback for good medical work--a short-supply commodity?].
In a nationwide survey of the working environment of Norwegian physicians every second respondent reported seldom or never being appreciated or praised for good work by their superiors. Nurses, colleagues and auxiliaries are more frequent sources of such appreciation. Very little of the variance in doctors' experience of positive feedback is explained by job variables: a doctor who does not receive supportive feedback cannot attribute this to unwise choice of specialty or type of employer, or to age, sex or position in the hierarchy. The experiences of male and female doctors are very much the same. Whether the doctors are appreciated and praised for good work seems to depend rather on certain traits of their personality.


[Epidemiology and prophylaxis of septic infectious complications in patients from critical and intensive therapy surgical units].
To investigate efficacy of the extended complex of preventive and antiepidemic measures for reduction of nosocomial infections incidence in patients treated in critical and intensive therapy (CIT) surgical units. From 2003 to 2005 CIT units of N.N. Burdenko Central Military Hospital conducted a study with participation of 200 patients aged 50 to 77 years after extended abdominal operations. The patients were divided into 2 groups. Group 1 (n = 100) received standard prophylaxis of infectious complications, group 2 (n = 100) received an extended complex of prophylactic and antiepidemic measures. First-line antibacterial therapy in all the patients included cephalosporines of the third generation and metronidasol. The extended complex included air decontamination with application of the system "Clean room complex"; prevention of nosocomial, particularly ventilator-associated pneumonia (VAP); prevention of catheter-associated sepsis; use of disposable sterile items. Group I patients developed sepsis in 30%, septic shock and polyorganic insufficiency (POI)--in 16% cases; lethality due to infectious complications was 13%. Gram-negative microflora was dominating. In group 2 sepsis was diagnosed in 22%, septic shock and POI--in 11%, lethality was 11%. The extended complex ofpreventive and antiepidemic measures significantly reduced the rate of severe infectious complications and related lethality. Among the agents of nosocomial infection the percentage of staphylococci and blue pus bacillus decreased while that of enterococci and E. coli increased. Contamination of the ambient air and CIT units reduced significantly.


Mutants of Escherichia coli lacking endonuclease I, ribonuclease I, or ribonuclease II.
To isolate mutants of Escherichia coli K-12 lacking endonuclease I activity (end), a method has been developed which detects, by differential methyl green staining, undegraded deoxyribonucleic acid (DNA) in colonies previously incubated in toluene. This procedure allows isolation of mutant strains in which DNA degradation is reduced. For half of these strains, this defect has been correlated with deficiencies of endonuclease I, ribonuclease I (rns), or ribonuclease II (rne) activities. The enzymatic deficiencies of the other strains remain unknown. An rne mutation is cotransducible with serA (which is located at 56 min on the genetic map). Most end mutations, called endA, are also cotransducible with serA and are located between serA and strA. One end mutation, called endB, is located between purE and trp (i.e., between 13 and 25 min on the genetic map).


Has conventional sphygmomanometry ended with the banning of mercury?
The banning of mercury from clinical practice will lead to the inevitable demise of traditional clinical sphygmomanometry. There are differences in approach to this important issue between European countries on the one hand, which generally have accepted that the mercury sphygmomanometer must be replaced with alternative devices, and the U.S. on the other, where the view is that the mercury sphygmomanometer should remain as the mainstay of blood pressure measurement. The availability of alternative devices for the mercury sphygmomanometer is improving but the problem of independent validation is a serious issue, which is being addressed by the European Society of Hypertension Working Party on Blood Pressure Monitoring, which has drafted an International Protocol for validating blood pressure measuring devices. The removal of the mercury sphygmomanometer from clinical practice has other implications, which merit careful consideration; the advent of automated devices must lead inevitably to the disappearance of the traditional clinical auscultatory technique of blood pressure measurement, and with the disappearance of mercury it will be argued that the Système International(SI) unit of measurement -- the kilopascal -- should replace the millimetre of mercury.


Expectancy theory prediction of the preference to remain employed or to retire.
Vroom's (1964) expectancy theory model was used to predict older workers' choices between continued employment or immediate retirement. It was hypothesized that a person's preference for one of the two alternatives would be a function of the differences between the instrumentality of employment and the instrumentality of retirement for the attainment of outcomes, multiplied by the valence of each outcome, summed over outcomes. To test this, 290 Israeli male workers, aged 57 to 64, were interviewed. Measures included: preference for employment or retirement; valences of 35 outcomes; perceived instrumentalities of employment and retirement. The results supported the hypothesis (R = .40; p less than .01). It is suggested that further research along these lines could equip organizations with a tool for assisting older employees in the transition to retirement or for encouraging those who are still capable of making a significant contribution to remain employed.


UbFluor: A Fluorescent Thioester to Monitor HECT E3 Ligase Catalysis.
HECT E3 ubiquitin ligases (∼28 are known) are associated with many phenotypes in eukaryotes and are important drug targets. However, assays used to screen for small molecule inhibitors of HECT E3s are complex and require ATP, Ub, E1, E2, and HECT E3 enzymes, producing three covalent thioester enzyme intermediates E1∼Ub, E2∼Ub, and HECT E3∼Ub (where ∼ indicates a thioester bond), and mixtures of polyubiquitin chains. To reduce the complexity of the assay, we developed a novel class of fluorescent probes, UbFluor, that act as mechanistically relevant pseudosubstrates of HECT E3s. These probes undergo a direct transthiolation reaction with the catalytic cysteine of HECT E3s, producing the catalytically active HECT E3∼Ub thioester accompanied by fluorophore release. Thus, a fluorescence polarization assay can continuously monitor UbFluor consumption by HECT E3s, and changes in UbFluor consumption rendered by biochemical point mutations or small molecule modulation of HECT E3 activity. © 2017 by John Wiley & Sons, Inc.


Transient ballooning of the left ventricle: a case report.
A 67-year-old woman was admitted to the coronary care unit for chest pain with ECG modifications suggestive of acute myocardial infarction. The clinical course of the disease and the absence of abnormalities of the epicardial vessels with reversible asynergy of the apical segments of the left ventricle were suggestive of the syndrome of transient apical ballooning of the left ventricle. To my knowledge, this is the first case of the disease described in the Italian population.


A preliminary investigation on boron and metal concentrations of the main drainage channel in Konya-Turkey.
In this work, the wastewaters and sediments of the main drainage channel in Konya (Turkey) were collected from three different sampling points and analyzed for metals, including iron, chromium, copper, lead, zinc and nickel by using inductively coupled plasma-atomic emission spectrometry (ICP-AES). It was found that for all sampling points sediment samples show a decrease in concentrations in the order Fe >> Zn > Cr > Ni > Cu > Pb. For all sampling points, heavy metal concentrations in wastewater did not exceed the maximum admissible discharge levels regulated by the Institute of Turkish Standards. However, it was found that boron concentration of wastewaters exceed the safe level for irrigation of farmland.


A conceptual framework for evaluation of community pharmacy pay-for-performance programs.
Recent interest in initiating pay-for-performance (P4P) programs indicates an underlying belief that economic incentives will have a direct impact on health care quality and efficiency. Evaluations of the impact of P4P programs on health care organizations and providers have been presented in the literature; however, none have focused on the impact of an incentive targeting community pharmacies. To propose a theory-derived conceptual framework of how a financial incentive might work in a community pharmacy. Studies from the fields of economics (agency theory), psychology (intrinsic and extrinsic motivators; expectancy theory), and organizational theory (ownership, institutional layers, organizational culture, and change management; quality improvement) were reviewed to inform the framework's components. This proposed conceptual framework also integrated and expanded on previous health care-related P4P models. P4P programs inherently use financial incentives to catalyze change; however, elements from psychology and organizational theories along with economic theory were identified as important considerations in how a financial incentive may operate when targeting a community pharmacy. Through the incorporation of these theories along with other P4P frameworks in health care, a conceptual framework was derived comprising 4 domains: incentive, pharmacy, other influencing factors, and P4P program measures. Hypothesized relationships among these domains were depicted. As focus on improving the quality of health care provision develops, opportunities for pharmacists to provide patient care services beyond dispensing will continue to advance, along with expanded reimbursement mechanisms extending beyond traditional product dispensing. The proposed theory-derived conceptual framework serves to depict how the integration of P4P and other factors may affect the pharmacy environment and subsequently affect a pharmacy's capability to perform well on medication-related quality measures. This framework may be used as a foundation on which to design studies to investigate the association between community pharmacy factors and performance in a P4P program.


Body-esteem in Swedish 10-year-old children.
This study examined body-esteem in 10-yr.-old children. The study group comprised 960 schoolchildren, 515 girls and 445 boys (M age= 10.4, SD=0.5). Analysis showed that girls who were overweight had more negative body-esteem on all dimensions (weight, appearance, and attribution). The overweight boys had more negative perceptions on only two dimensions (weight and appearance). Twice as many girls perceived themselves as too fat (20%) as too skinny (10%). Of the girls who perceived themselves as fat, only 31% were overweight; similarly only 33% of the boys who perceived themselves as fat were overweight. The children's perception of their weight seemed as important as their actual weight and was associated with their body-esteem in the same way. Although few children had dieted (7% of the girls and 5% of the boys), the ones who had dieted had more negative body-esteem than children who had not dieted.


Effects of respiratory burst inhibitors on nitric oxide production by human neutrophils.
Human neutrophils (PMN) activated by N-formylmethionyl-leucyl-phenylalanine (fMLP) simultaneously release nitric oxide (.NO), superoxide anion (O2.-) and its dismutation product, hydrogen peroxide (H2O2). To assess whether .NO production shares common steps with the activation of the NADPH oxidase, PMN were treated with inhibitors and antagonists of intracellular signaling pathways and subsequently stimulated either with fMLP or with a phorbol ester (PMA). The G-protein inhibitor, pertussis toxin (1-10 micrograms/ml) decreased H2O2 yield without significantly changing .NO production in fMLP-stimulated neutrophils; no effects were observed in PMA-activated cells. The inhibition of tyrosine kinases by genistein (1-25 micrograms/ml) completely abolished H2O2 release by fMLP-activated neutrophils; conversely, .NO production increased about 1.5- and 3-fold with fMLP and PMA, respectively. Accordingly, orthovanadate, an inhibitor of phosphotyrosine phosphatase, markedly decreased .NO production and increased O2.- release. On the other hand, inhibition of protein kinase C with staurosporine and the use of burst antagonists like adenosine, cholera toxin or dibutyryl-cAMP diminished both H2O2 and .NO production. The results suggest that the activation of the tyrosine kinase pathway in stimulated human neutrophils controls positively O2.- and H2O2 generation and simultaneously maintains .NO production in low levels. In contrast, activation of protein kinase C is a positive modulator for O2.- and .NO production.


Diagnostic and therapeutic strategies for eosinophilic esophagitis.
Eosinophilic esophagitis (EoE) is a recently recognized allergic disorder, characterized by eosophageal dysfunction, accumulation of ≥15 eosinophils/high-powered field, eosinophil microabssess, basal cell hyperplasia, extracellular eosinophilic granules in the esophageal epithelial mucosal biopsy and a lack of response to a 8-week proton pump inhibitor treatment. Despite the increased incidences and considerable progress made in understanding EoE pathogenesis, there are limited diagnostic and therapeutic options available for EoE. Currently, the only criterion for diagnosing EoE is repetitive esophageal endoscopic biopsies and histopathological evaluation. Antigen elimination or corticosteroid therapies are effective therapies for EoE but are expensive and have limitations, if continued in the long term. Hence, there is a great necessity for novel noninvasive diagnostic biomarkers that can easily diagnose EoE and assess effectiveness of therapy. Herein, we have provided an update on key molecules involved in the disease initiation, and progression and proposed novel noninvasive diagnostic molecules and strategies for EoE therapy.


Intra-articular injection and driving advice: a survey of UK rheumatologists' current practice.
To determine the current practice of UK rheumatologists regarding driving advice and intra-articular injection. A secondary objective was to clarify legal advice on driving after intra-articular injection. A link to an online questionnaire was sent out via the British Society of Rheumatology (BSR) monthly e-newsletter to all BSR members in January 2010. In addition, we contacted the Medical Defence union (MDU), Medical Protection Society (MPS), Driving and Vehicle Licensing Agency (DVLA) and insurance companies for statements regarding legal advice. A total of 134 responses were obtained. These were collected on a web-based database. The majority of forms returned were from consultant rheumatologists. Fifty-six per cent of respondents said that they routinely asked patients about driving prior to joint injection. Seventy-six respondents (57%) considered driving to be an issue when injecting joints. If a patient had driven to clinic, 30% of respondents said that they would inject as normal, 28% opting to inject but ask the patient to wait following injection. Only 12% (16 respondents) said that they would not undertake an injection if the patient was driving. Sixty-one (46%) respondents did not run an injection clinic. Of those who did (71 respondents) 55% pre-warned patients not to drive. There is no clear consensus among rheumatologists as to practice regarding driving following an intra-articular injection. Medico-legally, there is no absolute bar to driving following an intra-articular injection, and guidance points to clinicians' own judgement as to the safety of driving.


Metastatic malignant melanoma of the gallbladder presenting as biliary colic: a case report and review of literature.
Malignant melanoma (MM) is the most common cancer to metastasize to the gastrointestinal tract. Autopsy reports estimate that up to 15 per cent of these patients also have gallbladder metastases, and MM accounts for up to 60 per cent of metastatic lesions to the gallbladder. However, despite its prevalence, MM to the gallbladder is reported only sparingly in the literature. This discordance may be explained by the fact that these lesions are seldom symptomatic. Abdominal ultrasound remains the modality of choice in studying gallbladder pathology and has the ability to define metastatic lesions. The effect of screening for gallbladder metastases on improving survival is not well defined, and thus its role remains controversial. Cholecystectomy for melanoma metastases to the gallbladder seems to be mostly palliative, although there have been isolated reports of excellent long-term survival outcomes. The role for immunotherapy and chemotherapy in this population is not well defined, and overall prognosis is poor. Recent reports have advocated laparoscopic cholecystectomy as the treatment of choice, though there remains a concern for peritoneal port site seeding. We present the case of a 48-year-old man with MM metastatic to the gallbladder and a brief review of the literature.


[Identification of antiviral activity of Toddalia asiatica against influenza type A virus].
To identify antiviral activity of Toddalia asiatica against influenza virus type A in vitro. More than two hundred Chinese medicinal herb extracts were screened for antiviral activities against influenza A/PR/8/34 (H1N1) virus using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay for virus induced cytopathic effect (CPE) in a primary screening. Positive samples were picked up and were subjected to quantitative real-time polymerase chain reaction (PCR) to quantify reduction of H1N1 virus genomic RNA. Toddalia asiatica showed potent antiviral activities against H1N1 virus, with 50% effective concentration (EC50) value of 4.7 mg x L(-1) in MTS assay and 0.9 mg x L(-1) in quantitative PCR assay respectively. The cytotoxicity test of Toddalia asiatica generated a CC50 value of 187.2 mg x L(-1) and a selective index (SI) larger than 206 in quantitative PCR. Although the best antiviral activity of Toddalia asiatica was observed with co-treatment of influenza virus infection, it remained effective even when administrated 24 h before and after the initiation of infection. The results suggested that Toddalia asiatica compound extract could be a candidate for anti-H1N1 virus agent in the treatment of influenza.


Secondary-Sphere Effects in Molecular Electrocatalytic CO2 Reduction.
The generation of fuels and value-added chemicals from carbon dioxide (CO2) using electrocatalysis is a promising approach to the eventual large-scale utilization of intermittent renewable energy sources. To mediate kinetically and thermodynamically challenging transformations of CO2, early reports of molecular catalysts focused primarily on precious metal centers. However, through careful ligand design, earth-abundant first-row transition metals have also demonstrated activity and selectivity for electrocatalytic CO2 reduction. A particularly effective and promising approach for enhancement of reaction rates and efficiencies of molecular electrocatalysts for CO2 reduction is the modulation of the secondary coordination sphere of the active site. In practice, this has been achieved through the mimicry of enzyme structures: incorporating pendent Brønsted acid/base sites, charged residues, sterically hindered environments, and bimetallic active sites have all proved to be valid strategies for iterative optimization. Herein, the development of secondary-sphere strategies to facilitate rapid and selective CO2 reduction is reviewed with an in-depth examination of the classic [Fe(tetraphenylporphyrin)]+, [Ni(cyclam)]2+, Mn(bpy)(CO)3X, and Re(bpy)(CO)3X (X = solvent or halide) systems, including relevant highlights from other recently developed ligand platforms.


Bilateral multiple pulmonary artery aneurysms associated with cavitary pulmonary tuberculosis: a case report.
Pulmonary artery aneurysms constitute <1% of aneurysms occurring in the thoracic cavity. Congenital cardiac defects are responsible for the majority (>50%) of cases, however, pulmonary artery aneurysm is a rare sequelae of pulmonary tuberculosis reported in about 5% of patients with chronic cavitary tuberculosis on autopsy. The natural history of this potentially fatal condition remains poorly understood and guidelines for optimal management are controversial. A 24-year-old man, a nursing student of African descent, was referred to us from an up-country regional hospital with a 4-week history of recurrent episodes of breathlessness, awareness of heartbeats and coughing blood 3 weeks after completing a 6-month course of anti-tuberculosis drugs. A physical examination revealed conjuctival and palmar pallor but there were no stigmata of connective tissue disorders, systemic vasculitides or congenital heart disease. An examination of the cardiovascular system revealed accentuated second heart sound (S2) with early diastolic (grade 1/6) and holosystolic (grade 2/6) murmurs at the pulmonic and tricuspid areas respectively. Blood tests showed iron deficiency anemia, prolonged bleeding time, and mild hyponatremia. A chest radiograph revealed bilateral ovoid-shaped perihilar opacities while a computed tomography scan showed bilateral multiple pulmonary artery pseudoaneurysms with surrounding hematoma together with adjacent cystic changes, consolidations, and tree-in-bud appearance. Our patient refused to undergo surgery and died of aneurismal rupture after 9 days of hospitalization. The presence of intractable hemoptysis among patients with tuberculosis even after completion of anti-tuberculosis course should raise an index of suspicion for pulmonary artery aneurysm. Furthermore, despite of its rarity, early recognition and timely surgical intervention of pulmonary artery aneurysm is crucial to reducing morbidity and preventing the attributed mortality.


Study of suicides reported to the Coroner in Colombo, Sri Lanka.
Deaths from suicide reached a peak in Sri Lanka in 1995. Several interventions reduced the suicide rate of 48.7 per 100,000 in 1995 to 23 per 100,000 in 2006, though it is still a major socioeconomic problem. All suicides have to be reported to the Inquirer of Sudden Death (ISD) or 'Coroner', according to the Criminal Procedure Code. All deaths where a verdict of 'suicide' was given after an inquest at the Coroner's Court, Colombo, in 2006 were studied. Close relations or friends who attended the inquest were interviewed by medically qualified research assistants. Age, sex, marital and occupational status, level of education, living circumstances and method and reasons for the suicide were studied. During 2006, 151 deaths from suicide were documented, of which 93 (62%) were men. The majority (47%) were aged between 20 and 29 years. One-third of the victims was unemployed. At the time of committing suicide, 75% were living with family; 89 (59%) were married and 46 (31%) were single. Poisoning was the cause of death in 66 (44%), 48 (70%) of which were due to pesticides. Burns caused 51 (34%) deaths. Other common causes of death included hanging (11%), jumping in front of a train (7%) and drowning (3%). The commonest reason for suicide was dispute with the spouse/marital disharmony (30%). Other reasons were dispute with parents (8%), financial matters (7%), organic diseases (7%), alcoholism (7%), psychiatric illnesses (6%) and disputes in love affairs (5%). In 29 cases (19%), no definite reason for the suicide was evident. Self-poisoning and self-immolation were the commonest methods used to commit suicide. Marital disharmony was the main reason (30%). Psychiatric illnesses were responsible for only 6%. Future interventional activities should include secure access and restriction of the availability of pesticides and drugs, empowering people to manage anger and conflicts, and recognition and treatment of alcoholism and psychiatric illnesses. The success story of the reduction in the incidence of suicides in Sri Lanka should be a lesson to many developing countries where suicide is a major socioeconomic and health issue.


Dizziness in children.
There is no question that dizziness and vertiginous-like symptoms occur in children. The real difficulties lie in evaluating and managing the patient and the family. This article outlined differential diagnoses and some treatment options to facilitate this important task.


[Artificial intelligence-based literature data warehouse for vaccine safety].
Objective: To establish a sustainable updated literature data warehouse for global vaccine safety assessment, and provide data support for evidence-based vaccine safety assessment. Methods: Semi-automated construction and updating of a literature data warehouse were achieved through the continuous integration of standard operating steps of evidence-based reviews with artificial intelligence technologies. Following the standard procedure of a systematic literature review, the literatures about vaccine safety assessment published before November 29, 2020 were retrieved from 9 databases including OVID, Scopus, Web of Science, Cochrane Library, and ClinicalTrails.org in English and Wanfang, CNKI, VIP, and SinoMed in Chinese. Literatures were screened for two rounds in a semi-automatic manner (by artificial intelligence literature processing system and manual work) according to the inclusion/exclusion criteria. Furthermore, the literatures were classified according to the types of vaccines and adverse events. The updating strategy was established, and the literature data warehouse was updated regularly. Experts were organized to select specific vaccine safety topics and carry out special demonstration studies. Results: More than 0.41 million articles were retrieved. According to the inclusion/exclusion criteria, 23 304 articles were included after two rounds of screening. At present, we have selected and completed three prior topics as demonstration studies, including the systematic review of "DPT (diphtheria, pertussis and tetanus) vaccine and encephalopathy/encephalitis", and the classified management of literatures about allergic purpura and brachial plexus neuritis. Conclusions: The sustainable updated literature data warehouse of vaccine safety can provide high-quality research data for vaccine safety research, including evidence support for immunization related policy-making and adjustment and vaccine safety-related methodological research or clinical tool development; and further demonstration studies can provide references for building a new methodological framework system for timely and efficient completion of the evidence-based assessment of vaccine safety.


Stockpiling by pups and self-sacrifice by their fasting mothers observed in birth to weaning serum metabolomes of Atlantic grey seals.
During the uniquely short lactations of true seals, pups acquire a greater proportion of maternal body resources, at a greater rate, than in any other group of mammals. Mothers in many species enter a period of anorexia but must preserve sufficient reserves to fuel hunting and thermoregulation for return to cold seas. Moreover, pups may undergo a period of development after weaning during which they have no maternal care or nutrition. This nutritionally closed system presents a potentially extreme case of conflict between maternal survival and adequate provisioning of offspring, likely presenting strains on their metabolisms. We examined the serum metabolomes of five mother and pup pairs of Atlantic grey seals, Halichoerus grypus, from birth to weaning. Changes with time were particularly evident in pups, with indications of strain in the fat and energy metabolisms of both. Crucially, pups accumulate certain compounds to levels that are dramatically greater than in mothers. These include compounds that pups cannot synthesise themselves, such as pyridoxine/vitamin B6, taurine, some essential amino acids, and a conditionally essential amino acid and its precursor. Fasting mothers therefore appear to mediate stockpiling of critical metabolites in their pups, potentially depleting their own reserves and prompting cessation of lactation.


Bortezomib Increased Vascular Permeability by Decreasing Cell-Cell Junction Molecules in Human Pulmonary Microvascular Endothelial Cells.
Bortezomib (BTZ), a chemotherapeutic drug used to treat multiple myeloma, induces life-threatening side effects, including severe pulmonary toxicity. However, the mechanisms underlying these effects remain unclear. The objectives of this study were to (1) investigate whether BTZ influences vascular permeability and (2) clarify the effect of BTZ on the expression of molecules associated with cell-cell junctions using human pulmonary microvascular endothelial cells in vitro. Clinically relevant concentrations of BTZ induced limited cytotoxicity and increased the permeability of human pulmonary microvascular endothelial cell monolayers. BTZ decreased the protein expression of claudin-5, occludin, and VE-cadherin but not that of ZO-1 and β-catenin. Additionally, BTZ decreased the mRNA expression of claudin-5, occludin, ZO-1, VE-cadherin, and β-catenin. Our results suggest that BTZ increases the vascular permeability of the pulmonary microvascular endothelium by downregulating cell-cell junction molecules, particularly claudin-5, occludin, and VE-cadherin.


Long-term care quality: facing the challenges of an aging population.
As part of its continuing mission to serve trustees and staff of health foundations and corporate giving programs, Grantmakers In Health (GIH) convened a select group of grantmakers and national experts who have made a major commitment to improve the quality of long-term care, particularly the care provided in nursing homes. The roundtable explored various factors influencing both the quality of care provided to elderly patients, as well as the quality of their lives. The discussion ultimately centered upon the importance of grantmaker involvement to improve the quality of long-term care, including the services delivered, training for professional and paraprofessional staff, continued research and evaluation, and public policies regulating the long-term care industry. This report brings together key points from the day's discussion with factual information on demographic, financing, and public policy trends drawn from a background paper prepared for the meeting. When available, recent findings, facts, and figures have been incorporated.


New insights into the mechanisms and importance of the proteasome in intracellular protein degradation.
Recent studies of the 20S proteasome from Thermoplasma acidophilum have uncovered some fundamental new properties of its catalytic mechanism. Unlike conventional proteases, 20S and 26S proteasomes degrade protein substrates in a highly processive fashion. They cleave a protein substrate to small peptides before attacking another substrate molecule. This processive behavior is an inherent feature of the 20S particle not requiring cofactors or ATP hydrolysis. Recently, we have described a proteasome-like particle, HslVU, in Escherichia coli. HslVU is a two-component ATP-dependent protease composed of the proteasome-related peptidase HslV (beta-subunit) and the ATPase HslU. In active HslVU complex, cleavage of small peptides and proteins requires the presence of ATP. EM analysis revealed that HslV and HslU are both ring-shaped particles and that the active HslVU complex is a cylindrical four-ring structure, composed of HslV, a two-ring dodecamer, sandwiched between HslU rings. Elucidation of its mode of action may help us understand the role of ATP in function of the 26S proteasome. Several proteasome-specific inhibitors have been recently identified which block the function of proteasome in vivo. These agents have proven very useful to clarify the intracellular function of the proteasome. In mammalian cells, both the rapid degradation of short-lived regulatory proteins and of abnormal polypeptides and the slower degradation of long-lived proteins are blocked by these agents. Thus, in mammalian cells, the proteasome is the site for the degradation of most cell proteins. In contrast, in budding yeast, proteasome inhibitors block the degradation of short-lived proteins but not the breakdown of long-lived proteins, which can be blocked by inhibitors of vacuolar proteases. The inhibition of proteasome function in yeast and mammalian cells, presumably by causing an accumulation of unfolded proteins, triggers the expression of heat shock proteins and concomitantly increases cell resistance to high temperature and various toxic insults.


Neurochemical effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Wistar and Gunn rats.
Normal Wistar, heterozygous and homozygous Gunn rats were killed one week after a single intragastric dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 20 microgram/kg in acetone-olive oil. Control animals were treated similarly but without TCDD. The brain protein and RNA content were measured together with enzyme assays of lysosomal acid proteinase and soluble DT-diaphorase. Acid proteinase activity was increased in the brains of the normal Wistar rats after TCDD treatment. RNA and protein contents were lowered in the heterozygous Gunn rats whereas no changes were detected in the homozygous Gunn rats. The cerebral soluble DT-diaphorase activity was slightly enhanced (about 35%) by TCDD treatment only in normal Wistar rats. Our results may point at modified neurotoxic effects of TCDD in chronic exposure to bilirubin as in the case of Gunn rats.


The assessment and management of tinea capitis in children.
Tinea capitis is an infection of the scalp and hair shaft caused by dermatophyte fungi. It is seen in all age groups, and the incidence seems to be on the rise in North America. Clinical diagnosis of tinea capitis can be challenging, as symptoms can vary from minimal pruritus with no hair loss, to severe tenderness, purulence, and permanent scarring in inflammatory kerion lesions. The diagnosis of tinea capitis must be confirmed in the laboratory by using fungal stains or obtaining cultures, since treatment may be prolonged with potential side effects. Systemic therapy is needed because topical antifungals cannot effectively penetrate the hair shaft to eradicate the infection. Oral griseofulvin remains the standard treatment agent, but terbinafine and itraconazole are also effective alternatives (although currently without Food and Drug Administration approval).


A cold-active salmon goose-type lysozyme with high heat tolerance.
The Atlantic salmon (Salmo salar) goose-type lysozyme gene was isolated and revealed alternative splicing within exon 2 affecting the signal peptide-encoding region. The lysozyme was produced in Escherichia coli, and the recombinant enzyme showed a high specific lytic activity that was stimulated by low or moderate concentrations of mono- or divalent cations. Relative lytic activities of 70 and 100% were measured at 4 degrees C and 22 degrees C, respectively, and there was no detectable activity at 60 degrees C. However, 30% activity was retained after heating the enzyme for 3 h at 90 degrees C. This unique combination of thermal properties was surprising since the salmon goose-type lysozyme contains no cysteines for protein structure stabilization through disulphide bond formation. The results point to a rapid reversal of inactivation, probably due to instant protein refolding.


Post-transplant infection improves outcome of hepatocellular carcinoma patients after orthotopic liver transplantation.
Tumor recurrence after orthotopic liver transplantation (OLT) remains a serious threat for long-term survival of the recipients with hepatocellular carcinoma (HCC), since very few factors or measures have shown impact on overcoming HCC recurrence after OLT. Postoperative infection suppresses tumor recurrence and improves patient survival in lung cancer and malignant glioma probably via stimulating the immune system. Post-transplant infection (PTI), a common complication, is deemed to be harmful for the liver transplant recipients from a short-term perspective. Nevertheless, whether PTI inhibits HCC recurrence after OLT and prolongs the long-term survival of HCC patients needs to be clarified. To investigate the potential influence of PTI on the survival and tumor recurrence of patients with HCC after OLT. A total of 238 patients with HCC who underwent OLT between August 2002 and July 2016 at our center were retrospectively included and accordingly subdivided into a PTI group (53 patients) and a non-PTI group (185 patients). Univariate analyses, including the differences of overall survival (OS), recurrence-free survival (RFS), and post-recurrence survival (PRS), between the PTI and non-PTI subgroups as well as survival curve analysis were performed by the Kaplan-Meier method, and the differences were compared using the log rank test. The variables with a P-value < 0.1 in univariate analyses were included in the multivariate survival analysis by using a Cox proportional-hazards model. The 1-, 3-, and 5-year OS and RFS rates of the whole cohort were 86.6%, 69.0%, and 63.6%, and 75.7%, 60.0%, and 57.3%, respectively. The 1-, 3-, and 5-year OS rates for the PTI patient group (96.0%, 89.3%, and 74.0%) were significantly higher than those for the non-PTI group (84.0%, 63.4%, and 60.2%) (P = 0.033). The absence of PTI was an independent risk factor for dismal OS (relative risk [RR] = 2.584, 95%CI: 1.226-5.449) and unfavorable RFS (RR = 2.683, 95%CI: 1.335-5.390). Subgroup analyses revealed that PTI remarkably improved OS (P = 0.003) and RFS (P = 0.003) rates of HCC patients with vascular invasion (IV), but did not impact on OS (P = 0.404) and RFS (P = 0.304) of patients without VI. Among the patients who suffered post-transplant tumor recurrence, patients with PTI showed significantly better OS (P = 0.026) and PRS (P = 0.042) rates than those without PTI. PTI improves OS and RFS of the transplant HCC patients at a high risk for post-transplant death and tumor recurrence, which is attributed to suppressive effect of PTI on HCC recurrence.


Nanostructured monolinolein miniemulsions as delivery systems: Role of the internal mesophase on cytotoxicity and cell internalization.
Recent advances in nanoparticle systems for improved drug delivery display a great potential for the administration of active molecules. Here, lipid miniemulsions with various internal nanostructures were loaded with the chemotherapeutic agent Paclitaxel. The goal is to assess the impact of internal structures on their efficiency. Previously the structure, the stability and the physico-chemical properties of those carriers were characterized. Modalities of action were addressed by the evaluation of their effects on the tumor cells viability, their cellular uptake by flow cytometry and confocal microscopy detection of fluorescently labeled nanostructured miniemulsions. Nanostructured miniemulsions showed variations in the cell internalization process likely due to differences in the internal structure. All paclitaxel-loaded emulsions were active reservoirs from which Paclitaxel could be released, however bicontinuous cubosomes showed the best efficiency. Considering the fact that these delivery systems can offer a new life to bioactive compounds previously abandoned due to a low aqueous solubility, these data may represent an important step towards the development of new clinical therapeutic strategies against cancers.


Anti-mycobacterial nucleoside antibiotics from a marine-derived Streptomyces sp. TPU1236A.
Five new nucleoside antibiotics, named streptcytosines A-E (1-5), and six known compounds, de-amosaminyl-cytosamine (6), plicacetin (7), bamicetin (8), amicetin (9), collismycin B (10), and SF2738 C (11), were isolated from a culture broth of Streptomyces sp. TPU1236A collected in Okinawa, Japan. The structures of new compounds were elucidated on the basis of their spectroscopic data (HRFABMS, IR, UV, and 2D NMR experiments including 1H-1H COSY, HMQC, HMBC, and NOESY spectra). Streptcytosine A (1) belonged to the amicetin group antibiotics, and streptcytosines B-E (2-5) were derivatives of de-amosaminyl-cytosamine (6), 2,3,6-trideoxyglucopyranosyl cytosine. Compound 1 inhibited the growth of Mycobacterium smegmatis (MIC = 32 µg/mL), while compounds 2-5 were not active at 50 µg/disc. Bamicetin (8) and amicetin (9) showed the MICs of 16 and 8 µg/mL, respectively.


Haematopoietic and immunologic abnormalities in severe aplastic anaemia patients treated with anti-thymocyte globulin.
Thirty-five patients with severe aplastic anaemia (SAA) were extensively evaluated 0.3-12.4 years (median 3.8) after anti-thymocyte globulin (ATG) treatment. All but one were transfusion independent. Most patients revealed a normal Hb level and a granulocyte count over 1.5 x 10(9)/l but were still thrombocytopenic due to decreased platelet production. Lymphocytopenia and/or monocytopenia was found in about 30%. Two patients had a monocytosis. Although there was a great range in degree of recovery at various time intervals after ATG, patients tested more than 4 years after ATG tended to have higher cell counts. Lymphocyte counts correlated with the interval between ATG and evaluation, and with haematopoietic recovery. Qualitative abnormalities were found in all cell lines. Most patients showed a homogeneous macrocytic RBC population, and almost 50% a positive sucrose lysis test; only three patients showed evidence of haemolysis and only two of these showed a positive Ham test. Mean platelet volumes were reduced out of proportion to their number. Platelet function, determined by bleeding time and aggregometry, was impaired in over 30%. The granulocytic series showed a shift to the left in about 30%. Hypersegmentation and pseudo Pelger-Huet anomaly were seen in some patients. Lymphocyte subset distribution in blood and bone marrow was within the normal range but absolute blood levels of CD4 cells in particular were slightly decreased, and tended to increase gradually with time after ATG. IgG and IgA levels were significantly decreased. In only one patient cytogenetic analysis of unstimulated bone marrow cells revealed an abnormal karyotype, but in eight of eight patients an increased sensitivity of lymphocytes to X-rays was found. These data suggest impairment at the level of the very early haematopoietic progenitor cell in all patients up to 10 years after ATG. Since similar findings have been reported in clonal (pre-)malignant disease, SAA, improved after ATG treatment, might be prone to clonal (malignant) evolution.


Specific Surface Determination of Expansible Layer Silicates.
The vacuum-oven technique for quantitative sorption of a glycerol duointerlayer by montmorillonite at 35 degrees C is adapted to 130 degrees C to obtain a mono-inter-layer of glycerol, glycerol vapor relative pressure being controlled by temperature differential. Values obtained for montmorillonite agree closely with theoretical values based on liquid glycerol density, while vermiculite retains a mono-interlayer of somewhat less than liquid glycerol density.


Genetics and biogenesis of cytochrome b.
We have reviewed here the genetic methods used for isolating and manipulating nuclear and mitochondrial mutants of bakers' yeast that affect the function and biogenesis of complex III of the mitochondrial respiratory chain. All the methods have been used with success in the past, and it is hoped that this compilation will aid biochemists in using these techniques to study electron transfer.


Effective treatment of nail psoriasis with apremilast: report of two cases and review of the literature.
Nail psoriasis can cause great morbidity and a negative impact on the personal and work-related life of the patients. However, it responds more poorly to most drug therapies. Classically, the first line of treatment for nail psoriasis has been topical medication, but the new biological drugs seem to be the most effective treatment. Apremilast is another systemic oral drug that has shown a significant reduction of the severity in moderate-severe plaque psoriasis, as well as nail and scalp psoriasis. We present two cases of patients who exhibited a rapid response to treatment with apremilast.


MiR-147: Functions and Implications in Inflammation and Diseases.
MicroRNAs (miRNAs) are small non-coding RNAs (19~25 nucleotides) that regulate gene expression at a post-transcriptional level through repression of mRNA translation or mRNA decay. MiR-147, which was initially discovered in mouse spleen and macrophages, has been shown to correlate with coronary atherogenesis and inflammatory bowel disease and modulate macrophage functions and inflammation through TLR-4. Altered miR-147 level has been shown in various human diseases, including infectious disease, cancer, cardiovascular disease, neurodegenerative disorder, etc. This review will focus on the current understanding regarding the role of miR-147 in inflammation and diseases.


Simultaneous magnetic field and temperature measurement with high resolution based on cascaded microwave photonic filters.
A simultaneous magnetic field and temperature sensing scheme based on cascaded microwave photonic filters (MPFs) with high resolution is proposed and experimentally demonstrated. A polarization maintaining fiber bonded with a giant magnetostrictive material acts both as a magnetic field sensing probe and an important unit of a dispersion-induced MPF. A 500 m single mode fiber in a two-tap MPF is used to perform temperature compensation. The power fading frequency of the dispersion-induced MPF and the dip frequency of the two-tap MPF are selected to monitor the magnetic field and temperature changes. When temperature changes, both power fading frequency and dip frequency will change. While only power fading frequency shifts as magnetic field changes. Consequently, dual parameter sensing can be achieved by monitoring the characteristic microwave frequencies of the two MPFs. The temperature cross-sensitivity is well resolved in this way. In the experiment, the microwave frequency changes 5.84 MHz as external magnetic field increases by 1 mT. The corresponded theoretical resolution can reach 0.17 nT, which is only limited by the minimum resolution of vector network analyzer.


[Cerebellar ganglioglioma: a case report].
A case of cerebellar ganglioglioma is reported. A 22-year-old female was admitted to the Kurume University Hospital on August 19, 1985, suffering from headache, vomiting and gait disturbance. On admission, neurological examination revealed staggering gait and the right cerebellar ataxia showing dysmetria and dysdiadochokinesis. Mild choked disc in the right fundus was also noted. Plain CT scan showed the low-density area involving the right cerebellar hemisphere and the part of the vermis with internal hydrocephalus. Enhanced CT scan showed the high-density area adjacent to the low-density area suggesting a mural nodule. A vertebral angiogram in the arterial phase showed an expansive lesion in the posterior fossa and the tumor stain, which was also visualized in the venous phase. An emergency suboccipital craniectomy was then performed. With opening the tense dura mater, the cyst formation was noted and 30 ml of xanthochromic fluid was then aspirated. A well demarcated mural nodule was noted in the lateral wall of the cyst. The nodule was then extirpated in toto. The hypertrophy of the cerebellar cortex was not observed. Histologically, the tumor was consisted of nerve fiber, glial fiber and neuronal cells. Its architecture was differed distinctly from that of hamartomatous diffuse hypertrophy of the cerebellar cortex (Lhermitte-Duclos' disease). Immunohistochemically, the neuronal cells revealed positive staining for NSE and S-100, and the glial cells displayed positive staining for GFAP, S-100. The authors reviewed previously reported eleven cases of cerebellar ganglioglioma including the present case. These results showed that cerebellar gangliogliomas have some characteristic clinical features among general intracranial gangliogliomas.(ABSTRACT TRUNCATED AT 250 WORDS)


Novel clinical applications of dual energy computed tomography.
Dual energy CT (DECT) was conceived at the very beginning of the computed tomography era. However the first DECT scanner was developed in 2006. Nowadays there are three different types of DECT available: dual-source CT with 80(100) kVp and 140 kVp tubes (Siemens Medical Solution); dual-layer multi-detector scanner with acquisition 120 or 140kVp (Philips Healthcare); CT unit with one rapid kVp switching source and new detector based on gemstone scintillator materials (GE Healthcare). This article describes the physical background and principles of DECT imaging as well as applications of this innovative method in routine clinical practice (renal stone differentiation, pulmonary perfusion, neuroradiology and metallic implant imaging). The particular applications are illustrated by cases from author's material.


Prevalences and association of ECG findings and cardiovascular risk factor in Shinawatra employees.
There is significant incline trend in cardiovascular disease (CVD) mortality in developing countries such as Thailand and it is also the major contributor to the burden of premature mortality and morbidity throughout the world. In order to have well-stratified primary prevention plan, this study reports the prevalence of Electrocardiogram (ECG) abnormalities, as categorized by ECG Minnesota coding, and the association with major cardiovascular risk factors in Thailand. In this study, we use the same data from a previous survey at Shinawatra Employee but only subjects with available ECG's were recruited in our study. Standard supine 12-lead ECG data were collected; all amplitude and intervals were measured and entered into a computer manually. Then the ECG was coded according to Minnesota Coding system. The study characteristics, the prevalence of major cardiovascular risk factors and ECG abnormalities were calculated. A total of 1,485 subjects were recruited in this study, 638 (43.0%) were male and 847 (57.0%) were female. The overall mean aged was 34.4 (5.4). The level of major cardiovascular risk factors among men and women respectively were: total Cholesterol 215.6 (41.0) mg/dl (5.6 (1.1) mmol/l), 202.8 (35.3) mg/dl (5.3 (0.9) mmol/l); LDL-cholesterol 139.1 (37.0) (3.6 (1.0) mmol/l), 123.6 (31.9) (3.2 (0.8) mmol/l). Hypercholesterolemia was 65.3%, 49.8%. The mean systolic and diastolic blood pressures were 121.5 (13.9) mmHg and 81.4 (10.5) mmHg, 111.7 (12.2) mmHg and 74.5 (8.6) mmHg; hypertension 21.0%, 4.2%; fasting blood sugar 95.5 (15.8) mg/dl (5.3 (0.9) mmol/l), 88.0 (8.6) mg/dl (5.1 (0.5) mmol/l); diabetes mellitus 3.3%, 0.5%; body mass index 23.5 (3.5) (kg/m2), 21.3 (3.1) (kg/m2); obesity 30.7%, 11.0%; smoking 12.3%, 14.0%. The prevalence of ECG abnormalities, as categorized based on the Minnesota coding criteria, among men and women respectively were: Q/QS wave abnormalities (Code 1) 2.2%, 0.8%; S-T-J segment depression (Code 4) 0.5%, 1.4%; T-wave inversion (Code 5) 1.4%, 9.6%; atrioventricular conduction abnormalities (Code 6) 2.5%, 0.8%; and ventricular conduction abnormalities (Code 7) 0.2%, 0.2%. This study reports higher prevalence of having major cardiovascular risk factors as compared to previous epidemiological studies in Thailand which should heighten the Ministry of Public Health concern to launch a better stratified preventive plan to combat the rising of coronary artery disease in the future. Moreover, this study is also the first study to report the prevalence of ECG abnormalities, as determined on the basis of the Minnesota coding criteria, and the association between major cardiovascular risk factors and the prevalences of several electrocardiographic findings in adult men and women in Thailand.


Caspase-9 inhibition confers stronger neuronal and vascular protection compared to VEGF neutralization in a mouse model of retinal vein occlusion.
Retinal vein occlusion (RVO) is a sight-threatening condition typically treated with intravitreal injection of vascular endothelial growth factor (VEGF) antagonists. Treatment response to anti-VEGF therapies is highly variable, with poor visual outcomes and treatment response in patients with significant retinal nonperfusion following RVO. Recently, caspase-9 has been identified as a potent regulator of edema, gliosis, and neuronal dysfunction during acute retinal hypoxia. The purpose of this study was to compare the therapeutic effect of caspase-9 inhibition against VEGF-neutralization in an established mouse model of RVO. Adult male C57Bl/6 J mice were randomized to induction of RVO and treatment with either vehicle, intravitreal injection of anti-VEGF antibody, topical administration of a selective caspase-9 inhibitor (Pen1-XBir3), or a combination therapy. Animals were followed on days 1, 2, and 8 after RVO with fundus retinal imaging, and with optical coherence tomography (OCT) to capture retinal swelling, capillary nonperfusion (measured by disorganization of retinal inner layers, DRIL), hyperreflective foci (HRF), and retinal atrophy. Focal electroretinography (ERG) measurements were performed on day 7. Histology was performed on retinal sections from day 8. Both VEGF neutralization and caspase-9 inhibition showed significant retinal protection from RVO compared to vehicle treatment arm. Retinal reperfusion of occluded veins was accelerated in eyes receiving caspase-9 inhibitor, but not significantly different from vehicle in the anti-VEGF group. Retinal edema was suppressed in all treatment groups, with approximately 2-fold greater edema reduction with caspase-9 inhibition compared to VEGF neutralization. HRF were reduced similarly across all treatment groups compared to vehicle. Retinal detachment was reduced only in eyes treated with caspase-9 inhibitor monotherapy. Caspase-9 inhibition reduced retinal atrophy and preserved ERG response; VEGF neutralization did not prevent neurodegeneration following RVO. Caspase-9 inhibition confers stronger neuronal and vascular protection compared to VEGF neutralization in the mouse laser-induced model of RVO.


Poly(ethyl glyoxylate)-Poly(ethylene oxide) Nanoparticles: Stimuli-Responsive Drug Release via End-to-End Polyglyoxylate Depolymerization.
The ability to disrupt polymer assemblies in response to specific stimuli provides the potential to release drugs selectively at certain sites or conditions in vivo. However, most stimuli-responsive delivery systems require many stimuli-initiated events to release drugs. "Self-immolative polymers" offer the potential to provide amplified responses to stimuli as they undergo complete end-to-end depolymerization following the cleavage of a single end-cap. Herein, linker end-caps were developed to conjugate self-immolative poly(ethyl glyoxylate) (PEtG) with poly(ethylene oxide) (PEO) to form amphiphilic block copolymers. These copolymers were self-assembled to form nanoparticles in aqueous solution. Cleavage of the linker end-caps were triggered by a thiol reducing agent, UV light, H2O2, and combinations of these stimuli, resulting in nanoparticle disintegration. Low stimuli concentrations were effective in rapidly disrupting the nanoparticles. Nile red, doxorubin, and curcumin were encapsulated into the nanoparticles and were selectively released upon application of the appropriate stimulus. The ability to tune the stimuli-responsiveness simply by changing the linker end-cap makes this new platform highly attractive for applications in drug delivery.


[Identification and viability assessment of dermatophytes infecting nail based on quantitative PCR of dermatophyte actin (ACT) mRNA].
The diagnosis and choice of treatment for dermatophytoses are usually based on the result of microscopic observation of hyphal elements and culture. However, false negative cultures have sometimes been encountered and appropriate timing of discontinuation of treatment has not been formulated. In this study, we attempted the identification and viability assessment of dermatophytes based on the quantitative measurement of dermatophyte actin (ACT) mRNA. An internal fragment of the ACT, 725 to 762 bp, was isolated by PCR from the genomic DNA of dermatophytes and sequenced. ACT intron-based primers were dermatophyte species-specific and primer pairs crossing the intron were dermatophyte genus-specific. The LightCycler (LC) instrument, employing the two-step RT-PCR/fluorescent hybridization system, was used to quantify the actin mRNA (ACT) of dermatophytes. A 669 bp ACT cDNA fragment was used as a quantification standard. Several mg of samples were collected from skin scales or nail plates before and after the treatment using oral terbinafine. The results indicated that quantification of ACT mRNA correlated with the results of culture and KOH examination and that copy numbers of dermatophyte ACT mRNA per mg sample decreased with progression of the therapy. This method comprises a sensitive (1 fg), specific, rapid (< 4 h) and quantitative assessment of the viability and identification of dermatophytes in skin tissue.


Use of selective vasodilation in treatment of sickle cell disease.
Individuals with sickle cell disease and its genetic variants demonstrate a modest to severe hemolytic anemia. They are also prone to both acute and chronic vaso-occlusive phenomena, which may lead to irreversible tissue damage, organ failure, and premature death. To better understand these vaso-occlusive phenomena, it would be useful to determine the extent to which arteriolar microvascular obstruction might contribute to the pathogenesis of sickle cell disease. We studied the hematologic and ocular effects of orally administered nifedipine in several steady-state patients and compared these with a case-control group of patients not receiving nifedipine. In the nifedipine-treated patients, a striking reversal in ischemic retinal and conjunctival changes was observed, as well as a significant improvement in color vision performance. In addition, the treated subjects showed a slight but significant decline in the levels of both indirect serum bilirubin and plasma hemoglobin, suggesting a concurrent amelioration in the rate of hemolysis. These observations are consistent with the hypothesis that inappropriate vaso-constriction, or frank vasospasm, perhaps in response to the altered rheology of red cells containing polymerized hemoglobin S, may play an important role in the pathophysiology of sickle cell disease. Furthermore, selective vasodilation may prove to be a useful adjunctive approach to the treatment of the manifestations of the sickle syndromes.


New evidence about the "dark side" of social cohesion in promoting binge drinking among adolescents.
Adolescence is characterized by heightened susceptibility to peer influence, which makes adolescents vulnerable to initiating or maintaining risky habits such as heavy drinking. The aim of the study was to investigate the association of social capital with longitudinal changes in the frequency of binge drinking among adolescents at public and private high schools in the city of Diamantina, Brazil. This longitudinal study used two waves of data collected when the adolescents were 12 and 13 years old. At the baseline assessment in 2013 a classroom survey was carried out with a representative sample of 588 students. In 2014, a follow-up survey was carried out with the same adolescents when they were aged 13 years. The Alcohol Use Disorder Identification Test-C (AUDIT C) was employed for the evaluation of alcohol intake. Our predictor variables included sociodemographic and economic characteristics (gender, type of school, mother's education, family income) and Social Capital. For evaluation of social capital, we used the Social Capital Questionnaire for Adolescent Students (SCQ-AS). Descriptive and bivariate analyzes were performed (p <0.05). The log-binomial model was used to calculate prevalence ratios (PR) and 95% confidence intervals. The two-tailed p value was set at <0.05. The prevalence of binge drinking in 2013 was 23.1% and in 2014 the prevalence had risen to 30.1%. Gender (PR 1.48; 95% CI 0.87-2.52) and socioeconomic status (type of school and mother's education) were not associated with the increase in the frequency of binge drinking. However, higher social capital was significantly associated with an increase in binge drinking by students. Adolescents who reported that they had an increase in social cohesion in the community/neighborhood subscale were 3.4 times more likely (95%CI 1.96-6.10) to binge drink themselves. Our results provide new evidence about the "dark side" of social cohesion in promoting binge drinking among adolescents.


Dl-3-n-butylphthalide alleviates cognitive impairment in amyloid precursor protein/presenilin 1 transgenic mice by regulating the striatal-enriched protein tyrosine phosphatase/ERK/cAMP-response element-binding protein signaling pathway.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive impairment and the deposition of amyloid plaques in the brain. In a transgenic mouse model of AD, cognitive impairment and synaptic dysfunction were revealed to be associated with soluble amyloid oligomers and to occur prior to plaque formation. The results of our previous studies revealed that striatal-enriched protein tyrosine phosphatase (STEP)61 negatively regulated the β-amyloid protein-mediated ERK/cAMP-response element-binding protein (CREB) signaling pathway. Dl-3-n-butylphthalide (NBP) is a synthetic compound approved by the Food and Drug Administration of China for the treatment of ischemic stroke in 2002. Studies have shown that the neuroprotective effects of NBP involve multiple mechanisms. The present study further explored the mechanism of NBP therapy in amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mice, and the involvement of the STEP/ERK/CREB signaling pathway. The results suggested that NBP treatment effectively ameliorated the spatial learning and memory impairment of the APP/PS1 transgenic mice, which was assessed using a Morris water maze. In addition, NBP reduced amyloid-induced activation of STEP61 levels, while increasing phosphorylated (p)-ERK1/2 and p-CREB levels in the cerebral cortex and hippocampus of APP/PS1 transgenic mice by western blotting and immunostaining. In conclusion, the present study provided evidence to suggest that the new drug NBP improved amyloid-induced learning and memory deficits, likely through the regulation of the STEP/ERK/CREB pathway. The results revealed that NBP, as a multi-target drug, may exert a neuroprotective effect. Therefore, NBP may serve as an effective treatment for AD.


Identifying occupational health inequities in the absence of suitable data: are there inequities in access to adequate bathrooms in US workplaces?
Our research questions are often chosen based on the existence of suitable data for analysis or prior research in the area. For new interdisciplinary research areas, such as occupational health equity, suitable data might not yet exist. In this manuscript, we describe how we approached a research question in the absence of suitable data using the example of identifying inequities in adequate bathrooms in US workplaces. We created a conceptual model that hypothesises causal mechanisms for occupational health inequities, and from this model we identified a series of questions that could be answered using separate data sets to better understand inequities in adequate workplace bathrooms. Breaking up the analysis into multiple steps allowed us to use multiple data sources and analysis methods, which helped compensate for limitations in each data set. Using the conceptual model as a guide, we were able to identify some jobs that likely have inadequate bathrooms as well as subpopulations potentially at higher risk for inadequate bathrooms. We also identified specific data gaps by reflecting on the challenges we faced in our multistep analysis. These gaps, which indicated future data collection needs, included difficulty finding data sources for some predictors of inadequate bathrooms that prevented us from fully investigating potential inequities. We share our conceptual model and our example analysis to motivate researchers to avoid letting availability of data limit the research questions they pursue.


Artificial gene networks for objective comparison of analysis algorithms.
Large-scale gene expression profiling generates data sets that are rich in observed features but poor in numbers of observations. The analysis of such data sets is a challenge that has been object of vigorous research. The algorithms in use for this purpose have been poorly documented and rarely compared objectively, posing a problem of uncertainty about the outcomes of the analyses. One way to objectively test such analysis algorithms is to apply them on computational gene network models for which the mechanisms are completely know. We present a system that generates random artificial gene networks according to well-defined topological and kinetic properties. These are used to run in silico experiments simulating real laboratory microarray experiments. Noise with controlled properties is added to the simulation results several times emulating measurement replicates, before expression ratios are calculated. The data sets and kinetic models described here are available from http://www.vbi.vt.edu/~mendes/AGN/as biochemical dynamic models in SBML and Gepasi formats.


Treatment of hyperlipidemia from Japanese evidence.
The treatment of hyperlipidemia is aimed at preventing cardiovascular disease (CVD) and coronary heart disease (CHD). As the incidence of CHD in Japan is about one-third lower and that of stroke is two-fold higher compared to Western countries, and the doses of lipid-lowering drugs used in foreign randomized controlled clinical trials (RCTs) are much higher than in general use in Japan, it remains unclear whether the results of RCTs conducted in Western countries could be extrapolated to Japanese patients. Recently, two major large-scale, prospective, RCTs in Japanese hypercholesterolmic patients, the Management of Elevated Cholesterol in the Primary Prevention of Adult Japanese (MEGA) study and the Japan EPA Lipid Intervention Study (JELIS), have been reported. Japanese epidemiological studies and Japanese clinical studies are reviewed. The evidence suggests that hypercholesterolemia, hypertriglyceridemia, and low HDL-cholesterol are strongly associated with increased CHD risk. Lipid-lowering medication shows beneficial effects even in low-risk populations; however, the data did not support that lower cholesterol is better. The safety and efficacy of hyperlipidemia treatment in Japanese patients are discussed.


Total Synthesis of Thailanstatin A.
The total synthesis of the spliceosome inhibitor thailanstatin A has been achieved in a longest linear sequence of nine steps from readily available starting materials. A key feature of the developed synthetic strategy is the implementation of a unique, biomimetic asymmetric intramolecular oxa-Michael reaction/hydrogenation sequence that allows diastereodivergent access to highly functionalized tetrahydropyrans, which can be used for the synthesis of designed analogues of this bioactive molecule.


Application of mutated Clostridium difficile toxin A for determination of glucosyltransferase-dependent effects.
Mutation of tryptophan-101 in Clostridium difficile toxin A, a 308-kDa glucosyltransferase, resulted in a 50-fold-reduced cytopathic activity in cell culture experiments. The mutant toxin A was characterized and applied to distinguish between glucosyltransferase-dependent and -independent effects with respect to RhoB up-regulation as a cellular stress response.


Antifibrotic Effects of Kangxian Ruangan Capsule on Rats with Nonalcoholic Fatty Liver Fibrosis and Hepatic Stellate Cells through Regulation of TGF-β and TLR4 Signaling Pathways.
Kangxian ruangan (KXRG) is a traditional Chinese medicine (TCM) formula consisting of 12 herbs. TCM syndrome differentiation proposes that KXRG exerts pharmacological effects against nonalcoholic fatty liver disease (NAFLD) fibrosis. This work investigates the effect of KXRG on NAFLD fibrosis in vivo and in vitro. In vivo, the NAFLD fibrosis model was constructed in Wistar rats using methionine- and choline-deficient (MCD) diet, followed by KXRG (0.92 g/kg/d) treatment for 8 weeks. In vitro, primary hepatic stellate cells (HSCs) were activated using platelet-derived growth factor (PDGF) and treated with KXRG. Molecular mechanisms underlying fibrosis were investigated. After 8 weeks, compared with the control groups, the histological lesions, degree of fibrosis, and inflammatory reaction increased with the MCD diet as demonstrated by histological changes and increased fibrosis-related (α-SMA, TGF-β, COL1A1, and desmin, P < 0.01) and inflammation-related factors (TNF-α, MCP-1, and F4/80, P < 0.01), whereas they decreased with KXRG treatment (P < 0.01). KXRG not only inhibited the proliferation of activated HSCs and promoted their apoptosis but also resulted in G0-G1 arrest. Furthermore, KXRG suppressed HSC activation (P < 0.01), collagen synthesis (P < 0.01), and α-SMA expression (P < 0.01) with PDGF stimulation. In both the MCD diet-induced animal model and PDGF-induced cell model, KXRG inhibited TGF-β and TLR4 signaling (P < 0.01), similar to corresponding small-molecule inhibitors. These results demonstrated that KXRG might exert suppressive effects against NAFLD fibrosis via regulating TGF-β and TLR4 signaling. KXRG may act as a natural and potent therapeutic agent against NAFLD.


Combinatorial interventions inhibit TGFβ-driven epithelial-to-mesenchymal transition and support hybrid cellular phenotypes.
Epithelial-to-mesenchymal transition (EMT) is a developmental process hijacked by cancer cells to leave the primary tumor site, invade surrounding tissue and establish distant metastases. A hallmark of EMT is the loss of E-cadherin expression, and one major signal for the induction of EMT is transforming growth factor beta (TGFβ), which is dysregulated in up to 40% of hepatocellular carcinoma (HCC). We aim to identify network perturbations that suppress TGFβ-driven EMT, with the goal of suppressing invasive properties of cancer cells. We use a systems-level Boolean dynamic model of EMT to systematically screen individual and combination perturbations (inhibition or constitutive activation of up to four nodes). We use a recently developed network control approach to understand the mechanism through which the combinatorial interventions suppress EMT. We test the results of our in silico analysis using siRNA. Our model predicts that targeting key elements of feedback loops in combination with the SMAD complex is more effective than suppressing the SMAD complex alone. We demonstrate experimentally that expression of a majority of these elements is enriched in mesenchymal relative to epithelial phenotype HCC cell lines. An siRNA screen of the predicted combinations confirms that many targeting strategies suppress TGFβ-driven EMT measured by E-cadherin expression and cell migration. Our analysis reveals that some perturbations give rise to hybrid states intermediate to the epithelial and mesenchymal states. Our results indicate that EMT is driven by an interconnected signaling network and many apparently successful single interventions may lead to steady states that are in-between epithelial and mesenchymal states. As these putative hybrid or partial EMT states may retain invasive properties, our results suggest that combinatorial therapies are necessary to fully suppress invasive properties of tumor cells.


IGFBP-3 expression in hepatocellular carcinoma involves abnormalities in TGF-beta and/or Rb signaling pathways.
Insulin-like growth factor binding protein-3 (IGFBP-3) is a mediator of growth suppression signals and a putative tumor suppressor gene. The growth suppression mechanisms of IGFBP-3 have not been well clarified. We examined the expression of IGFBP-3 transcripts in human hepatocellular carcinoma (HCC) and the relationship between IGFBP-3 expression and the transforming growth factor-beta (TGF-beta) and/or retinoblastoma (Rb) signaling pathways. In situ hybridization revealed IGFBP-3 transcripts in cancer cells in 6 of 57 (10%) HCCs, including moderately and poorly differentiated HCCs with intrahepatic metastasis. In contrast, all lung metastatic nodules of 4 HCCs showed IGFBP-3 transcripts in cancer cells. The cDNA microarray showed that genes for the TGF-beta pathway and Rb were up-regulated in IGFBP-3-expressing HCCs. In 6 HCCs presenting IGFBP-3, immunohistochemical analyses showed abnormalities in the TGF-beta and/or Rb pathways; the loss of phosphorylated-Smad2 was observed in 2, and overexpression of phosphorylated-Rb was observed in the remaining 4 HCCs. The present study suggests that IGFBP-3 mediates growth suppression signals via the TGF-beta and/or Rb pathways in HCC.