Morphology, Ultrastructure and Possible Functions of Antennal Sensilla of Sitodiplosis mosellana Géhin (Diptera: Cecidomyiidae).
To better understand the olfactory receptive mechanisms involved in host selection and courtship behavior of Sitodiplosis mosellana (Diptera: Cecidomyiidae), one of the most important pests of wheat, scanning and transmission electron microscopy were used to examine the external morphology and ultrastructure of the antennal sensilla. The moniliform antennae exhibit obvious sexual dimorphism: antennae of the males are markedly longer than those of the females. Furthermore, each male flagellomere consists of two globular nodes, whereas each female flagellomere is cylindrical. Seven types of sensilla were identified in both sexes. Two types of s. chaetica have a lumen without dendrites and thick walls, suggesting that they are mechanoreceptors. S. trichodea and s. circumfila are typical chemoreceptors, possessing thin multiporous walls encircling a lumen with multiple dendrites. There are significantly more s. trichodea in female than in male, which may be related to host plant localization. In contrast, male s. circumfila are highly elongated compared to those of females, perhaps for pheromone detection. Peg-shaped s. coeloconica are innervated with unbranched dendrites extending from the base to the distal tip. Type 1 s. coeloconica, which have deep longitudinal grooves and finger-like projections on the surface, may serve as olfactory or humidity receptors, whereas type 2 s. coeloconica, smooth with a terminal pore, may be contact chemoreceptors. Also, this is the first report of Böhm' bristles at proximal scape on antennae of Cecidomyiid species potentially functioning as mechanoreceptors.


Relative importance of bird species as hosts for immature Ixodes dammini (Acari: Ixodidae) in a suburban residential landscape of southern New York State.
Abundance of birds and their tick parasites were estimated in a residential community located in Westchester County, NY, where Lyme disease is endemic. In total, 36 bird species (416 captures) were collected, of which 25 species (69%) were parasitized by ticks. Ixodes dammini Spielman, Clifford, Piesman & Corwin composed 96.4% of the 1,067 ticks found on birds. The bird species most heavily parasitized was house wren, Troglodytes aedon Vieillot (11.1 Ixodes dammini per bird). Relative density estimates of birds, using fixed circle radius counts, revealed dominance by the American robin, Turdus migratorius L. (29.3%), followed by the common grackle, Quiscalus quiscula (L.) (9.3%). Bird density estimates were combined with tick abundance data to calculate an importance value for each bird species as a host for immature I. dammini. The American robin was most important, accounting for 72.7% of all larval I dammini found on birds, followed by the common grackle (8.2%) and the house wren (5.9%). Both the American robin and house wren are reservoir competent for the Lyme disease spirochete Borrelia burgdorferi Johnson, Schmid, Hyde, Steigerwalt & Brenner and therefore may contribute to the risk of Lyme disease for humans. During August when larvae were most prevalent, 39% of the American robins and 70% of the common grackles were observed on lawns. These species are probable contributors to nymphal I. dammini populations found on lawns.


Identification of components of grape powder with anti-apoptotic effects.
This study is to investigate the mechanism underlying the anti-apoptotic effects of freeze-dried grape powder (FDGP) and identify the polyphenolic compounds involved. We examined apoptotic signaling pathways affected by FDGP and by its active components, including epicatechin, cyanidin, quercetin, and resveratrol, in human Huh7 hepatoma cells by assaying cell viability assays, the activities of caspase 3 and caspase 7, and the expression of endoplasmic reticulum stress-associated proteins. FDGP dramatically decreased taurodeoxycholic acid (TDCA)-induced production of reactive oxygen species (ROS). Assessment of individual active components revealed that at concentrations corresponding to 300 μg/mL FDGP, only quercetin demonstrated cytoprotective effects against mitochondrial-mediated apoptosis. In contrast, increased concentrations of other individual polyphenolic compounds were required to produce measurable cytoprotective effect. Only combinations of all four polyphenolic compounds (epicatechin, cyanidin, quercetin, and resveratrol) restored a degree of the anti-apoptotic effects seen with FDGP. The pretreatment of FDGP at 30 μg/mL concentration could reverse the thapsigargin-induced effects on the expression of endoplasmic reticulum stress-associated proteins. In conclusion, FDGP reduced oxidative stress, endoplasmic reticulum stress, and apoptosis. The mechanisms involved in the anti-apoptotic effects of FDGP included reduced generation of ROS, and reduced processing of certain caspases. We demonstrated that quercetin, epicatechin, and cyanidin are active compounds within FDGP that attenuate apoptosis. These findings contribute to our understanding of the molecular mechanisms of anti-apoptotic and anti-oxidant effects of grape and are expected to assist in developing clinical protocols to treat a variety of stress-mediated conditions.


Data mining approaches for genome-wide association of mood disorders.
Mood disorders are highly heritable forms of major mental illness. A major breakthrough in elucidating the genetic architecture of mood disorders was anticipated with the advent of genome-wide association studies (GWAS). However, to date few susceptibility loci have been conclusively identified. The genetic etiology of mood disorders appears to be quite complex, and as a result, alternative approaches for analyzing GWAS data are needed. Recently, a polygenic scoring approach that captures the effects of alleles across multiple loci was successfully applied to the analysis of GWAS data in schizophrenia and bipolar disorder (BP). However, this method may be overly simplistic in its approach to the complexity of genetic effects. Data mining methods are available that may be applied to analyze the high dimensional data generated by GWAS of complex psychiatric disorders. We sought to compare the performance of five data mining methods, namely, Bayesian networks, support vector machine, random forest, radial basis function network, and logistic regression, against the polygenic scoring approach in the analysis of GWAS data on BP. The different classification methods were trained on GWAS datasets from the Bipolar Genome Study (2191 cases with BP and 1434 controls) and their ability to accurately classify case/control status was tested on a GWAS dataset from the Wellcome Trust Case Control Consortium. The performance of the classifiers in the test dataset was evaluated by comparing area under the receiver operating characteristic curves. Bayesian networks performed the best of all the data mining classifiers, but none of these did significantly better than the polygenic score approach. We further examined a subset of single-nucleotide polymorphisms (SNPs) in genes that are expressed in the brain, under the hypothesis that these might be most relevant to BP susceptibility, but all the classifiers performed worse with this reduced set of SNPs. The discriminative accuracy of all of these methods is unlikely to be of diagnostic or clinical utility at the present time. Further research is needed to develop strategies for selecting sets of SNPs likely to be relevant to disease susceptibility and to determine if other data mining classifiers that utilize other algorithms for inferring relationships among the sets of SNPs may perform better.


Hepatic uptake and biliary excretion of d-tubocurarine and trimethyltubocurarine in the rat in vivo and in isolated perfused rat livers.
The clearance from perfusion medium and the biliary excretion of d-tubocurarine (d-TC) and trimethyltubocurarine (tMeTC) was studied in isolated perfused rat livers. Despite the related structure, d-TC exhibited considerably higher lipophilicity and plasma protein binding than its trimethyl derivative. Significant differences in hepatic disposition of the two agents were found. The clearance constant of elimination from the perfusate for d-TC was 2.00 and 0.41 ml/min for tMeTC. Fifty-one percent of the administered d-TC was excreted in the bile during 2 hours of perfusion. For tMeTC this amounted to only 16%. Bile/plasma concentration ratios of d-TC were 10 times those of tMeTC. There was no evidence for biotransformation of the substances. The unequal biliary output cannot be explained by differences in subcellular distribution. After injection into rats in vivo, the major part of drug in the liver is confined to the particulate fractions. Subfractionation studies indicate binding to lysosomes. The hepatocyte cytosol concentrations of d-TC and tMeTC are in the same order and are lower than the concomitant plasma concentrations. Both bile/liver and liver/plasms concentration ratios were higher for d-TC. The results support the idea that the balance of hydrophilic and hydrophobic properties is an important factor determining hepatic transport of organic compounds.


[Clinical evaluation of the tolerance for a soy-based special milk formula in children with cow's milk protein intolerance/allergy (CMPI/CMPA)].
A study aiming to assess the clinical tolerance of a special follow-up soybean milk formula (Neo-Soyal 2) in children with cow's milk protein intolerance or allergy (CMPI/CMPA) has been conducted in 17 infants and children (9 girls and 8 boys) aged from 6 months to 3 years. All the patients had a past history suggestive of CMPI/CMPA and were fed a restricted hypoallergenic diet with a semi-elemental formula based on protein hydrolysates. At the time of initiation of the study, all the patients were asymptomatic with normal growth while on a semi-elemental diet. The formula with protein hydrolysates was substituted by the test milk (Neo-Soyal 2) and blood samples were taken before and after 2 months. The clinical tolerance to the follow-up soybean formula was considered excellent in 16 children who remained asymptomatic with normal growth velocity. Only one patient developed a severe diarrhoea within 72 hours after introduction of the soybean formula which was stopped. However, after one month he was able to tolerate a certain amount of the soybean milk (240 ml) without symptoms. For all the patients studied, there was no change in the nutritional parameters measured in the blood before and after 2 months of the trial. Likewise, the plasma amino acid levels determined in 2 patients remained unchanged before and after the experimental period. These data indicate that the soybean milk formula used here (Neo-Soyal 2) can be safely given as a substitute of semi-elemental diets during the follow-up of children with CMPI/CMPA after the age of 6 months.


Novel anti-angiogenic PEDF-derived small peptides mitigate choroidal neovascularization.
Abnormal migration and proliferation of endothelial cells (EC) drive neovascular retinopathies. While anti-VEGF treatment slows progression, pathology is often supported by decrease in intraocular pigment epithelium-derived factor (PEDF), an endogenous inhibitor of angiogenesis. A surface helical 34-mer peptide of PEDF, comprising this activity, is efficacious in animal models of neovascular retina disease but remains impractically large for therapeutic use. We sought smaller fragments within this sequence that mitigate choroidal neovascularization (CNV). Expecting rapid intravitreal (IVT) clearance, we also developed a method to reversibly attach peptides to nano-carriers for extended delivery. Synthetic fragments of 34-mer yielded smaller anti-angiogenic peptides, and N-terminal capping with dicarboxylic acids did not diminish activity. Charge restoration via substitution of an internal aspartate by asparagine improved potency, achieving low nM apoptotic response in VEGF-activated EC. Two optimized peptides (PEDF 335, 8-mer and PEDF 336, 9-mer) were tested in a mouse model of laser-induced CNV. IVT injection of either peptide, 2-5 days before laser treatment, gave significant CNV decrease at day +14 post laser treatment. The 8-mer also decreased CNV, when administered as eye drops. Also examined was a nanoparticle-conjugate (NPC) prodrug of the 9-mer, having positive zeta potential, expected to display longer intraocular residence. This NPC showed extended efficacy, even when injected 14 days before laser treatment. Neither inflammatory cells nor other histopathologic abnormalities were seen in rabbit eyes harvested 14 days following IVT injection of PEDF 336 (>200 μg). No rabbit or mouse eye irritation was observed over 12-17 days of PEDF 335 eye drops (10 mM). Viability was unaffected in 3 retinal and 2 choroidal cell types by PEDF 335 up to 100 μM, PEDF 336 (100 μM) gave slight growth inhibition only in choroidal EC. A small anti-angiogenic PEDF epitope (G-Y-D-L-Y-R-V) was identified, variants (adipic-Sar-Y-N-L-Y-R-V) mitigate CNV, with clinical potential in treating neovascular retinopathy. Their shared active motif, Y - - - R, is found in laminin (Ln) peptide YIGSR, which binds Ln receptor 67LR, a known high-affinity ligand of PEDF 34-mer.


Clinical and morphological findings in acrylamide toxicity.
Clinical features of acrylamide toxicity consist of sensorimotor peripheral neuropathy. In subacute intoxication ataxia occurs and encephalopathy also in severe acute poisoning. Slight reduction in maximal nerve conduction velocity in animals is due to degeneration of large diameter fibres. Neurofilaments accumulate within axons, both in PNS and CNS. Other changes may be important in initiation of degeneration.


Influence of molecular weight on transdermal delivery of model macromolecules using hydrogel-forming microneedles: potential to enhance the administration of novel low molecular weight biotherapeutics.
With a view to improve the current monoclonal antibody-based therapies dominating the pharmaceutical market, low molecular weight (MW) protein-based macromolecules, such as recombinant antibody fragments, typically within the range of 10-70 kDa, have been developed. Previously, our group successfully delivered Avastin®, a monoclonal antibody (mAb) across the skin using hydrogel-forming microneedles (MN). However, it is thought that this delivery system can be further enhanced using novel, lower MW biomolecules. To address this perception, in the current study, FITC-dextran of different MWs (10, 70 and 150 kDa) was used to model the transdermal delivery of low MW biotherapeutics and mAbs with MWs of approximately 150 kDa. Conversely, fluorescein sodium was the compound selected to model hydrophilic, low MW drugs. As expected, fluorescein sodium produced the greatest cumulative permeation (637.4 ± 42.69 μg). The amounts of FITC-dextran 10 kDa and 150 kDa which permeated across neonatal porcine skin in vitro were 462.17 ± 65.85 μg and 213.54 ± 15.19 μg after 24 h, respectively. The results collated here suggest that the delivery of emerging novel biotherapeutics, via'super swelling' hydrogel-forming MNs, have the potential to result in greater permeation across human skin, compared to the delivery of mAbs delivered via the same route.


[Cloning, expression and glucose regulation activity of human FGF-21].
Fibroblast growth factor (FGF)-21 is a recently discovered glucose regulator and has potential to become therapeutics for treatment of type 2 diabetes. The aim of this study was to clone and express human FGF-21 gene and characterize its bioactivity for glucose regulation. The hFGF-21 cDNA was cloned from human liver by RT-PCR and subcloned into the pSUMO vector after sequencing confirmation. The recombinant plasmid was transformed into Escherichia coli Rosetta strain. The FGF-21 protein expression was induced by IPTG and purified by Ni-NTA agarose. The FGF-21 product was verified by Western blotting analysis with specific antibody. The bioactivity of the purified protein was examined by glucose uptake assay in 3T3-L1 adipocytes. The cloned hFGF-21 gene consisted of 546 bp, which was in agreement with the published data in GenBank. SDS-PAGE analysis showed that hFGF-21 expressed in the E. coli system was 19.4 kDa in size. The glucose uptake assay in 3T3-L1 adipocytes indicated that the purified hFGF-21 could stimulate glucose uptake in a dose-dependent manner, and glucose transporters (GLUT1) is the functional unit.


Alchemical poetry in medieval and early modern Europe: a preliminary survey and synthesis. Part I--Preliminary survey.
This article provides a preliminary description of medieval and early modern alchemical poetry composed in Latin and in the principal vernacular languages of western Europe. It aims to distinguish the various genres in which this poetry flourished, and to identify the most representative aspects of each cultural epoch by considering the medieval and early modern periods in turn. Such a distinction (always somewhat artificial) between two broad historical periods may be justified by the appearance of new cultural phenomena that profoundly modified the character of early modern alchemical poetry: the ever-increasing importance of the prisca theologia, the alchemical interpretation of ancient mythology, and the rise of neo-Latin humanist poetry. Although early modern alchemy was marked by the appearance of new doctrines (notably the alchemical spiritus mundi and Paracelsianism), alchemical poetry was only superficially modified by criteria of a scientific nature, which therefore appear to be of lesser importance. This study falls into two parts. Part I provides a descriptive survey of extant poetry, and in Part II the results of the survey are analysed in order to highlight such distinctive features as the function of alchemical poetry, the influence of the book market on its evolution, its doctrinal content, and the question of whether any theory of alchemical poetry ever emerged. Part II is accompanied by an index of the authors and works cited in both parts.


Pathologic findings in reintroduced Przewalski's horses (Equus caballus przewalskii) in southwestern Mongolia.
The Przewalski's horse (Equus caballus przewalskii) was extinct in the wild by the mid 1960s. The species has survived because of captive breeding only. The Takhin Tal reintroduction project is run by the International Takhi Group; it is one of two projects reintroducing horses to the wild in Mongolia. In 1997 the first harem group was released. The first foals were successfully raised in the wild in 1999. Currently, 63 Przewalski's horses live in Takhin Tal. Little information exists on causes of mortality before the implementation of a disease-monitoring program in 1998. Since 1999, all dead horses recovered (n = 28) have been examined and samples collected and submitted for further investigation. Equine piroplasmosis, a tick-transmitted disease caused by Babesia caballi or Theileria equi, is endemic in Takhin Tal and was identified as the cause of death of four stallions and one stillborn foal. In December 2000, wolf predation was implicated in the loss of several Przewalski's horses. However, thorough clinical, pathologic, and bacteriologic investigations performed on dead and surviving horses of this group revealed lesions compatible with strangles. The extreme Mongolian winter of 2000-2001 is thought to have most probably weakened the horses, making them more susceptible to opportunistic infection and subsequent wolf predation. Other occasional causes of death since 1999 were trauma, exhaustion, wasting, urolithiasis, pneumonia, abortion, and stillbirth. The pathologic examination of the Przewalski's horses did not result in a definitive diagnosis in each case. Several disease factors were found to be important in the initial phase of the reintroduction, which could potentially jeopardize the establishment of a self-sustaining population.


Novel use of hand fracture fixation plates in the surgical stabilisation of flail chest.
Plastic surgeons specialize in working closely with other surgical colleagues to help solve clinical problems. In this case, we performed surgical stabilisation of a large flail chest fragment in conjunction with the cardiothoracic surgical team, using the mini-plating set more commonly used for hand fracture fixation. The use of this fixation system for flail chest has not previously been described, but offers advantages over other reported methods, primarily by dispensing with the need for an extensive thoracotomy incision and by providing robust stabilisation without the presence of prominent hardware.


Resistance emergence mechanism and mechanism of resistance suppression by tobramycin for cefepime for Pseudomonas aeruginosa.
The panoply of resistance mechanisms in Pseudomonas aeruginosa makes resistance suppression difficult. Defining optimal regimens is critical. Cefepime is a cephalosporin whose 3' side chain provides some stability against AmpC β-lactamases. We examined the activity of cefepime against P. aeruginosa wild-type strain PAO1 and its isogenic AmpC stably derepressed mutant in our hollow-fiber infection model. Dose-ranging studies demonstrated complete failure with resistance emergence (both isolates). Inoculum range studies demonstrated ultimate failure for all inocula. Lower inocula failed last (10 days to 2 weeks). Addition of a β-lactamase inhibitor suppressed resistance even with the stably derepressed isolate. Tobramycin combination studies demonstrated resistance suppression in both the wild-type and the stably derepressed isolates. Quantitating the RNA message by quantitative PCR demonstrated that tobramycin decreased the message relative to that in cefepime-alone experiments. Western blotting with AmpC-specific antibody for P. aeruginosa demonstrated decreased expression. We concluded that suppression of β-lactamase expression by tobramycin (a protein synthesis inhibitor) was at least part of the mechanism behind resistance suppression. Monte Carlo simulation demonstrated that a regimen of 2 g of cefepime every 8 h plus 7 mg/kg of body weight of tobramycin daily would provide robust resistance suppression for Pseudomonas isolates with cefepime MIC values up to 8 mg/liter and tobramycin MIC values up to 1 mg/liter. For P. aeruginosa resistance suppression, combination therapy is critical.


Ancestral diversity in lipoprotein(a) studies helps address evidence gaps.
The independent and causal cardiovascular disease risk factor lipoprotein(a) (Lp(a)) is elevated in >1.5 billion individuals worldwide, but studies have prioritised European populations. Here, we examined how ancestrally diverse studies could clarify Lp(a)'s genetic architecture, inform efforts examining application of Lp(a) polygenic risk scores (PRS), enable causal inference and identify unexpected Lp(a) phenotypic effects using data from African (n=25 208), East Asian (n=2895), European (n=362 558), South Asian (n=8192) and Hispanic/Latino (n=8946) populations. Fourteen genome-wide significant loci with numerous population specific signals of large effect were identified that enabled construction of Lp(a) PRS of moderate (R2=15% in East Asians) to high (R2=50% in Europeans) accuracy. For all populations, PRS showed promise as a 'rule out' for elevated Lp(a) because certainty of assignment to the low-risk threshold was high (88.0%-99.9%) across PRS thresholds (80th-99th percentile). Causal effects of increased Lp(a) with increased glycated haemoglobin were estimated for Europeans (p value =1.4×10-6), although inverse effects in Africans and East Asians suggested the potential for heterogeneous causal effects. Finally, Hispanic/Latinos were the only population in which known associations with coronary atherosclerosis and ischaemic heart disease were identified in external testing of Lp(a) PRS phenotypic effects. Our results emphasise the merits of prioritising ancestral diversity when addressing Lp(a) evidence gaps.


Histone deacetylase inhibitors in multiple myeloma: from bench to bedside.
Histone deacetylases (HDACs) deacetylate the lysine residues of both histones and non-histone proteins. Histone acetylation results in a loose local chromatin structure that regulates gene-specific transcription. Non-histone proteins can also be acetylated, leading to dynamic changes in their activity and stability. For these reasons, HDAC inhibition has emerged as a potential approach for the treatment of MM. Specifically, combination treatment with HDAC inhibitors and proteasome inhibitors or immunomodulatory drugs shows remarkable anti-MM activity in both preclinical and clinical settings. However, the clinical studies using non-selective HDAC inhibitors also cause unfavorable side effects in patients, leading us to develop more isoform- and/or class-selective HDAC inhibitors to enhance tolerability without diminishing anti-MM activity, thereby improving patient outcome in MM.


Galpha(i2), Galpha(i3)and Galpha(o) are all required for normal muscarinic inhibition of the cardiac calcium channels in nodal/atrial-like cultured cardiocytes.
The cardiac L-type calcium current (I(Ca,L)) is an important regulator of myocardial contractility. It is activated by sympathetic stimulation and inhibited by parasympathetic activity via muscarinic acetylcholine receptors. Muscarinic inhibition of I(Ca,L) occurs via activation of pertussis toxin (PTX)-sensitive heterotrimeric G-proteins. Although recent studies have shown that expression of G(oalpha) is important for this effect in adult mouse ventricular cells, two other PTX-sensitive G-proteins (G(i2) and G(i3)) are also expressed in cardiocytes and are activated. Their role in the regulation of I(Ca,L) has not been examined. In addition, it is not known whether nodal/atrial cardiac cells use the same G-proteins. We show that gene inactivation of each of the three PTX-sensitive Galpha-proteins (alpha(i2), alpha(i3), and alpha(o)) affects muscarinic inhibition of cardiac I(Ca,L) in embryonic stem (ES) cell-derived cardiocytes. Inactivation of either alpha(i2) or alpha(i3) markedly slows the time course of muscarinic inhibition of I(Ca,L), and in cells where both alpha(i2) and alpha(i3) are inactivated the effects are not additive. We also establish an essential role for alpha(o)in this atrial/nodal-like cardiocyte system and show that alpha(o)acts proximal to NO generation. NO generation plays a critical role in I(Ca,L) regulation since the nitric oxide synthase (NOS) antagonist, l -NMMA, blocked the inhibition of I(Ca,L) in WT and in alpha(i2)/alpha(i3)-null cells. In WT cells, the NO generating agent SIN-1 inhibited I(Ca,L) and the addition of carbachol resulted in faster inhibition, suggesting that pathways in addition to NO are also activated. This study shows that alpha(i2) and alpha(i3) play a critical role in the normal inhibition of cardiocyte I(Ca,L). Thus, all muscarinic receptor activated G-proteins (G(i2), G(i3) and G(o)) are necessary for normal inhibition and act through both NO and non-NO signaling pathways.


Potentiometric analysis of the cytochromes of an Escherichia coli mutant strain lacking the cytochrome d terminal oxidase complex.
A combination of potentiometric analysis and electrochemically poised low-temperature difference spectroscopy was used to examine a mutant strain of Escherichia coli that was previously shown by immunological criteria to be lacking the cytochrome d terminal oxidase. It was shown that this strain is missing cytochromes d, a1, and b558 and that the cytochrome composition of the mutant is similar to that of the wild-type strain grown under conditions of high aeration. The data indicate that the high-aeration branch of the respiratory chain contains two cytochrome components, b556 (midpoint potential [Em] = +35 mV) and cytochrome o (Em = +165 mV). The latter component binds to CO and apparently has a reduced-minus-oxidized split-alpha band with peaks at 555 and 562 nm. When the wild-type strain was grown under conditions of low aeration, the components of the cytochrome d terminal oxidase complex were observed: cytochrome d (Em = +260 mV), cytochrome a1 (Em = +150 mV) and cytochrome b558 (Em = +180 mV). All cytochromes appeared to undergo simple one-electron oxidation-reduction reactions. In the absence of CO, cytochromes b558 and o have nearly the same Em values. In the presence of CO, the Em of cytochrome o is raised, thus allowing cytochromes b558 and o to be individually quantitated by potentiometric analysis when they are both present.


Freeze-fracture analysis of membrane events during early neogenesis of cilia in Tetrahymena: changes in fairy-ring morphology and membrane topography.
A freeze-fracture analysis of early neogenesis of somatic and oral cilia of Tetrahymena was conducted using exponentially grown cultures and also cells induced to undergo oral reorganization. In this report, presumptive ciliary domains (PCDs), sites of future outgrowth of somatic cilia, are identified and their membrane structure is described in detail. The fairy ring, an array of membrane particles that occurs within the PCD and appears to be a precursor of the ciliary necklace, is described. A sequence of early stages in the formation of the ciliary necklace of somatic cilia is deduced from topographical information and membrane particle arrangements and numbers. Evidence is presented that basal bodies are seated at the cell surface prior to initiation of necklace assembly and a possible role for the basal body in necklace assembly is suggested. In dividing cells, new oral cilia grow out prior to orientation of cilia-parasomal sac complexes relative to cell axes. In dividing cells and during oral reorganization, new cilia also develop prior to their alignment into membranelles. Thus, growth of cilia is independent of their spatial orientation. Fairy rings were not observed during oral reorganization. During cell division, proliferation of new cilia is accompanied by the formation of a network of junctions between a cortical system of membranous cisternae, the cortical 'alveoli'. These interalveolar junctions may serve as tracks for early positioning and orientation of new oral basal bodies.


Early detection of fragile X syndrome: applications of a novel approach for improved quantitative methylation analysis in venous blood and newborn blood spots.
Standard fragile X syndrome (FXS) diagnostic tests that target methylation of the fragile X mental retardation 1 (FMR1) CpG island 5' of the CGG expansion can be used to predict severity of the disease in males from birth, but not in females. We describe methylation specific-quantitative melt analysis (MS-QMA) that targets 10 CpG sites, with 9 within FMR1 intron 1, to screen for FXS from birth in both sexes. The novel method combines the qualitative strengths of high-resolution melt and the high-throughput, quantitative real-time PCR standard curve to provide accurate quantification of DNA methylation in a single assay. Its performance was assessed in 312 control (CGG <40), 143 premutation (PM) (CGG 56-170), 197 full mutation (FM) (CGG 200-2000), and 33 CGG size and methylation mosaic samples. In male and female newborn blood spots, MS-QMA differentiated FM from control alleles, with sensitivity, specificity, and positive and negative predictive values between 92% and 100%. In venous blood of FM females between 6 and 35 years of age, MS-QMA correlated most strongly with verbal IQ impairment (P = 0.002). In the larger cohort of males and females, MS-QMA correlated with reference methods Southern blot and MALDI-TOF mass spectrometry (P < 0.05), but was not significantly correlated with age. Unmethylated alleles in high-functioning FM and PM males determined by both reference methods were also unmethylated by MS-QMA. MS-QMA has an immediate application in FXS diagnostics, with a potential use of its quantitative methylation output for prognosis in both sexes.


Smoking and children.
Tobacco use by children and adolescents is a major health threat. A number of carcinogens and other harmful compounds have been identified in tobacco smoke. The major component, nicotine, is highly addictive. In India, approximately 5500 children and adolescents start using tobacco products daily, some as young as 10 years old. The majority of users have first tried tobacco prior to age 18. Children and adolescents are exposed to the harmful effects of nicotine from smoking or second hand smoke from others; and from use of smokeless tobacco. There is increased prevalence of respiratory disease, ear and sinus infections, asthma, oral disease, and many long-term complications such as cardiovascular disease and cancers due to tobacco use. Prevention and treatment strategies include behavioural approaches and pharmacotherapy. There is an increased urgency especially, for countries like India to address the problem of tobacco use by children and adolescents as the tobacco industry faces legal and public opinion obstacles in Western countries like United States. The medical practitioner can play an important role by implementing the preventive and treatment strategies in his or her practice.


Crystal cluster growth and physical properties of the EuSbSe3 and EuBiSe3 phases.
Syntheses of europium metal, selenium powder, and the Sb(2)Se(3)/Bi(2)Se(3) binaries were observed to produce crystal clusters of the EuSbSe(3) and EuBiSe(3) phases. These phases crystallize with the P2(1)2(1)2(1) space group and can be easily identified based on their growth habits, forming large clusters of needles. Previous literature suggested that their structure is charge-balanced with all europium atoms in the divalent state and one-quarter of the selenium atoms forming trimers. Physical property measurements on a pure sample of EuSbSe(3) revealed typical Arrhenius-type electrical resistivity, being approximately 3 orders of magnitude too large for thermoelectric applications. Electronic structure calculations indicated that both EuSbSe(3) and EuBiSe(3) are narrow-band-gap semiconductors, in good agreement with the electrical resistivity data. The valence and conduction band states near the Fermi level are dominated by the Sb/Bi and Se p states, as expected given their small difference in electronegativity.


[Surgical treatment of chondroblastoma of bone].
During 10 years the authors were observing 22 chondroblastoma cases which constituted 0.8% of all the cases of bone tumors or 3.5% of all the observed cases of cartilaginous tumors of the skelton. The most of the patients were at the age under 20. All the patients were operated upon; marginal resection or excochleation of the tumor followed by the alloplasty were performed. The recurrence happened in 1 case only the follow-up has been lasting from 3 months to 10 years.


[Age-related characteristics of the human acromioclavicular joint].
By birth in the acromioclavicular joint the acromial end of the clavicle is osseous, and the acromion of the scapula is cartilaginous. The most intensive formation of the relief and configuration of the articular surfaces of the joint occurs from 1 to 3 years of age. In mature persons the form of the articular surface of the acromial end of the clavicle is often oval and that of the acromion of the scapula--ellipsoid. In newborns the areas of the articular surfaces are nearly equal. The area of the articular surface of the acromial end of the clavicle is significantly more than that of the acromion of the scapula during the periods from 1 to 3, from 13 to 17 and from 21 to 30 years of age. The articular cleft is revealed in the roentgenograms by 17 years of age, when synostosis process of the acromion of the scapula is completed. The thickness of the articular cartilage at different poles of the articular surfaces from birth up to 70 years of age is not equal and therefore it is possible to judge about nonequivalent functional loading on different areas of the articular cartilage. The articular cartilage of the acromial end of the clavicle from birth to 16 years of age is hyaline, after 17 years of age, they acquire the structure of the fibrous cartilage. In the articular cartilage of the acromion of the scapula, this rearrangement is realized more slowly: its fibrous structure is revealed after 23-24 years of age. Involutional changes in the joint are revealed during the fourth decade.(ABSTRACT TRUNCATED AT 250 WORDS)


In vitro hepatic differentiation of human umbilical cord blood and bone marrow cells.
The purpose of the present study was to investigate whether human umbilical cord blood (UCB) as well as bone marrow (BM) can generate hepatocyte lineage cells in a simple culture condition. Mononuclear cells (MNCs) separated from UCB and BM were cultured in the presence of fibroblast growth factor (FGF)-1, FGF-2, stem cell factor (SCF), and hepatocyte growth factor (HGF). The cultured cells were analyzed for morphology and for the expression of mRNAs and/or proteins of hepatocyte lineage markers. Both the UCB and BM MNCs grown in the given culture condition yielded large, round cells that were adherent to the culture dishes. RT-PCR analysis showed that mRNAs of albumin (ALB), cytokeratin (CK)-18, and alpha-fetoprotein were expressed from day 7 in both the UCB- and BM-derived cells. Immunofluorescent staining showed that the large, round cells expressed not only ALB and CK-19 but also proliferating cell nuclear antigen, implying the proliferative potential of hepatocyte lineage cells. Therefore, UCB as well as BM can give rise to hepatocyte lineage cells in the simple culture condition with HGF, SCF, FGF-1, and FGF-2. These cells may be one of the potential candidates of cell sources for the cytotherapy of hepatic disease, although it remains to be determined if the hepatocyte lineage cells are derived from plastic hematopoietic stem cells or from liver stem cells that reside in UCB or BM.


Transductive Transfer Learning for Domain Adaptation in Brain Magnetic Resonance Image Segmentation.
Segmentation of brain images from Magnetic Resonance Images (MRI) is an indispensable step in clinical practice. Morphological changes of sub-cortical brain structures and quantification of brain lesions are considered biomarkers of neurological and neurodegenerative disorders and used for diagnosis, treatment planning, and monitoring disease progression. In recent years, deep learning methods showed an outstanding performance in medical image segmentation. However, these methods suffer from generalisability problem due to inter-centre and inter-scanner variabilities of the MRI images. The main objective of the study is to develop an automated deep learning segmentation approach that is accurate and robust to the variabilities in scanner and acquisition protocols. In this paper, we propose a transductive transfer learning approach for domain adaptation to reduce the domain-shift effect in brain MRI segmentation. The transductive scenario assumes that there are sets of images from two different domains: (1) source-images with manually annotated labels; and (2) target-images without expert annotations. Then, the network is jointly optimised integrating both source and target images into the transductive training process to segment the regions of interest and to minimise the domain-shift effect. We proposed to use a histogram loss in the feature level to carry out the latter optimisation problem. In order to demonstrate the benefit of the proposed approach, the method has been tested in two different brain MRI image segmentation problems using multi-centre and multi-scanner databases for: (1) sub-cortical brain structure segmentation; and (2) white matter hyperintensities segmentation. The experiments showed that the segmentation performance of a pre-trained model could be significantly improved by up to 10%. For the first segmentation problem it was possible to achieve a maximum improvement from 0.680 to 0.799 in average Dice Similarity Coefficient (DSC) metric and for the second problem the average DSC improved from 0.504 to 0.602. Moreover, the improvements after domain adaptation were on par or showed better performance compared to the commonly used traditional unsupervised segmentation methods (FIRST and LST), also achieving faster execution time. Taking this into account, this work presents one more step toward the practical implementation of deep learning algorithms into the clinical routine.


Progressive Tandem Learning for Pattern Recognition With Deep Spiking Neural Networks.
Spiking neural networks (SNNs) have shown clear advantages over traditional artificial neural networks (ANNs) for low latency and high computational efficiency, due to their event-driven nature and sparse communication. However, the training of deep SNNs is not straightforward. In this paper, we propose a novel ANN-to-SNN conversion and layer-wise learning framework for rapid and efficient pattern recognition, which is referred to as progressive tandem learning. By studying the equivalence between ANNs and SNNs in the discrete representation space, a primitive network conversion method is introduced that takes full advantage of spike count to approximate the activation value of ANN neurons. To compensate for the approximation errors arising from the primitive network conversion, we further introduce a layer-wise learning method with an adaptive training scheduler to fine-tune the network weights. The progressive tandem learning framework also allows hardware constraints, such as limited weight precision and fan-in connections, to be progressively imposed during training. The SNNs thus trained have demonstrated remarkable classification and regression capabilities on large-scale object recognition, image reconstruction, and speech separation tasks, while requiring at least an order of magnitude reduced inference time and synaptic operations than other state-of-the-art SNN implementations. It, therefore, opens up a myriad of opportunities for pervasive mobile and embedded devices with a limited power budget.


Increased saturated fatty acids in obesity alter resolution of inflammation in part by stimulating prostaglandin production.
Extensive evidence indicates that nutrient excess associated with obesity and type 2 diabetes activates innate immune responses that lead to chronic, sterile low-grade inflammation, and obese and diabetic humans also have deficits in wound healing and increased susceptibility to infections. Nevertheless, the mechanisms that sustain unresolved inflammation during obesity remain unclear. In this study, we report that saturated free fatty acids that are elevated in obesity alter resolution of acute sterile inflammation by promoting neutrophil survival and decreasing macrophage phagocytosis. Using a targeted mass spectrometry-based lipidomics approach, we found that in db/db mice, PGE2/D2 levels were elevated in inflammatory exudates during the development of acute peritonitis. Moreover, in isolated macrophages, palmitic acid stimulated cyclooxygenase-2 induction and prostanoid production. Defects in macrophage phagocytosis induced by palmitic acid were mimicked by PGE2 and PGD2 and were reversed by cyclooxygenase inhibition or prostanoid receptor antagonism. Macrophages isolated from obese-diabetic mice expressed prostanoid receptors, EP2 and DP1, and contained significantly higher levels of downstream effector, cAMP, compared with wild-type mice. Therapeutic administration of EP2/DP1 dual receptor antagonist, AH6809, decreased neutrophil accumulation in the peritoneum of db/db mice, as well as the accumulation of apoptotic cells in the thymus. Taken together, these studies provide new insights into the mechanisms underlying altered innate immune responses in obesity and suggest that targeting specific prostanoid receptors may represent a novel strategy for resolving inflammation and restoring phagocyte defects in obese and diabetic individuals.


Polymorphism of alpha-estrogen receptor and aryl hydrocarbon receptor genes in dementia patients in Shanghai suburb.
To explore the possible association of different polymorphic forms of human alpha-estrogen receptor (ER-alpha) and aryl hydrocarbon receptor gene (Ahr) with the risk to senile dementia in farmers in Shanghai suburb. Senile dementia patients (n=52) were examined for ER-alpha and Ahr gene polymorphism genotyping. Healthy individuals (n=125) in the same area were selected as a community control group. Two polymorphic loci, Pvu II locus and Xba I locus, of human ER- a gene were investigated by a PCR-RFLP-based procedure. The population frequencies of two polymorphic loci in exon 10 of Ahr gene, G1721A (R554K) and G1768A (V570I) were compared between patients and healthy controls using an allele-specific PCR (AS-PCR) procedure. The mutant allele frequencies of ER-alpha gene in the AD group were significantly higher than those in the control group (P=0.023, OR=2.94, 95 % CI 1.13-7.71 for Pvu II locus; P=0.046, OR=2.28, 95 % CI 1.003-5.17 for Xba I locus). The mutant allele frequencies among female AD patients were higher than those in the female controls (P=0.016, OR=3.68, 95 % CI 1.22-11.08 for Pvu II locus, P=0.029, OR=2.95, 95 % CI 1.10-7.94 for Xba I locus). The mutant form, neither in the homozygous, nor in the heterozygous form was detected at the locus of Ahr G1768A in a normal local population. No significant difference of Ahr genotype frequency at locus G1721A was noticed between the patients and healthy individuals. The distribution of ER polymorphisms was significantly different between Chinese and some other ethnic populations. The results suggested that ER-alpha gene polymorphisms might be related to the individual susceptibility to AD, especially in the females. However, it did not support the association of Ahr gene polymorphism with higher risk of senile dementia.


Production of a signal by irradiated cells which leads to a response in unirradiated cells characteristic of initiation of apoptosis.
This study investigated the ability of medium from irradiated cells to induce early events in the apoptotic cascade, such as mobilization of intracellular calcium, loss of mitochondrial membrane potential and increase in reactive oxygen species, in cells which were never exposed to radiation. Medium from irradiated human keratinocytes was harvested and transferred to unirradiated keratinocytes. Endpoints characteristic of the initiation of apoptosis were monitored for a period of 24 h following medium transfer. Clonogenic survival was also measured. Rapid calcium fluxes (within 30 s), loss of mitochondrial membrane potential, increases in reactive oxygen species (from 6 h after medium transfer), an increase in the number of apoptotic cells (48 hours after medium transfer) and a marked reduction in clonogenic survival (after 9 days) were observed. There was no significant difference between medium generated by cells irradiated at 0.5 Gy or 5 Gy. The data suggest that initiating events in the apoptotic cascade were induced in unexposed cells by a signal produced by irradiated cells.


Evaluation of the effect of signalment and body conformation on activity monitoring in companion dogs.
To evaluate the effect of signalment and body conformation on activity monitoring in companion dogs. 104 companion dogs. While wearing an activity monitor, each dog was led through a series of standard activities: lying down, walking laps, trotting laps, and trotting up and down stairs. Linear regression analysis was used to determine which signalment and body conformation factors were associated with activity counts. There was no significant effect of signalment or body conformation on activity counts when dogs were lying down, walking laps, and trotting laps. However, when dogs were trotting up and down stairs, there was a significant effect of age and body weight such that, for every 1-kg increase in body weight, there was a 1.7% (95% confidence interval, 1.1% to 2.4%) decrease in activity counts and for every 1-year increase in age, there was a 4.2% (95% confidence interval, 1.4% to 6.9%) decrease in activity counts. When activity was well controlled, there was no significant effect of signalment or body conformation on activity counts recorded by the activity monitor. However, when activity was less controlled, older dogs and larger dogs had lower activity counts than younger and smaller dogs. The wide range in body conformation (eg, limb or body length) among dogs did not appear to significantly impact the activity counts recorded by the monitor, but age and body weight did and must be considered in analysis of data collected from the monitors.


Sizing up the future of microRNA analysis.
In less than 20 years, our appreciation for micro-RNA molecules (miRNAs) has grown from an original, curious observation in worms to their current status as incredibly important global regulators of gene expression that play key roles in many transformative biological processes. As our understanding of these small, non-coding transcripts continues to evolve, new approaches for their analysis are emerging. In this critical review we describe recent improvements to classical methods of detection as well as innovative new technologies that are poised to help shape the future landscape of miRNA analysis.


Lorazepam vs diazepam for pediatric status epilepticus: a randomized clinical trial.
Benzodiazepines are considered first-line therapy for pediatric status epilepticus. Some studies suggest that lorazepam may be more effective or safer than diazepam, but lorazepam is not Food and Drug Administration approved for this indication. To test the hypothesis that lorazepam has better efficacy and safety than diazepam for treating pediatric status epilepticus. This double-blind, randomized clinical trial was conducted from March 1, 2008, to March 14, 2012. Patients aged 3 months to younger than 18 years with convulsive status epilepticus presenting to 1 of 11 US academic pediatric emergency departments were eligible. There were 273 patients; 140 randomized to diazepam and 133 to lorazepam. Patients received either 0.2 mg/kg of diazepam or 0.1 mg/kg of lorazepam intravenously, with half this dose repeated at 5 minutes if necessary. If status epilepticus continued at 12 minutes, fosphenytoin was administered. The primary efficacy outcome was cessation of status epilepticus by 10 minutes without recurrence within 30 minutes. The primary safety outcome was the performance of assisted ventilation. Secondary outcomes included rates of seizure recurrence and sedation and times to cessation of status epilepticus and return to baseline mental status. Outcomes were measured 4 hours after study medication administration. Cessation of status epilepticus for 10 minutes without recurrence within 30 minutes occurred in 101 of 140 (72.1%) in the diazepam group and 97 of 133 (72.9%) in the lorazepam group, with an absolute efficacy difference of 0.8% (95% CI, -11.4% to 9.8%). Twenty-six patients in each group required assisted ventilation (16.0% given diazepam and 17.6% given lorazepam; absolute risk difference, 1.6%; 95% CI, -9.9% to 6.8%). There were no statistically significant differences in secondary outcomes except that lorazepam patients were more likely to be sedated (66.9% vs 50%, respectively; absolute risk difference, 16.9%; 95% CI, 6.1% to 27.7%). Among pediatric patients with convulsive status epilepticus, treatment with lorazepam did not result in improved efficacy or safety compared with diazepam. These findings do not support the preferential use of lorazepam for this condition. clinicaltrials.gov Identifier: NCT00621478.


Adiposity and insulin resistance correlate with telomere length in middle-aged Arabs: the influence of circulating adiponectin.
Studies in obesity have implicated adipocytokines in the development of insulin resistance, which in turn may lead to accelerated aging. In this study, we determined associations of chromosomal telomere length (TL) to markers of obesity and insulin resistance in middle-aged adult male and female Arabs with and without diabetes mellitus type 2 (DMT2). One hundred and ninety-three non-diabetic and DMT2 subjects without complications (97 males and 96 females) participated in this cross-sectional study. Clinical data, as well as fasting blood samples, were collected. Serum glucose and lipid profile were determined using routine laboratory methods. Serum insulin, leptin, adiponectin, resistin, tumor necrosis factor-α, and PAI-1 were quantified using customized multiplex assay kits. High sensitive C-reactive protein (hsCRP) and angiotensin II (ANG II) were measured using ELISAs. Circulating leukocyte TL was examined by quantitative real-time PCR. Circulating chromosomal leukocyte TL had significant inverse associations with body mass index (BMI), systolic blood pressure, fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), low-density lipoprotein (LDL)- and total cholesterol, ANG II and hsCRP levels. Adiponectin, BMI, systolic blood pressure, and LDL cholesterol predicted 47% of the variance in TL (P<0.0001). HOMA-IR was the most significant predictor for TL in males, explaining 35% of the variance (P=0.01). In females, adiponectin accounted for 28% of the variance in TL (P=0.01). Obesity and insulin resistance are associated with chromosomal TL among adult Arabs. Evidence of causal relations needs further investigation. The positive association of adiponectin to TL has clinical implications as to the possible protective effects of this hormone from accelerated aging.


Ossifying fibroma of the inferior turbinate.
Hypertrophy of inferior turbinate is a common condition, especially with nasal septum deviation. Sometimes, the cause of hypertrophy of inferior turbinate can be fibro-osseous lesions. Benign, rare, and non-aggressive fibro-osseous neoplasms such as ossifying fibroma can affect paranasal sinuses. Isolated inferior turbinate involvement is extremely rare in ossifying fibroma. In this article, we present a 28-year-old female suffering from nasal obstruction due to septal deviation and hypertrophy of inferior turbinate. Preoperative and postoperative investigation show that cause of hypertrophy of inferior turbinate is ossifying fibroma. To our knowledge, that this is the second case of ossifying fibroma reported in the English-language literature due to its isolated localization. However, if the patients with inferior turbinate hypertrophy are examined carefully, we can prevent unnecessary medical treatment and surgery for inferior turbinate hypertrophy.


Pregnancy intention and preterm birth: differential associations among a diverse population of women.
Studies published to date provide mixed evidence on the relationship between unintended pregnancy and preterm birth, and none take into consideration that the meaning of unintended pregnancy may vary across racial and ethnic groups. Data from the 1999-2003 rounds of the Maternal and Infant Health Assessment, a population-based, representative survey of postpartum women in California, were used to assess the relationship between pregnancy intention and preterm birth. For racial and ethnic groups in which an association was found, sequential logistic regression was conducted to further examine the relationship while controlling for socioeconomic characteristics. In unadjusted results, pregnancy intention was associated with preterm birth among both whites and immigrant Latinas, but not among blacks or U.S.-born Latinas. Among whites, compared with women who reported that their pregnancy was intended, those who were unsure about their pregnancy had elevated odds of preterm birth (odds ratio, 1.4), as did those who reported their pregnancy was unwanted (1.7) or mistimed (1.4). Among immigrant Latinas, those who reported being unsure about their pregnancy were at higher risk of preterm birth than were those who reported an intended pregnancy (1.6). After adjustment for socioeconomic factors, the association remained significant for immigrant Latinas who were unsure about their pregnancy (1.5), but none of the associations remained significant for whites. Women's interpretations of questions about pregnancy intention and their social experiences regarding pregnancy intention may vary by race or ethnicity. Studies on the association between pregnancy intention and preterm birth may need to be group-specific.


Neighborhood based Levenberg-Marquardt algorithm for neural network training.
Although the Levenberg-Marquardt (LM) algorithm has been extensively applied as a neural-network training method, it suffers from being very expensive, both in memory and number of operations required, when the network to be trained has a significant number of adaptive weights. In this paper, the behavior of a recently proposed variation of this algorithm is studied. This new method is based on the application of the concept of neural neighborhoods to the LM algorithm. It is shown that, by performing an LM step on a single neighborhood at each training iteration, not only significant savings in memory occupation and computing effort are obtained, but also, the overall performance of the LM method can be increased.


Densification Induced Decoupling of Electrical and Thermal Properties in Free-Standing MWCNT Films for Ultrahigh p- and n-Type Power Factors and Enhanced ZT.
Generating sufficient power from waste heat is one of the most important things for thermoelectric (TE) techniques in numerous practical applications. The output power density of an organic thermoelectric generator (OTEG) is proportional to the power factors (PFs) and the electrical conductivities of organic materials. However, it is still challenging to have high PFs over 1 mW m-1 K-2 in free-standing films together with high electrical conductivities over 1000 S cm-1 . Herein, densifying multi-walled carbon nanotube (MWCNT) films would increase their electrical conductivity dramatically up to over 10 000 S cm-1 with maintained high Seebeck coefficients >60 µV K-1 , thus leading to ultrahigh PFs of 7.25 and 4.34 mW m-1 K-2 for p- and n-type MWCNT films, respectively. In addition, it is interesting to notice that the electrical properties increase faster than the thermal conductivities, resulting in enhanced ZT of 3.6 times in MWCNT films. An OTEG made of compressed MWCNT films is fabricated to demonstrate the heat-to-electricity conversion ability, which exhibits a high areal output power of ∼12 times higher than that made of pristine MWCNT films. This work demonstrates an effective way to high-performance nanowire/nanoparticle-based TE materials such as printable TE materials comprised of nanowires/nanoparticles.


Enhanced Li-ion transport in divalent metal-doped Li2SnO3.
The improvement of Li-ion transport properties and doping engineering in Li-ion batteries are currently active research topics in the search for next-generation energy storage devices. In this theoretical work, the intrinsic defect formation and transport properties of divalent metal-doped Li2SnO3, which is being considered as an electrode and coating electrode material, are explored using atomistic simulations. Defect formation simulations reveal that all divalent dopants (Zn, Sc, Cd and Eu) occupy the Li site with charge compensation through Li vacancies. Molecular dynamics simulations show that the divalent dopants significantly reduce the activation energy for ionic diffusion and conduction compared to the undoped sample. The effects of both grains and grain boundaries on the Li-ion transport properties are investigated. Our calculated results demonstrate a marked improvement in the properties of Li2SnO3 that can be achieved either in current commercial and next-generation Li-ion battery technologies through divalent doping in mono- and polycrystalline Li2SnO3 samples.


C3 glomerulonephritis and autoimmune disease: more than a fortuitous association?
C3 glomerulonephritis (C3GN) results from genetic or acquired dysregulation of the alternative complement pathway. A subset of patients may have clinical and biochemical characteristics compatible with an autoimmune disorder. We studied a cohort of 85 patients with confirmed C3GN (2007-2014), of which ten patients (3 male, 7 female; mean age 38.5 years) had an associated autoimmune disorder. All patients had abnormal ANA titers, 6 also had positive ds-DNA titers. At the time of presentation with C3GN, all 7 female patients had autoimmune-related presentations. Of the 3 male patients, only 1 patient had autoimmune-related presentations. Kidney biopsy showed predominantly mesangial proliferative or membranoproliferative glomerulonephritis. In 5 patients, the alternative pathway was evaluated. All had allele variants/polymorphisms associated with C3GN. One patient was also positive for C3Nefs. Treatment varied form conservative management to the use of prednisone alone or with cytotoxic therapy. Mean serum creatinine decreased from 2.0 to 1.4 mg/dL while proteinuria decreased from 2300 to 994 mg/24 h in 8 patients with follow-up. The study highlights the association between C3GN and autoimmune disorders, particularly in female patients. The study suggests that an autoimmune milieu may act as a trigger for the development of C3GN in genetically susceptible patients. Short-term prognosis of C3GN associated with autoimmune disorders appears excellent.


Reciprocity and social capital in sibling relationships of people with disabilities.
Sibling relationships are some of the longest-lasting relationships people experience, providing ample opportunities to build connections across the life span. For siblings and people with intellectual and developmental disabilities (IDD), these connections take on an increased significance as their families age and parents can no longer provide care. This article presents findings from a qualitative study that addresses the question, "How do siblings support each other after parents no longer can provide care to the person with IDD?" Findings in this study suggest that siblings with and without disabilities experience reciprocity as a transitive exchange, which occurs through the creation of social capital in their families and community, and that nondisabled siblings mobilize their social capital to provide support to their sibling after parents pass away. Implications for future research as well as policy and practice are discussed.


The importance of prolonged incubation for the synthesis of dimethylnitrosamine by enterobacteria.
Tests with 140 strains representing Escherichia coli, Klebsiella aerogenes, K. ozaenae, Proteus mirabilis, P. vulgaris, P. rettgeri and P. morganii in a defined medium supplemented with 0-09M dimethylamine (DMA) and 0-1M potassium nitrate showed that at least 89% of the 136 strains able to reduce nitrates produced up to 9mM dimethylnitrosamine (DMN) in 70h at 37 degrees C. Four nitratase-negative strains produced DMN from DMA in the presence of sodium nitrate. Prolonged incubation was the most important factor in determining DMN production. Stasis and persistent infection in the urinary tract, by simulating prolonged incubation of a culture, may be of importance in determining whether the potential carcinogen, DMN, could be produced in vivo by bacterial action on DMA and nitrate in urine.


How do small groups make decisions? : A theoretical framework to inform the implementation and study of clinical competency committees.
In the competency-based medical education (CBME) approach, clinical competency committees are responsible for making decisions about trainees' competence. However, we currently lack a theoretical model for group decision-making to inform this emerging assessment phenomenon. This paper proposes an organizing framework to study and guide the decision-making processes of clinical competency committees.This is an explanatory, non-exhaustive review, tailored to identify relevant theoretical and evidence-based papers related to small group decision-making. The search was conducted using Google Scholar, Web of Science, MEDLINE, ERIC, and PsycINFO for relevant literature. Using a thematic analysis, two researchers (SC & JP) met four times between April-June 2016 to consolidate the literature included in this review.Three theoretical orientations towards group decision-making emerged from the review: schema, constructivist, and social influence. Schema orientations focus on how groups use algorithms for decision-making. Constructivist orientations focus on how groups construct their shared understanding. Social influence orientations focus on how individual members influence the group's perspective on a decision. Moderators of decision-making relevant to all orientations include: guidelines, stressors, authority, and leadership.Clinical competency committees are the mechanisms by which groups of clinicians will be in charge of interpreting multiple assessment data points and coming to a shared decision about trainee competence. The way in which these committees make decisions can have huge implications for trainee progression and, ultimately, patient care. Therefore, there is a pressing need to build the science of how such group decision-making works in practice. This synthesis suggests a preliminary organizing framework that can be used in the implementation and study of clinical competency committees.


Risk factors for chronic anemia in pediatric orthotopic liver transplantation: analysis of data from the SPLIT registry.
Risk factors for chronic anemia in the post-transplant period have not been clearly delineated in pediatric liver transplant recipients. We analyzed data from children transplanted from 2000 to 2008 with at least two consecutive hemoglobin values from follow-up between six months and five yr post-transplant. A multivariate model was derived to determine independent risk factors associated with chronic anemia. Of 1026 children in this analysis, 242 (23.6%) were found to have chronic anemia. On multivariate analysis, GI bleeding (OR 11.83 [2.08-67.49], p = 0.0054), presence of leukopenia (OR 9.55 [95% CI 3.71-24.62], p < 0.0001), use of cyclosporine (OR 3.69, [95% CI 1.56-8.76], p = 0.0039) and corticosteroids (OR 2.90 [95% CI 1.94-4.33], p < 0.0001), and cGFR <90 mL/min/1.73 m(2) (OR 4.62 [95% CI 2.47-8.67], p < 0.0001) represented the most significant risk factors for chronic anemia. Use of antihypertensive medications (OR 1.89 [95% CI 1.23-2.91], p = 0.0039) was also significantly associated with a higher risk. In summary, chronic anemia is common in children following liver transplant. Our findings underscore the need to define the mechanisms by which these risk factors, some of which are modifiable, result in chronic anemia in pediatric liver transplant recipients.


Polyphenols: well beyond the antioxidant capacity: gallic acid and related compounds as neuroprotective agents: you are what you eat!
Gallic acid (3,4,5-trihydroxybenzoic acid) is a phenolic acid widely distributed in many different families of higher plants, both in free state, and as a part of more complex molecules, such as ester derivatives or polymers. In nature, gallic acid and its derivatives are present in nearly every part of the plant, such as bark, wood, leaf, fruit, root and seed. They are present in different concentrations in common foodstuffs such as blueberry, blackberry, strawberry, plums, grapes, mango, cashew nut, hazelnut, walnut, tea, wine and so on. After consumption, about 70% of gallic acid is adsorbed and then excreted in the urine as 4-O-methylgallic acid. Differently, the ester derivatives of gallic acid, such as catechin gallate ester or gallotannins, are hydrolyzed to gallic acid before being metabolized to methylated derivatives. Gallic acid is a well known antioxidant compounds which has neuroprotective actions in different models of neurodegeneration, neurotoxicity and oxidative stress. In this review, we discuss about the neuroprotective actions of gallic acid and derivatives and their potential mechanisms of action.


X-ray absorption and natural circular dichroism spectra of C84: A theoretical study using the complex polarization propagator approach.
The x-ray absorption and circular dichroism K-edge spectra for the D(2)-isomer of C(84) have been determined using the complex polarization propagator method in conjunction with Kohn-Sham density functional theory. The circular dichroism spectrum is rich in details and, in comparison to the absorption spectrum, it provides a superior resolution of the electronic transitions below the ionization threshold.


The role of clockwork orange in the circadian clock of the cricket Gryllus bimaculatus.
The circadian clock generates rhythms of approximately 24 h through periodic expression of the clock genes. In insects, the major clock genes period (per) and timeless (tim) are rhythmically expressed upon their transactivation by CLOCK/CYCLE, with peak levels in the early night. In Drosophila, clockwork orange (cwo) is known to inhibit the transcription of per and tim during the daytime to enhance the amplitude of the rhythm, but its function in other insects is largely unknown. In this study, we investigated the role of cwo in the clock mechanism of the cricket Gryllus bimaculatus. The results of quantitative RT-PCR showed that under a light/dark (LD) cycle, cwo is rhythmically expressed in the optic lobe (lamina-medulla complex) and peaks during the night. When cwo was knocked down via RNA interference (RNAi), some crickets lost their locomotor rhythm, while others maintained a rhythm but exhibited a longer free-running period under constant darkness (DD). In cwoRNAi crickets, all clock genes except for cryptochrome 2 (cry2) showed arrhythmic expression under DD; under LD, some of the clock genes showed higher mRNA levels, and tim showed rhythmic expression with a delayed phase. Based on these results, we propose that cwo plays an important role in the cricket circadian clock.


Minireview: The sodium-iodide symporter NIS and pendrin in iodide homeostasis of the thyroid.
Thyroid hormones are essential for normal development and metabolism. Thyroid hormone biosynthesis requires iodide uptake into the thyrocytes and efflux into the follicular lumen, where it is organified on selected tyrosyls of thyroglobulin. Uptake of iodide into the thyrocytes is mediated by an intrinsic membrane glycoprotein, the sodium-iodide symporter (NIS), which actively cotransports two sodium cations per each iodide anion. NIS-mediated transport of iodide is driven by the electrochemical sodium gradient generated by the Na(+)/K(+)-ATPase. NIS is expressed in the thyroid, the salivary glands, gastric mucosa, and the lactating mammary gland. TSH and iodide regulate iodide accumulation by modulating NIS activity via transcriptional and posttranscriptional mechanisms. Biallelic mutations in the NIS gene lead to a congenital iodide transport defect, an autosomal recessive condition characterized by hypothyroidism, goiter, low thyroid iodide uptake, and a low saliva/plasma iodide ratio. Pendrin is an anion transporter that is predominantly expressed in the inner ear, the thyroid, and the kidney. Biallelic mutations in the SLC26A4 gene lead to Pendred syndrome, an autosomal recessive disorder characterized by sensorineural deafness, goiter, and impaired iodide organification. In thyroid follicular cells, pendrin is expressed at the apical membrane. Functional in vitro data and the impaired iodide organification observed in patients with Pendred syndrome support a role of pendrin as an apical iodide transporter.


Efficacy of injection immunotherapy with ragweed and birch pollen in elderly patients.
The role of specific immunotherapy (SIT) in elderly allergic patients is still debated. The aim of this study was to assess whether SIT is associated with a better control of symptoms and a better quality of life also in older allergic patients. The effect of injection SIT was assessed in 39 patients [age >54 years, median 59; 29 patients (74%) with asthma, otherwise healthy] monosensitized to birch (n = 20) and ragweed (n = 19). Thirty-three younger subjects [age <50 years, median 35; 26 patients (79%) with asthma, otherwise healthy] monosensitized to birch (n = 10) and ragweed (n = 23), and 37 subjects >54 years old (25 males/12 females; age 55-79 years, median 59 years) monosensitized to birch (n = 18) and ragweed (n = 19) who refused to undergo SIT were enrolled as positive and negative controls, respectively. All groups had a disease duration <10 years; the disease was inadequately controlled with standard drug therapies in all cases. SIT was carried out using the same extracts and was administered using a perennial schedule both in patients and controls. Seasonal therapies were the same in all groups and were not changed after SIT was started. After 1-5 years of SIT, patients and controls were asked to quantify symptom reduction on a visual analogue scale: reductions >50% were considered significant. Moreover, the use of cetirizine and/or salbutamol as an adjunct to standard therapies during the last pollen season was assessed as an objective measure of SIT outcome. 37/39 (95%) patients versus 32/33 (97%) controls submitted to SIT reported a symptom reduction >50% after 1-5 years of SIT (nonsignificant). The median clinical efficacy of SIT was 80% in both groups (nonsignificant). 27/37 controls not submitted to SIT did not report any change in symptom severity at the follow-up visits, whereas 10/37 reported a more severe disease (4 subjects reported the appearance of seasonal asthma) (p < 0.001 vs. patients submitted to SIT). Patients used less frequently cetirizine (p < 0.001) and/or salbutamol (p < 0.05) than controls not submitted to SIT. Injection SIT can be considered an effective therapeutic option in otherwise healthy elderly patients with a short disease duration whose symptoms cannot be adequately controlled by drug therapies alone.


WEB Treatment of Ruptured Intracranial Aneurysms: Long-Term Follow-up of a Single-Center Cohort of 100 Patients.
The Woven EndoBridge device (WEB) was introduced for the intrasaccular treatment of wide-neck aneurysms without the need for adjunctive devices. We used the WEB as a primary treatment for 100 ruptured aneurysms regardless of neck size or location. In this study, we present the long-term follow-up of 78 surviving patients. Between February 2015 and April 2017, one hundred ruptured aneurysms were treated with the WEB. For surviving patients, angiographic and clinical follow-up was scheduled at 3 months, and 3T MRA and clinical follow-up, at 6, 12, 36, and 60 months. Of 100 patients, 18 died during hospital admission, and in 4, the ruptured aneurysm was additionally treated. The remaining 78 patients had a mean follow-up of 51 months (median, 52 months; range, 5-84 months). There were 57 women and 21 men, with a mean age of 58.5 years (median, 59 years; range, 24-80 years). Of 78 aneurysms with long-term follow-up, 52 (66%) had a wide neck. Of 78 ruptured aneurysms, 56 (72%) remained completely occluded and 17 (22%) had a stable small neck remnant. Five of 78 aneurysms (6%; 95% CI, 2.4%-14.5%) reopened during follow-up and were additionally treated. There were no rebleeds during follow-up. Treatment of ruptured aneurysms with the WEB was safe and effective and has long-term results comparable with those of simple coiling of small-neck aneurysms. The WEB proved to be a valuable alternative to coils for both wide- and small-neck ruptured aneurysms without the need for stents, balloons, or antiplatelet therapy.


Serine racemase regulated by binding to stargazin and PSD-95: potential N-methyl-D-aspartate-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (NMDA-AMPA) glutamate neurotransmission cross-talk.
D-Serine, an endogenous co-agonist for the glycine site of the synaptic NMDA glutamate receptor, regulates synaptic plasticity and is implicated in schizophrenia. Serine racemase (SR) is the enzyme that converts L-serine to D-serine. In this study, we demonstrate that SR interacts with the synaptic proteins, postsynaptic density protein 95 (PSD-95) and stargazin, forming a ternary complex. SR binds to the PDZ3 domain of PSD-95 through the PDZ domain ligand at its C terminus. SR also binds to the C terminus of stargazin, which facilitates the cell membrane localization of SR and inhibits its activity. AMPA receptor activation internalizes SR and disrupts its interaction with stargazin, therefore derepressing SR activity, leading to more D-serine production and potentially facilitating NMDA receptor activation. These interactions regulate the enzymatic activity as well as the intracellular localization of SR, potentially coupling the activities of NMDA and AMPA receptors. This shuttling of a neurotransmitter synthesizing enzyme between two receptors appears to be a novel mode of synaptic regulation.


A distinct death mechanism is induced by 1-methyl-4-phenylpyridinium or by 6-hydroxydopamine in cultured rat cortical neurons: degradation and dephosphorylation of tau.
We examined whether the well-known neurotoxins 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium ion (MPP(+)) recruit distinct cell death mechanisms using primary cultured neurons derived from day 16 embryonic rat cortices. Electron microscopy revealed that cell death induced by both 6-OHDA and MPP(+) was typified by a condensation of chromatin while prominent mitochondrial swelling was observed only in those cells treated with MPP(+). Co-treatment of cells with a pan-caspase inhibitor, Z-VAD-fmk, attenuated 6-OHDA-induced chromatin condensation and neuronal death. Co-treatment with such antioxidants as N-acetylcysteine or Mn-TBAP also suppressed 6-OHDA-induced cell death. None of these treatments attenuated MPP(+)-induced cell death although caspase inhibition abolished MPP(+)-induced chromatin condensation. Interestingly, in these paradigms of cell death, the N-terminus of tau was specifically cleaved and the levels of phosphorylated tau were markedly decreased following 6-OHDA treatment. By contrast, the C-terminus of tau was cleaved in MPP(+)-induced cell death while the levels of phosphorylated tau remained largely unaltered. Taken together, our results indicate that distinct cellular mechanisms appear to underlie neurotoxin-induced cortical neuronal cell death.


Reduced accuracy accompanied by reduced neural activity during the performance of an emotional conflict task by unmedicated patients with major depression: A CAN-BIND fMRI study.
We studied 48 MDD and 30 HC who performed an emotional conflict task in a functional magnetic resonance imaging (fMRI) scanner. On the emotional conflict task, MDD and HC demonstrated a robust emotional Stroop effect in reaction time and accuracy. Overall, accuracy was lower in MDD compared to HC with no significant reaction time differences. The fMRI data indicated lower BOLD activation in MDD compared to HC on comparisons of all trials, congruent, incongruent, and incongruent > congruent trials in regions including right inferior temporal gyrus, lateral occipital cortex, and occipital fusiform gyrus. Behavioural and neuroimaging data indicated no group differences in fearful versus happy face processing. Inclusion of a neutral condition may have provided a valuable contrast to how MDD and HC process stimuli without emotional valence compared to stimuli with a strong emotional valence. MDD and HC demonstrated a robust emotional Stroop effect. Compared to HC, MDD demonstrated an overall reduced accuracy on the emotional conflict task and reduced BOLD activity in regions important for face perception and emotion information processing, with no differences in responding to fearful versus happy faces. These findings provide support for the theory of emotion context insensitivity in individuals with depression.


Measuring personality and emotional functioning in multiple sclerosis: a cautionary note.
Changes in personality and emotional status are common in individuals with multiple sclerosis (MS). The purpose of this study was to examine results based on the MMPI-2 before and following application of a statistical correction procedure (Gass, 1992). This was done to help determine changes in scale score elevations when items containing actual physical symptoms are identified and statistically removed. Twenty-eight participants with MS were administered the MMPI-2, then retested 1 year later. Stability of MMPI-2 scores over time was demonstrated. Results showed that when the correction procedure was applied to the MMPI-2, eight standard clinical scale scores dropped an average of 6.66 T-score points. Significant differences were obtained between standard MMPI-2 scored profiles and corrected profiles on Scales 1-3 and 8. Cautious interpretation of MMPI-2 results for neurological samples was indicated. This study extended prototypic research by using patients with MS, examining the stability of results over time (1 year), and introducing a more reliable method of deriving standard T-scores in the correction procedure.


Ovarian Reserve Assessed by the Anti-Mullerian Hormone and Reproductive Health Parameters in Women With Crohn´s Disease, a Case-Control Study.
According to several studies, women with Crohn's disease (CD) had reduced fertility, which is mostly due to voluntary decisions and reduced ovarian reserve. In our study, we aimed to compare reproductive health parameters (RHP), previous pregnancy complications and outcomes, and ovarian reserve (OR) assessed by the anti-Mullerian hormone (AMH) in CD patients with healthy controls. In CD patients, we also compared OR according to disease phenotypes. Consecutive pre-menopausal women with CD from two IBD centers were included. The control group consisted of age and BMI-matched healthy controls. We used a questionnaire that included RHP, CD phenotype, and CD activity. Serum AMH was assessed by the Elecsys AMH plus essay. We enrolled 50 patients and 56 controls with a median age of 31 years. All CD patients were in clinical remission. We observed no difference in RHP or AMH (median 2.6 vs. 2.1 ug/l, p = 0.98), or the proportion of low OR (AMH<1,77, 38 vs. 41.1 %, p=0.84). The slope of age-related decrease did not differ between the groups. The subgroup of CD patients after surgery and those older than 30 years with CD for >5years had a steeper decrease in AMH (slope -0.12 vs. -0.29, p = 0.04 and -0.31 vs. -0.2, p = 0.029). In a multivariate analysis, age was the single independent predictor of low OR (OR=1.25). In women with Crohn's disease, once the disease activity is under control, the reproductive health and ovarian reserve do not substantially differ from healthy controls.


Prevalence and spectrum of electroencephalogram-identified epileptiform activity among patients with long QT syndrome.
Congenital long QT syndrome (LQTS) is a heritable cardiac disease whereby patients are at an increased risk for LQTS-triggered syncope, seizures, and sudden cardiac arrest. Seizure episodes are common in LQTS and most often seen in patients with type 2 LQTS (LQT2). To determine the prevalence of electroencephalogram (EEG)-identified epileptiform activity among patients with LQTS. A retrospective electronic medical record review of 610 patients with LQTS (250 [41%] men), evaluated between 2000 and 2012, was performed to identify (1) all patients with LQTS who presented with seizures/seizure-like episodes, (2) patients with LQTS who underwent a subsequent neurologic evaluation and EEG study, and (3) patients with LQTS and abnormal EEG recordings that showed epileptiform activity during sinus rhythm, confirming a seizure independent from cardiac arrhythmia. Overall, seizures/seizure-like episodes were recorded in 68 of 610 (11%) patients with LQTS. Ten patients were diagnosed with a seizure disorder by an epileptologist on the basis of the clinical findings and EEG studies, giving a prevalence of 10 of 610 (1.6%; 95% confidence interval 0.8%-3%) among patients with LQTS. A diagnosis of epilepsy was overrepresented in patients with LQT2 (7 of 190 [3.7%]) in comparison to all other LQT subgroups (3 of 420 [0.7%]; P = .0126). While the overall prevalence of epilepsy among patients with LQTS is low, 10 of 68 (15%) of the patients who presented with seizures/seizure-like episodes had EEG-identified epileptiform activity. Confirming earlier observational reports, epilepsy is more common in patients with LQT2, further supporting the shared pathogenetic link hypothesis of this KCNH2-encoded potassium channel that is expressed in both the heart and the brain.


Interplay between PTB and miR-1285 at the p53 3'UTR modulates the levels of p53 and its isoform Δ40p53α.
p53 and its translational isoform Δ40p53 are involved in many important cellular functions like cell cycle, cell proliferation, differentiation and metabolism. Expression of both the isoforms can be regulated at different steps. In this study, we explored the role of 3'UTR in regulating the expression of these two translational isoforms. We report that the trans acting factor, Polypyrimidine Tract Binding protein (PTB), also interacts specifically with 3'UTR of p53 mRNA and positively regulates expression of p53 isoforms. Our results suggest that there is interplay between miRNAs and PTB at the 3'UTR under normal and stress conditions like DNA damage. Interestingly, PTB showed some overlapping binding regions in the p53 3'UTR with miR-1285. In fact, knockdown of miR-1285 as well as expression of p53 3'UTR with mutated miR-1285 binding sites resulted in enhanced association of PTB with the 3'UTR, which provides mechanistic insights of this interplay. Taken together, the results provide a plausible molecular basis of how the interplay between miRNAs and the PTB protein at the 3'UTR can play pivotal role in fine tuning the expression of the two p53 isoforms.


Experimental infection of chickens with an atypical Mycoplasma gallisepticum strain: comparison of diagnostic methods.
Fifteen chickens were inoculated with the atypical Mycoplasma gallisepticum (MG) K703 strain. On different dates post inoculation, tracheal swab samples were collected for mycoplasma culture and blood samples were analysed by slide agglutination test (SA) with commercial or homologous antigen and enzyme-linked immunosorbent assay (ELISA) with three different kits. Results showed that MG isolation rate was low on several sampling dates. The SA with commercial antigen did not yield positive results, although birds were positive when tested with homologous antigen. With commercial ELISA kits, the numbers of positive samples remained low. These results illustrate the difficulty of diagnosis of infections with such MG variant strains.


Cash and in-kind transfers lead to excess weight gain in a population of women with a high prevalence of overweight in rural Mexico.
There is a growing concern that food or cash transfer programs may contribute to overweight and obesity in adults. We studied the impact of Mexico's Programa de Apoyo Alimentario (PAL), which provided very poor rural households with cash or in-kind transfers, on women's body weight. A random sample of 208 rural communities in southern Mexico was randomly assigned to 1 of 4 groups: food basket with or without health and nutrition education, cash with education, or control. The impact on women's weight was estimated in a cohort of 3010 women using a difference-in-difference model. We compared the impact between the food basket and cash groups and evaluated whether the impact was modified by women's BMI status at baseline. With respect to the control group, the program increased women's weight in the food basket (550 ± 210 g; P = 0.004) and the cash group (420 ± 230 g; P = 0.032); this was equivalent to 70 and 53% increases in weight gain, respectively, over that observed in the control group in a 23-mo time period. The greatest impact was found in already obese women: 980 ± 290 g in the food basket group (P = 0.001) and 670 ± 320 g in the cash group (P = 0.019). Impact was marginally significant in women with a preprogram BMI between 25 and 30 kg/m2: 490 ± 310 g (P = 0.055) and 540 ± 360 g (P = 0.067), respectively. No program impact was found in women with a BMI <25 kg/m2. Providing households with a considerable amount of unrestricted resources led to excess weight gain in an already overweight population. Research is needed to develop cost-effective behavior change communication strategies to complement cash and in-kind transfer programs such as PAL and to help beneficiaries choose healthy diets that improve the nutritional status of all family members.


Improving the well-being for young people living with rheumatic heart disease: A peer support pilot program through Danila Dilba Health Service.
Aboriginal and Torres Strait Islander peoples in Australia have an inequitable burden of acute rheumatic fever (ARF) and rheumatic heart disease (RHD), concentrated among young people and necessitating ongoing medical care during adolescence. There is an unmet need for improved well-being and support for these young people to complement current biomedical management. This pilot program initiative aimed to determine the suitability and appropriate format of an ongoing peer support program to address the needs of young people living with RHD in urban Darwin. Five participants took part in three sessions. Findings demonstrated the peer-support setting was conducive to offering support and enabled participants to share their experiences of living with RHD with facilitators and each other. Satisfaction rates for each session, including both educational components and support activities, were high. Learnings from the pilot program can inform the following elements of an ongoing peer-support program: characteristics of co-facilitators and external presenters; program format and session outlines; possible session locations; and resourcing. SO WHAT?: Peer support programs for chronic conditions have demonstrated a wide range of benefits including high levels of satisfaction by participants, improved social and emotional well-being and reductions in patient care time required by health professionals. This pilot program demonstrates the same benefits could result for young people living with RHD.


Unconventional face-on texture and exceptional in-plane order of a high mobility n-type polymer.
Substantial in-plane crystallinity and dominant face-on stacking are observed in thin films of a high-mobility n-type rylene-thiophene copolymer. Spun films of the polymer, previously thought to have little or no order are found to exhibit an ordered microstructure at both interfaces, and in the bulk. The implications of this type of packing and crystalline morphology are discussed as they relate to thin-film transistors.


Autocatalysis in Eschenmoser Coupling Reactions.
The Eschenmoser coupling reaction (ECR) of thioamides with electrophiles is believed to proceed via thiirane intermediates. However, little is known about converting the intermediates into ECR products. Previous mechanistic studies involved external thiophiles to remove the sulfur atom from the intermediates. In this work, an ECR proceeding without any thiophilic agent or base is studied by electrospray ionization-mass spectrometry. ESI-MS enables the detection of the so-far elusive polysulfide species Sn, with n ranging from 2 to 16 sulfur atoms, proposed to be the key species leading to product formation. Integrating observations from ion mobility spectrometry, ion spectroscopy, and reaction monitoring via flow chemistry coupled with mass spectrometry provides a comprehensive understanding of the reaction mechanism and uncovers the autocatalytic nature of the ECR reaction.


In Utero Exposure to Norbuprenorphine, a Major Metabolite of Buprenorphine, Induces Fetal Opioid Dependence and Leads to Neonatal Opioid Withdrawal Syndrome.
Buprenorphine is the preferred treatment of opioid use disorder during pregnancy but can cause fetal opioid dependence and neonatal opioid withdrawal syndrome (NOWS). Notably, withdrawal severity is independent of maternal buprenorphine dose, suggesting that interindividual variance in pharmacokinetics may influence risk and severity of NOWS. Using a rat model of NOWS, we tested the hypothesis that clinically relevant doses of the active metabolite norbuprenorphine (NorBUP) can induce in utero opioid dependence, manifested as naltrexone-precipitated withdrawal signs in the neonate. Pregnant Long-Evans rats were implanted with 14-day osmotic minipumps containing vehicle, morphine (positive control), or NorBUP (0.3-10 mg/kg per day) on gestation day 9. By 12 hours post-delivery, an intraperitoneal injection of the opioid antagonist naltrexone (1 or 10 mg/kg) or saline was administered to pups. Precipitated withdrawal signs were graded by raters blinded to treatment conditions. In a separate group, NorBUP concentrations in maternal and fetal blood and brain on gestation day 20 were determined by liquid chromatography-tandem mass spectrometry. Steady-state maternal blood concentrations of NorBUP in dams infused with 1 or 3 mg/kg per day were comparable to values reported in pregnant humans treated with buprenorphine (1.0 and 9.6 ng/ml, respectively), suggesting a clinically relevant dosing regimen. At these doses, NorBUP increased withdrawal severity in the neonate as shown by an evaluation of 10 withdrawal indicators. These findings support the possibility that NorBUP contributes to fetal opioid dependence and NOWS following maternal buprenorphine treatment during pregnancy.


Opioids as modulators of cell death and survival--unraveling mechanisms and revealing new indications.
Opioids are powerful analgesics but also drugs of abuse. Because opioid addicts are susceptible to certain infections, opioids have been suspected to suppress the immune response. This was supported by the finding that various immune-competent cells express opioid receptors and undergo apoptosis when treated with opioid alkaloids. Recent evidence suggests that opioids may also effect neuronal survival and proliferation or migrating properties of tumor cells. A multitude of signaling pathways has been suggested to be involved in these extra-analgesic effects of opioids. Growth-promoting effects were found to be mediated through Akt and Erk signaling cascades. Death-promoting effects have been ascribed to inhibition of nuclear factor-kappaB, increase of Fas expression, p53 stabilization, cytokine and chemokine release, and activation of nitric oxide synthase, p38, and c-Jun-N-terminal kinase. Some of the observed effects were inhibited with opioid receptor antagonists or pertussis toxin; others were unaffected. It is still unclear whether these properties are mediated through typical opioid receptor activation and inhibitory G-protein-signaling. The present review tries to unravel controversial findings and provides a hypothesis that may help to integrate diverse results.


Construct validity of six sentiment analysis methods in the text of encounter notes of patients with critical illness.
Sentiment analysis may offer insights into patient outcomes through the subjective expressions made by clinicians in the text of encounter notes. We analyzed the predictive, concurrent, convergent, and content validity of six sentiment methods in a sample of 793,725 multidisciplinary clinical notes among 41,283 hospitalizations associated with an intensive care unit stay. None of these approaches improved early prediction of in-hospital mortality using logistic regression models, but did improve both discrimination and calibration when using random forests. Additionally, positive sentiment measured by the CoreNLP (OR 0.04, 95% CI 0.002-0.55), Pattern (OR 0.09, 95% CI 0.04-0.17), sentimentr (OR 0.37, 95% CI 0.25-0.63), and Opinion (OR 0.25, 95% CI 0.07-0.89) methods were inversely associated with death on the concurrent day after adjustment for demographic characteristics and illness severity. Median daily lexical coverage ranged from 5.4% to 20.1%. While sentiment between all methods was positively correlated, their agreement was weak. Sentiment analysis holds promise for clinical applications but will require a novel domain-specific method applicable to clinical text.


The growing landscape of lysine acetylation links metabolism and cell signalling.
Lysine acetylation is a conserved protein post-translational modification that links acetyl-coenzyme A metabolism and cellular signalling. Recent advances in the identification and quantification of lysine acetylation by mass spectrometry have increased our understanding of lysine acetylation, implicating it in many biological processes through the regulation of protein interactions, activity and localization. In addition, proteins are frequently modified by other types of acylations, such as formylation, butyrylation, propionylation, succinylation, malonylation, myristoylation, glutarylation and crotonylation. The intricate link between lysine acylation and cellular metabolism has been clarified by the occurrence of several such metabolite-sensitive acylations and their selective removal by sirtuin deacylases. These emerging findings point to new functions for different lysine acylations and deacylating enzymes and also highlight the mechanisms by which acetylation regulates various cellular processes.